Hälsoekonomiska analyser bygger på de förutsättningar som finnes vid tidpunkten för analyserna. Nedan är exempel på hälsoekonomisk modell för en godkänd GLP-1-analog från ett företag. 

Nya just publicerade studier, som LEADER Study N Engl J Med 160614 (Victoza® liraglutide) på ADA, med 22% minskad kardiovaskulär mortalitet kan sannolikt påverka resultat i annan riktning. För detta behövs att den hälsoekonomiska modellen uppdateras.
 
Texten belyser hur TLV ser på betydelsen av hälsoekonomi vid godkännande subvention av ett läkemedel för typ 2 diabetes.

Press info från Lilly AB

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Hälsoekonomiska utvärderingar, ett krav för subvention inom diabetes – kostnadseffektivitet med GLP-1 behandling

Författare: Stina Johansson1, MSc, PhD, Harald Borgeke2, MSc, MBA och Anders Toll2, MSc, PhD

1IMS Health Sweden AB, Pyramidvägen 7, 169 56 Solna

2Eli Lilly Sweden AB, Gustav III Boulevard 42, P.O. box 721, 169 27 Solna

Sammanfattning

Eftersom det är viktigt att både utreda effekterna och kostnaderna av att använda ett visst läkemedel eller annan behandlingsmetod så blir hälsoekonomiska analyser blir allt vanligare.

Vanligen görs någon typ av modellanalys för att utvärdera om ett läkemedel är kostnadseffektivt. I denna artikel belyser vi diabetesläkemedlet Trulicity (dulaglutid) som är en GLP-1 agonist som började förskrivas av svenska läkare 2015 och som har utvärderats hälsoekonomiskt med IMS Health Core Diabetes Modell (CDM).

IMS Health CDM är en välvaliderad transparent hälsoekonomisk modell som är vanlig att använda för utvärdering av läkemedel mot diabetes. De hälsoekonomiska analyserna av Trulicity har bl.a. visat att Trulicity är kostnadseffektivt i jämförelse med Victoza (liraglutid) 1,2 mg och 1.8 mg och TLV har baserat på de analyser som presenterats för dem beslutat att Trulicity ska ingå i högkostnadsskyddet med vissa begränsningar.

Ökande användning av GLP-1 agonister i Sverige

I takt med att kunskapen om och erfarenheten av behandling med inkretinläkemedel ökar förskrivs GLP-1 agonister i en allt högre utsträckning i Sverige. De senaste fem åren har försäljningen av GLP-1 agonister ökat från 20,5 miljoner kr 2010 till 192 miljoner kr 2015 (baserat på apotekens utförsäljningspris, AUP) (IMS Health, 2016).

I dag finns det fem olika GLP-1 agonister på marknaden i Sverige. Byetta (exenatid) var den första som lanserades 2007 och ca tre år senare introducerades Victoza (liraglutid) på den svenska marknaden. Bydureon (exenatid med långsam frisättning) kom 2012 och därefter i tät följd Lyxumia (lixisenatid) och Trulicity (dulaglutid) under 2015. GLP-1 agonisterna skiljer sig åt på en del områden, exempelvis när det gäller klinisk effekt, farmakodynamik, farmakokinetik och administration.

Trulicity och Bydureon ges exempelvis en gång per vecka, medan de övriga preparaten kräver daglig administrering för optimal terapeutisk effekt (FASS, 2016, IMS Health, 2016, Prasad-Reddy och Isaacs, 2015).

Hälsoekonomiska analyser blir allt viktigare

Med tanke på att läkemedelskostnaderna ökar och landstingens budgetar är begränsade är det viktigt att man inom hälso- och sjukvården förstår både de ekonomiska och de kliniska effekterna av att använda ett visst läkemedel.

Även om ett läkemedel i en prisjämförelse kostar mer än ett annat som kan användas för behandling av samma sjukdom är det viktigt att också jämföra effekterna av de två läkemedlen, eftersom användning av det mer kostsamma läkemedlet kan innebära en bättre effekt och rent av lägre kostnader på lång sikt. Hälsoekonomiska utvärderingar av läkemedel får därmed en allt större betydelse.

Många kliniska prövningar är relativt korta, oftast mellan 3 till 24 månader, och fångar sällan in information om exempelvis kvalitetsjusterad livslängd och kostnader över tid. I kliniska prövningar jämförs oftast inte heller alla substanser i en viss läkemedelsgrupp med varandra, vanligen gör man studier mot placebo eller enstaka andra läkemedel. Genom att göra en hälsoekonomisk utvärdering kan man få en tydligare helhetsbild av ett läkemedel, där man tar hänsyn till både kliniska resultat och ekonomiska faktorer. Man kan också i en hälsoekonomisk utvärdering jämföra läkemedel som inte ingått i samma kliniska prövning, dvs. göra en indirekt jämförelse.

I Sverige utför Tandvårds- och läkemedelsförmånsverket (TLV) hälsoekonomiska utvärderingar av nya produkter som ansökts om att få ingå i läkemedelsförmånen samt på produkter som redan ingår i förmånen för att bedöma om de ska fortsätta att subventioneras. TLV gör även hälsoekonomiska bedömningar av vissa läkemedel som används inom slutenvården inom det så kallade klinikläkemedelsuppdraget (TLV, 2016).

Vanliga mått i en hälsoekonomisk utvärdering

I en hälsoekonomisk utvärdering av ett nytt läkemedel jämförs vanligtvis två relativt likvärdiga läkemedel med varandra med avseende på kostnader och effekter. De läkemedel som man jämför ska helst vara så lika varandra som möjligt. Vanligt är att man jämför två preparat inom samma läkemedelsgrupp.  

I den hälsoekonomiska analysen vill man framför allt veta hur de totala kostnaderna förändras vid användning av det nya läkemedlet jämfört med det gamla och ställa det i relation till skillnader i samlade effekter. Om det visar sig att det nya läkemedlet kostar mer men har en bättre effekt än jämförelsealternativet, vilket ofta kan vara fallet, vill man ta reda på hur mycket mer man får betala för att uppnå en bättre effekt med det nya läkemedlet.

I denna jämförelse används en inkrementell kvot, så kallad ICER (“Incremental Cost Effectivness Ratio”) för att beräkna ev. merkostnad per vunnen effektenhet av att använda ett nytt läkemedel. ICER = (Kostnad läkemedel A - Kostnad läkemedel B) / (Effekt läkemedel A - Effekt läkemedel B) (Drummond et al., 2005).

Kostnader som inkluderas i denna analys är bl.a. direkta kostnader för behandling och sjukvård.  Även indirekta kostnader som produktionsbortfall vid oförmögenhet att arbeta kan inkluderas. Om man tar med de sista innebär det att läkemedel som används av personer före pensionsåldern potentiellt kan värderas högre.

Olika effektmått kan användas i den hälsoekonomiska analysen. Ett effektmått kan vara sjukdomsspecifikt, t.ex. den blodglukossänkande effekten hos patienten av ett nytt läkemedel som används vid behandling av diabetes. Dock är det vanligare att ett mer generellt effektmått används, eftersom sjukdomsspecifika effektmått begränsar möjligheten att jämföra preparat mellan olika terapiområden.

Ett vanligt förekommande effektmått som gör det möjligt att jämföra läkemedel mellan olika områden är antal vunna levnadsår, förutsatta att de påverkar livslängden.

Det vanligaste är att QALY (“Quality Adjusted Life Year”, kvalitetsjusterat levnadsår) används som ett generellt effektmått i den hälsoekonomiska analysen.

För att beräkna QALY justeras antalet levnadsår med den hälsorelaterade livskvaliteten för olika tillstånd. Full livskvalitet sätts till 1 och justering kan därifrån ske nedåt ända till 0, vilket innebär död. Det finns olika etablerade metoder som man kan använda för att bygga upp ett index och därigenom beräkna QALYs. Implikationen av beräkningen av QALYs är att värdet av ett levnadsår med full livskvalitet är lika stor som värdet av t.ex. två levnadsår med 50% livskvalitet (Drummond et al., 2005).

I hälsoekonomiska utvärderingar görs ofta så kallade modellanalyser för att bl.a. kunna göra antaganden om framtida händelseförlopp och studera längre tidsperspektiv. Olika typer av analysmetoder/modeller kan användas. I en kostnadseffektivitetsmodell samlas information om effekter och kostnader ihop. Även viss annan information kan inkluderas modellen, t.ex. information om risken att drabbas av sjukdomskomplikationer och risken för att dö. Informationen kommer vanligen från många olika källor t.ex. kliniska prövningar, observationsstudier, prislistor och kostnadsdatabaser etc.

En vanlig hälsoekonomisk modell som ofta används för att beräkna långsiktiga framtida effekter är Markov-modellen. Markov-modellen är en matematisk beräkningsmodell som är uppdelad på olika sjukdomsstadium och beskriver sannolikheten eller risken att övergå från ett sjukdomsstadium till ett annat. Specifika kostnader och hälsoeffekter är förknippade med varje sjukdomsstadium. Modellen simulerar vad som händer med avseende på kostnader och effekter i en patientpopulation över ett relativt långt tidsintervall, tiotals år (Drummond et al., 2005).

Det finns naturligtvis en viss osäkerhet i de framräknade konsekvenserna, inte minst eftersom ett flertal antaganden ligger till grund för beräkningarna. För att testa resultatens robusthet görs regelmässigt många känslighetsanalyser där dessa antaganden ändras på olika sätt. Om de övergripande resultaten inte förändras särskilt mycket vid olika antaganden så stärker det trovärdigheten för dessa.

Subventionsbeslut från TLV

När TLV beslutar om subvention för ett visst läkemedel utgår de från lagen om läkemedelsförmåner samt hälso- och sjukvårdens övergripande mål om en god hälsa och en vård på lika villkor. I sin utvärdering tar de hänsyn till tre grundläggande principer:
1) människovärdesprincipen som grundar sig på att vården ska respektera alla människors lika värde,
2) behovs- och solidaritetsprincipen där de som har störst behov ska få mer av vårdens resurser än de med lägre behov samt
3) kostnadseffektivitetsprincipen som innebär att läkemedelskostnaden ska vara rimlig sett från ett medicinskt, humanitärt och samhällsekonomiskt perspektiv (TLV, 2016).

Då TLV inte bara fokuserar på om ett läkemedel är kostnadseffektivt utan även tar hänsyn till andra värden när de beslutar huruvida ett läkemedel ska ingå i högkostnadsskyddet innebär detta att även läkemedel med relativt höga kostnadseffektivitetsvärden (ICER etc.) kan komma att få positiva subventionsbeslut och därmed ingå i högkostnadsskyddet. Exempelvis kan vissa onkologiläkemedel, som påverkar överlevnad och livskvalitet i slutet av livet och där andra behandlingsalternativ är begränsade, ha relativt höga kostnadseffektivitetskvoter och ändå vara subventionerade.

Diabetesläkemedel ligger vanligen på kostnadseffektivitetskvoter som är lägre än de för onkologiläkemedel, om de ingår i högkostnadsskyddet. TLV har i dag inga formellt uttalade gränsvärden för vad en godtagbar ICER är för att ett läkemedel ska få subvention. Varje läkemedel bedöms individuellt.

IMS Health Core Diabetes Modell kan användas för hälsoekonomiska utvärderingar av diabetesläkemedel

IMS Health Core Diabetes Modell (CDM) är en modell som ofta används för att utvärdera nya läkemedel för behandling av diabetes. Modellen har accepterats för att utvärdera nya diabetesläkemedel av myndigheter (TLV eller motsvarande) i många olika länder bl.a. i de nordiska länderna, men även i t.ex. Storbritannien, Belgien, Tyskland, Italien och USA (IMS Health CDM, 2016, Palmer et al., 2004a).

IMS Health CDM är en välvaliderad Markov-modell som både kan användas för utvärdering av läkemedel inom diabetes typ 1 och diabetes typ 2 (Palmer et al., 2004a och McEwan et al., 2014). Modellen används främst för att studera långsiktiga kliniska utfall (“outcomes”) och kan ibland ses som ett alternativ till att göra kostsamma kliniska studier som tar många år och inkluderar mycket stora patientgrupper (Palmer et al., 2004a).

IMS Health CDM har bl.a. används för att utvärdera kostnadseffektiviteten av Trulicity. I modellen jämförde man bl.a. Trulicity 1,5 mg med Victoza 1,8 mg och Victoza 1,2 mg för behandling av patienter med diabetes typ 2 i Sverige. Resultaten visade på att Trulicity var både mer effektivt och kostade mindre än om patienten behandlades med Victoza (1,2 mg och 1,8 mg) (Raibouaa et al., 2015). Kostnadseffektivitetsresultat från IMS Health CDM har presenterats för TLV och utifrån dessa resultat, där man bl.a. visar att Trulicity är mer kostnadseffektiv än Victoza 1,8 mg, har TLV beslutat att Trulicity ska vara subventionerat och ingå i högkostnadsskyddet för patienter som först har prövat metformin, sulfonureider eller insulin eller när metformin eller sulfonureider inte är lämpliga. Trulicity subventioneras endast för patienter som inte behandlas i kombination med basinsulin. Hälsoekonomiska utvärderingar har även gjorts för bl.a. Bydureon, Byetta, Victoza och Lyxumia av TLV. Exakt vilka hälsoekonomiska modeller som använts för att utvärdera dessa läkemedel framgår inte alltid av TLV:s offentligt publicerade beslut.

IMS Health CDM är en välvaliderad transparent modell

Data från IMS Health CDM publicerades för första gången 2004, och därefter har modellen beskrivits i mer än 80 vetenskapliga artiklar och presenterats på en rad olika konferenser. Minst 7 av de 10 globala läkemedelsföretag som marknadsför diabetesläkemedel använder modellen. Sedan 2004 har uppdateringar kontinuerligt gjorts i modellen för att återspegla den senaste vetenskapen och tekniken (IMS Health CDM, 2016).

Då modellen genom åren kontinuerligt uppdateras är det också viktigt att säkerställa IMS Health CDM:s trovärdighet genom att ständigt validera den. Initialt validerades modellen 2004 för att visa på den operativa och prediktiva validiteten av modellen (Palmer et al., 2004b). År 2014 publicerades ytterligare en stor valideringsstudie av IMS Health CDM som visade att modellen är en trovärdig modell för att utvärdera kostnadseffektiviteten av olika diabetesläkemedel. I denna studie utfördes 112 valideringssimuleringar och resulterade i ett totalt R2-värde (determinationskoefficient) på 0,90 (se McEwan et al., 2014 för fler valideringsresultatresultat).

Beskrivning av IMS Health CDM

IMS Health CDM är uppdelad på fyra olika element: ett användargränssnitt, input-databaser, en dataprocessor och en output-databas, se figur 1 (Palmer et al., 2004a).

I användargränssnittet kan användaren av modellen definiera vilka olika parametrar och analyser som ska användas i modellen. Man kan t.ex. definiera karaktärerna i kohorten (alt. använda en fördefinierad kohort), definiera behandlingar och behandlingssekvens, lägga in kostnads- och kliniska data, bestämma vilka typer av analyser som ska göras inklusive val av typ av kohort (öppen eller stängd), vilka känslighetsanalyser som ska utföras och om budgetpåverkansanalyser (“budget impact analysis”) ska inkluderas. I detta fönster definieras även vilka scenarier som ska jämföras i base-case samt i känslighetsanalyserna, tidshorisonten och antal patienter.

Informationen som specificerats från användaren sparas i input-databaser tillsammans med redan existerande data hämtad från tidigare publicerade källor. Input-databaserna består av en kohortdatabas, en klinisk databas, en behandlingsdatabas och en ekonomisk databas. Dessa databaser utgör grunden för de beräkningar som behöver göras i modellen.

I kohortdatabasen finns information om kohorten t.ex. ålder, kön, etnicitet, antal år med diabetes, HbA1c-värden, blodtryck, kolesterolvärden, BMI (“Body Mass Index”), cigarettförbrukning, alkoholkonsumtion och diabeteskomplikationer när patienten går in i modellen (dvs. “at baseline”).

Den kliniska databasen innehåller alla medicinska och epidemiologiska data som implementeras i modellen för att beräkna kliniska utfall (“outcomes”). Databasen innehåller en samling av sannolikheter för att övergå från ett kliniskt sjukdomsstadium till ett annat samt riskfaktorer för sjukdomsprogression och uppkomst av akuta tillstånd eller komplikationer.

Behandlingsdatabasen innehåller information om behandlingar och behandlingssekvens, effekter av behandling och förändringar i fysiologiska parametrar som en konsekvens av olika behandlingar och/eller patienthantering.

I den ekonomiska databasen samlas all data som behövs för den ekonomiska analysen, t.ex. direkta och indirekta kostnader, diskonteringskvoter och livskvalitetsdata (“quality of life data”) associerade med olika diabeteskomplikationer t.ex. kardiovaskulära sjukdomar.

Modellen är förprogrammerad att visa ett antal standardresultat för varje simulering t.ex. överlevnadskurvor, totala kumulativa direkta och indirekta kostnader, kostnader per diabeteskomplikation och per läkemedelsbehandling, incidens av komplikationer, tiden tills att en viss typ av komplikation uppkommer, förväntad livslängd, förväntad kvalitetsjusterad livslängd (QALY), ICER (baserad på QALYs) samt känslighetsanalyser och budgetpåverkansanalyser (IMS Health CDM, 2016, Palmer et al., 2004a).

En hälsoekonomisk modell är ett viktigt verktyg

Sammanfattningsvis är en hälsoekonomisk modell ett viktigt verktyg för att utvärdera både de kliniska och ekonomiska aspekterna av ett läkemedel. IMS Health CDM är ett bra exempel på en välvaliderad transparent hälsoekonomisk modell som har använts i många studier för utvärdering av olika diabetesläkemedel t.ex. Trulicity.

 

Figur 1: Strukturen i IMS Health CDM (Palmer et al., 2004a).
www.dagensdiabetes.se saknar möjlighet att publicera figurer på www

Referenser

1.     Drummond MF, Sculpher MJ, Torrance GW, O'Brien JB, Stoddart GL, Methods for the Economic Evaluation of Health Care Programmes 3rd Edition, Oxford (UK): Oxford University Press, 2005.

2.     FASS, www.fass.se, 2016.

3.     IMS Health, 2016.

4.     IMS Health CDM, www.core-diabetes.com, 2016.

5.     McEwan P, Foos V, Palmer JL, Lamotte M, Lloyd A, Phil M, Grant D, Validation of the IMS CORE Diabetes Model, Value in Health, 2014, 17, 714-724.

6.     Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, Lammert M, Spinas GA, The CORE Diabetes Model: Projecting Long-term Clinical Outcomes, Costs and Cost-effectiveness of Interventions in Diabetes Mellitus (Types 1 and 2) to Support Clinical and Reimbursement Decision-making, Current Medical Research and Opinion, 2004a, 20(1), S5-S26.

7.     Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, Lammert M, Spinas GA, Validation of the CORE Diabetes Model Against Epidemiological and Clinical Studies, Current Medical Research and Opinion, 2004b, 20(1), S27-S40.

8.     Prasad-Reddy L, Isaacs D, A Clinical Review of GLP-1 Receptor Agonists: Efficacy and Safety in Diabetes and Beyond, Drugs in Context, 2015; 4: 212283.

9.     Raibouaa A, Borgeke H, Alexiou D, Lowin J, Norrbacka K, Cost-effectiveness of Dulaglutide 1.5 mg Once Weekly for the Treatment of Patients with Type 2 Diabetes Mellitus in Sweden (poster presentation), ISPOR 18th Annual European Congress, 2015.

10.  TLV, www.tlv.se, 2016.

Riksdagsledamoten Christina Örnebjär har förtjänstfullt engagerat sig i VAB-frågan för föräldrar till barn med typ 1 diabetes

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En utmärkt intepellationsdebatt med socialförsäkringsminister Annika Strandhäl, skriver patientföreningen Svenska Diabetesförbundet på sin www.

Under debatten lämnade Christina en utförlig och bra beskrivning av situationen och hur både barn och föräldrar hamnar i kläm.

Svaret från ministern är dessvärre att avvakta samt att hänvisa till regeringens satsningar med ökad personaltäthet m.m.

Följ länken för att lyssna på debatten - den tar cirka 20 min men det är det värt! Clicka här!

Reductions in glucagon, cortisol, catecholamine, and sympathetic nerve responses to hypoglycemia

Gastric bypass (GBP) surgery is associated with reduced symptoms and neurohormonal responses to hypoglycemia, according to a study published online June 16 in Diabetes.

From HealthDay

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Noting that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes, Niclas Abrahamsson, M.D., Ph.D., from Uppsala University in Sweden, and colleagues examined symptoms and hormonal and autonomic nerve responses in patients exposed to hypoglycemia before and after GBP. Twelve obese patients without diabetes underwent hyperinsulinemic hypoglycemic clamp before and after GBP surgery.

The researchers found that after surgery the Edinburgh Hypoglycemia symptom delta scores during clamp were attenuated from 10.7 to 5.2. Marked reductions in glucagon, cortisol, catecholamine, and sympathetic nerve responses to hypoglycemia were seen after surgery. A delayed response was seen in growth hormones, but to a higher peak level. During hypoglycemia, glucagon-like peptide-1 and gastric inhibitory peptide increased, but to a lesser extent after surgery.

"GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia," the authors write. "Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery."

ABSTRACT

Gastric bypass reduces symptoms and hormonal responses in hypoglycemia

Niclas Abrahamsson, Joey Lau Börjesson, Magnus Sundbom, Urban Wiklund, F Anders Karlsson, Jan WEriksson

Diabetes 2016 Jun; db160341. http://dx.doi.org/10.2337/db16-0341
Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP-patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after GBP to hypoglycemia and examined symptoms, hormonal and autonomic nerve responses. 12 obese, non-diabetes patients, 8 women, age 43.1 years (SD 10.8), BMI 40.6 kg/m2 (3.1), were examined before and 23 (19-25) weeks after GBP surgery with hyperinsulinemic hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L).The Edinburgh Hypoglycemia symptom delta scores during clamp were attenuated from 10.7 (6.4) before to 5.2 (4.9) after surgery. There were also marked post-surgery reductions in glucagon, cortisol, catecholamine and sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. GLP-1 and GIP rose during hypoglycemia, but less post- vs. pre-surgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

Efterfrågan på nya kontinuerliga glukosmätare utmanar landstingens budgetar. I ett pilotprojekt ska TLV därför göra en hälsoekonomisk utvärdering av de medicintekniska produkterna, skriver Ingrid Helander www.lakemedelsvarlden.se

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Sveriges kommuner och landsting, SKL, har inlett en förstudie om ordnat införande av medicintekniska produkter. Inom ramen för den ska nu Tandvårds- och läkemedelsförmånsverket, TLV, göra en hälsoekonomisk utvärdering av kontinuerliga glukosmätare, CGM, och flash-glukosmätare, FGM, för diabetiker.

Med dessa produkter behöver inte patienterna mäta sitt glukosvärde med blodprov och stickor flera gånger per dag. I dag finns glukosmätare av CGM-typ på marknaden och dessa mäter blodglukos kontinuerligt och larmar om det är någon avvikelse.

Vad gäller typen flash-glukosmätare finns än så länge endast en sådan produkt på marknaden. Med hjälp av en avläsare scannar man av en sensor som sitter på baksidan av armen och får vid avläsningen aktuellt blodglukosvärde. Sensorn byter man ut var fjortonde dag.

– Det här är en helt ny typ av produkt som innebär att många patienter kan få en ökad livskvalitet, men som också innebär en stor kostnadsökning för landstingens budget, säger Malin Blixt, chef för TLVs enhet för medicinteknik.

Årskostnaden för flash-glukosmätaren beräknas till cirka 13 000 kronor per patient och att använda CGM-system kostar ungefär dubbelt så mycket.

Eftersom de kontinuerliga glukosmätarna innebär betydligt högre kostnader än för teststickor har landstingen, som bekostar dem, önskat att de utvärderas med avseende på hälsoekonomi och även introduceras på ett ordnat sätt, liknande som för läkemedel.

– Med en hälsoekonomisk bedömning kan vi se hur denna kostnad förhåller sig till andra kostnader och baserat på det ge förutsättningar för ett ordnat införande och jämlik tillgång över hela landet.

Landstingens och kommunernas kostnader för medicintekniska produkter ligger i dag på cirka 22 miljarder kronor per år, och de tros öka.

I dag finns cirka 700 000 medicintekniska produkter, jämfört med cirka 4 000 läkemedel, och det tillkommer runt 50 000 nya produkter per år. Alla är dock inte nya och innovativa med väsentlig förbättring för patienterna, men de som är det skulle kunna komma i fråga för ordnat införande i någon form.

Ett exempel är ny teknik för att ta ut stora blodproppar ur hjärnan vid stroke, så kallad trombektomi med hjälp av stentretrievers. Metoden har visat mycket goda resultat och risken för allvarliga handikapp minskade med upp till 31 procent i de studier som gjorts. De goda resultaten innebär att fler än i dag kan komma ifråga för behandlingen.

– Ingreppet kan dock bara göras på de stora universitetssjukhusen vilket innebär att patienterna måste skickas dit, till ökade kostnader. Därför behöver vi utvärdera metoden ur ett hälsoekonomiskt perspektiv, säger Malin Blixt.

I dag används modellen för ordnat införande för vissa nya läkemedel som bedöms ha stor nytta för patienterna men som kommer med en hög kostnad. Till gruppen hör bland annat de nya antivirala läkemedlen för behandling av hepatit C.

– Ordnat införande är en bra modell förjämlik tillgång till kostnadseffektiva läkemedel. Där har man också horizon scanning som gör att man vet vad som är på gång.

För medicintekniska produkter finns inget liknande system utan de flesta produkterna upphandlas var för sig utan att granskas av TLV. Det gör att det är svårt att förutsäga vad som kommer och säkerställa en jämlik hantering.

Och med tanke på den stora mängd medicintekniska produkter som finns på marknaden kan modellen med ordnat införande inte appliceras på alla. Långt ifrån.

– Vi måste vara noga när vi väljer vilka produkter vi skulle kunna använda modellen för ordnat införande på och fråga oss om det är en produkt som löser ett problem där det inte finns någon behandling i dag, om det innebär stora kostnader och en stor risk för landstingen, säger Malin Blixt.

TLV planerar att starta den hälsoekonomiska utvärderingen av kontinuerliga glukosmätare under sommaren. Målet är att utvärderingen och större delen av pilotförsöket ska vara klart innan årsskiftet.

 

Poverty is a significant, independent risk factor for death in patients with diabetes, even when these patients have equal access to healthcare resources, a population-based Swedish registry study indicated.
From www.medscape.com
Nyhetsinfo
www red DiabetologNytt

Diabetes patients with low socioeconomic status had almost twice the risk for all-cause-, cardiovascular-, and diabetes-related death as high-income patients, even after controlling for other risk factors associated with mortality, reported Araz Rawshani, MD, PhD, of Sahlgrenska University Hospital in Gothenburg, Sweden, and colleagues in JAMA Internal Medicine.
Comparison of hazard ratios for the lowest versus highest income quintiles revealed that:
  • The hazard ratios for all-cause-, cardiovascular-, diabetes-, and cancer-related mortality were 1.71 (95% CI 1.60-1.83), 1.87 (95% CI 1.72-2.05), and 1.80 (95% CI 1.61-2.01), and 1.28 (95% CI 1.14-1.44), respectively.
  • Compared with native Swedes, hazard ratios for all-cause, cardiovascular, diabetes-, and cancer-related mortality for non-Western immigrants were 0.55 (95% CI 0.48-0.63), 0.46 (95% CI 0.38-0.56), 0.38 (95% CI 0.29-0.49), and 0.72 (95% CI 0.58-0.88), respectively.
  • Hazard ratios for patients with a college/university degree compared with 9 years or less of education were 0.85 (95% CI 0.80-0.90), 0.84 (95% CI 0.78-0.91), and 0.84 (95% CI 0.76-0.93) for all-cause, cardiovascular, and cancer mortality, respectively.
 
The study setting is important because, compared with the U.S., socioeconomic status should have less impact in Sweden on access to health services and their utilization, where the healthcare system is largely taxpayer-funded and open to all.
"In general, low compared with high income was associated with almost twice the risk of all-cause-, cardiovascular- and diabetes-related mortality and a 30% elevated risk of overall cancer mortality," the researchers wrote.
The study included 217,364 diabetic patients in Sweden who were younger than age 70 (mean age 58.3±9.3) when enrolled in the Sweden National Diabetes Register from 2003 through 2010. The patients (60.2% male) were monitored through Dec. 31, 2012. Cox proportional hazards regression modelling with up to 17 covariates was used for analysis.
A total of 17,589 of the patients included in the analysis were non-Western immigrants, including 1,699 (9.7%) from Latin America and the Caribbean, 2,902 (16.5%) from East or South Asia, and 10,506 (59.7%) from sub-Saharan Africa. These patients tended to be younger than native Swedes (mean age 52.1±9.8).
"Non-Western immigrants were approximately six years younger at diagnosis of diabetes and had lower income, higher education levels, and a higher prevalence of albuminuria," the researchers wrote.
During the follow-up there were a total of 19,105 all-cause deaths, including 11,423 (59.8%) associated with cardiovascular causes, 6,984 (36.6%) associated with diabetes, and 6,438 (33.7%) associated with cancer.
 
Marital status was also linked to mortality, with married patients having a lower risk for death than single patients in fully adjusted models (hazard ratio for all-cause mortality 0.73, 95 CI 0.70-0.77; for cardiovascular death 0.67, 95% CI 0.63-0.71; and for diabetes death 0.62, 95% CI 0.57-0.67). Marital status was not associated with overall cancer mortality, but married men had a 33% lower risk of prostate cancer mortality compared with single men.
The observational design of the study and limited information on alcohol use and smoking status were cited by the researchers as study limitations.
In an editorial published with the study, Victor Montori, MD, and colleagues from the Mayo Clinic, Rochester, Minn., wrote that the disproportionate burden of type 2 diabetes among people living in poverty "shines light on the problematic way in which we have chosen to respond."
 
"This approach -- to prevent diabetes one person at a time -- has hampered our response as a society to the diabetes epidemic," they wrote.
In 2013 the American Diabetes Association issued a scientific statement on socioeconomic determinants of prediabetes and type 2 diabetes, which encouraged addressing social context as a strategy to curb the diabetes epidemic.
Montori and colleagues argue that this advice has been largely ignored, with efforts to reduce diabetes incidence and morbidity still focused on getting the individual patient to change.
"The current paradigm, then, endorses improving each individual patient and clinician's behavior as the solution yet obviates the social, environmental, and economic factors that drive the epidemic," they wrote -- adding, "Prospects for change are not encouraging."
 
Funding for this research was provided by the Swedish National Diabetes Register, the Swedish Heart and Lung Foundation, the Swedish Research Council, and others.The researchers declared no relevant relationships with industry related to this study.Montori and colleagues reported no relevant relationships with industry.

Vegetabiliskt fett skyddar inte hjärtat, visar en ny amerikansk jättestudie. Men därmed är det inte fritt fram för LCHF – svenska forskare kritiserar studien och barnläkare varnar för att kolhydratfattig kost kan vara livsfarlig.

Maria Backman,

Frilansjournalist

Nyhetsinfo www red

DiabetologNytt

 

LCHF (Low Carb High Fat) är en diet med högt intag av fett och lågt intag av kolhydrater. En av förespråkarna för LCHF-kost är allmänläkaren Andreas Eenfeldt, känd för hälsobloggen Kostdoktorn. Han menar att vi kan äta oss ifrån övervikt, diabetes typ 2 och metabolt syndrom (övervikt, blodfettsrubbning, diabetes och högt blodtryck) genom att äta rätt mat – det vill säga äta mer fett och mättat fett och undvika socker och stärkelserik mat.

Hittills har det dock saknats långtidsstudier av effekterna med kolhydratfattig kost. Men i en stor amerikansk studie som nyligen publicerades i British Medical Journal visar det sig att risken för hjärtsjukdomar inte minskar  genom att man ersätter mättat fett med vegetabiliskt – tvärtom. När forskarna gick igenom information från en av de största studier som gjorts inom området, omfattande 9 400 personer som levde på sex olika mentalsjukhus under 1968-73, visade det sig att risken för hjärtsjukdomar ökade om kosten var rik på fleromättat fett.

Vegetabiliska oljor som är rika på linolsyra sänker blodets kolesterolhalt och anses därmed ha en skyddande effekt mot hjärtsjukdomar. Och hos de deltagare som fick vegetabiliskt fett sänktes mycket riktigt kolesterolhalten. Trots detta hade alltså de deltagare som fick vegetabilisk olja en ökad risk för kranskärlsjukdom jämfört med de som fick en kost som liknade amerikansk genomsnittskost på den tiden.

Innebär den amerikanska studien att det mättade fettet börjar bli rumsrent?

Ingrid Larsson, näringsfysiolog på Sahlgrenska Universitetssjukhuset, känner väl till studien. Huvudpublikationen publicerades 1989, och det finns flera svagheter i både den äldre och den nu aktuella studien som inte kommit fram, berättar hon.

- Den allmänna nedläggningen av mentalsjukhus som skedde redan under studiens första år fick till följd att 75 procent av deltagarna försvann redan inledningsvis. Den sista delstudien baseras på obduktioner av bara 150 personer.

Dessutom är studien inte relevant för hur vi äter idag, påpekar Ingrid Larsson: - På den tiden hade man ännu inte så mycket kunskap om olika fettsyrors effekt på hälsan. Man tog helt enkelt bort mättat fett ur kosten och la istället till omättat fett i form av majsolja som har hög halt av omega 6-fettsyror. Därigenom förlorade man andra viktiga fettsyror. Idag vet vi att vi bör få i oss  mer omega 3 än omega 6. Den här kosten var därigenom inte representativ för befolkningen i övrigt. Inte minst förändringen av fettsyror gör att det är svårt att dra slutsatser av den som är aktuella för dagens hälsosamma mat. Så studien säger egentligen inte så mycket, utan är mer att betrakta som ett  dokument över en historisk studie.

I studien utpekades ju linolsyra som boven i dramat?

- Linolsyra är egentligen positivt, men om man bara äter linolsyra kan det ha en negativ effekt. Det bästa är att kombinera olika fettsyror. Det var detta som saknades i studien. Man tog helt enkelt bort det ena fettet.

I de Nordiska näringsrekommendationerna framgår att en viss del omega 3 och en viss del omega 6 skyddar mot hjärt-kärlsjukdom genom att blodfettnivån minskar. Omättade fettsyror hjälper också till att stabilisera hjärtrytmen, berättar Ingrid Larsson.

Men många som äter LCHF upplever sig ju må bättre?

- Det kan bero på att de undviker gluten, och mår bättre på grund av detta. En kraftig viktnedgång ger dessutom positiva hälsoeffekter i sig, säger Charlotte Erlanson-Albertsson, professor vid Institutionen för experimentell medicinsk vetenskap, Lunds Universitet.

- Vissa mättade fetter har blivit rumsrena, som kokosfett och kokosolja. Men detta är mycket individuellt. En del kan äta 100 gram mättat fett utan att det syns i blodet medan andra inte kan äta mer än fem gram. Så det är fortfarande ett debattämne.

Inte minst under våren har debattens vågor gått höga, då barnläkare varnat i media för att ge barn LCHF-diet - i synnerhet barn med typ 1 diabetes. På nätet har det förespråkats att sådana barn skulle kunna minska sin insulinbehandling kraftigt genom att äta mer fett och undvika kolhydrater, eftersom denna kost kan stabilisera blodsockernivåerna.

Barnläkare varnar dock för att dessa råd inte bara är vetenskapligt felaktiga utan också kan vara rent livsfarliga. Det är fler faktorer än blodsocker som spelar in vid diabetes. Insulin är ett livsnödvändigt hormon och de medicinska konsekvenserna kan bli svåra vid alltför låg dos.

Så till den ständigt återkommande frågan: vad ska vi då egentligen äta?

Vi kommer hela tiden tillbaka till att lagom är bäst, säger Ingrid Larsson.

- Men även om du väljer nyttigt fett gäller det att hålla koll på mängderna. Det handlar om mycket energitäta livsmedel. Det är en vanlig snubbeltråd, man tänker att det ju är så nyttigt och stoppar kanske i sig en påse nötter. Men 8-10 nötter per dag är tillräckligt för att få de positiva hälsoeffekterna av nötter.

Hennes råd är att välja magert kött och magra mejerier för att minska mängden mättat fett.

- Äter du en kost baserad mer på fisk får du i dig bra fettsyror, men tänk på att äta varierat.

Charlotte Erlanson-Albertsson berättar att vi ofta äter för mycket omega 6-fettsyror och för lite omega 3. Det beror på att det finns mycket omega 6 den västerländska kosten, inte minst i helfabrikat. Istället borde förhållandet vara det omvända: bara en tiondel av det fleromättade fettet bör komma från omega 6. Välj aktivt sådant som du vet innehåller omega 3 såsom rapsolja,  valnötter, linfrön och fet fisk som lax, sill och makrill.

Charlotte Erlanson-Albertssons råd till den som vill vara försiktig är att undvika animalisk föda helt, eller åtminstone hålla sig till vitt kött, som kyckling.

- Framför allt: undvik ister och bacon.

Fakta-ruta:

Fettsyror indelas i mättade fetter och omättade fetter. Omättade fetter indelas  i enkelomättade fetter samt fleromättade fetter (omega 3 och omega 6).

Fakta:

LCHF (Low Carb High Fat) är en diet med högt intag av fett och lågt intag av kolhydrater.

+ Många går ner i vikt, får minskat sötsug och lägre blodsocker, blodsocker och kolesterolvärden.

+ I kött, ost och mejeriprodukter finns proteiner, järn (i kött), kalk, D-vitamin och vissa B-vitaminer.

- Fettsyror behövs från olika källor, inte bara från mättat fett i första hand.

- Utan kolhydrater missar vi vitaminer, mineraler och fibrer som finns i spannmål, baljväxter, grönsaker och frukt.

- Immunförsvaret kan påverkas negativt.

- Risk för förstoppning, illamående, yrsel, huvudvärk.

-- Personer med diabetes bör vara försiktiga.

- Rekommenderas ej till barn och ungdomar.

 

 

Rapport Gun Forsander

Nyhetsinfo

www red DiabetologNytt

 

Fortsatt Rapport del 2

Desmond Schatz, som är pediatriker och president för ”Medicin och vetenskap” inom ADA, höll ett brandtal om vikten av fortsatt forskning för att lösa ”diabetesgåtan”. Han lanserade begreppet ”Diabetes@212°F” för att hetta upp aktiviteten att finna prevention och bot. 

Vid 212 grader Fahrenheit (=100 grader Celcius) är vatten på kokpunkten och denna metafor för behov av intensifierad diabetesforskning diskuterades. Kostnadsutvecklingen för diabetes i USA kan finnas på www.cdc.gov/diabetes. Det uppgavs att diabetes nu upptar 20 % av kostnaderna inom sjuk- och hälsovård. Trots att det finns dubbelt så många individer med diabetes som med cancer i USA är forskningsanslagen för diabetes bara en knapp tiondel i jämförelse. 

Det positiva är att med hjälp av forskning och klinisk tillämpning av denna har på tjugo år, från 1990 till 2010, förekomsten av diabetesrelaterade komplikationer sjunkit betydande. Som exempel gavs: hjärtinfarkt har minskat med 68%, stroke 52%, amputationer 52%, ESRD (end stage renal disease) 28%, grava HG 64%. 

”Advocacy, Education, Research” är även fortsättningsvis ledord för ADA´s verksamhet! 

 

Prof Barbara Kahn, Harvard Medical School

och Beth Israel Deaconess Medical Centre, mottog som första kvinna ADA´s främsta utmärkelse, Banting-priset. Hon höll en mycket intressant föreläsning om fettväven, inter-organ kommunikation och utveckling till T2D. Hon och ett stort antal doktorander har kartlagt mekanismerna bakom insulinresistens och den molekylära patogenesen bakom fetma och T2D. Bl.a. har hennes forskargrupp upptäckt en grupp lipider med insulinkänslighetshöjande egenskaper som också är anti-inflammatoriska och stimulerar GLP-1 och insulinsekretion. Prof Kahns forskning har lagt grunden för förståelsen av att fettväven är ett endokrint organ och har haft stor betydelse för utveckling av läkemedel vid T2D. En hel del forskning har också skett tillsammans med professor Ulf Smith vid Sahlgrenska Universitetssjukhuset, Göteborg.

”Is there a racial difference in mean glucose measured as CGM in relation to HbA1c?” 

Tidigare studier har indikerat att det är så, dvs att ”african-americans” har ett högre HbA1c än individer med kaukasiskt ursprung med samma glukosvärden mätt som p/glukos. En ny studie presenterades där man använt FGM, dvs Abbot Libre. Det visade sig att HbA1c vid ett genomsnittligt glukosvärde på 200 mg/dl (= 11.1 mmol/l ) låg +0.4 % högre. Följande data presenterades: 

Afro-amerikanskt ursprung Kaukasiskt ursprung 

6.5% = 6.3% 

7.0% = 6.8% 

8.0% = 7.7% 

9.0% = 8.7% 

10% = 9.6% 

11% = 10.5% 

Eftersom glykosyleringsgraden är en markör för kärlskada kan man därför befara en ökad komplikationsrisk för färgade individer. Dock fann man inte denna korrelation med fruktosamin eller glykosylerat albumin där studien visade identiska värden för försökspersonerna i förhållande till medelglukos. 

Man sammanfattade sina resultat med att säga att den inter-individuella skillnaden i glykosyleringsgrad, oavsett genetiskt ursprung, är betydande och har kliniskt större betydelse. Viktigt att anteckna medel CGM och glukosvariation, ex mätt som SD, i journal/register. Våra råd till patienterna bör fokusera mer på dessa mått och inte enbart på HbA1c. 

Data från den internationella och viktiga Teddy-studien

presenterades avslutningsdagen. I denna har 8676 barn med genetiskt ökad risk för T1D deltagit från 3 månader till 15 års ålder och det finns en skattkista av information att hämta avseende utveckling av T1D och öcells-autoimmunitet. 

Kumulativa, dvs upprepade, negativa livshändelser för barnet ger signifikant ökad risk för utvecklande av autoimmunitet och T1D före 6 års ålder hos dem med HLA DR3/4. Enstaka negativa händelser för barnet och föräldrastress kunde inte påvisa högre risk . 

Cirka 25% av samtliga barn i studien upplevde någon typ av negativ livshändelse under sina första 6 år och hela 10% av barnen var år efter år utsatta för detta. 

Barndomen är för många en period av svår utsatthet och Barnkonventionens grundidé att alla minderåriga måste skyddas och att alla vuxna har en skyldighet att bidra till detta, är oerhört viktig. 

Sammantaget

ADA-mötet gav fortsatt inspiration till både kliniskt arbete och forskning inom diabetesområdet. 

Mycket är gjort - men: det finns så mycket kvar att göra! 

Rapport Gun Forsander 160622

Nyhetsinfo

www red DiabetologNytt

RAPPORT

Då över 18 000 delegater ska samsas på en begränsad yta blir intrycket en välorganiserad myrstack, sjudande av positiv energi, glada återseenden och fokuserat intresse på diabetessjukdomens alla perspektiv. 

En snabb reflektion redan första dagen: Så fantastiskt bra resultat vi har i Sverige avseende HbA1c och så goda möjligheter våra patienter har att få tillgång till modern teknik. De flesta avancerade hjälpmedel som används i Sverige är av amerikanskt ursprung men målgruppen i USA har ännu inte möjlighet att använda de senaste, förutom inom studier. Detta gäller exempelvis Medtronic 640 G-pumpen och Abbot Flash Libre som ännu inte ens får visas i USA enligt FDA, trots att Impactstudien påvisar en kraftig signifikant sänkning av hypoglykemi hos typ 1 diabetes-användare. 

Alberto Pugliese berättade första dagen om nPOD

=network for pancreatic organ donors with diabetes, www.jdrfnpod.org. Även pankreastransplanterade individer med T1D accepteras för detta register som efter bildandet 2007 ligger till grund för cirka 170 olika studier, alla med fokus på den hittills relativt obesvarade frågan: Vad är det egentligen som ger T1D? Är virusinfektioner verkligen inblandade? Vilka är de viktigaste kliniska fenotyperna och ser B- och T-cellsfunktionerna ut? Över 140 T1D-donatorer och några MODY-donatorer finns i registret. Av icke-diabetessjuka pankreasdonatorer hade 0.2% diabetesspecifika antikroppar och hos dessa med multipla antikroppar påvisades insulit och högrisk HLA. 

Flera intressegrupper inom nPOD-registret har bildats; ex nPODvirusgroup, nPODomicsgroup, nPOD islet isolation group. Det går nu att in vivo mäta beta-cellsmassa och man kan använda proteomix för virusanalys. Den gamla uppfattningen att det vid diabetesdiagnos finns genomsnittligt 10 % kvar av betacellsmassan/funktionen är troligen inte alls sann. Hittas metoder att spara resterande betacellsfunktion kan det ha stor betydelse för den kliniska sjukdomsutvecklingen. 

På eftermiddagen hölls ett ”Joint ADA/ISPAD-symposium”

där olika pediatriska diabetesregister presenterades, ex vårt initialt europeiska diabetesregister Sweet som nu utvidgas till olika världsdelar, DPV som är det tyska registret samt T1DExchange, ett USA-register varifrån mycket forskningsdata hämtas. Välskötta, nationella diabetesregister som svenska NDR och SWEDIABKIDS borde framhållas mer än vad som är fallet på internationella möten med våra solida, närmast heltäckande data. Reinhard Holl beskrev att inom DPV kan man knappt se någon sänkning av HbA1c-värdena under de senaste 20 åren utan medel HbA1c är 7.9% = 62.8 mmol/mol trots färre DKA och fler pumpar. Av tyska småbarn med diabetes har nu 80% insulinpump. Våra svenska data för metabol kontroll ställer sig i jämförelse otroligt bra. 

Flera sessioner under ADA-mötet diskuterade givetvis Closed Loop;

särskilt i år med inriktning på ”bihormonal pumps” eller dual pumps, dvs pumpar som kan bromsa hypoglykemi med hjälp av glukagon. Tyvärr är glukagon fortfarande instabilt i lösning med halveringstid på 6 minuter varför tillförseln till pumpen måste ske dagligen. Vuxenstudier kunde påvisa att medelglukosvärdet gick att sänka signifikant med dual 

pump jfrt med konventionell pump med också sänkt andel HG. Några biverkningar, ex i form av illamående vid dual pump-användning med glukagon, tycks det inte bli. 

Allt fler studier med Closed Loop-teknik genomförs nu världen över i hemmiljö, också på ungdomar och resultaten verkar mycket lovande. 

85% av CGM-användare har i USA pump men på mötet framhölls att också ”stand-alone-system” har stort värde. CGM-användare har lägre HbA1, lägre glukosvariabilitet och färre hypoglykemier oavsett om insulintillförsel sker via pump eller injektion. 

Ytterligare förbättring inom pumpområdet blir sk HHM-pumpar

som ligger steget närmast före den riktiga Closed Loop-tekniken. HHM betyder Hypo-Hyper-Minimizer och innebär att pumpen sensorstyrt både kan gasa och bromsa insulintillförseln. Denna typ av pump visades ge bäraren signifikant längre tid inom normalområdet för glukos, lägre glukosmedelvärde och lägre variabilitet. Minibolus ges vid värden inom normalområdet men där trenden visar stigande glukosvärden. 

En annan spännande session handlade om bolusberäkning                                                                                                       - hur stort inflytande har fett och protein på insulinbehovet?

Amir Shafat inledde med att ge åhörarna viss bakgrundsinformation. Det dagliga kolhydratintaget bör hos vuxen ligga runt 250 g. Plasmaglukos på 70 mg/dl = 3.9 mmol/l innebär cirka 6 g kolhydrat i blodet. Cirka 15% av kolhydratintaget går direkt och insulinoberoende till hjärnan, cirka 30% till muskulaturen. Magsäckstömningens hastighet förklarar runt 30% av glykemiska responsen efter måltid och redan 8% ändring av denna hastighet ger mycket stor påverkan på glukosvärdet efter måltid. Både fett och protein förlångsammar tömningen vilket minskar det initiala insulinbehovet. Å andra sidan induceras insulinresistens som ökar insulinbehovet. Sättet att bemästra detta vid fett- och/eller proteinrik måltid är att vid pumpanvändning ge kombibolus, ex 60/40 på 4 timmar. 

Garry Steil redogjorde för studier där man jämfört insulinbehovet vid måltider med samma kolhydratmängd men olika fett- och proteininnehåll; LFLP(low fat low protein) med HFHP (high fat high protein). Vid LFLP blir glukosvärdet som högst 1-2 timmar efter måltiden medan HFHP ger peak efter 4-5 timmar. HFHP-måltider behövde i studie 65% mer insulin för att undvika högt glukosvärde men stor interindividuell range, (17-108%!). Ett praktiskt tips från föreläsaren var att vid måltid med mycket fett ge 30% högre insulindos än vad som beräknats baserat på kolhydratinnehållet; ge dosen som kombi under 2-4 timmar och utvärdera effekten. 

Olga Kordonouri från Hanover har utvärderat den polska modellen av Ewa Pankowska att algoritmiskt inkludera fett/protein och funnit att den stämmer bra. Dock har man återgått till en mer pragmatisk modell och föreslår numera en kombibolus med 70/30-fördelning på 4 timmar vid fettrik måltid, ex pizza. Har man inte insulinpump kan direktverkande insulin ersättas med snabbverkande, ex skift från Humalog till Actrapid, framför allt till fettrikt kvällmål. 

Carmel Smart, forskningsaktiv dietist från Australien, menade att vid en måltid som innehåller 60 g kolhydrat gör en felräkning på 10 g ingen skillnad. LF-mål innebär 5 g fett, HF-mål 40 g fett i studier. Samma gäller protein, dvs LP 5 g protein, HP 40 g. 

Färre hypoglykemier har noterats efter HP-mål men inte efter HF-mål. Enbart protein vid måltiden påverkade inte glukosvärdet förrän efter 3-4 timmar. Samma dos insulin krävs efter 5 g protein som 1 g kolhydrat - men proteinet ger alltså sen respons till skillnad från kolhydrat som ger snabb respons. Insulindosen måste anpassas i anslagstid efter detta. Betydelsen av protein i måltiden, dvs ökat insulinbehov, blir signifikant vid > 25 g. Exempel gavs där >20 g fett och >25g protein ökar behovet av insulin med 20% (->40%). Kombibolus 60/40 på 3 timmar föreslogs. Samtliga föreläsare var eniga om att basaldosen ska hållas låg, runt 30 % av totala dagliga dosen. Den polska traditionen är att basalen ska vara så låg som 20 %. 

Att barn inte är som små vuxna vet vi alla men ett symposium hade denna rubrik

Peter Gottlieb beskrev den mer aggressiva form av autoimmunitet som drabbar barn vid diabetesinsjuknande i T1D. Man har nu alltmer kommit att indela detta i sju stadier: 

1) Genetisk risk 

2) Immunaktivering 

3) Immunrespons 

4) Stadium 1; minst 2 autoantikroppar men normala glukosvärden 

5) Stadium 2; minst 2 autoantikroppar och patologiska glukosvärden 

6) Stadium 3; minst 2 autoantikroppar och kliniska symtom på diabetes 

7) Mångårig diabetes 

Vid stadium 1 är risken att insjukna inom 15 år cirka 80 %, samma för alla oavsett etnisk tillhörighet. Små barn får snabbare progression. 

Vid stadium 2 utvecklas IGT (Impaired Glucose Tolerance) snabbare om man är <20 år. ”Innate immunity may be triggered by different microbion” 

Immunsystemet svarar olika på triggers, även skillnad hos monocygota tvillingar varför det inte enbart är genetiskt styrt. Viktigt att barnstudier görs men också betydelsefullt att etiken diskuteras extra noga när det gäller forskning på icke-beslutsmyndiga individer. 

Desmond Schatz som är pediatriker och president för ADA höll ett brandtal

om vikten av fortsatt forskning för att lösa ?"diabetesgåtan”. Han lanserade begreppet ”Diabetes@212°F” (212 grader Fahrenheit är den temperatur då vattnet kokar, 100 grader Celsius) för att hetta upp aktiviteten för att snarast finna prevention och bot, påverka politiker och beslutsfattare måste engageras än mer.

Han jämförde med cancer, HIV och hepatit, där politiska beslut med kraftfull ekonomisk satsning möjliggjort snabb och förbättrad forskning, som i sin tur möjliggjort botande behandling. En nystart behövs i USA och world wide för att få ansvariga att förstå att diabetes typ 1 och 2 är en allvarlig sjukdom, som kan och ska forskas mer på, åtgärdas kurativt genom bätetre medicinering och andra botande åtgärder, ju förr desto bättre.

Fortsättning i nytt inlägg

 

Nyhetsinfo

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Får patienter med kroniska sjukdomar rätt till innovationer?

Arrangör:
Sanofi
Dag:
5/7 2016 13:00 - 14:00
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Ämnesområde 2:
Forskning
Språk:
Svenska
Plats:
Almedalens Hotell, Strandvägen 8
Platsbeskrivning:

Beskrivning av samhällsfrågan

Under de senaste decennierna har sjukvåden utvecklats och nya behandlingsmetoder införts, samtidigt har det inte riktats något fokus på innovation för de kroniskt och långvarigt sjuka. Frågan är alltså återigen hur även kroniskt sjuka ska få tillgång till alla nya innovationer.

Utökad beskrivning av samhällsfrågan

Syftet med detta seminarium är att fortsätta fjolårets seminarium och se var vi står idag i förändrings- och innovationsarbete för gruppen kroniskt och långvarigt sjuka. Sverige är världsledande på många områden inte minst när det gäller IKT, men varför har så lite hänt på detta område inom hälso- och sjukvården? Är svensk hälso- och sjukvård konservativ, och har svårt att ta till sig nya behandlingsformer och ny teknik? Eller är problemet att ny teknik och nya behandlingsformer introduceras för långsamt och att betalningsviljan är låg? Finns det ett motsatsförhållande mellan spjutspetsteknologi inom slutenvården och implementering av nya behandlingsformer inom primärvården? Kanske är det så att det är de kroniskt sjuka som behöver tillgång till dessa innovationer allra mest.

Medverkande: 
  • Anders Lönnberg, nationell samordnare life science
  • Sofia Wallström, generaldirektör, TLV
  • Magnus Löndahl, överläkare, Skånes Universitetssjukhus
  • Gunnar Karlsson, ordförande, FH Sverige
  • Elisabeth Wallenius, förbundsordförande, Sällsynta diagnoser
  • Fredrik Löndahl, förbundsordförande, Diabetesförbundet
  • Nina Lagh (M), vice ordförande ls, Landstinget i Uppsala län
  • Jonas Andersson (L), ordförande hsn, Västra Götalandsregionen
  • Ingrid Lennerwald (S), ordförande beredningen för framtidens sjukvård, Region Skåne
  • Henrik Hammar, moderator
  •  
Kontaktperson 1:
Bengt-Ivar Fransson, Sanofi, 0703011116, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 
Förtäring
Ja
Sökord:
Innovation, Kroniska sjukdomar, Patienten i centrum
 

Min individuella Min

Behandlingsplan – vart tog den vägen?

Arrangör:
Sanofi
Dag:
5/7 2016 11:00 - 12:00
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Ämnesområde 2:
Forskning
Språk:
Svenska
Plats:
Almedalens Hotell, Strandvägen 8
Platsbeskrivning:
 

Beskrivning av samhällsfrågan

Personer med kroniska sjukdomar efterfrågar genom sina patientföreningar möjligheten att i högre grad vara delaktiga i sin egen vård. Seminariet ställer sig frågan – vart tog den individuella behandlingsplanen vägen?

Utökad beskrivning av samhällsfrågan

I december 2015 släppte Socialstyrelsen sin lägesrapport ”Utvecklingen av vården för personer med kroniska sjukdomar” Den beskriver ett antal vårdstrukturella faktorer som bidragit till att vi i Sverige idag har få allmänläkare och en svag primärvård. Primärvården är av största betydelse för vården av personer med kronisk sjukdom. Den nationella strategin är en satsning som syftar till att utveckla vården för personer med kroniska sjukdomar och viktiga förbättringar finns inom centrala områden som patientcentrerad och kunskapsbaserad vård. Vad kan vara mer patientcentrerat än en individuell behandlingsplan? När blir den en verklighet för personer med kroniska sjukdomar?

Medverkande: 
  • Carina Nordqvist Falk, vd, Modern vård i Norden AB
  • Dag Larsson (S), ordförande, sjukvårdsdelegationen, SKL
  • Anders Åkesson (MP), regionråd, Region Skåne
  • Mats Eriksson (M), ordförande, regionstyrelsen, Region Halland
  • Marit Jenset, generalsekreterare, Neuroförbundet
  • Inger Ros, ordförande, Riksförbundet HjärtLung
  • Kristina Söderlund, politiskt sakkunnig, Reumatikerförbundet
  • Henrik Hammar, moderator
  •  
Kontaktperson 1:
Bengt-Ivar Fransson, Sanofi, 0703011116, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 
Förtäring
Ja
Sökord:
Behandlingsplan, Kroniska sjukdomar, Patienten i centrum, Patientens delaktighet

We certainly have important education to accomplish with patients and health professionals regarding the new higher concentration insulin products that are available only in a pen, including U-300 TOUJEO (insulin glargine), U-200 TRESIBA  (insulin degludec), and U-200 HUMALOG (insulin lispro). U-500 insulin is also available in a pen (HUMULIN), although vials remain on the market. Patients may not understand proper dosing and dose measurement with these higher concentrations of insulin products.

From www.diabetesincontrol.com

Nyhetsinfo

www red DiabetiologNytt

A patient who was previously using LANTUS (insulin glargine) U-100 was switched to Toujeo U-300. He was given pen needles to use with Toujeo, but at home, he decided to use the insulin pen cartridge as a vial. He drew up a dose with a leftover U-100 syringe, filling it to the 1000 unit mark, the same daily Lantus dose he had been taking. This resulted in a dose of 300 units of Toujeo, which led to hypoglycemia requiring hospital admission.

Although the safety of using pen cartridges as a vial is questionable, health professionals who administer insulin have also used insulin pen cartridges as vials, sometimes even with hospital authorization. Using a U-100 syringe to measure higher concentrations of insulin could lead to a serious overdose, as in the above case. It is also a risk if insulin pump users take insulin from U-200 or U 300 and use in the syringe to the insulin pump, instead of ordinary insulin pump insulin 100 Units/ml

With U-500, not only is there a risk of an overdose, but under dosing is also possible. In the past, many patients using vials of U-500 insulin measured their dose with a U-100 syringe but, used the syringe scale to measure only 20% of the actual dose. For example, 40 units on the U-100 syringe scale is 200 units of U-500 insulin. If patients now use the new U-500 pen and dial only the number of units they previously measured (40 units), the patient would receive only one-fifth of the prescribed dose.

With the various high concentration insulin products now available in pens, it is important to be informed and warn both patients and health professionals about these new potential insulin coma risks. 

RACIAL DIFFERENCES IN A1C EXIST BUT DIFFERENCES WITHIN RACES MORE PROFOUND

Drs. Rich Bergenstal and Roy Beck presented (on behalf of the Jaeb Center) compelling results confirming that racial differences exist in the relationship between mean glucose and HbA1c – yet, they ultimately concluded that difference were small in the context of even greater variation in the mean glucose-A1c relationship within races.

From www CloseConcerns Knowledgebase

Nyhetsinfo

www red DiabetologNytt

 

The multi-center observational study (n=208) recruited 104 non-Hispanic African American and 104 non-Hispanic white participants to wear the blinded FreeStyle Libre Pro for 12 weeks. Topline results were consistent with the prevailing hypothesis – data showed a 0.8% increase in mean A1c between African Americans and Whites that reflected only a 10 mg/dl difference in mean glucose. The glycemic difference was very clear though Dr. Bergenstal broke this elevated A1c into two possible components: (i) non-glycemic factors [e.g., genetics, biology]; and (ii) glycemic factors [e.g., access to care, technology, social determinants of health]. Importantly, he stressed that the study group has now shown a specific impact of the first component, thereby confirming that biological racial difference in the A1c-mean glucose relationship exist. Specifically, results showed that African Americans had an average 0.3% increase in A1c for a given mean glucose level. Dr. Bergenstal termed this a “small but real” overestimation.

  • Dr. Bergenstal shared that African Americans’ increased rate of glycation is “unlikely to be clinically meaningful.” He cited that the 0.3% A1c increase represents less than half of the overall A1c difference (0.8%) between the two cohorts and – more importantly – that there is considerable variation in mean-glucose A1c relationship irrespective of race.
    • He shared findings that mean glucose could range 80 mg/dl for a given A1c – e.g., an estimated A1c of 8.0% could correspond to a mean glucose of 120 mg/dl or 200 mg/dl for either cohort – suggesting that looking at A1c alone could be dangerously misleading. [We’ve seen similar data from Dr. Irl Hirsch before.] With this in mind, the results ultimately appear to tell more about variation in A1c with average glucose than race. Indeed, as Dr. Bergenstal noted, the implication is that while A1c is an established measure of risk of developing complications, we would be wise to personalize diabetes and treatment decisions based on glucose values. This is not groundbreaking by any means – we’ve long known that A1c in isolation simply is not the best metric. However, Dr. Bergenstal’s words seem to go further, stressing that A1c is not simply inadequate but can be dangerously misleading and clinically ignorant (e.g., treating a patient with mean glucose of 120 mg/dl and 200 mg/dl the same because the A1c reads 8.0%).
    • Dr. Beck added valuable commentary to this discussion, emphasizing that A1c does remain a very valuable endpoint in clinical trials as a metric for hyperglycemia reduction. He argued that A1c is a “fabulous” and reliable outcome when groups are randomized to eliminate difference but that for individual patients, looking at glucose is critical.
  • Drs. Irl Hirsch and Stephanie Amiel added their VERY valuable perspective during a fascinating Q&A, arguing: (i) for the importance of moving to glucose as a primary metric rather than A1c; and (ii) for the need to establish a relationship between blood glucose and long-term risk of developing complications. We bring you their thoughts below:
    • "Historically, we started using A1c because we didn’t have access to glucose. Over time, we learned all these limitations to A1c and all these other biomarkers. In my practice, we don’t know about the difference between Asian Americans and Hispanics, but in the big scheme of things, there is SO MUCH variability between what any one A1c means in terms of glucose. The bigger concerns I have in term of clinical medicine is that very few people do fingerstick glucose testing until they go on insulin. We’re making decisions about whether or not a patient should go on a certainly therapy based on a number that could be 80 or 90 mg/dl off. The paradigm by which we treat type 2 diabetes is wrong, and we’ve been doing it wrong for the past 30 years. As we read about hypoglycemia in elderly, it’s not A1c I’m interested in. It’s the glucose. Simply put, I believe we need to use more fingerstick testing in type 2 diabetes.” – Dr. Hirsch
    • "The epidemiological data suggests that the A1c threshold for complications is not different between races, but we need to look at this for glucose. What are we going to do with the patient who has A1c of 8.0% but a mean glucose of 110 mg/dl? They are NOT going to have same risk as a patient with an A1c of 8.0% and a mean glucose 200 mg/dl. But on the other hand, as far as I know, we simply don’t know that that’s not true. We need data.” – Dr. Amiel 

VICTORY FOR DATA STANDARDIZATION: ROCHE, ABBOTT, DIASEND, GLOOKO SAY YES TO AGP

In a victory for data standardization, we learned that the International Diabetes Center has signed two agreements in the past week to license its one-page, standardized Ambulatory Glucose Profile (AGP) to two diabetes device makers (Roche and Abbott) and two diabetes data management companies (Diasend and Glooko). 

This was good news to hear – we’re eager to see greater standardization of data and use of that data to drive therapeutic change. The partnerships give the companies the right to use the AGP in all their diabetes devices and existing software; the agreement with Abbott extends the groups’ existing partnership to other devices since Abbott already uses the AGP report to visualize downloaded FreeStyle Libre glucose data.

Clinicians have for a long time told us how much they like this standardized report and it’s fantastic to see that companies are beginning to sign on, especially after hearing for years the laundry list of reasons why industry was hesitant: (i) a desire to maintain control of data due to liability concerns; (ii) a desire to protect against competition by building their own proprietary software; (ii) a desire to preserve their direct relationship with patients; and (iv) the antiquated view that patients do not need access to their data (though we’d note that this is almost gone now.) Indeed, on all these levels, the willingness of Abbott, Roche, Diasend, and Glooko to license the report is a real win for patients and providers alike – after all, not every company is going to get what they want with a standardized report, but the field will benefit significantly from consensus.

We’re hopeful this creates momentum and these partnerships set the stage for this standardization movement to reach a critical mass – will Dexcom and Medtronic sign on? Along these lines, we learned that AGP partnerships with three additional device companies and aggregators are slated for “the next month,” and we’ll be watching closely for updates on the IDC team’s recently launched website: AGPreport.org.

NOTABLE POSTERS ON OPENAPS; MEDTRONIC ENLITE 3, HARMONY 1; SENSEONICS; AND ONETOUCH VIA

  • Medtronic presented accuracy data from a pivotal study of its fourth-generation sensor (Enlite 3), to be used with the MiniMed 670G or the Guardian Connect mobile app. The new sensor demonstrated an overall MARD of ~10.5% vs. YSI values measured on days one, three, and seven at 12-hour in-clinic visits (an impressive 23,709 total paired CGM-YSI points). MARD was ~13% on day 1, ~9% on day 3, and ~10% on day 7, with an equal balance of data points collected on each day. Eight-nine participants took part in the study, each wearing two sensors on the abdomen. More details below.
  • Another Medtronic poster shared a larger data set on its fifth-generation sensor (i.e., Harmony 1), featuring one calibration per day, 10-day wear, and an overall MARD of 11.4% vs. the Bayer Contour Next Link meter (n=142 sensors, 12,602 evaluation points). See all the data below.
  • An illuminating poster presented fascinating data from 18 out of the first 40 users of OpenAPS, the DIY automated insulin delivery system created by Ben West, Dana Lewis, and Scott Leibrand (now over 150,000 hours of AID use outside any clinical trial setting!). While using OpenAPS, self-reported outcome measures showed median A1c dropped from 7.1% to 6.2%, an impressive 0.9% reduction in a well-controlled and motivated population. Self-reported median percent time-in-range (80-180 mg/dl) increased from 58% to 81% - consistent with presentations of actual data we’ve seen recently from Mark Wilson (Day #1) and Chris Hanneman (D-Data last fall). Fourteen out of 15 respondents reported some improvement in sleep quality, and 56% reported a large improvement. Respondents were “extremely satisfied with the “life changing” improvements associated with using an APS,” even if they “require significant effort to build and maintain” and “cannot be considered a technological cure.” More perspective below, plus a picture of the setup!
  • A Senseonics poster shared full accuracy data from the 180-day EU pivotal study of its Eversense implantable CGM system, showing an encouraging MARD of 11.6% vs. YSI, though only 40% of sensors lasted to 180 days. 
  • The single-arm, multicenter investigation enrolled 71 patients with type 1 diabetes, who had two sensors inserted bilaterally into their upper arm (Clinical Trials Identifier: NCT02154126).
  • Six-month accuracy was encouraging with Clarke Error Grid analysis showing 84% of measurements in Zone A and 15% in Zone B (# of paired points unreported). Pre-specified secondary endpoints showed accuracy was diminished in the hypoglycemic range (MARD = 22% <70 mg/dl). The median sensor life was just shy of five months at 149 days.
  • See below for positive user experience data on J&J’s OneTouch Via (formerly Calibra Finesse), showing it is easy to use and very easy to train. Great patient and provider feedback in an early ease of use study.

JDRF/NIH CLOSED LOOP MEETING: DESIGNING AP PIVOTAL STUDIES, STANDARDIZING OUTCOMES METRICS

Two major artificial pancreas papers will soon be published in Diabetes Care:  Artificial Pancreas Pivotal Study Design Considerations and A Consensus Report on Outcome Measures for Artificial Pancreas Clinical Trials. The former is authored by Drs. Steven Russell and Roy Beck, while the latter includes 24 luminaries in the field. Wow! We include a snapshot of both papers below, which we heard at the JDRF/NIH Closed-Loop Research Meeting. We found Dr. Russell’s overview of design considerations particularly valuable. Stanford’s Dr. Korey Hood also revealed that by fall 2016, a full set of validated questionnaires will be available to assess the psychosocial impact of AID. Yes! That is fantastic news. Enormous thanks to the Helmsley Charitable Trust and JDRF for funding this major project. We’ll be back in our full report with more from this as-always outstanding evening event; see the highlights below.

Big Picture Highlights

1. ADA PRESIDENT DES SCHATZ ON DIABETES AT 212 DEGREES

In a moving and most compelling presidential address, ADA President Dr. Desmond Schatz (University of Florida, Gainesville, FL) underscored the need to bring diabetes to 212 degrees – “the boiling point of water where it erupts with urgency” – to transform the “invisible disease” to a highly visible crisis. Dr. Schatz detailed the many ways in which diabetes is invisible, hidden, and ignored: people hide the reality of living with diabetes from their friends and families, healthcare providers are largely absent in the daily management of the disease, and patients with type 2 diabetes often choose to be invisible due to stigma and feelings of failure. Specifically, he discussed how diabetes remains invisible in the healthcare community, where missed and delayed type 1 and type 2 diabetes diagnoses can lead to DKA and even premature death. In fact, according to Dr. Schatz, almost 20% of children with type 1 diabetes present with DKA, despite the fact that many visit a clinic during the week prior to their diagnosis. We loved the video of an adolescent Katie who described the “real world” of being a person with diabetes, including how she often felt guilty even talking about her diabetes because she didn’t want her family to feel worried. (Nods from through the room from those with diabetes ensued.) In addition, Dr. Schatz emphasized that although diabetes is far more prevalent, NIH funding for the disease pales in comparison to that for HIV/AIDS and cancer – an incredible $35 per patient for diabetes vs. $2,500 for HIV/AIDS and $372 for cancer, another byproduct of its invisibility. To that end, he advocated for taking a page out of the book of successful movements such as those for HIV/AIDS and even the recent Zika epidemic (which recently received a $1.1 billion compromise bill), where people have rallied around a strategic vision and inspired a “fiery sense of urgency”. Throughout the talk, the hashtag #nomoreworry emerged. He concluded his presentation with a powerful call to action: “When all is said and done, the people responsible for real action, who are capable of turning the tide of this epidemic and finding a cure … are likely sitting right next to you in this room!”

Honorable Mentions

AWARD-9 RESULTS SHOW GREATER A1C REDUCTIONS WITH TRULICITY VS. PLACEBO

In front of a standing-room-only crowd, Dr. Paolo Pozzilli (University Campus Bio-Medico, Rome, Italy) presented the results of AWARD-9, a double-blind, 28-week superiority trial comparing the effects of dulaglutide (Lilly’s Trulicity) vs. placebo on A1c and weight when added to insulin glargine in patients with type 2 diabetes. The trial randomized 300 patients with inadequate glycemic control (A1c 7-10.5%) to dulaglutide 1.5mg (n=150) or placebo (n=150) on top of once-daily glargine titrated to a FPG target of 71-99 mg/dl (± metformin). Baseline characteristics were similar between both groups (please see below). Data at 28 weeks showed that compared to placebo, dulaglutide provided significantly greater reductions in A1c (0.67 vs. 1.44, respectively), and in fasting serum glucose (28 vs. 45 mg/dl, respectively; p<0.001 for both comparisons). No difference in the rate of hypoglycemia was observed. Patients on dulaglutide experienced a weight loss (4.2 lbs [1.91 kg]), compared to a weight gain with placebo (1.1 lbs [0.50 kg]; p<0.001). In addition, insulin glargine requirements were statistically significantly lower in the dulaglutide group (13U) versus the placebo group (26U).

POSITIVE WEIGHT LOSS RESULTS FOR INVOKANA + PHENTERMINE

In a late-breaking poster, in some of the first major obesity news of the meeting, phase 2 results of the co-administration of J&J’s Invokana (canagliflozin) and phentermine showed significantly greater weight loss vs. placebo in adults with overweight and obesity. This study was a four-arm, 26-week study and evaluated the efficacy and safety of Invokana + phentermine, phentermine alone, Invokana alone, and placebo in 334 adults with BMIs of 30-50 kg/m2 and without type 2 diabetes or with hypertension and/or dyslipidemia and BMIs of 27-50 kg/m2. The findings demonstrated that at 26 weeks, from a mean baseline BMI of ~37 kg/m2, the Invokana + phentermine group achieved significantly greater weight loss (7.5%) compared to the other groups (4.1%, 1.9%, and 0.6% for Invokana, phentermine, and placebo, respectively). In addition, the combination therapy group had a significantly higher proportion of participants achieving ≥5% weight loss compared to placebo (67% vs. 18%). Only 18% and 42% of the Invokana and phentermine groups’ participants achieved weight loss of at least 5%. On other secondary endpoints, the combination therapy group also had a significant reduction in systolic blood pressure, with a placebo-subtracted reduction of 4.2 mmHg. Regarding safety and tolerability, no new signals emerged from these data; however, the combination therapy, phentermine, and Invokana groups all experienced increases in heart rate of 3.5 bpm, 4.1 bpm, and 0.7 bpm, respectively – an observation whose potential consequences on cardiovascular events have not yet been determined and will likely warrant further investigation. Ultimately, these findings are powerful in support of using phentermine with SGLT-2 inhibitors in chronic weight management, and we are interested to see whether Janssen will move forward with phase 3 trials, and ultimately pursue an obesity indication. Combination therapies have certainly gained significant attention within obesity management (in addition to diabetes), and we have specifically heard greater enthusiasm for the potential of GLP-1 agonists and SGLT-2 inhibitors in weight management. With so much evidence already accumulated on these various diabetes drugs, we look to see how industry, healthcare providers, and the FDA envision the movement of these products into obesity, given the troubled commercial environment for obesity compounds to date and given the extreme high need for therapy to help patients.  

HIGHER MORTALITY FOLLOWING NON-FATAL CV EVENTS IN EXAMINE; NO DIFFERENCE BETWEEN TREATMENT GROUPS

Takeda presented a post-hoc analysis from EXAMINE (as a poster [1090-P] and in a press briefing) demonstrating significantly higher mortality among patients who experienced non-fatal CV events during the trial than those who did not, with no difference between the Nesina (alogliptin) and placebo groups. The overall EXAMINE results (first presented at ESC 2013) demonstrated a comparable effect on CV outcomes with Nesina vs. placebo, both in addition to standard of care. Among all trial participants, the hazard ratio was 0.85 (95% CI: 0.66-1.10) for cardiovascular death and 0.80 (95% CI: 0.57-1.12) for sudden cardiac death. This analysis compared mortality rates in patients who experienced a major non-fatal CV event (MI, hospitalization for unstable angina or heart failure, or stroke) during the trial vs. those who did not. Results demonstrated a significant increase in CV mortality following any non-fatal event, with the most startling effect in patients hospitalized for heart failure. One in 10 of those patients died within three to four months of the hospitalization and approximately one third died within the next 20 months. There was no difference in mortality between the Nesina and placebo groups in patients hospitalized for heart failure (22.7% vs. 34.1% mortality; HR = 1.02; 95% CI: 0.51-2.02) or in the control group of patients who did not experience any CV events (4.5% vs. 5.8% mortality; HR = 0.81; 95% CI: 0.63-1.05). These results underscore the significant morbidity and mortality associated with heart failure in patients with type 2 diabetes and reinforce its importance as an endpoint in CVOTs for diabetes drugs. They also provide some degree of reassurance that Nesina does not worsen heart failure-related outcomes; the FDA recently added a warning to Nesina’s label based on the non-significant imbalance in hospitalization for heart failure in EXAMINE, but there is still no clear consensus in the field on the legitimacy of that finding.

GREATER A1C REDUCTIONS WITH ERTUGLIFLOZIN/SITAGLIPTIN COMBINATION VS. INDIVIDUAL COMPONENTS

Merck/Pfizer presented interim, 26-week results in a poster (125-LB) from an ongoing phase 3 trial demonstrating significantly greater A1c reductions with Merck/Pfizer’s ertugliflozin plus sitagliptin (Merck’s Januvia) versus either drug alone in patients with type 2 diabetes. The study recruited 1,233 patients inadequately controlled (A1c 7.5-11%) on stable metformin (≥8 wks at ≥1,500 mg/day), who were randomized to one of five groups: ertugliflozin 5mg or 15mg daily plus sitagliptin 100mg daily, ertugliflozin 5mg or 15mg daily alone, or sitagliptin 100mg daily alone. Data at 26 weeks showed that co-administration of ertugliflozin with sitagliptin led to significantly greater reductions in A1c (1.5% for both groups) compared to either drug alone (1%-1.1% across the three groups; p<0.002). A similar effect was observed with fasting plasma glucose and percentage of patients achieving A1c <7%. Co-administration also led to significantly greater reductions in body weight and systolic blood pressure compared to sitagliptin alone. Static beta-cell responsivity increased across all treatment arms and no difference was observed with the co-administration groups.

  • Merck/Pfizer also presented a poster (130-LB) with interim, 26-week results from the ongoing VERTIS MONO trial demonstrating significantly greater A1c reductions with Merck/Pfizer’s ertugliflozin vs. placebo in patients with type 2 diabetes. The study recruited 461 patients with inadequate glycemic control on diet and exercise (A1c 7-10.5% with no anti-diabetic agents taken within 8 weeks of starting the study), who were randomized to placebo (n=153), ertugliflozin 5mg daily (n=156), or ertugliflozin 15mg daily (n=152). Twenty-six-week data showed that both ertugliflozin doses provided statistically significantly greater A1c reductions vs. placebo (0.99% for the 5mg dose and 1.16% for the 15mg dose); similar results were observed for fasting plasma glucose, body weight, and 2-hour post-prandial glucose. In addition, a greater proportion of patients achieved an A1c <7% in the ertugliflozin groups vs. placebo (28.2% with ertugliflozin 5 mg and 35.8% with ertugliflozin 15 mg vs. 13.1% with placebo).

ADA PARTNERS WITH IBM

In the opening of the presidential address, ADA CEO Mr. Kevin Hagan announced the ADA’s new long-term partnership with IBM Watson Health to improve diabetes prevention and management. IBM Watson General Manager Mr. David Kenny joined Mr. Hagan on stage to briefly discuss the collaboration, a tremendous signal of IBMs investment in this partnership, which will leverage Watson’s computing brainpower and artificial intelligence (AI) capabilities and the ADA’s enormous repository of clinical data to create a sophisticated diabetes advisor to help inform treatment decisions. We’re not entirely sure what specific output could result from this agreement, but clinical decision support and more personalized therapy are under consideration. In addition, the partnership will develop a cloud-based data and insights service to optimize scientific research; new offerings may also leverage Watson’s unique artificial intelligence capabilities, such as natural language processing and predictive analytics. Said Mr. Kenny, “AI can help scale the expertise of professionals in this room… Our goal is to power up your big ideas and create new products that will transform the lives of people with diabetes.” In addition, he announced a Watson-based innovation challenge that pushes developers to propose cognitive apps that will advance the use of technology to improve the lives of people with diabetes or prediabetes. According to the press release issued during the presentation, Watson will also be trained to understand diabetes data to identify potential risk factors and create recommendations for both patient and providers – important steps forward in our pursuit of personalized medicine. This expands on IBM Watson’s diabetes partnerships with Medtronic (building a personal diabetes assistant, SugarWise) and Novo Nordisk (no details shared since last December).

TECH EXHIBIT HALL – BD/MEDTRONIC INFUSION SET TO LAUNCH IN US/FRANCE BY “END OF 2016”

In the tech exhibit hall, we learned that BD/Medtronic’s MiniMed Pro FlowSmart Infusion Set will launch in the US and France “by the end of 2016.” We also have coverage of Ascensia, InSpark Technologies, and Valeritas in addition to all the companies we visited yesterday.

Detailed Discussion and Commentary

Oral Presentations: Treatment Choices after Orals in Type 2 Diabetes

EFFICACY AND SAFETY OF ONCE-WEEKLY SEMAGLUTIDE VS. SITAGLIPTIN AS ADD-ON TO METFORMIN AND/OR THIAZOLIDINEDIONES AFTER 56 WEEKS IN SUBJECTS WITH TYPE 2 DIABETES

Bo Ahrén, MD, PhD (Lund University, Sweden)

In the double-blinded, double-dummy, active-controlled, parallel-group SUSTAIN 2 trial (n=1231), semaglutide 0.5 mg produced a 0.77% greater A1c reduction (p<0.0001) and semaglutide 1.0 mg produced a 1.06% greater A1c reduction (p<0.0001) than Merck’s Januvia (sitagliptin 100 mg) after 56 weeks of treatment. Participants had type 2 diabetes and were on metformin, TZDs, or both. In total, semaglutide 0.5 mg produced a 1.3% A1c reduction and semaglutide 1.0 mg produced a 1.6% A1c reduction, compared to sitagliptin’s 0.5% A1c reduction (baseline A1c=8.1%, p<0.0001). Participants treated with semaglutide 0.5 mg and 1.0 mg experienced a 17.4 mg/dl and 26.74 mg/dl reduction in fasting plasma glucose (FPG), respectively, compared to participants treated with sitagliptin (baseline FPG=169.4 mg/dl, p<0.0001). Overall, participants experienced FPG reductions of 37.4 mg/dl, 46.7 mg/dl, and 20.8 mg/dl on semaglutide 0.5 mg, semaglutide 1.0 mg, and sitagliptin, respectively. End-of-trial 7-point SMPG profiles were lower at every point for participants treated with semaglutide compared to sitagliptin and compared to baseline. 78% of participants in the semaglutide 1.0 mg group and 69% of participants in the semaglutide 0.5 mg group achieved an end-of-trial A1c of <7.0% at 56 weeks, compared to 36% of the sitagliptin-treated group. 66% of the semaglutide 1.0 mg group and 53% of the semaglutide 0.5 mg group achieved a target A1c of ≤6.5% at 56 weeks, compared to 20% of the sitagliptin-treated group.

  • 62% of participants on semaglutide 1.0 mg and 46% of participants on semaglutide 0.5 mg achieved ≥5% weight loss, compared to 18% of participants in the sitagliptin group. Furthermore, 24% of participants in the semaglutide 1.0 mg group and 13% of participants in the semaglutide 0.5 mg group experienced even more impressive weight loss of ≥10%, compared to just 3% of the sitagliptin-treated group. Semaglutide 0.5 mg and 1.0 mg produced a 2.37 kg (~5.22 lbs) and 4.22 kg (~9.3 lbs) greater weight loss, respectively, than sitagliptin (p<0.0001). In total, participants on semaglutide 0.5 mg lost a mean 4.3 kg (~9.5 lbs) of body weight while participants on semaglutide 1.0 mg lost a mean 6.1 kg (~13.4 lbs), compared to 1.9 kg (~4.2 lbs) with sitagliptin (baseline body weight=89 kg [~196 lbs]). Like the A1c results, Dr. Ahmann highlighted the early and dramatic divergence in weight loss between the semaglutide and the exenatide groups.
  • 74% of participants in the semaglutide 1.0 mg group and 63% of participants in the semaglutide 0.5 mg group achieved a composite endpoint of (i) A1c <7.0%, (ii) no severe or blood-glucose confirmed symptomatic hypoglycemia, and (iii) no weight gain. Only 27% of participants in the sitagliptin-treated group were able to achieve this endpoint. Thus, participants on semaglutide appear 2-3 times more likely to achieve this very clinically relevant composite outcome.
  • Overall, serious, and severe adverse event rates were comparable across all three treatment groups, though adverse events leading to discontinuation were higher in the two semaglutide groups. Not surprisingly, Dr. Ahrén attributed the higher discontinuation rate of the semaglutide groups to increased GI side effects – 18% of participants in both semaglutide groups experienced nausea at least once throughout the study (vs. 7% in the sitagliptin group), 13% experienced diarrhea (vs. 7%), and 8%-10% experienced vomiting (vs. 3%). That said, Dr. Ahrén emphasized that the vast majority of cases of nausea were classified as “mild,” the percentage of patients experiencing nausea at any single time point in the study never exceeded 10%, and the percentage of patients experiencing nausea tapered off as the trial progressed. Hypoglycemia, pancreatitis, and malignant neoplasms were similar across all the groups. Participants in the two semaglutide groups experienced a 2 beats/min increase in heart rate, compared to a 1 beat/min increase in the sitagliptin group.

SUSTAIN 2 Results Summary

 
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Treatment Semaglutide 0.5 mg Difference between 0.5 mg and sitagliptin Semaglutide 1.0 mg Difference between 1.0 mg and sitagliptin
A1c -1.3% -0.77%, p<0.0001 -1.6% -1.06%, p<0.0001
Fasting Plasma Glucose (FPG) -37.4 mg/dl -17.4 mg/dl, p<0.0001 -46.7 mg/dl -26.74 mg/dl, p<0.0001
% Achieving A1c <7.0% 69%   78%  
% Achieving A1c <6.5% 53%   66%  
Weight -4.3 kg (~9.5 lbs) -2.37 kg (~5.22 lbs), p<0.0001 -6.1 kg (~13 lbs) -4.22 kg (~9.3 lbs), p<0.0001
% Achieving ≥5% Body Weight Loss 62%   46%  
% Achieving ≥10% Body Weight Loss 13%   24%  
% Achieving A1c <7.0% with no severe/symptomatic hypoglycemia and no weight gain 63%   74%  
 

EFFICACY AND SAFETY OF ONCE-WEEKLY SEMAGLUTIDE VS. EXENATIDE ER IN SUBJECTS WITH TYPE 2 DIABETES (SUSTAIN 3)

Andrew Ahmann, MD (Oregon Health & Science University, Portland, OR)

In the open-label, active-controlled, parallel-group SUSTAIN 3 (n=813) trial, participants treated with semaglutide 1.0 mg experienced a 0.62% greater A1c reduction (p<0.0001) than participants treated with exenatide ER 2.0 mg (AZ’s once-weekly Bydureon). Overall, those in the semaglutide-treated group experienced a mean A1c reduction of 1.5%, compared to a 0.9% reduction in the exenatide-treated group (baseline A1c=8.3%, p<0.0001). Dr. Ahmann emphasized that the A1c curves for the semaglutide and exenatide groups diverged early on and stayed significantly different throughout the trial. End-of-trial 7-point SMPG profiles were lower at every point for participants treated with semaglutide compared to exenatide and compared to baseline, though the difference appeared to be less dramatic than the separation between the semaglutide and sitagliptin SMPG profiles (as expected, given the generally accepted greater glucose-lowering efficacy of GLP-1 agonists compared to DPP-4 inhibitors) – it would have been more helpful from our view to have CGM data. 67% of participants in the semaglutide group achieved an end-of-trial A1c of <7.0% at 56 weeks, compared to 40% of the exenatide-treated group. 47% of the semaglutide group achieved a target A1c of ≤6.5% at 56 weeks, compared to 22% of the exenatide-treated group.

  • 52% of participants treated with semaglutide in SUSTAIN 3 achieved ≥5% weight loss, compared to 17% of those treated with exenatide. 21% of semaglutide-treated patients achieved ≥10% weight loss compared to only 4% of exenatide-treated patients. Participants treated with semaglutide experienced a 3.78 kg (~8.3 lbs) greater weight loss than those treated with exenatide (p<0.0001). In total, the semaglutide-treated group experienced a mean weight loss of 5.6 kg (~12.3 lbs) compared to a mean weight loss of 1.9 kg (~4.2 lbs) with exenatide (baseline body weight = 95.8 kg [~211 lbs]).
  • With semaglutide treatment, 57% of participants were able to achieve a composite endpoint of A1c <7% with no severe or symptomatic hypoglycemia and no weight gain. This is about twice the proportion of participants in the exenatide-treated group that achieved this composite endpoint (29%).
  • Overall adverse events were similar between the semaglutide and the exenatide groups, but serious AEs, severe AEs, and AEs leading to discontinuation were slightly higher in the semaglutide group (9% vs. 7%). This was likely driven by the increased GI side effects seen with semaglutide. In particular, as was previously reported, participants in the semaglutide group experienced almost twice as much nausea as those in the exenatide group (22% vs. 12%). Participants in the semaglutide group also experienced higher rates of diarrhea (11% vs. 8%), decreased appetite (8% vs. 5%), vomiting (7% vs. 6%), dyspepsia (7% vs. 5%), and constipation (6% vs. 5%). The side effect profile is consistent with what has been reported across the SUSTAIN phase 3 development program. Our sense is that semaglutide is a more potent GLP-1 agonist, offering greater A1c and weight loss efficacy – though some suggest it may have an accompanying higher GI side effects, with most in single digits, we’re not too worried about that – although to what degree “hand holding” in the trial would have reduced those reporting nausea etc we don’t know. Either way, there are obviously a high percentage of patients that would seem to be able to benefit from this therapy and we look forward to seeing the move toward the market for it.

SUSTAIN 3 Results Summary

 
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Treatment Semaglutide 1.0 mg Exenatide ER 2.0 mg
A1c -1.5% -0.9%
% Achieving A1c <7.0% 67% 40%
% Achieving A1c <6.5% 47% 22%
Weight -5.6 kg (~12.3 lbs) -1.9 kg (~4.2 lbs)
% Achieving ≥5% Body Weight Loss 52% 17%
% Achieving ≥10% Body Weight Loss 21% 4%
% Achieving A1c <7.0% with no severe/symptomatic hypoglycemia and no weight gain 57% 29%

SUPERIOR EFFICACY OF ITCA 650 VS. SITAGLIPTIN IN UNCONTROLLED TYPE 2 DIABETES ON METFORMIN: THE FREEDOM-2 RANDOMIZED, DOUBLE-BLIND, 1-YEAR STUDY

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock presented results from the phase 3 FREEDOM-2 study demonstrating significantly greater A1c reductions (1.5% vs. 0.8%; p<0.001) and weight loss (4 kg vs. 1.3 kg; p<0.001) with Intarcia’s ITCA 650 vs. Merck’s Januvia (sitagliptin). Intarcia announced topline results from the trial in August. The double-blind trial randomized 535 patients with type 2 diabetes on metformin to receive either ITCA 650 + oral placebo or Januvia + implantable placebo for 52 weeks. Patients received the initiation dose of ITCA 650 for 13 weeks and switched to the maintenance dose for the remaining 39 weeks. The A1c difference between the groups was already significant at six weeks and stabilized at week 26; final reductions were 1.5% with ITCA 650 vs. 0.8% with Januvia (baseline = 8.6%-8.7%; p<0.001). ITCA 650 also produced significantly greater reductions in fasting plasma glucose (47 mg/dl vs. 28 mg/dl; p<0.001). Weight loss followed a similar pattern as the A1c reductions, with a fairly early separation that stabilized at around week 26 and remained stable throughout the trial. The final weight reduction was 4 kg (~8.8 lbs) with ITCA 650 vs. 1.3 kg (~2.9 lbs) with Januvia (baseline BMI = 33 kg/m2; p<0.001). ITCA 650 was also superior in terms of the percentage of patients achieving the composite endpoint of A1c reduction >0.5% and weight loss ≥2 kg (61% vs. 28%; p<0.001) and the percentage achieving A1c targets of <7% (61% vs. 42%) and <6.5% (44% vs. 21%). As expected, there were more GI events in the ITCA 650 group, though the discontinuation rates due to these events were low (4.5% for nausea and 2.3% for vomiting). Importantly, the rate of procedure-related adverse events was quite low (<1%) in both groups. Dr. Rosenstock also emphasized that nausea rates peaked when the initial dose was started and when the dose was escalated, but rates were quite low throughout the rest of the trial.

  • We are particularly impressed with the durability of the A1c and weight reductions – the difference between the groups held steady from week 26 through the end of the trial. We also found the results for the composite endpoint especially compelling and expect that payers will as well. Intarcia has reported results from three additional trials for ITCA 650: results from FREEDOM-1 and FREEDOM-HBL demonstrating significant A1c reductions vs. placebo were presented at ADA 2015 and topline results from the FREEDOM-CVO trial demonstrating a neutral effect on CV outcomes were announced in May. The impressive efficacy and guaranteed adherence should make ITCA 650 an appealing option for a wide range of patients and could significantly expand use of the GLP-1 agonist class. That said, we would not be surprised if the product’s commercial performance falls somewhat short of the very high expectations some in the field have set for it – the company typically frames ITCA 650 as a completely disruptive innovation for the entire type 2 diabetes market, but we imagine that some patients and providers might be wary of an implanted device or might prefer an agent like Novo Nordisk’s Victoza (liraglutide) with a demonstrated benefit on CV outcomes.

Questions and Answers

Q: Are there any issues around removal in terms of fibrosis?

A: There were no issues of fibrosis. The technique has been highly revised. It’s now done with a delivery device and different tools to ensure the placement is very superficial. Before there was not a tool to really make sure the device was not placed too deep. Now they have a device where you can’t get too deep, so that’s no longer an issue.

Q: Do you have to take the device out to change the dose?

A: Yes. This device could be used for six months, and eventually it will be one year. Taking it out takes less than two minutes.

CLINICAL IMPACT OF TITRATABLE FIXED-RATIO COMBINATION OF TITRATABLE FIXED-RATIO COMBINATION OF INSULIN GLARGINE/LIXISENATIDE VS. EACH COMPONENT ALONE IN TYPE 2 DIABETES INADEQUATELY CONTROLLED ON ORAL AGENTS: LIXILAN-O TRIAL

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock presented results from the phase 3 LixiLan-O trial demonstrating significantly greater A1c reductions with Sanofi’s iGlarLixi (formerly LixiLan) vs. either of its components in patients with type 2 diabetes on oral agents. Sanofi announced topline results from the trial in July 2015 and the dataset was included in the company’s briefing documents for the recent FDA Advisory Committee meeting for iGlarLixi. The open-label trial randomized 1,170 patients with type 2 diabetes not at goal on metformin and another oral agent to receive either iGlarLixi (n=469), Lantus (insulin glargine; n=467), or lixisenatide (n=234) for 30 weeks. A1c reductions were significantly greater with iGlarLixi (1.6%) vs. both Lantus (1.3%) and lixisenatide (0.9%) (baseline = 8.1%; p<0.0001). A significantly higher percentage of patients achieved an A1c <7% with the combination (74%) compared to Lantus (59%) and lixisenatide (33%). Fasting plasma glucose reductions were comparable with iGlarLixi (62 mg/dl) and Lantus (59 mg/dl) and less impressive with lixisenatide (27 mg/dl) (baseline = 176-178 mg/dl; p<0.0001). As expected, lixisenatide’s greatest contribution was on postprandial glucose. iGlarLixi was superior to both Lantus (by 43 mg/dl) and lixisenatide (by 20 mg/dl) on two-hour postprandial glucose; the combination was superior to Lantus (by 38 mg/dl) but inferior to lixisenatide (by 16 mg/dl) on postprandial glucose excursions. Seven-point glucose profiles showed lower overall glucose throughout the day with iGlarLixi and lower peaks compared to Lantus, especially at breakfast. The combination also demonstrated a 1.4 kg weight benefit compared to Lantus and allowed a significantly higher percentage of patients to achieve the composite endpoint of A1c <7% with no weight gain (43% vs. 25% with Lantus and 28% with lixisenatide). 

  • Especially relevant in light of the AdComm discussion, Dr. Rosenstock highlighted the potential for dosing flexibility with the two iGlarLixi pens. Sanofi plans to market iGlarLixi in two pens, one (pen A) with a 2:1 insulin glargine/lixisenatide ratio and insulin doses ranging from 10-40 U/day and another (pen B) with a 3:1 insulin glargine/lixisenatide ratio and insulin doses ranging from 40-60 U/day. Dr. Rosenstock emphasized that this allows insulin titration up to 60 U without going above the maximum dose of 20 mcg lixisenatide. Data on the final dose distribution in LixiLan-O showed that 56% of patients achieved good control with pen A, 44% required intensification to pen B, and only 8% reached the maximum dose of 60 U without achieving target. A number of panelists at the AdComm meeting expressed concerns about distinguishing between the two pens and about the nomenclature of “units” used to dose the combination. These concerns were fairly unexpected to us, and we hope Sanofi and the FDA can work together to resolve them in short order.
  • Adverse events were generally similar between groups in the trial. Nausea rates were substantially lower with iGlarLixi (9.6%) compared to lixisenatide (24%), confirming one of the main expected with these combinations compared to GLP-1 agonists alone. Dr. Rosenstock highlighted the fact that only 0.4% of the iGlarLixi group discontinued treatment due to nausea (compared to 2.6% in the lixisenatide group). The rate of documented symptomatic hypoglycemia was low and comparable between the iGlarLixi and Lantus groups (1.4 vs. 1.2 events/patient-year).

Questions and Answers

Q: Given the short duration of action of lixisenatide, might it make more sense to use it twice a day?

A: That sounds like common sense but you don’t need to. With the results you get, why would you need to? You get an effect on postprandial glucose mainly in the morning, you do have some carry over for lunch, and by dinner there’s not much, but you get down to 6.5%. We shouldn’t use it twice a day because it’s not approved.

Q: Would you use it twice a day if A1c deteriorates over time?

A: I don’t know. We need longer-term studies.

Q: I’d like to see a study where you challenge the fixed-ratio combination not only to glargine + lixisenatide but to degludec + liraglutide, comparing the fixed ratio with split injections. I think it would highlight the convenience of the fixed ratio and on the other side the ability to individualize the combination because we know patients have different characteristics.

A: There’s no question that what you suggest would be a nice study. The question is whether simultaneous therapy is better than sequential. All these years we’ve done sequential. We have a bit of indirect evidence on this from GetGoal Duo 1, where patients were on basal insulin for 12 weeks and then added lixisenatide. That got people down to 7% and here we got down to 6.5%. The important bottom line is that we get down to 6.5%. The same was true with IDegLira. Both combinations get people down to levels we were never able to get before with any of the components alone.

Q: What concentration of insulin glargine was used?

A: U100.  

Oral Presentations: Beyond Basal Insulin in Type 2 Diabetes – Treatment Intensification Options

EFFICACY AND SAFETY OF THE INSULIN GLARGINE/LIXISENATIDE FIXED-RATIO COMBINATION VS. INSULIN GLARGINE IN PATIENTS WITH T2DM: THE LIXILAN-L TRIAL

Vanita Aroda, MD (MedStar Health Research Institute, Hyattsville, MD)

Dr. Vanita Aroda presented results from the phase 3 LixiLan-L trial demonstrating significantly greater A1c reductions with Sanofi’s iGlarLixi (formerly LixiLan) vs. Lantus (insulin glargine) in patients with type 2 diabetes on basal insulin, driven by improvements in postprandial glucose. Sanofi announced topline results from the trial in September 2015 and the dataset was included in the company’s briefing documents for the FDA Advisory Committee meeting for iGlarLixi. The open-label trial randomized 736 patients not at goal on basal insulin and oral drugs to treatment with iGlarLixi (n=367) or Lantus (n=369) for 30 weeks. The insulin glargine dose in both groups was titrated to a fasting glucose target of 80-100 mg/dl and the dose was capped at 60 U/day (to match the maximum dose in the combination). A1c reductions were significantly greater with iGlarLixi (1.2%) than Lantus (0.6%) (baseline = 8.1%). A significantly higher percentage of patients achieved an A1c <7% with iGlarLixi (55%) than with Lantus (30%; p<0.0001). Fasting plasma glucose reductions were similar in both groups (21 mg/dl vs. 23 mg/dl), as expected given the almost identical average daily doses of insulin glargine at the end of the trial (46 vs. 47 U). The main contribution of lixisenatide to the combination was on postprandial glucose: iGlarLixi produced significantly greater reductions in both two-hour postprandial glucose (85 mg/dl vs. 25 mg/dl) and postprandial excursions (70 mg/dl vs. 8 mg/dl) compared to Lantus. Seven-point glucose profiles illustrated this improvement in postprandial control, particularly after breakfast. iGlarLixi led to a 1.4 kg weight benefit and comparable hypoglycemia rates to Lantus. The combination also allowed a greater percentage of patients to achieve an A1c <7% without weight gain (34% vs. 13%), an A1c <7% without hypoglycemia (32% vs. 19%), and an A1c <7% without weight gain or hypoglycemia (20% vs. 9%) – while the benefit is encouraging, the low absolute percentages in both groups illustrate the remaining need for more effective therapies.

Questions and Answers

Q: Do you think the weight loss is less when lixisenatide is used in combination with insulin vs. separately when added to insulin or without insulin?

A: I would refer you to the LixiLan-O trial, where we saw greater weight loss with lixisenatide alone. Here we have mitigation of the weight gain with insulin glargine.

Q: But the average weight loss seems to be less here than when you add on a GLP-1 agonist without insulin or even separately.

A: Part of it might be the final dose, which was 17 mcg of lixisenatide on average.

Q: I’m guessing the combination was administered before breakfast. Was the administration of glargine alone done at the same time?

A: Glargine could be administered at any time and it was consistent throughout the trial. The combination was injected an hour before breakfast.

Q: From the seven-point profile, it’s obvious that the main effect is on that first meal, yet it was a fixed schedule of dosing before breakfast. Do you think the results would be different if it was administered with the largest meal rather than breakfast? My patients don’t all eat breakfast, and dinner is typically the biggest meal in the US.

A: That’s an intriguing question that can only be answered by a trial. There was a sub-study looking at dosing at the main meal vs. the morning and the main effect seems to be in the morning, but we would need a trial to know.

Q: You didn’t save a single dose of insulin by adding lixisenatide and you had the same rate of hypoglycemia. Is there any information on the PK/PD data? Were the profiles of both components really preserved? It seems like a very weak effect.

A: The PK data were consistent with what was seen in the lixisenatide standalone program. Your point is appreciated that there’s not necessarily an insulin-sparing effect. I would also state here that we had a greater A1c reduction down to 6.9% without increased hypoglycemia. We’re looking at two different end A1cs with comparable hypoglycemia.

Q: Looking at the meal data in the control group, you still have glucose values of 230 mg/dl two hours after a meal – people are clearly not well controlled. Would you anticipate different results if you had a more well-controlled group?

A: The 230 mg/dl was from a mechanistic substudy highlighting the mechanism of action of iGlarLixi on postprandial glucose. The 7-point SMPG, reflective of control in the comparator group, showed the control we typically see with titration with insulin glargine (postprandial glucose of 160s-190s during the day). This, along with detailed review of titration, superimposable fasting glucoses, and insulin doses all support appropriate titration in the control group.

IMPROVED GLYCEMIC CONTROL AND WEIGHT LOSS WITH ONCE-WEEKLY DULAGLUTIDE VS. PLACEBO, BOTH ADDED TO TITRATED DAILY INSULIN GLARGINE, IN TYPE 2 DIABETES PATIENTS (AWARD-9)

Paolo Pozzilli, MD (University Campus Bio-Medico, Rome, Italy), City, State/Country)

In front of a standing-room-only crowd, Dr. Paolo Pozzilli presented the results of AWARD-9, a double-blind, 28-week superiority trial comparing the effects of dulaglutide (Lilly’s Trulicity) vs. placebo on A1c and weight when added to insulin glargine in patients with type 2 diabetes. The trial randomized 300 patients with inadequate glycemic control (A1c 7-10.5%) to dulaglutide 1.5mg (n=150) or placebo (n=150) on top of once-daily glargine titrated to a FPG target of 71-99 mg/dl (± metformin). Baseline characteristics were similar between both groups (please see below). Data at 28 weeks showed that compared to placebo, dulaglutide provided significantly greater reductions in A1c (0.67 vs. 1.44, respectively), and in fasting serum glucose (28 vs. 45 mg/dl, respectively; p<0.001 for both comparisons). No difference in the rate of hypoglycemia was observed. Patients on dulaglutide experienced a weight loss (4.2 lbs [1.91 kg]), compared to a weight gain with placebo (1.1 lbs [0.50 kg]; p<0.001). In addition, insulin glargine requirements were statistically significantly lower in the dulaglutide group (13U) versus the placebo group (26U). 

  • The rate of retention was similar between the dulaglutide and placebo groups (92% and 89%, respectively). The two groups also had similar baseline characteristics, with an average age of 60 years, percent female of 41-43%, percent Caucasian of 92-95%, BMI of 33 kg/m2, diabetes duration of 13 years, A1c of 8.3-8.4%, fasting serum glucose of 156-157 mg/dl, and percent on metformin of 87-89%.
  • Table 1: 28-week data on the effect of dulaglutide vs. placebo on glucose measurements, weight, and glargine requirements.
 
  •  
  •  
  •  
  •  
  •  
Primary Endpoint Dulaglutide Placebo Difference p value
A1c reduction  (%) 1.44 0.67 0.77 p <0.001
% pt with A1c <7% 69% 35% -- p <0.001
% pt with A1c <6.5% 51% 17% -- p <0.001
Reduction in FSG (mg/dl) 45 28 17 p <0.001
Weight change -1.91 kg (4.2 lbs) +0.50 kg (1.1 lbs) -2.41 kg (5.3 lbs) p <0.001
Change in glargine dose 13U 26U -13U p <0.001
  • The dulaglutide and placebo groups had similar rates of overall hypoglycemia (82% vs. 76%, respectively), documented symptomatic hypoglycemia (53% vs. 45%, respectively), and nocturnal hypoglycemia (42% vs. 43%, respectively). The dulaglutide group had one episode of severe hypoglycemia, compared to zero in the placebo group.
  • Regarding adverse events, more gastrointestinal symptoms were observed in the dulaglutide groups. Dr.  Pozzilli noted that these events only led to discontinuation of therapy in very few patients.

Questions and Answers

Q: Can you give us an idea on how the insulin was adjusted?

A: The basal insulin glargine dose was given according to the classical algorithm used for a patient with basal-only insulin. It was then titrated by 2 units.

Q: You had a baseline A1c of 8.4%, which came down to 6.92 – so about 7. But you only had a fraction of people achieve an A1c <7%, suggesting that there were nonresponders. Did you look at those non-responders?

A: The patients had an excellence response if you look at the standard deviation. You see that there is minimal variation, suggested that nearly all the patient responded to therapy. The difference between the two groups was highly significant between the two groups.

Q: Dr. Stephano Del Prato: There is something that is not completely clear to me. People in the placebo group required 26 more units of glargine compared to 13 units for dulaglutide, yet there was no difference in the rate of hypoglycemia. What is the explanation? Because one of the things that we have been exposed to is that the combination of insulin plus a GLP-1 agonist often comes with a reduction in hypoglycemia. Is it because of the titration?

A: Yes, I think it is the titration.

Dr. Stephano Del Prato: Do you have the time course of the hypoglycemic events?

A: [Dr. Pozzilli showed the slide with the hypoglycemia data, which is written in an above bullet point].

COMPARISON BETWEEN SGLT2 INHIBITORS AND DPP-4 INHIBITORS ADDED TO INSULIN THERAPY IN TYPE 2 DIABETES: A SYSTEMATIC REVIEW WITH INDIRECT COMPARISON META-ANALYSIS

Se Hee Min, MD (Seoul National University Hospital, Seoul, South Korea)

Dr. Se Hee Min presented the results of an indirect meta-analysis that compared the effect of SGLT-2 inhibitors plus insulin (SGLT-2i/INS) vs. DPP-4 inhibitors plus insulin (DPP-4i/INS) in type 2 patients. The group performed a systematic review that yielded 14 studies which investigated either SGLT-2i/INS vs. placebo/INS or DPP-4i/INS vs. placebo/INS (5 and 9 studies, respectively). Results of the covariate-adjusted indirect comparison using meta-regression analyses showed that SGLT-2i/INS provided greater reductions in A1c (weighted mean difference [WMD] of -0.24%; 95% CI: -0.43 to -0.05%), as well as greater reductions in fasting plasma glucose (WMD -18.0; 95% CI: -28.5 to -7.6 mg/dl) and body weight (WMD -2.38 kg [lbs]; 95% CI: -3.18 kg [7.0 lbs] to -1.58 kg [3.5 lbs]). No difference in hypoglycemia was observed with SGLT-2i/INS compared to DPP-4i/INS (RR 1.19; 95% CI: 0.78-1.82). Dr. Min remarked that in the absence of head-to-head comparisons, these results could serve as the best available evidence for selecting oral agents in patients uncontrolled on insulin.  

  • Dr. Min noted that her group focused on SGLT-2 inhibitors and DPP-4 inhibitors because the drugs do not require injections and do not contribute to significant weight gain. Thus, the team views them as preferable add-on agents compared to GLP-1 agonists and TZDs. Furthermore, Dr. Min highlighted that SGLT-2 inhibitors and DPP-4 inhibitors have complementary effects to insulin with regards to hypoglycemia and weight gain.
  • To perform their systematic review, Dr. Min and colleagues searched Medline, Embase, LILACS, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials before June 2015 that compared either SGLT-2i/INS vs. placebo/INS or DPP-4i/INS vs. placebo/INS. They included only trials that were ≥12 weeks long and that measured A1c as an endpoint. The searches yielded 14 trials – five SGLT-2 inhibitor studies and nine DPP-4 inhibitor studies.
  • The indirect analysis involved comparing each drug’s efficacy over placebo. After the initial evaluation yielded no differences between SGLT-2i/INS and DPP-4i/INS, the authors performed a meta-regression that guided a subsequent covariate adjustment, which yielded the results presented above.

Questions and Answers

Q: The DPP4i/INS studies generally looked at a single dose while the SGLT-2i/INS studies usually had a lower dose and a higher dose. Did you include both doses or the maximum dose?

A: We included the data from the maximum approved dose.

Q: I’m not sure if you could do this because you would need patient-level data, but would you consider comparing the two drugs by baseline A1c category?

A: Thank you for your question. We did not stratify the patients by A1c.

Posters

EFFECT OF ERTUGLIFLOZIN PLUS SITAGLIPTIN ON GLYCEMIC CONTROL VS. EITHER TREATMENT ALONE IN SUBJECTS WITH T2DM INADEQUATELY CONTROLLED WITH METFORMIN (125-LB)

R Eldor, R Pratley, G Golm, S Huyck, Y Qiu, S Sunga, J Johnson, S Terra, J Mancuso, S Engel, B Lauring

Dr. Eldor and colleagues presented interim, 26-week results from an ongoing 52-week randomized, double-blind, phase 3 trial comparing the safety and efficacy of Merck/Pfizer’s ertugliflozin plus sitagliptin (Merck’s Januvia) versus either drug alone in patients with type 2 diabetes. The study recruited 1,233 patients inadequately controlled (A1c 7.5-11%) on stable metformin (≥8 wks at ≥1,500 mg/day), who were randomized to one of five groups: ertugliflozin 5mg or 15mg daily plus sitagliptin 100mg daily, ertugliflozin 5mg or 15mg daily alone, or sitagliptin 100mg daily alone. Data at 26 weeks showed that co-administration of ertugliflozin with sitagliptin led to significantly greater reductions in A1c (1.5% for both groups) compared to either drug alone (1%-1.1% across the three groups; p<0.002). A similar effect was observed with fasting plasma glucose and percentage of patients achieving A1c <7%. Co-administration also led to significantly greater reductions in body weight and systolic blood pressure compared to sitagliptin alone. Static beta-cell responsivity increased across all treatment arms and no difference was observed with the co-administration groups.  

  • The retention rate across all groups at 26 weeks was 92-96%. The authors provided the ranges of baseline characteristics across all five groups: average age of 55 years, % male of 51-62%, mean A1c of 8.50-8.57%, duration of T2DM of 6-7 years, eGFR of 92 mL/min/1.73m2, weight of 88-90 kg [194-198 lbs], and BMI of 32-33 kg/m2.

Table 1: Data from 26 weeks showing greater reductions in A1c, FPG, weight, and SBP with combined ertugliflozin + sitagliptin versus either drug alone. 

 
  •  
  •  
  •  
  •  
  •  
  •  
Reduction from baseline: ERTU 5mg ERTU 15mg SITA 100mg ERTU 5mg + SITA 100mg
n 250 248 247 243
A1c (%) 1 1.1 1.1 1.5*
FPG (mg/dl) 35.5 37.1 25.9 44.4*
Body weight 2.7 kg  [6.0 lbs] 3.7 kg [8.2 lbs] 0.7 kg [1.5 lbs] 2.5 kg# [5.5 lbs]
SBP 3.9 3.7 0.7 3.4#
Pt with A1c  <7% 66 (26%) 79 (32%) 83 (34%) 127 (52%)∏

* p<0.002 vs. individual treatments

# p<0.005 vs. sitagliptin treatments (comparisons to ertugliflozin alone were not performed)

 p<0.001 based on model-estimated odds ratio comparing ERTU+SITA vs. individual treatments

  • The safety profiles were similar between the five groups, with the exception of a higher observed rate of genital mycotic infections in the groups that included ertugliflozin. The authors note that there was no meaningful difference in urinary tract infection incidence between the groups, and that the rate of hypovolemia and symptomatic hypoglycemia were low across treatment groups.

ERTUGLIFLOZIN EFFECTIVELY IMPROVES GLYCEMIC CONTROL AS MONOTHERAPY IN PATIENTS WITH T2DM (130-LB)

S Dagogo-Jack, M Davies, J Frias, G Derosa, A Darekar, K Focht, G Golm, J Johnson, D Saur, S Terra

Dr. Dagogo-Jack and colleagues presented interim, 26-week results from the ongoing 52-week, randomized, double-blinded, phase 3 VERTIS MONO trial investigating the safety and efficacy of Merck/Pfizer’s ertugliflozin in patients with type 2 diabetes. The study recruited 461 patients with inadequate glycemic control on diet and exercise (A1c 7-10.5% with no anti-diabetic agents taken within 8 weeks of starting the study), who were randomized to placebo (n=153), ertugliflozin 5mg daily (n=156), or ertugliflozin 15mg daily (n=152). Twenty-six-week data showed that both ertugliflozin doses provided statistically significantly greater A1c reductions vs. placebo (0.99% for the 5mg dose and 1.16% for the 15mg dose); similar results were observed for fasting plasma glucose, body weight, and 2-hour post-prandial glucose. In addition, a greater proportion of patients achieved an A1c <7% in the ertugliflozin groups vs. placebo. 

  • Participants who met glycemic rescue criteria received open-label metformin. The FPG thresholds for rescue were >270 mg/dl from day 1 to week 6; >240 mg/dl from week 6 to week 12; and >200 mg/dl from week 12 to 16.  The placebo group had a higher rate of patients receiving glycemic rescue (26%) compared to the ertugliflozin 5mg (2%) and 15mg group (3%).
  • The three groups had comparable baseline characteristics, with an average age of 56-57 years, % male of 54-59%, duration of type 2 diabetes of 5 years, body weight of 91-94 kg [201-207 lbs], BMI of 33 kg/m2, A1c of 8.1-8.4%, FPG of 179-181 mg/dl, baseline 2-hr PPG of 256-263 mg/dl, SBP of 130 mmHg, DBP of 78-79 mmHg, and eGFR of 86-89 mL/min/1.73m2.
  • The retention rate through week 26 was 90% across the three groups and 83% for the study drug. 
  • Table 1: Change in A1c from baseline to 26 weeks
 
  •  
  •  
  •  
  •  

Treatment

Baseline

Week 26

Change from baseline to wk 26

 

n

Mean

n

Mean

n

Mean

Placebo

153

8.11

89

7.76

153

-0.09

Ertugliflozin 5mg

155

8.16

133

7.31

156

-0.80

Ertugliflozin 15mg

151

8.35

124

7.28

151

-1.04

  • Table 2: Results of primary and secondary endpoints at 26 weeks. 
 
  •  
  •  
  •  

Endpoint

Ertugliflozin 5mg vs. placebo

Ertugliflozin 15mg vs. placebo

 

Difference#

p value

Difference#

p value

A1c (%)

-0.99

p<0.001

-1.16

p<0.001

FPG (mg/dl)

-34.5

p<0.001

-44.0

p<0.001

Body Weight

-1.76 kg [3.9 lbs]

p<0.001

-2.16 kg [4.8 lbs]

p<0.001

2-h PPG (mg/dl)

-69.0

p<0.001

-67.3

p<0.001

SBP (mmHg)

-3.31

0.015*

-1.71

0.213

DBP (mmHg)

-1.80

0.039*

-0.37

0.669*

 

Odds Ratio

p value

Odds Ratio

p value

Proportion of pt with A1c <7%

3.6

p<0.001

6.8

p<0.001

* Nominal p value

# Difference in least squares means based on a constrained longitudinal data analysis model

  • Regarding adverse events, genital mycotic infections were more common in female participants receiving ertugliflozin vs. placebo. In male participants, genital mycotic infections were numerically higher with ertugliflozin vs. placebo. The incidence of UTI was numerically highest in the placebo group. Furthermore, the rates of symptomatic hypoglycemia and hypovolemia were similar between the three groups.

The Value of Continuous Glucose Monitoring in Patients with Type 1 Diabetes Using Multiple Daily Injections – DIaMonD Study

RESULTS

Elena Toschi, MD, PhD (Joslin Diabetes Center, Boston, MA)

Joslin’s Dr. Elena Toschi reported very positive results from Dexcom’s DIaMonD study, which randomized MDI users not at goal (baseline A1c: 8.6%) to six months of CGM (n=105) or six months of usual care (n=53). A1c declined a strong 0.9% with CGM at six months vs. -0.4% with usual care, for an adjusted mean difference of -0.6% in favor of CGM (p<0.001). The advantage for CGM was impressively consistent across age, baseline hypoglycemia, education, and diabetes numeracy – 60+ year-old CGM users saw the same benefit as 25-60 year-old users! At the same time A1c declined, hypoglycemia significantly improved with CGM: a 30% improvement in time <70 mg/dl (-23 mins/day; p=0.006) and a strong 50% improvement in time <50 mg/dl (-11 mins per day; p=0.005), both outperforming 17% and 21% improvements with usual care (-15 mins, -6 mins). While the absolute reductions are not huge here, we’d note the high baseline patients were not experiencing an overwhelming amount of hypoglycemia at baseline. On the high end, CGM users were spending 83 fewer minutes per day above range (>180 mg/dl) at 24 weeks, while the usual care group was spending nine more minutes per day above range (p=0.04). That translated to CGM users spending an hour more per day in range (70-180 mg/dl ) at 24 weeks, while the usual care group spent 15 fewer minutes per day in range (p=0.006). CGM trended towards less severe hypoglycemia: a 2% rate (two out of 105 patients) vs. a 4% rate in usual care (two out of 53 patients). Glycemic variability also significantly improved with CGM (median CV: 42% to 38%), but did not change in usual care (42% to 42%) (p<0.001). Daily SMBG tests declined as expected in the CGM group (from 5.1/day to 3.6/day), but stayed roughly similar in the usual care group (5.1/day to 4.6/day) (p<0.001). CGM wear >6 days per week was seen in an impressive 89% of patients at six months, a testament to the better technology and the tight adherence criteria (>85% wear) patients had to demonstrate during the blinded CGM phase before randomization – that ensured, of course, that patients would actually wear CGM and see benefit during the study. The presentation only said the “latest” Dexcom CGM was used, which we assume means the G4 sensor with Software 505. More study details below!

  • Overall, these are very strong and positive results for Dexcom and the entire CGM field, which has primarily shown data over the years in patients using pumps – clearly the group that can benefit from CGM is much larger. DIaMonD shows that MDI users not at glycemic target can get a meaningful reduction in A1c (-0.9% from baseline), shave off highs, cut their time in mild and dangerous hypoglycemia, and improve variability. We hope this large randomized study can help influence more prescribing of CGM in MDIs, and more importantly, influence professional guidelines. DIaMonD is also a milestone for Dexcom, who has never run an outcomes study, and will need to do more to keep up with Medtronic’s and Abbott’s growing lists. This study enrolled some patients with type 2 and collected healtheconomic data, but neither was presented today – we look forward to seeing much more on this front. Phase 2 of the study will cross some of the MDI patients over to pumps, so we’ll eventually see if insulin delivery method makes a difference. The power of CGM to drive therapeutic change is obviously very high and we also look forward to learning more about what is the best method to identify and drive change.

A1c Results

  • A1c declined 0.9% with CGM at six months vs. -0.4% with usual care, for an adjusted mean difference of -0.6% in favor of CGM (baseline: 8.6%; p<0.001). The effect was similar at 12 and 24 weeks, suggesting the benefits occurred quickly and were maintained at six months.
 
  •  
  •  
  •  
  •  
  •  

 

Baseline

Week 12

Week 24

 

CGM

8.6%

7.6%

7.7%

P<0.001

Usual Care

8.6&

8.1%

8.2%

    • CGM’s A1c advantage rose to -0.8% vs. usual care in those with a baseline A1c >8.5% (-1.3% vs. -0.5% from baseline-24 weeks), and a -0.4% A1c advantage in those with a baseline A1c <8.5% (-0.6 vs. -0.2% from baseline-24 weeks).
    • Notably, the A1c results were consistent across age: 60+ year-old CGM users saw a -1.0% A1c improvement from baseline, the same as 25-60 year-old users. The usual care group also saw the same -0.4% A1c change in both age groups.
    • A notable 52% of CGM users saw an A1c reduction of >1% compared to only 19% of the usual care group(p<0.001). Only 18% of the CGM group got to an A1c <7%, though that quadrupled the 4% of patients that did so in the usual care group (p=0.02). This was not too surprising, as patients started at a very high baseline (8.6%), making an A1c <7% difficult to achieve. We’ll be very eager in the future to better understand what drives success once patients have a full picture of their glycemic profile.

Time In Range Results

  • At 24 weeks, CGM users were spending an extra hour per day in range (70-180 mg/dl ) from baseline, while the usual care group spent 15 minutes fewer per day in range (p=0.006). This translated to an 11% improvement in time-in-range for the CGM group vs. a 2% decrement in the usual care group.
 
  •  

Minutes Per Day in 70-180 mg/dl 
(median)

 

Baseline

Week 24

Change

CGM

662

734

+61 minutes

+11%

Usual Care

648

633

-15 minutes

-2%

Hypoglycemia Results

  • Hypoglycemia significantly improved with CGM, including a 30% improvement in time <70 mg/dl (p=0.006) and a strong 50% improvement in time <50 mg/dl (p=0.005); both outperformed 17% and 21% improvements, respectively, in the usual care group. Time in hypoglycemia was relatively low in both groups at baseline (~5% of the day – an artifact of the high A1c baseline), so there wasn’t a huge runway to improve here. [For comparison, Abbott’s IMPACT study saw three hours per day in hypoglycemia at baseline stemming from the 6.7% starting A1c, while this study saw ~1-1.5 hours per day.] There was a slight imbalance at baseline, as the usual care group saw more hypoglycemia, and thus, had more room to improve during the study. Still, the relative improvement was nearly twice as big with CGM for <70 mg/dl, and more than twice as big for <50 mg/dl.
 
  •  

Minutes Per Day <70 mg/dl 
(median)

 

Baseline

24 weeks

Change

CGM

76

53

-23 minutes

-30%

Usual Care

90

75

-15 minutes

-17%

 

 
  •  

Minutes Per Day <50 mg/dl 
(median)

 

Baseline

24 weeks

Change

CGM

22

11

-11 minutes

-50%

Usual Care

29

23

-6 minutes

-21%

 
  • CGM drove a 79% reduction in nocturnal hypoglycemia (<60 mg/dl) vs. a 40% improvement for usual care (p=0.005). Daytime hypoglycemia was halved with CGM vs. no change in usual care (p=0.02). Again, the amount of hypoglycemia was pretty low here, but like automated insulin delivery, CGM really offers benefits at night.

Nighttime % of Readings <60 mg/dl

 

Baseline

24 weeks

Change

CGM

2.9%

0.6%

-79%

Usual Care

4.0%

2.4%

-40%

Hyperglycemia Results

  • At 24 weeks, CGM users were spending 83 fewer minutes per day above range (>180 mg/dl ) from baseline, while the usual care group spent nine more minutes per day above range (p=0.04). This translated to a 12% improvement in time-above-range for the CGM group vs. a 1% decrement in the usual care group.

Minutes Per Day >180 mg/dl 
(median)

 

Baseline

24 weeks

Change

CGM

687

604

-83 minutes

-12%

Usual Care

725

734

+9 minutes

+1%

Other Results

  • Glycemic variability significantly improved with CGM (median CV: 42% to 38%), but did not change in usual care (42% to 42%) (p<0.001). We wish the investigators had shown modal day plots, but perhaps the difference would have been difficult to detect graphically.
  • CGM trended towards less severe hypoglycemia: a 2% rate (two out of 105 patients) vs. a 4% rate in usual care (two out of 53 patients). This was not a focus of the commentary or conclusions, though it implies less severe hypoglycemia in the CGM group – a long sought after end point, and a clear coup on the payer front. There was no p-value on the slide, and presumably a larger and longer study with a hypoglycemia-enriched population would be needed to show a significant benefit on severe hypoglycemia.
    • There were no DKA events in either group.
  • Daily SMBG test declined by 24 weeks in the CGM group (from 5.1/day to 3.6/day), but stayed roughly similar in the usual care group (5.1/day to 4.6/day) (p<0.001). This is to be expected with CGM, and though insulin-dosing data was not collected, we assume many patients were using readings to dose insulin without a confirmatory fingerstick.
  • DIaMonD saw very good CGM adherence: at week 24, 89% of patients were using CGM >6 days per week. This was fairly consistent with week 4 (94%), down very slightly from week 12 (96%), but better than other studies like STAR-3 (23% adherence on Dr. Wolpert’s slide).
    • In hallway chatter, some pointed out that the pre-randomization criteria required >85% adherence to the blinded CGM during the run-in, ensuring patients would stick with the technology once in the study. This could detract from the “real-world” aspect of the study, though we’ll be interested to hear more commentary.
  • All study results were intention to treat, and DIaMonD saw outstanding retention: of 105 enrolled in the CGM arm, 103 completed the study (98%). Of 53 enrolled in usual care, 53 completed the study (100%). What a way to run a trial!

Study Background and Baseline Characteristics

  • The 24-site US study included patients with a mean age of 48 years, a mean A1c of 8.6%, and a mean BMI of 28 kg/m2 at baseline. Eleven percent of patients had a severe hypoglycemia event in the last 12 months, and 1% had DKA in the last 12 months. The study population was 44% female, 84% white, and 44% had less than a bachelor’s degree.
  • The DIaMonD study randomized MDI users (n=158) not at A1c goal (baseline: 8.6%) to six months of CGM (n=105) vs. six months of usual care (n=53). After a screening period, a two-week run-in with blinded CGM established baseline glycemia in both groups. Patients were then randomized to 24 weeks of CGM vs. usual care (continued SMBG) for 24 weeks. Two cohorts were included – type 1 and type 2 – though only type 1 data was reported today. Healtheconomic data was also collected in phase 1, though not included today. In phase 2 of the study, patients on MDI will switchover to a pump to see if there are any benefits to change insulin delivery method.
    • The study design limited clinical encounters to ensure real-world outcomes. Weeks 1-3 included device initiation, and the CGM group had a clinic visit at week 1 to troubleshoot the device. Both groups received phone calls in weeks 2-3. At weeks 4 and 12, diabetes management visits occurred, and the clinician downloaded devices and reviewed glucose data (either CGM or SMBG) and made insulin adjustments per usual care in both groups. The usual care group had clinic visits to place a blinded CGM placed at weeks 11 and 23. All patients received one initial session of general diabetes education, and the CGM group received some basic advice on how to use CGM data, adjust insulin doses based on trends, etc.

DISCUSSION

Howard Wolpert, MD (Joslin Diabetes Center, Boston, MA)

Dr. Howard Wolpert succinctly summarized the positive implications of the DIaMonD study results: “Clinicians should consider recommending CGM to all patients with type 1 diabetes who have not attained their glycemic goals.” Presumably glycemic goals are A1cs about 7%, or A1cs below 7% with too much hypoglcyemia though this was not discussed at length. He noted the consistency of these A1c outcomes with the JDRF CGM trial and STAR-3 trials (~0.5% reduction). However, this trial was more real world, with fewer visits and phone calls than in either the JDRF or STAR-3 trials – see the picture below. He also pointed out the high sensor adherence (>6 days per week) in DIaMonD, which exceeded usage in other CGM studies (in STAR 3, only 23% used the CGM >80% of the time) – this is expected as sensors improve (this would also have exceeded adherence using the STS, for example, of the Seven, old Dexcom sensor platforms. CGM compliance, said Dr. Wolpert, is all about the tradeoff between benefits and demands – with better technology now (accurate, reliable, easier to use), the benefits are starting to outweigh the hassles for more patients. Indeed, Dr. Wolpert characterized the glucose-monitoring field as “at an inflection point.” The transition from urine testing to intermittent fingersticks in the DCCT era reduced A1c, but increased hypoglycemia. Now we’re making the transition from intermittent fingersticks to CGM, which reduces A1c and brings fewer hypoglycemia events. To close his remarks, Dr. Wolpert noted that among MDI users in the T1D exchange, 93% are using SMBG alone, and only 7% are using CGM. This large randomized study supports the benefits of CGM in those on MDI, and we expect it to drive further penetration of the technology in MDIs. 

Posters

ACCURACY OF A FOURTH-GENERATION GLUCOSE SENSOR THROUGHOUT ITS FUNCTIONAL LIFE (897-P)

R Brazg, M Christiansen, B Bode, T Bailey, S Garg, R Slover, S Huang, J Shin, S Lee

Medtronic presented accuracy data from a pivotal study of its fourth-generation sensor (Enlite 3), to be used with the MiniMed 670G or the Guardian Connect mobile app. The new sensor demonstrated an overall MARD of ~10.5% vs. YSI values measured on days one, three, and seven at 12-hour in-clinic visits (an impressive 23,709 total paired CGM-YSI points). MARD was ~13% on day 1, ~9% on day 3, and ~10% on day 7, with an equal balance of data points collected on each day. Eight-nine participants took part in the study, each wearing two sensors on the abdomen (one paired to the 640G pump and one paired to Guardian Connect mobile app; we have averaged the data for brevity). Enlite 3 was calibrated once at the start of every 12-hour in-clinic visit, and not again unless the device asked for a smart calibration. A separate poster showed that 13% of glucose values (YSI) were collected <75 mg/dl, 56% were 76-180 mg/dl, and 31% were >180 mg/dl. Of the 89 study participants, 26 had type 2 diabetes (of whom 16 did not require insulin). Overall, this sensor is a clear improvement over Enlite and Enlite Enhanced, and we’ve heard from 670G trial participants that it is a big upgrade. How it compares to Dexcom and Abbott’s accuracy and reliability is an unknown, but we’re glad to see Medtronic making strides. At some point, further improvements in accuracy (for any company) will offer diminishing marginal value, and we continue to believe the future of CGM innovation will be in dramatically cutting cost, reducing calibrations, improving on-body wearability, and offering valuable software that augments the data. Obviously, it needs to give the data people expect too! Getting the right balance of all these factors is the tricky part, and Dexcom and Medtronic are both talking about multiple product lines with different indications (e.g., the fully disposable Medtronic/Qualcomm professional CGM, Dexcom/Verily).  

  • As we reported at ATTD, the seven-day wear Enlite 3 sensor has an improved algorithm with intelligent diagnostics that determine if it is safe to enter closed loop. The algorithm will also request a calibration when the system detects the overall performance can be improved, and data is not displayed when it detects poor sensor performance.

FIFTH GENERATION CONTINUOUS GLUCOSE MONITORING SENSOR SYSTEM WITH EXTENDED WEAR AND FEWER CALIBRATIONS (905-P)

J Ulloa, A Varsavsky, R Gautham, I Premakumar

Following its ATTD poster hall debut, a Medtronic poster shared a larger data set on its fifth-generation sensor (i.e., Harmony 1), featuring one calibration per day, 10-day wear, and an overall MARD of 11.4% vs. the Bayer Contour Next Link meter (n=142 sensors, 12,602 evaluation points). This accuracy study included 37 participants with diabetes who wore up to four sensors on the abdomen or arm for 10 days. Meal challenges were administered at three in-clinic session (days 1, 7, 10), and blood glucose measurements were recorded every 15 minutes for three to four hours with the Bayer Contour Next Link meter. Participants were also asked to take 8-10 blood glucose measurements daily when at home. Overall MARD was 11.4% (12.3% on the abdomen and 10.5% on the arm), including a day #1 MARD of 13.3%. Mean absolute difference (MAD) in hypoglycemia (<70 mg/dl) was 11 mg/dl, and 85% of overall points were within 20 mg/dl or 20%. Sensors lasted a mean of 9.5 days, though an unspecified number were removed from analysis early due to adhesiveness or battery failures – the percentage was not specified, and both are critical question marks for Medtronic’s clamshell transmitter design (larger on the body and less secure than Dexcom and Abbott sensors). Roughly 45% of sensors had a MARD of 10% or less. The fifth-gen CGM includes a 90-minute warm up, redundancy via two sensor flexes, a proprietary fusion algorithm to combine the two outputs, and intelligent diagnostics to assist with fault detection and sensor health. Overall, this feasibility data looks encouraging, though the accuracy is behind what Dexcom has said it expects for its ten-day wear, one calibration per day G6 (similar to the current MARD of 9.0%). As of Medtronic’s Analyst Meeting last week, a launch of Harmony 1 is expected by April 2019.

REAL-WORLD USE OF OPEN SOURCE ARTIFICIAL PANCREAS SYSTEMS (104-LB)

D Lewis, S Leibrand, and the #OpenAPS Community

This illuminating poster presented self-reported outcomes from 18 out of the first 40 users of OpenAPS, the DIY automated insulin delivery system created by Ben West, Dana Lewis, and Scott Leibrand (now over 150,000 hours of AID use outside any clinical trial setting!). While using OpenAPS, self-reported outcome measures showed median A1c dropped from 7.1% to 6.2%, an impressive 0.9% reduction in a well-controlled and motivated population. Self-reported median percent time-in-range (80-180 mg/dl) increased from 58% to 81% - consistent with presentations of actual data we’ve seen recently from Mark Wilson (Day #1) and Chris Hanneman (D-Data last fall). Fourteen out of 15 respondents reported some improvement in sleep quality, and 56% reported a large improvement. Respondents were “extremely satisfied with the “life changing” improvements associated with using an APS,” even if they “require significant effort to build and maintain” and “cannot be considered a technological cure.” The poster notes that OpenAPS is designed to be, and has been, far safer than standard pump/CGM therapy, as measured by duration of hypoglycemia and hyperglycemia, with no reports of severe hypoglycemia or hyperglycemic events. The OpenAPS design considerations posted here are pretty instructive on the safety front (only temp basals, no automatic correction boluses, etc. – much like the 670G hybrid closed loop!). Our takeaways from this poster and inspiring community are: (i) automated insulin delivery can make a huge difference, even for well-controlled patients; (ii) even though the system is burdensome to set up and wear, patients would not do it and use it unless the benefits were worthwhile; (iii) lots of learning is occurring in the OpenAPS community that could be leveraged for commercial systems; (iv) OpenAPS could push the FDA and industry to move faster, and that is a good thing; and (v) the relative risks here seem low, given the setup burden, the solid design for safety, and real-world dangers of insulin therapy.  

  • As an aside, and as would be expected, patient – researchers like any other researchers buy badges to present this poster – that is part of the support of the ADA bringing together so many researchers for discussion. However, patient-researchers do not have the support of work environments like manufacturers or universities. This creates a wonderful opportunity for a foundation or other organization to endow funds to create a pathway for patient researchers to not lose savings to present their data. We hope patient research will increasingly be supported by the existing healthcare community, since greater dialogue can be particularly beneficial. We are eager to see more patient learning make its way into professional organizations, such as Dr. Joyce Lee’s commentary from “Digital Health: Hope or Hype?” and we hope that can change. We salute Dana and Scott for submitting this poster and getting it accepted as a late-breaker and we look to the field to come up with creative solutions to support this work.
  • OpenAPS now has over 80 users worldwide, though only 40 were using the system at the time of abstract submission, which makes this 18-person evaluation a near 50% response rate. Of course, as with any other research, the self-reported component of the outcomes may be interpreted cautiously.
  • The poster has an instructive discussion section, noting that some healthcare providers are supportive of OpenAPS, and others showed a “lack of interest.” However, OpenAPS experiences “are instructive for what patients can expect from commercial APS when they become widely available, and can help HCPs be prepared to set patients’ expectations properly when discussing or recommending APS.”  We totally agree and hope to see more dialogue between the traditional healthcare community and the OpenAPS community. 
  • The poster’s questions for HCPs to consider are also fascinating: 
    • Artificial pancreas systems are already here. One of your patients may already be building one. Would you know it if they are? Do you discuss with your patients which tools they choose to use to help manage their diabetes?
    • APS are a powerful tool, but not a cure. Patients and HCPs will still need to do a lot of work to use them effectively to improve diabetes management. 
    • Patients and HCPs must educate themselves and each other on how APS can be used effectively in daily life. 
  • Though OpenAPS has improved in wearability and form factor, it still requires carrying extra gear, as accessing pump commands remains difficult. The community has posted all the reference design, documentation, code, and community channels at www.openAPS.org, though this system requires a fair amount of effort and motivation to put together – hence why we don’t see it as high risk right now. In the process of building it, users must intimately understand how it works, and it is certainly not plug and play. We know smart people using the system now that spent hundreds of hours setting it up.

ACCURACY AND LONGEVITY OF AN IMPLANTABLE CONTINUOUS GLUCOSE SENSOR IN THE PRECISE STUDY: A 180-DAY, PROSPECTIVE, MULTICENTER, PIVOTAL TRIAL (892-P)

A Senseonics poster shared full accuracy data from the 180-day EU pivotal study of its Eversense implantable CGM system, showing an encouraging MARD of 11.6% vs. YSI, though only 40% of sensors successfully reported data over the 180-day period. The single-arm, multicenter investigation enrolled 71 patients with type 1 diabetes, who had two sensors inserted bilaterally into their upper arm (Clinical Trials Identifier: NCT02154126). At first glance, six-month accuracy was relatively encouraging and consistent with preliminary 90-day data first seen at DTM 2015 – overall MARD was 11.6% with Clarke Error Grid analysis showing 84% of measurements in Zone A and 15% in Zone B (# of paired points unreported). Pre-specified secondary endpoints showed accuracy diminished in the hypoglycemic range (<70 mg/dl), where overall MARD was 22%. The median sensor life was just shy of five months, and only 40% of sensors successfully reported continuous glucose data out to 180 days. Naturally, the findings beg the question of how much this adds to Eversense’s product profile, and how it will compete with next-gen offerings from Abbott, Dexcom, and Medtronic - of course, we're always glad to see expanded options and form factors, since CGM penetration is far too low. We look forward to seeing how initial commercialization goes this year in Europe, and what Senseonics can get in its label with this updated long-term data (e.g., 150-day wear? 180-day wear?). 

  • As a reminder, Senseonics does have plans to submit a CE Mark amendment for its second-gen transmitter in 3Q16 that features a number of form factor improvements. We wonder whether the updated design will include improvements in durability.
  • Senseonics has long discussed the extension of its sensor life from 90 to 180 days as a priority, though we wonder if these results will support that labelThis was previously slated for a 2Q16 CE Mark submission, and we’re not sure if this has happened yet. We assume the 180-day results will not materially impact ongoing launches in Sweden and Norway/Denmark or upcoming launches in Germany, Italy, and the Netherlands. For more details on Senseonics upcoming plans, see our coverage of the 1Q16 update.

PATIENT USER EXPERIENCE EVALUATION OF BOLUS PATCH INSULIN DELIVERY SYSTEM

V Zraick, D Dreon, R Naik, D Shearer, S Crawford, J Bradford, and B Levy

This poster presented solid data demonstrating that patients (n=44; 40 with type 2, four with type 1) were very pleased with J&J’s OneTouch Via (formerly Calibra’s Finesse), a “discreet, wearable, on-demand, mealtime insulin delivery solution.” Over 50% of the cohort completed product training within a half hour – a strong testament to the usability of the bolus-only, three-day wear device. Following the eight-week trial, 86% of users reported being extremely/very satisfied with the system, and 79% were extremely/very likely to request a prescription from their HCP. Similarly, 74% of patients said that they would incorporate the Via into their routine. There was an interesting learning curve that emerged in the data: After week one, patients reported that they dosed with the Via the same number of times that they typically would with their pen/syringe. By the midway and end points of the study, patients had adjusted to the device, and >50% reported injecting prandial and snack-time insulin more frequently than they had with their pens/syringes. Of course, because information about dosing frequency was self-reported, it’s hard to know how dosing actually changed. We will be curious to see the results of the ongoing OneTouch Via outcomes study (n=312), which has a primary completion date set for this December. J&J reported at its Medical Device Business Review last month that it will file OneTouch Via for approval in 2H16, and we’ve learned from the company that it will be commercially available in select markets outside the US by late 4Q16, with US to follow soon thereafter in early 2017 – this is an update from the Medical Device Business review, which called for a launch within the next 12 months (by May 2017). 

  • HCPs were also big fans of the OneTouch Via! Every single one was satisfied at the end of the eight-week usage period and was likely to recommend. A large majority also viewed the Via favorably when compared with syringes and pens.
  • This simple device has the potential to improve regimen adherence. With the Via, the majority of users in this study reported satisfaction with their abilities to (i) discreetly and easily administer a bolus in public without painful injections, (ii) worry less about the possibility of forgetting pens/syringes, and above all, (iii) lead less stressful lives. Thus the Via overcomes many barriers to usage associated with MDI.

JDRF/NIH Closed-Loop Research Meeting

PIVOTAL STUDY DESIGN

Steven Russell, MD, PhD (MGH, Boston, MA)

Dr. Steven Russell summarized a paper he co-authored with Dr. Roy Beck, soon to be published in Diabetes Care. The table below highlights his commentary on pivotal study design for artificial pancreas systems, building off the question we asked last year, “What is the appropriate control group for an artificial pancreas pivotal study?”

Design Consideration Recommendation Alternative Comment
RCT Type Parallel Crossover Crossover Design requires long washout
Study Population Representative of population, patients who use MDI and CSII, with few exclusions. Range of A1c’s. Adults-only, high-risk patients excluded Given the potential for off-label use, the FDA may not approve if the device is not demonstrated to be safe in a broad population and payers may limit coverage to only the population that was studied
Randomization (artificial pancreas: Control) 2:1 1:1 2:1 randomization provides greater exposure to artificial pancreas, 1:1 randomization will require a smaller sample size or give greater power for same sample size if equal variance.
Control group Usual care SAP Both scientifically valid, usual care has numerous pragmatic advantages
Superiority vs. non-inferiority Superiority Non-inferiority Non-inferiority may be insufficient for approval but is not likely to drive reimbursement and adoption
Run-in period Blinded CGM monitoring Unblinded CGM (SAP training) Unblinded run-in must be sufficient to achieve competency for SAP trial enrolling non-SAP users
Duration 6-12 months 3 months 3 months min for A1c; longer duration shows continuation of use and durability of effect
Primary outcome(s) A1c, time <60 mg/dl A1c only A1c does not capture hypoglycemia; CGM more reliable and quantitative than participant recall
 

OUTCOME MEASURES FOR ARTIFICIAL PANCREAS CLINICAL TRIALS: A CONSENSUS REPORT

David Maahs, MD (Barbara Davis Center, Aurora, CO)

Dr. David Maahs also summarized a soon-to-be-published Diabetes Care paper focused on standardizing a short set of basic, easily interpreted outcomes in artificial pancreas studies. The paper has 24 authors, many of whom are considered leading thinkers in the field. The goal is to facilitate interpretation and basic comparison between studies, and more importantly, to accelerate adoption of artificial pancreas technologies via regulators, HCPs, payers, and patients. As an aside, Dr. Maahs has accepted a position to join Stanford pediatric endocrinology team – congratulations to Dr. Bruce Buckingham – again!!

Key Outcome Metrics Comment

A1c

Mean CGM glucose

If intervention >3 months)

% time in 70-140 mg/dl

% time in 70-180 mg/dl

% time <50, <60, <70 mg/dl

% time >180, >250, >300

All CGM measures should be reported for the overall 24-hour period, and also stratified by daytime and nighttime period. The time midnight to 6am is proposed as a nighttime definition.

Standard Deviation

Coefficient of Variation

 
Severe hypoglycemia As defined by ADA (adults) and ISPAD (children/adolescents)
DKA events ADA definition
% of time closed loop active  

TDD of insulin

TDD of glucagon or other hormones

 

Other considerations:

# of symptomatic hypoglycemia events per week

CGM calibration, MARD

Study design and stratification into relevant subgroups

ITT analysis

Report medians (quartiles) instead of mean if not normally distributed

 

Exhibit Hall

ASCENSIA

Ascensia has come to ADA 2016 with a bang! The company’s large bold booth at the back of the exhibit hall was decked out in the new purple and blue colorway, and it was refreshing to see a big investment in ADA real estate after the company’s absence at ADA 2015. Reps informed us that the transition to a standalone company has really allowed the teams to flourish, citing the company’s recently launched Contour Next One and Contour Plus One Bluetooth-connected BGM systems (currently launched in Switzerland and Poland respectively; CE Mark in May 2016). Additional EU launches are planned for later in 2016. The Contour Next One system is still being reviewed by FDA and the company anticipate clearance before the end of 2016.

BD

Reps in BD’s booth shared new news that the MiniMed Pro FlowSmart Infusion Set with exclusive partner Medtronic will launch in the US and France “by the end of 2016.” This is the most concrete forecast we can recall hearing to date and confirms previously disclosed plans to orchestrate a “limited launch” in 2016. It’s great to hear that patients in the US will have access during this soft launch period (we’re hoping we’ll have the chance to try it out!) but assume that this will be fairly low-key at first. The purpose of the soft launch is to gather feedback from early users to inform the subsequent full-scale rollout. Back to the booth, the infusion set itself was not on display as BD – per usual – focused its exhibit on injection counseling technique. We were sad to see that BD has retired its classic lipohypertrophy demo (“Lipo Larry”) but very excited to see what he was replace with – two virtual reality simulations! The demo allowed us to experience an injection technique counseling session as a patient with type 2 diabetes who had just been instructed to go on insulin, with one video documenting common mistakes physicians make and the other documenting best practices. Kudos to BD for bringing this experience to attendees! We’ve heard the demo has been wildly successful, sharing that multiple providers have asked to have access to the videos in their clinic (to show peers) while one promised to changed the way he addressed patients after watching the video – we’d very much hope to hear more of that. 

  • Consistent with the injection technique theme, BD’s booth also shared data that showed improved clinical outcomes at three months for type 1 and type 2 insulin-treated patients who optimized their injection technique. Patients (n=346) in this uncontrolled study received intensive education on the value of rotating injection sites and instructions to switch to BD’s Ultra-Fine Nano 4 mm x 32 gauge pen needles. Results looked encouraging – patients in the intervention cohort saw: (i) a 0.6% reduction in A1c (baseline not provided; p<0.05); (ii) a 14.2 mg/dl reduction in fasting glucose (baseline not provided; p<0.05); (iii) a two units reduction in total daily dose (baseline not provided; p<0.05); and (iv) a 0.5 kg/m2 BMI reduction (baseline not provided; NS).
  • BD has unveiled new branding. The company has: (i) embraced a “lighter, brighter” look following the acquisition of CareFusion; (ii) updated its logo – see the new look below; and (iii) has updated its slogan from “Helping people live healthy lives” to “Advancing the world of health.”

Diabetes Technology Highlights

DEXCOM’S DIAMOND STUDY SHOWS CGM BENEFITS MDI AT SIX MONTHS: STRONG -0.6% A1C ADVANTAGE, +61 MORE MINUTES IN RANGE PER DAY

Joslin’s Dr. Elena Toschi reported positive results from Dexcom’s DIaMonD study, which randomized MDI users to six months of CGM (n=105) or six months of usual care (n=53).

HbA1c declined a strong 0.9% with CGM at six months vs. -0.4% with usual care (baseline: 8.6%), for an adjusted mean difference of -0.6% in favor of CGM (p<0.001). 

From press release Dexcom.

Nyhetsinfo

www red DiabetologNytt

 

The advantage for CGM was impressively consistent across age, baseline hypoglycemia, education, and diabetes numeracy – 60+ year-old CGM users saw the same benefit as 25-60 year-old users in this study

At the same time HbA1c declined, hypoglycemia significantly improved with CGM: a 30% improvement in time <70 mg/dl (-23 mins/day; p=0.006) and a strong 50% improvement in time <50 mg/dl (-11 mins per day; p=0.005), both outperforming 17% and 21% improvements with usual care (-15 mins, -6 mins).

While the absolute reductions are not huge here, the high HbA1c baseline patients were not experiencing an overwhelming amount of hypoglycemia at baseline.

On the high end, CGM users were spending 83 fewer minutes per day above range (>180 mg/dl) at 24 weeks, while the usual care group was spending nine more minutes per day above range (p=0.04). That translated to CGM users spending an hour more per day in range (70-180 mg/dl ) at 24 weeks, while the usual care group spent 15 fewer minutes per day in range (p=0.006). CGM trended towards less severe hypoglycemia: a 2% rate (two out of 105 patients) vs. a 4% rate in usual care (two out of 53 patients). 

Glycemic variability also significantly improved with CGM (median CV: 42% to 38%), but did not change in usual care (42% to 42%) (p<0.001). 

Daily SMBG tests declined as expected in the CGM group (from 5.1/day to 3.6/day), but stayed roughly similar in the usual care group (5.1/day to 4.6/day) (p<0.001). CGM wear >6 days per week was seen in an impressive 89% of patients at six months, a testament to the better technology and the tight adherence criteria (>85% wear) patients had to demonstrate during the blinded CGM phase before randomization.

The presentation said the “latest” Dexcom CGM was used, which we assume means the G4 sensor with Software 505. More study details below.

  • Overall, these are very strong and positive results for Dexcom and the entire CGM field, which has given most of its data around patients on pumps for years. The DIaMonD shows that MDI users not at glycemic target can get a meaningful reduction in A1c (-0.9% or 9 mmol/mol from baseline), shave off highs, cut their time in mild and dangerous hypoglycemia, and improve variability.
  • We hope this large randomized study can help influence more prescribing of CGM in MDIs, and more importantly, influence professional guidelines. DIaMonD is also a milestone for Dexcom, who has never run an outcomes study, and will need to do more to keep up with Medtronic’s and Abbott’s growing lists.
  • Dr. Howard Wolpert succinctly summarized the positive implications of the DIaMonD study results: “Clinicians should consider recommending CGM to all patients with type 1 diabetes who have not attained their glycemic goals.” He noted the consistency of these HbA1c outcomes with the JDRF CGM trial and STAR-3 trials (~0.5% reduction), but with fewer in-clinic visits than in either trial (see below). 
  • Dr. Wolpert also pointed out the high sensor adherence (89% wore >6 days per week) in DIaMonD, which exceeded usage in other CGM studies (e.g., in STAR 3, only 23% used the CGM >80% of the time). CGM compliance, said Dr. Wolpert, is all about the tradeoff between benefits and demands – with better technology now (accurate, reliable, easier to use), the benefits are starting to outweigh the hassles for more patients.
  • Indeed, Dr. Wolpert characterized the glucose-monitoring field as “at an inflection point.” The transition from urine testing to intermittent fingersticks in the DCCT era reduced A1c, but increased hypoglycemia. Now we’re making the transition from intermittent fingersticks to CGM, which reduces A1c and brings fewer hypoglycemia events. 
  • To close his remarks, Dr. Wolpert noted that among MDI users in the T1D exchange, 93% are using SMBG alone, and 7% are using CGM. This large randomized study supports the benefits of CGM in those on MDI, and hopefully, will drive further penetration of the technology in MDIs.

From department of clinical Science and Education, Sachs´ Children and adolescent Hospital, Södersjukhuset

Karolinska Institutet, Stockholm, Sweden

On macrovascular and renal complications in type 1 diabetes mellitus:
some aspects on glycemic memory

Björn Rathsman

 

Stockholm 2015

 

 

All previously published papers were reproduced with permission from the publisher.

Published by Karolinska Institutet.

Printed by E-Print AB 2015

© Björn Rathsman, 2015

ISBN 978-91-7549-912-3

 

 

Institutionen för klinisk forskning och utbildning
On macrovacular and renal complications in type 1 diabetes mellitus:
some aspects on glycemic memory

 

Medicinsk avhandling

av

Björn Rathsman

Leg.läkare

 

Huvudhandledare:

Docent Thomas Nyström

Karolinska Institutet

Institutionen för klinisk forskning och utbildning

Medicinkliniken, Södersjukhuset

 

Bihandledare:

Docent Kerstin Jensen-Urstad

Karolinska Institutet

Institutionen för klinisk forskning och utbildning

Fysiologkliniken, Södersjukhuset

 

Svante Norgren MD, PhD

Karolinska Institutet

Institutionen för kvinnor och barns hälsa

Astrid Lindgrens Barnsjukhus, Karolinska Universitetssjukhuset

 

Fakultetsopponent:

Docent Stig Attvall

Göteborgs Universitet

Sahlgrenska Akademin

Diabetescentrum, Sahlgrenska Universitetssjukhuset

 

Betygsnämnd:

Docent Gun Jörneskog

Karolinska Institutet

Institutionen för kliniska vetenskaper

Medicinkliniken, Danderyds sjukhus

 

Docent Soffia Gudbjörnsdottir

Göteborgs Universitet

Sahlgrenska Akademin

Medicinkliniken, Sahlgrenska Universitetssjukhuset

 

Docent Erik Moberg

Karolinska Institutet

Institutionen för medicin, Huddinge

Kliniken för endokrinologi, metabolism och diabetes, Karolinska Universitetssjukhuset

 

 

 

 

To all children and adolescents with type 1 diabetes. Time is on your side.

 

 

 

 

 

Abstract

There is a substantially increased risk of premature mortality and morbidity in cardiovascular disease (CVD) among type 1 diabetes individuals compared to individuals without diabetes. Development of microangiopathy and markers of macrovascular complications precedes these events. The SDIS and subsequent DCCT/EDIC trials conclusively established already in 1993 that early intensified insulin treatment halts microvascular complications. This has also been shown for macrovascular complications in the DCCT/EDIC trial, a finding suggested to be due to glycemic memory.   

In this thesis we first (Study I) aimed to investigate early signs of atherosclerosis, measured as carotid intima-media thickness (cIMT), and its relation to insulin sensitivity in young type 1 diabetes individuals.Then we compared (Study II) skin microvascular function in the foot and the time to first of hospitalization for ischemic foot ulcer in between the two groups in the SDIS cohort. We also investigated (Study III) long-term follow-up complications in the SDIS cohort, comparing incidence in all-cause mortality, mortality in CVD, as well as incidences in CVD events, i.e. myocardial infarction and stroke, and diabetic nephropathy, between patients earlier randomized for 7.5 years to intensive insulin treatment vs. standard treatment. Finally, we investigated (Study IV) long-term survival in individuals with type 1 diabetes, type 2 diabetes and without diabetes following coronary artery bypass grafting (CABG).  In this study we combined the SWEDEHEART and the Swedish national diabetes registers. The outcome measures were all-cause mortality, mortality in CVD death and any major adverse coronary event, i.e. myocardial infarction, heart failure, stroke or need of revascularization.

In study I, young type 1 diabetes individuals had an increased cIMT concomitant with insulin resistance compared to the non-diabetic group. In a multivariate analysis, insulin resistance was significantly associated to an increase in cIMT. In study II, 13 patients developed ischemic foot ulcer during the median 28 years of follow-up. Foot skin microcirculation blood flow was higher in the earlier intensively insulin-treated group compared with the standard treated group. Glycemic control measured as HbA1c levels was independently associated with endothelial-dependent vasodilatation and capsaicin-induced vasodilatation. In study III, during 28 years of follow-up 22 persons died. There was no significant difference between groups for all-cause mortality, mortality in myocardial infarction, stroke or ESRD, or for morbidity in myocardial infarction or stroke. One person in the ICT group compared with seven in the ST group developed ESRD. HbA1c did not differ between the two groups during the last 16 years of follow-up. In study IV, with a mean follow-up time of 5.9 years, a total of 6,765 out of 39,235 patients died: 17 % of whom had no diabetes, 21 % had type 1 diabetes, and 19 % had type 2 diabetes. The risk for all-cause mortality was doubled in type 1 diabetes, compared to type 2 diabetes. The risk of death was similar among type 1 diabetic men and women.

Adolescents with type 1 diabetes show early signs of atherosclerosis compared to a matched control group. This was demonstrated together with insulin resistance. Earlier intensively insulin-treated type 1 individuals from the SDIS trial seem to have a favorable prognosis regarding the development of foot ulcers and diabetic nephropathy, compared to the standard treated individuals. This was demonstrated despite the same glycemic control for the last 16 years in the follow-up. Type 1 diabetes individuals have much poorer outcome after CABG intervention compared to type 2 diabetes individuals.

 

 

lIST OF SCIENTIFIC PAPERS

  1.  

Rathsman B, Rosfors S, Sjöholm A, Nyström T. Early signs of atherosclerosis are associated with insulin resistance in non-obese adolescent and young adults with type 1 diabetes. Cardiovasc Diabetol. 2012 Nov 27;11:145

 

  1.  

Rathsman B, Jensen-Urstad K, Nyström T. Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study.
Diabetologia. 2014 Aug;57(8):1703-10

 

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Rathsman B, Donner M, Ursing C, and Nyström T. Intensified insulin treatment decreases the risk of end stage renal disease in type 1 diabetes: a long-term follow-up study. Diabetic Medicine 10.1111/dme.12897

 

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Holzmann MJ, Rathsman B, Eliasson B, Kuhl J, Svensson AM, Nyström T, Sartipy U. Long-term Prognosis in Patients with Type 1 and Type 2 Diabetes Mellitus After Coronary Artery Bypass Grafting. J Am Coll Cardiol 2015;65:1644–52

 

 

 

Permission to reprint received from BioMed Central, Springer Science and Business Media and Elsevier B.V.

 

 

content

1.... Introduction. 1

1.1    Diabetes. 2

1.2    Cardiovascular Disease and type 1 diabetes. 3

1.2.1    Atherosclerosis. 4

2.... Epidemiology of Macrovascular disease in Type 1 Diabetes. 4

2.1    Coronary Heart Disease. 6

2.2    Stroke. 6

2.3    Peripheral artery disease. 7

2.4    Diabetes nephropathy. 8

2.5    CVD risk factors in type 1 diabetes. 9

2.5.1    Genetics. 9

2.5.2    Smoking. 9

2.5.3    Hyperglycemia. 9

2.5.4    Dyslipidemia. 10

2.5.5    Hypertension. 11

2.5.6    Insulin resistance. 11

2.5.7    Diabetes nephropathy. 12

2.5.8    Risk factors in childhood and adolescence. 13

2.5.9    Hypoglycemia. 13

2.5.10  Microvascular complications. 14

2.6    Treatment of modifiable risk factors in type 1 diabetes. 14

2.7    Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) 15

2.8    Stockholm diabetes intervention study (SDIS) 16

2.9    Glycemic memory. 17

2.10  Revascularization in type 1 diabetes. 18

3.... Hypothesis. 19

4.... AIMS. 19

5.... Methods. 21

5.1    Study Patients. 21

5.1.1    Study I 21

5.1.2    Study II and III 21

5.1.3    Study IV.. 23

5.2    Study protocols. 23

5.2.1    Study I 23

5.2.2    Study II and III 23

5.2.3    Study IV.. 24

5.3    Study outcome. 25

5.3.1    Study I 25

5.3.2    Study II 25

5.3.3    Study III 25

5.3.4    Study IV.. 25

5.4    Routine Biochemical analyses. 25

5.5    Hyperinsulinemic clamp. 26

5.6    Carotid Intima-media thickness. 27

5.7    HbA1c 27

5.8    eGFR.. 28

5.9    Iontophoresis and ankle-brachial index. 28

5.10  National Registers. 29

5.11  Statistical methods. 31

5.11.1  Study I 31

5.11.2  Study II and III 31

5.11.3  Study IV.. 31

6.... Ethical Considerations. 32

7.... Results. 33

7.1    Study I 33

7.2    Study II 34

7.3    Study III 36

7.4    Study IV.. 38

8.... General Discussion. 40

9.... Conclusions. 43

10.. Study limitations. 44

11.. Future perspectives. 44

12.. Svensk Sammanfattning. 45

13.. Acknowledgements. 46

14.. References. 49

 

 

 

List of abbreviations

ABI

Ankle-brachial index

ACEI

Angiotensin-converting enzyme inhibitor

ACh

Acetylcholine

AGE

Advanced glycation end product

ARB

Angiotensin receptor blocker

BMI

Body mass index

CABG

Coronary artery bypass graft

CAD

Coronary artery disease

CCA

Common carotid artery

CDR

The Swedish Cause of death register

CHD

Coronary heart disease

CIMA

Carotid intima media area

cIMT

Carotid intima-media thickness

CVD

Cardiovascular disease

eGDR

Estimated glucose disposal rate

ESRD

End-stage renal disease

GFR

Glomerular Filtration Rate

GIR

Glucose infusion rate

HDL

High density lipoprotein

HR

Hazard ratio

IPR

The Swedish Inpatinet register

LDL

Low density lipoprotein

MACE

Major adverse coronary event

NDR

Swedish national diabetes register

PAD

Peripheral artery disease

PU

Perfusion unit

sBP

Systolic blood pressure

Si

Insulin sensitivity

SNP

Sodium nitroprusside

 

1       Introduction

 

I sat down with a two year old child and his parents in a small emergency ward room. This was our first talk about type 1 diabetes, but many were to follow. The child’s random taken plasma glucose being above 20 mmol/L left no alternative. For me, this was a routine situation. For the parents in front of me, it was a shock and scare. The father asked all the questions I expected - how, why, what will the treatment be?  Then the mother turned to me and asked: “What is his life going to be like, is he going to live to be old?”  As I remember it,  my answer at that time was something about us together doing all we could to make the boy’s quality of life as good as possible, and that the future for someone with diabetes was ever changing for the better due to research and advances in treatment.  However, after the meeting, alone in my room, her question kept coming back to me. It contained many layers. Life is certainly complicated for a child with diabetes. Many daily considerations are needed, blood tests taken, injections given, meals eaten and frustrations handled. Surprisingly, all this is often very manageable. Of course, it was impossible to give her a detailed answer, but did I really know what to expect? What was I to look for, except optimizing treatment? At what age should I introduce preventive treatments? What do we really know about the development of complications? These questions recurred to me and I realized I needed to know more.

This thesis project started out as a brief discussion between Dr Anna Kernell and me regarding hypertension and the risk of cardiovascular problems for the young type 1 diabetes patients we encountered in our daily work at the pediatric outpatient unit. The idea of evaluating their actual situation, and search for possible signs of development of vascular complications, very slowly progressed into the initiation of the first study. We began by enrolling adolescents from our everyday work, and Dr Kernell and I also visited schools in the southern area of Stockholm to recruit controls. Very sadly, Dr Kernell passed away and left me stumbling with my thesis project. Fortunately my co-supervisors stepped in, and others were recruited, enabling my thesis work to continue.

After finishing the first study I and my co-workers realized the need for experience in the long-term and adult diabetes perspective to come further with our questions. Most fortunately I was introduced to the dedicated work of Dr Per Reichards in the Stockholm Diabetes Intervention study, addressing microvascular complications in type 1 diabetes and the role of glycemic control. I was entrusted with the remains of this landmark study and given the opportunity to trace the participating patients and follow up his data. This process lead to something similar to a detective investigation, with us looking for clues to find data in cardboard boxes stacked away in various units of the hospital.

I could not have done this project without the help from my supervisors. Also, I am in great debt to Dr Kernell and Dr Reichard. I hope this thesis is something they would have appreciated.

 

 

1.1      Diabetes

 

Type 1 diabetes is an autoimmune-mediated or immune-associated destruction of insulin-producing islet β-cells in the pancreas, eventually leading to a loss of insulin secretion [1]. Due to the loss of β-cells, persons developing type 1 diabetes are dependent on exogenous insulin treatment.  Even though the disease may develop at any age, the peak incidence is in childhood or in puberty [2]. The incidence of type 1 diabetes varies a lot between countries in the world, with the highest rates in Finland [3]. An increased incidence has been observed in many countries over the last two to three decades [4], though the incidence in Sweden has been stable during the last years [5]. Type 1 diabetes is diagnosed based on typical age, the clinical finding of hyperglycemia, polyuria, polydipsia and weight loss, low fasting C-peptide levels and detection of autoantibodies against glutamic acid decarboxylase 65 (GAD); tyrosine phosphatase-like insulinoma antigen 2 (IA2); insulin (IAA); and β-cell-specific zinc transporter 8 autoantibodies (ZnT8). The diagnosis is strengthened by existence of HLA risk types (most frequent HLA DR3/DR4) [6, 7]. There is also a less frequent type 1 diabetes subtype, type 1 diabetes b, which is also characterized by β-cell destruction but without any evidence for the involvement of autoimmune assault in its etiology [8]. Type 2 diabetes, on the other hand, is by far the most common form of diabetes (accounting for 90-95 % of cases) and mostly affects middle-aged and older patients [9]. The mechanism behind type 2 diabetes is thought to be initiated by the development of insulin resistance, mainly in skeletal muscle and the liver. Usually this is adjusted for by an enhanced insulin secretion by the pancreatic β-cells [9]. However, persons developing type 2 diabetes are unable to compensate the insulin resistance by adequately increasing insulin secretion. Obesity is a major factor inducing insulin resistance and it frequently coexists with type 2 diabetes. The incidence of type 2 diabetes is increasing rapidly worldwide and most probably due to a more sedentary lifestyle with excess caloric intake and decreased exercise, leading to obesity, and to generally older populations in many countries [10]. Type 2 diabetes, in contrast to type 1 diabetes, is also strongly influenced by genetic predisposition.

 

The diagnosis of diabetes is confirmed by finding random plasma glucose concentration ≥11.1 mmol/L or fasting plasma glucose concentration ≥7.0 mmol/L at two separate occasions. Fasting is defined as no caloric intake for at least 8 h. The diagnosis can also be made by the finding of a two hour postload glucose concentration ≥11.1 mmol/L during an oral glucose tolerance test. A random finding of a non-fasting plasma glucose concentration ≥11.1 mmol/L and classic clinical symptoms is also diagnostic. In 2011 WHO stated that a level of HbA1c >48 mmol/mol at two separate occasions is also diagnostic [11], a definition now also recommended by the American Diabetes Association [7].

 

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommend the use of mmol/mol as an international standard unit for HbA1c and this method is used in Sweden since 2011. Therefore the mmol/mol unit will be used throughout this thesis. However, HbA1c expressed in % (DCCT standard) is often applied in reports and medical journals and will also, to some extent, be presented in the thesis.  

 

 

1.2      Cardiovascular Disease and type 1 diabetes

The Banting and Best discovery of insulin in 1921 and the subsequent development of better and more sophisticated treatments for type 1 diabetes have dramatically changed not only the prognosis of survival in type 1 diabetes but also the spectrum of complications from acute, e.g. diabetes ketoacidosis, to chronic [12]. The long-term complications can be further divided into micro- and macrovascular. The macrovascular complications are mainly divided into coronary heart disease (CHD), ischemic stroke and peripheral artery disease (PAD). A brief exposé of microvascular complications will be presented in section 2.5.10. 

Throughout the world, cardiovascular disease (CVD) mortality has declined in the general population [13, 14]. This trend is similar in diabetic patients. Gregg and associates analyzed the incidence of acute myocardial infarction, stroke, lower leg amputation, nephropathy and death in hypoglycemic crisis in the United States (between 1990 and 2010), comparing diabetic individuals with the background population. For acute myocardial infarction there were 96 fewer cases per 10,000 persons per year, and 60, 30 and 8 fewer cases per 10,000 persons per year for stroke, lower-extremity amputation and end-stage renal disease (ESRD), respectively. One limitation of this study is that it does not discriminate between the two major diabetes types [15]. Despite the lower incidence of CVD in diabetic individuals, type 1 diabetes is still associated with an increased risk of CVD [16], which in turn is the most common cause of death in this patient group [17].

Diabetes is also associated with a shorter life-expectancy [18]. In the Allegheny County, Pennsylvania, registry of type 1 diabetes individuals, mortality rate after 30 years of diabetes was demonstrated to be six times higher than in the general population [19].  In the Pittsburgh Epidemiology Diabetes Centre (EDC) study, two sub-cohorts, i.e. diabetes diagnosis between 1950-1964 and 1965-1980, respectively, were compared, demonstrating life-expectancy to be approximately 15 years longer for the latter group [18]. This clearly demonstrates a substantial progress in avoiding complications, e.g. improvement in type 1 diabetes therapy. On the other hand, a group in Scotland recently showed, in a nationwide prospective cohort study of type 1 diabetes individuals, that life-expectancy, from age 20 years, was 11 and 13 year shorter, in men and women, respectively, compared to non-diabetic individuals [20]. The excess mortality in type 1 diabetes individuals was also recently demonstrated in a Swedish nationwide register-based study including more than 30,000 type 1 diabetes individuals, revealing a doubled risk of death (all-cause or from CVD) despite good glycemic control compared to a matched control group [21], a risk substantially increased with increased levels of HbA1c [21].

In the 30 year follow-up part of the Diabetes Control and Complication Trial (DCCT), i.e. the Epidemiology of Diabetes Interventions and Complications (EDIC) study, it was again demonstrated that the highest proportion of deaths was attributed to CVD [22]. Even though evidence points towards a decline in mortality and CVD mortality incidence in diabetes, there is still a substantially increased risk of CVD mortality in type 1 diabetes individuals [19-21].

1.2.1     Atherosclerosis

Atherosclerosis is the primary cause of stroke and CHD, contributing to about 50% of all the deaths in the western countries [23]. Macrovascular complications begin with atherosclerosis, a chronic and multifactorial disease associated with a wide range of independent risk factors, including traditional risk factors such as smoking, hypertension, dyslipidemia, increasing age, family history, obesity and diabetes [24, 25].

Atherosclerosis is considered an inflammatory disease and the first observed lesion is the formation of fatty streaks, i.e. mainly macrophages and T-lymphocytes, within the vessel wall of large and middle size arteries. These early changes have been observed already in children and adolescents [26]. The current hypothesis of atherosclerosis development points out endothelial dysfunction to be an early event and the result of injury caused by e.g. dys­lipidemia, hypertension, smoking, diabetes, infections or genetic factors. Low-density lipoprotein (LDL) cholesterol, modified by for example oxidation or glycation (in diabetes), is today considered the major cause of endothelial injury. The injury causes increased endothelial permeability and adhesiveness of leukocytes and platelets, as well as a pro­coagulation state [24, 25]. The subsequent event is migration and proliferation of smooth muscle cells leading to thickening of the artery wall and, as the inflammation proceeds, more macrophages and lymphocytes are recruited to the lesion. They cause a local activation of cytokines, chemokines, hydrolytic enzymes and growth factors eventually leading to necrosis and formation of a fibrous cap protruding into the vessel lumen. The artery can, to some extent, compensate these events by dilation but at some point the blood flow may be affected causing distal ischemia [24]. However, the fibrous cap may rapidly rupture leading to formation of a thrombosis and, for example, if it involves coronary arteries or brain arteries, an acute coronary syndrome or an ischemic stroke, respectively.   

A large number of studies have conclusively demonstrated that individuals with type 1 diabetes have an early onset and a higher degree of atherosclerosis compared to a non-diabetic population. It is typically also more disseminated and aggressive as compared to non-diabetic individuals. Type 1 diabetes patients therefore carry an additionally higher risk of CVD events [27]. Also, type 1 diabetes individuals have a higher frequency of hypertension, dyslipidemia and nephropathy, all contributing to the increased risk of CVD [28-30].

2       Epidemiology of Macrovascular disease in Type 1 Diabetes

First to investigate CVD in a population-based study was the Framingham Heart study. This study was initiated in 1948 as a community-based prospective cohort study including more than 50,000 adult individuals from the general population. Participants underwent physical examination and laboratory tests every other year and were followed up regarding all-cause mortality, CVD mortality and morbidity, and associated risk factors [31]. In 1971, children of couples participating in the study and their spouses were invited to the Framingham Off­spring Cohort Study. They also underwent physical examination and laboratory tests, as well as ECG every four years [32]. The Framingham study clearly demonstrated that diabetes (mainly type 2) is a major risk factor of developing CVD regardless of gender [33]. However, it was later confirmed by others that women with diabetes carry an even higher risk of developing CVD [34].

The Pittsburgh EDC study recruited insulin-dependent diabetes patients under the age of 17 at disease onset, and within one year after the diagnosis of diabetes [35]. The individuals were followed-up every second year regarding the development of nephropathy, retinopathy, neuropathy and macrovascular disease (i.e. PAD, CHD and stroke). The 10-year follow-up results demonstrated that 10 % of the participants developed CVD during 30 years of diabetes [35]. There were no significant gender differences in the outcomes, except for PAD demonstrating a three-fold higher incidence rate in women after 25 years [35].

In the EURODIAB cross sectional complication study, more than 3,000 type 1 diabetes individuals from 14 European countries, with an age of 15-59 years old, were enrolled. The prevalence of CVD in this study was shown to be 25 % in the group aged 45-59 years, whereas the diabetes duration also had a great impact on CVD prevalence: 15 % and 13 % with diabetes duration of ≥15 years, in men and women, respectively [36].

 

In the Diabetes UK cohort study 23,751 patients with insulin-treated diabetes diagnosed under the age of 30 years were recruited between 1972 and 1993. Primary outcome was mortality from CHD, in which 1,437 deaths were registered during a mean follow-up of 17 years. CHD in men accounted for 8 % of deaths in the age 20-39, being increased to 47 % in age 40-84 [37]. Roughly the same incidence of CHD mortality was observed in women, 11 % vs. 40 % in the same ages [37]. Most notable was that the absolute excess risk of dying from CHD in the age groups 20-29 and 30-39 years was the same for women and men; however, the standardized mortality ratio (SMR) for women was 45 and 42 in those age groups, respectively, compared to the general female population [37].

 

In the UK General Practice Research database (GPRD) with 7,479 type 1 diabetes patients, CVD events developed 10 to15 years earlier compared to the general population [16]. In this study, CVD events were significantly higher in women compared to men [16].

 

As early as in the Framingham cohort 20 years follow-up study, CVD was demonstrated to be six times more prevalent in diabetic women aged 45-54 years compared to a matched population [12]. Over the years, studies have yielded conflicting results; with less risk for women [38], increased risk  [37, 39, 40], or relatively the same risk [41], as for men. A recent meta-analysis, including more than 200,000 individuals with type 1 diabetes, demonstrated a 40 % greater relative risk of all-cause mortality and more than doubled the risk for CHD in women, compared to men [42]. 

In the context of epidemiological cohort studies of CVD in type 1 diabetes individuals one needs to mention the DCCT and the follow-up EDIC study. Recently the DCCT/EDIC writing group demonstrated a similar pattern with a decrease for all-cause mortality in the intensive insulin treatment group, the highest proportion of deaths (20%) were attributed to CVD [22]. The DCCT study and the contemporary Stockholm Diabetes Intervention Study (SDIS) were landmark studies demonstrating the benefits of improving glycemic control to lower the incidence of microvascular complications [43, 44]. They will be thoroughly discussed later on in this thesis.

2.1      Coronary Heart Disease

 

Diagnosis of CHD in diabetes may be challenging. Myocardial ischemia is often silent in diabetes patients due to autonomic and somatic sensory neuropathy. The majority of myocardial infarctions may be asymptomatic [45], or presenting in a highly atypical manner (e.g. syncope, sudden shortness of breath or nausea), and therefore diagnosed much later by electrocardiogram (ECG) screening, or with myocardial scintigraphy or stress echocardiography.

Over the years, mounting evidence has been supporting an increased risk of CHD in type 1 diabetes individuals [37, 46, 47]. Among studies reporting the incidence of CVD in type 1 diabetes, CHD consistently stands out as the most common [16, 20, 48, 49]. In the UK GPRD study, the relative risk of acute CHD events was demonstrated to be 3.0 (95% CI 2.2–4.1) for men, and 7.6 (95% CI 4.9–12.0) for women compared to non-diabetics [16]. Age-adjusted cumulative incidence of CHD in type 1 diabetes individuals differs between studies, but the average cumulative incidence seems to be around 15 % during a 15-20-year follow-up period [48]. This high incidence rate of CHD was also reported in the Diabetes UK cohort study, in which nearly 25 % of the all-cause mortality was attributed to CHD [16]. The age-specific mortality data from the UK GPRD study showed that the SMR for CHD, compared to the general population, was highly elevated. Most striking was the increased SMR for CHD in women (all ages) compared to men [37].

2.2      Stroke

Stroke is generally divided into two subtypes, i.e. ischemic and hemorrhagic stroke. Hyper­tension and proteinuria are believed to be the most important risk factors for development of stroke [50, 51]. The clinical evaluation is important and stroke scales like National Institute of Health Stroke Scale (NIHSS) are useful tools [52]. The NIHSS is based on eleven parameters ranging from level of consciousness, visual field and eye movement tests to motor function, sensory function, speech, language and attention testes. Each area renders a score from 0 to 4 and the resulting sum defines stroke severity from no stroke to severe stroke and also predicts likelihood of recovery [53]. The diagnosis of stroke is usually confirmed by the use of MRI or CT scanning, demonstrating thrombotic lesions (ischemia) or bleeding.

The incidence of premature morbidity and mortality in stroke is markedly increased in type 1 diabetes patients [54, 55]. This risk is further increased in case of hypertension or proteinuria [56]. It was recently demonstrated in a Swedish registry study that middle-aged (<50 years old) individuals with type 1 diabetes were shown to have a considerably higher risk of stroke as compared to the general population, with even a higher risk for women [54]. The incidence rates were excessively elevated if the patients also had diabetic nephropathy or retinopathy [54]. The incidence of stroke was also investigated in the Finnish Diabetic Nephropathy (FinnDiane) study [57]. The major findings were that diabetes duration, diabetes nephro­pathy, poor glycemic control, higher systolic blood pressure (sBP), history of smoking and indirect measures of insulin resistance, i.e. estimated glucose disposal rate (eGDR), were all independent risk factors of ischemic stroke. However, risk factors partly differed from that of hemorrhagic stroke.

The only other study looking at independent risk factors for stroke in type 1 diabetes is the Pittsburgh EDC study [58]. It was found that diabetes duration, sBP, low levels of high-density lipoprotein (HDL) cholesterol and diabetic nephropathy were strong risk factors for ischemic stroke. However, sBP was confounded as a risk factor by nephropathy in that study [58].

In the 27-year DCCT/EDIC follow-up study all-cause mortality risk was moderately, albeit significantly, lower in the previously intensively treated group [22]. The major cause of death in this long-term follow-up study was CVD with no discrimination between CHD and stroke [22]. There was an association between overall mortality and mean HbA1c level during the 6.5 year in DCCT, demonstrating glycemic control as an important factor [22]. This was also pointed out in the FinnDiane study, i.e. poor glycemic control is a risk factor for ischemic stroke [57]. These studies indicate a beneficial role of good glycemic control for the risk of suffering an ischemic stroke.

2.3      Peripheral artery disease

 

The definition of PAD currently used by the European Society of Cardiology guidelines includes atherosclerotic lesions in the extra-cranial carotid and vertebral, upper and lower extremity, mesenteric and renal arteries [59]. These central atherosclerotic changes are often accompanied by lesions located distally in patients with diabetes, most often in the popliteal artery or in the vessels of the lower leg. The diagnosis of PAD is based on typical symptoms of intermittent claudication and clinical investigations, including auscultation and palpation of peripheral arterial pulses. Ankle-brachial index (ABI) is an objective measurement of peripheral artery disease in the lower extremity and is calculated by dividing the systolic blood pressure at the tibial or dorsalis pedal arteries level with the brachial systolic pressure. An ABI index of <0.8 or a mean of three ABIs <0.9 is diagnostic for lower extremity artery disease, and an index of <0.5 indicates high risk of amputation [59].

 

Diabetes-related foot disease is a major cause of morbidity and mortality [60, 61]. The reported rates in lower extremity amputations vary from 2.8 to 43.9/100,000/year between countries in the world, and 25-90 % of these are associated to diabetes [61]. It is estimated that about 5 % of all diabetes patients have had a history of foot ulcers [62]. The life-time risk of a diabetes-related foot ulcer is reported to be as high as 25 % [63]. There is a clear association between peripheral neuropathy and foot ulceration [64]. A comparative study of PAD in diabetic and non-diabetic patients confirmed that diabetic patients had more distal disease and a poorer outcome with respect to amputation and mortality [65]. Other reported contributing risk factors in the development of foot ulcers are foot deformities, micro­vascular complications, increase in plantar foot pressure due to deformities, infection and diabetes duration [66]. The ultimate consequence of PAD and foot ulcers is the need for lower-extremity amputation. Some later studies point toward a decrease over time in the incidence of amputations. A Scottish nation-wide study demonstrated a 30 % decrease in the incidence of lower extremity amputations in diabetes patients from 2004-2008 [67]. Also, from the Steno Diabetes Center in Denmark, it was recently demonstrated that the incidence of amputations have decreased significantly during the last decade [68]. This is suggested to be due to implementing a multidisciplinary team-work [67].

2.4      Diabetes nephropathy

Diabetes-related kidney disease is graded into microalbuminuria, macroalbuminuria, or ESRD and/or categorized according to the extent of impairment in glomerular filtration rate (GFR). Microalbuminuria is defined as an albumin excretion rate of 30-299 mg/24 h (alt. 20-200 µg/min), whereas macroalbuminuria is defined as an albumin excretion rate of ≥300 mg/24 h (≥200 µg/min) [69]. It should be noted that the definition of diabetic nephropathy includes macroalbuminuria and ESRD, but not microalbuminuria.

The incidence of diabetic nephropathy has been investigated in many cohorts over the years. In the Steno epidemiological study, it was reported that 41 % of the individuals developed diabetic nephropathy [28]. The prevalence was similar in the Pittsburg EDC 10 year follow-up study, showing that 40 % of the individuals developed diabetic nephropathy during 30 years of diabetes duration [35]. In the Steno study, the incidence in proteinuria among patients diagnosed from 1933-1942 and from 1953-1962 was investigated. Findings revealed a 30 % decreased incidence of proteinuria in the younger population compared to the older group; this clearly (and perhaps not so surprisingly) indicates that diabetes duration is an important risk factor for developing diabetic nephropathy [28].

Progression in the extent of diabetic nephropathy has been shown to correlate to an elevated risk of mortality in several studies [70-73]. In the FinnDiane study, an independent graded association was observed between the severity of kidney failure and mortality [71, 74]. However, absence of albuminuria in type 1 diabetes individuals seems to be protective so that the mortality rate is similar to the general population [71, 74].

The impact of glycemic control on the risk of developing renal disease is paramount; lowering HbA1c levels is associated with less albuminuria [44] [43]. It was recently shown in a Swedish followed-up cohort study of type 1 diabetes patients from diagnosis that 23 % of the individuals with long-term (20-24 years) mean HbA1c of >80 mmol/mol developed diabetic nephropathy, whereas none with HbA1c <60 mmol/mol did [75].

Longevity in diabetes is substantially decreased with lower eGFR [20]. On the other hand, there is still a shorter survival for those with type 1 diabetes in the presence of a normal eGFR (≥90 mL/min/1.73 m2), indicating that factors other than solely nepropathy influence the risk of premature development of CVD and death [20]. The association between loss of kidney function and premature death per se and CVD has been hypothesized to be due to that the degree of functional renal impairment reflects a general atherosclerotic development and severity [76]. On the other hand, a long list of other factors (all involved in CVD) is associated with declining renal function, such as male sex, hypertension and dyslipidemia [77], as well as oxidative stress [78], endothelial dysfunction [79], advanced glycemic end products (AGEs) [80], left ventricular hypertrophy [81], and insulin resistance [82]. Good glycemic control and strict blood pressure control are probably the two most important factors decreasing the risk of diabetic nephropathy [83].

2.5      CVD risk factors in type 1 diabetes

Many factors are associated with an increased risk of CVD in type 1 diabetes, figure 1. Some are non-modifiable, such as age, diabetes duration and heredity; whereas others, such as smoking, hypertension, lipid levels, obesity, albuminuria and glycemic control, are modifiable. Most of these factors are discussed in the different sections but will be more thoroughly scrutinized in the following part.

Figure 1 Factors contributing to development of Cardiovascular Disease in type 1 diabetes

2.5.1     Genetics

A growing body of evidence points to different genetic variations being associated with the heightened risk of CVD in type 1 diabetes. One example is the haptoglobin 2-2 (Hp2) genotype, which has been associated with both subclinical atherosclerosis and increased risk of CHD [84, 85]. There are three possible haptoglobin genotypes: 1-1, 2-1 and 2-2, of which Hp2 possesses less antioxidant capacity due to its larger molecular size and the lower oxidative capacity may reduce reverse cholesterol transport via altered modification of apolipoprotein A-I [86].

2.5.2     Smoking

Cigarette smoking is closely coupled to the increased risk of developing not only microvascular [87] but also macrovascular complications [88, 89] in type 1 diabetes. As regards macrovascular complications, the association is strongest for the risk of contracting PAD. The negative effect of smoking is probably due to endothelial dysfunction and inflammation [90].

2.5.3     Hyperglycemia

Brownlee has proposed a model connecting hyperglycemia and oxidative stress with atherosclerosis [91]. In this model, the increases in glycolysis and tricarboxylic acid cycle activity (driven by hyperglycemia) generate an overproduction of superoxide in the mitochondrial electron-transport chain in the endothelial cells [91]. This excess superoxide production is proposed to cause an inhibition of glycolytic enzymes, resulting in an accumulation of metabolites and cell damage in the blood vessels. In addition, intracellular hyperglycemia is hypothesized to increase the osmotic pressure and vascular permeability [91]. This would allow lipoproteins, such as LDL-cholesterol, to transmigrate into the vessel, accompanied by pro-inflammatory cells, e.g. monocytes [24].

AGEs can be formed via oxidation of glucose and lipids and through the polyol pathway [92]. Patients with diabetes have been shown to exhibit increased amounts of tissue AGEs com­pared to non-diabetics [93]. Increased skin AGE levels are predictive for microvascular complications in type 1 diabetes [94], indicating a connection between hyperglycemia and AGE concentrations. Measurements of skin collagen AGEs from subjects in the DCCT have demonstrated AGE levels to be closely associated to the development of microvascular complications [80].

A strong association between chronic hyperglycemia, e.g. measured as HbA1c, and micro­vascular complications has been unequivocally established in several large epidemiological studies [43, 95, 96]. In contrast, the importance of glycemic control in the development of CHD has been very much debated and remains a controversial issue. Some data suggest a relation­ship [97], while some do not [36, 98]. Others have demonstrated an important role of hyper­glycemia in the pathogeneses of stroke and myocardial infarction [37, 95, 99, 100], in which chronic hyperglycemia is associated with CVD, independent of age and other classic risk factors [101]. It has been demonstrated (in large epidemiological studies) that every one percent increase in HbA1c above the upper normal range is associated with a 20-30 % increase in CVD events [101]. However, not all studies have arrived at the same conclusions. The EURODIAB study failed to demonstrate any association between HbA1c levels and CHD in women but did so in men [102]; neither did the Pittsburgh EDC 10 year follow-up study show any association between glycemic control and CVD events [103]. A comparison between the two cohorts revealed no association between HbA1c levels and CHD in men but did so among women [104]. Moreover, a later report from the Pittsburgh EDC study demonstrated that hyperglycemia aggravated the CHD risk even more if albuminuria was also present [105]. The DCCT/EDIC study also conclusively and unequivocally established that strict glycemic control is one major factor in modifying the risk of all-cause mortality and CVD in the long-term perspective [22].

According to the current guidelines from European Association for the Study of Diabetes (EASD) and the American Association of Diabetes (ADA), the target HbA1c level -- in terms of preventing vascular complications -- is <52 mmol/mol [106], a level also recommended by the Swedish National Board of Health and Welfare (Socialstyrelsen). However, in select diabetic patients, e.g. elderly with short expected life expectancy and patients with long diabetes duration with previous CVD events, (particularly type 2 diabetes individuals), the over-arching goal may, or even should, not be to strive for achieve normal HbA1c levels [107].

2.5.4     Dyslipidemia

Generally, lipid levels (and their subfractions) seem to be of about the same magnitude in adult type 1 diabetics with good glycemic control as in non-diabetic individuals [108]. On the other hand, studies have demonstrated higher lipid levels in adolescent and young adults with type 1 diabetes compared to matched control individuals [30]. Good glycemic control can to some extent improve or even normalize certain components of diabetic dyslipidemia, especially hypertriglyceridemia [109]. Other established factors contributing to higher lipid levels are BMI and insulin resistance [110]. In the Framingham offspring study (general population) low HDL-cholesterol, high LDL-cholesterol and high triglyceride levels were found to be associated with an increased risk of CVD [111]. In the Coronary Artery Calcification in Type 1 diabetes (CACTI) study, elevated fasting levels of triglycerides were independently associated with increased coronary artery calcification progression [112]. Low HDL-cholesterol levels in individuals with type 1 diabetes are associated with an increased risk of CHD [113]. In the Pittsburgh EDC study, LDL-cholesterol levels >2.6 mmol/L were found to be associated with an increased CVD risk [114]. Whereas it is generally agreed that the utility of lowering LDL-cholesterol levels in type 2 diabetes patients nowadays is undisputed [115], controversy lingers as to whether this is also the case in type 1 diabetes. However, treatment, chiefly by statins, indicates that LDL-lowering can be beneficial in reducing CVD incidence also in patients with type 1 diabetes [116, 117].

2.5.5     Hypertension

Hypertension is a common and over-represented co-morbidity among both type 1 and type 2 diabetes patients [29, 118], compared to the general population, and is a strong predictor of CVD events [104]. Both the ADA and the EASD recommend a blood pressure goal of <130/80 mmHg for diabetes individuals [119, 120]. The CACTI study demonstrated that only 42% reached the blood pressure goal (<130/80 mmHg) set for adults [121]. In the SEARCH Diabetes in Youth Study, the prevalence of hypertension was 6 % and the prevalence increased in obese adolescents and individuals with poor glycemic control [122]. There is a clear association between hypertension and poor glycemic control as well as diabetic nephro­pathy [118, 123]. This was demonstrated in, among other studies, the DCCT/EDIC in which higher HbA1c levels were associated with hypertension; in this study intensive insulin replacement therapy was also found to decrease the risk of incident hypertension [124]. It might be speculated as to whether, or to what extent, this is due to insulin’s vasodilatory features. In type 1 diabetes, hypertension is most often treated with ACEi or ARBs, often­times with low-dose thiazide diuretics or calcium channel antagonists as add-on therapy, if deemed necessary. It is particularly important to strive for rigorous blood pressure control if the type 1 diabetes patient also has albuminuria.

2.5.6     Insulin resistance

Increased risk for diabetes-related vascular complications is associated with components of the metabolic syndrome, in which insulin resistance is an important factor. This has been conclusively shown particularly in type 2 diabetes individuals [73, 125]. The Pittsburgh EDC used eGDR as a surrogate marker for insulin resistance, and attempted to investigate the relation between this marker and the risk of incident CHD. They demonstrated eGDR to be a predictor, but not glycemia, of CHD in type 1 diabetes [103, 126]. In the DCCT/EDIC study, patients with the highest degree of insulin resistance, as estimated by eGDR at baseline, were found to have the highest risk of developing both micro- and macrovascular complications, irrespective of which treatment group they were randomized to. This gives some clues, or at least hints, that insulin resistance per se may be an important risk factor for diabetic angiopathy not only in type 2 diabetes but also in type 1 diabetes [127]. It has been proposed, in a mathematical model, that prevention of  insulin resistance would lower rates of  myocardial infarction as much as 40 % regardless of the other risk factors involved in the metabolic syndrome [128].

The quantitative impact of insulin resistance on CVD is not easy to dissect out, since it is co-incident with several other traditional CVD risk factors, e.g. hypertension, obesity, and dyslipidemia [128]. Nonetheless, some epidemiologic studies lend support to the notion that insulin resistance is pathogenically important for CVD development also in type 1 diabetes. In the Pittsburgh EDC study, the hazard ratio of CHD was increased for those with a family history of type 2 diabetes, even after adjustments for known confounding factors in the insulin resistance syndrome [129]. The term “double diabetes” has been coined to describe the phenomenon that type 1 diabetes patients with family history of type 2 diabetes often­times are also overweight and have sub-optimal glycemic control despite high insulin doses [130]. Theoretically, it has been debated if these findings and the autoimmune development of type 1 diabetes are two independent processes, or if insulin resistance triggers or facilitates/accelerates the autoimmune process [131].

Excessive weight gain, not infrequently occurring as a direct consequence of intensified insulin treatment, has been considered as a cause for concern of contributing to CVD events in type 1 diabetes [132]. This was addressed among adult DCCT patients where it was found that the quartiles who gained most weight in both treatment groups also had the highest blood pressure and lipid levels [132]. A later study confirmed that markers of macro­vascular complications were significantly correlated with weight gain (both in the intensive and conventional treatment groups) [133]. This also forms part of the rationale for the clinical practice of sometimes treating obese type 1 diabetes patients, albeit ‘off-label’, with metformin as add-on therapy to insulin. On the other hand, a recent publication from the DCCT/EDIC group report consistent lower all-cause and CVD mortality in the group previously intensively treated with insulin [22].

2.5.7     Diabetes nephropathy

Diabetes nephropathy is strongly associated to CVD. The Steno-2 study clearly demonstrated that the risk of CVD was four times higher in type 1 diabetes individuals with micro­albuminuria, as compared to those without [134]. Macroalbuminuria renders the diabetes patients susceptible to developing CVD. In the FinnDiane study, as well as in the Pittsburgh EDC study, both micro- and macroalbuminuria and ESRD correlated significantly with increasing mortality risk for each stage of renal compromise [71, 74].

Conversely, it is important to keep in mind that an improvement in glycemic control reduces the incidence of microalbuminuria. This was firmly demonstrated in the SDIS and slightly later confirmed in the DCCT in 1993 [43, 44]. The continuing DCCT/EDIC study has confirmed these findings and also demonstrated that improvement in glycemic control and hypertension may reverse the degree of albuminuria [83].

2.5.8     Risk factors in childhood and adolescence

Both the ADA and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have recently published guidelines addressing CVD risk factors in children and adolescents with diabetes [135, 136]. They both state that major risk factors for CVD include hyper­tension, dyslipidemia and hyperglycemia. Traditionally, they have been differing in goals set for HbA1c, with the ADA giving age-specific targets of 70 mmol/mol (DCCT 8.5%) <6 years of age, 64 mmol/mol (DCCT 8%) between 6–12 years of age and 58 mmol/mol (DCCT 7.5%) between 13–18 years of age and the ISPAD recommendation is setting a target of 58 mmol/mol (DCCT <7.5%) for all children with diabetes mellitus. Recently, ADA has adopted the ISPAD recommendation as well.

Management approaches for dyslipidemia are the same between the organizations, i.e. lifestyle changes (diet and exercise) and statin use if LDL-cholesterol levels exceed 2.6 mmol/L. Similar approaches apply for the treatment of hypertension, i.e. lifestyle changes and ACEi or ARBs if blood pressure > 95th percentile for age and height. The guidelines also emphasize smoking avoidance/cessation, physical activity promotion and treatment of obesity as important interventions. Hypertension is quite common in children and adolescents with type 1 diabetes [122], in whom obesity, hyperglycemia and diabetic nephropathy aggravate this situation [137]. These and other studies make it clear that elevated traditional CVD risk factors, such as high levels of HbA1c, blood pressure and cholesterol, not only are all quite common during childhood and adolescence of patients with type 1 diabetes [138], but also that surprisingly few of the patients receive antihypertensive or lipid-lowering medications, in spite of current guidelines from both the ADA, EASD and ISPAD.

2.5.9     Hypoglycemia

Hemodynamic changes evoked by hypoglycemia include increased heart rate, widening of pulse pressure, due to reduced central blood pressure and peripheral artery resistance, as well as increased peripheral blood pressure [139]. Increased stroke volume and cardiac output, in synergy with these changes, may cause a temporary and abnormal workload of the heart which may be extra harmful for type 1 diabetes individuals with a propensity for CVD that may has hitherto remained asymptomatic/subclinical [139, 140].

Hypoglycemia is also assumed to cause malignant arrhythmias by prolonging the QT interval and cardiac repolarization, thereby increasing the risk of sudden death. In one autopsy study, it was demonstrated that sudden death was four times more common in type 1 diabetics compared to non-diabetic persons [141]. It is tempting to speculate that counter-regulatory hormonal response to hypoglycemia, not least including excessive release of catecholamine’s (e.g. epinephrine and norepinephrine) and other ‘stress hormones’, may elicit deleterious effects on the diabetic heart by for instance increasing heart rate and oxygen demand and restricting coronary blood flow.

Type 1 diabetes individuals are at great risk of iatrogenic hypoglycemia, not least due to the fact that insulin resistance is much less of a problem in type 1 diabetes as most of these patients are non-obese. Both in the DCCT and the SDIS studies, an increased incidence of severe hypoglycemia in the intensively insulin-treated groups was demonstrated [43, 44]. Notwithstanding this, none of these studies was designed to address long-term CVD consequences of severe hypoglycemia. In a Swedish registry study, 1,839 type 1 diabetes subjects with CVD complications were investigated. Of these subjects, 22 % had a history of previous hospitalization for severe hypoglycemia. Further a dose-response relationship between the numbers of previous hypoglycemia and survival after CVD, as well as CVD mortality, was demonstrated [142].

2.5.10 Microvascular complications

The present thesis project has its focus on macrovascular complications of diabetes. On the other hand, study II has a combined micro- and macrovascular approach with chronic foot ulcers as the primary outcome measure. The development of diabetic foot ulcers usually starts with neuropathy, but is also closely related to the development of PAD. Therefore, micro­vascular complications, including diabetic nephropathy, are also discussed with the attempts to address possible mutual mechanisms between micro- and macrovascular complications in type 1 diabetes.

The long-term microvascular diabetic complications are traditionally divided into retino­pathy, neuropathy and nephropathy. In the Pittsburgh EDC study 10-year follow-up, results demonstrated that almost all participants developed mild retinopathy during the first 20 years after diagnosis and -- by 30 years of disease duration -- almost 70% developed proliferative retinopathy [35]. Moreover, in the same study, some 70 % of the participants developed peripheral neuropathy. In the 25-year follow-up of Wisconsin Epidemiologic Study of Diabetic Retinopathy, the overall incidence of any retinopathy was as high as 97 %, with a cumulative incidence of progression to proliferative retinopathy of 42%. Over the years of follow-up, the level of glycemia -- both at baseline and at the follow-up study years -- was closely related to the progression of retinopathy [143].

A strong association between chronic hyperglycemia and microvascular complications has been conclusively demonstrated in several large epidemiological studies [95, 96, 144]. As mentioned above, the SDIS and -- slightly later -- the DCCT trials were both pioneering and groundbreaking studies demonstrating that intensified insulin treatment halts microvascular complications in type 1 diabetes due to improved glycemic control [43, 44].

This treatment had also long-term beneficial effects on the macrovascular complications [99]. Whether microvascular dysfunction precedes the development of macrovascular complications remains a controversial and elusive issue. However, microvascular complications in type 1 diabetes, such as peripheral neuropathy [145], nephropathy [146] and retinopathy [147], are all independent risk factors for macrovascular disease.   

2.6      Treatment of modifiable risk factors in type 1 diabetes

The DCCT and SDIS trials both found an undisputable effect on diminishing microvascular complications by means of intensive insulin treatment and thereby improved glycemic control [43, 44]. The DCCT/EDIC study also lends robust support to the view that early and intensive insulin replacement therapy is a major beneficial factor in alleviating the risk of microvascular complications , and of all-cause mortality and CVD in the long-term perspective [22]. A similar pattern has been demonstrated for type 2 diabetes in the UK Prospective Diabetes Study (UKPDS), with firm effects on microvascular complications, and later on evidence for CVD risk reduction [148].

2.7      Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)

In the 1960´s, the standard treatment regimen of type 1 diabetes was a single morning dose of long-acting insulin. Self-monitoring of blood glucose levels did not exist; urinary glucose excretion was sometimes monitored. Sometimes short-acting insulin was introduced as well. During the 1970´s and more so in the 1980´s, the frequency of insulin doses increased with the introduction of pen-injectors and the first insulin pumps and so the number of short-acting insulin injections, needed to curb prandial glucose excursions, per day increased. This, in conjunction with the establishment of HbA1c measurements and blood glucose self-monitoring, made it possible to improve glycemic control more easily.

The DCCT was launched in 1983, eventually enrolling 1,441 patients with type 1 diabetes. They were randomly assigned to receive either intensified anti-hyperglycemic treatment or standard treatment with a mean follow-up of 6.5 years and evaluated with respect to incidence and development of microvascular complications, i.e. retinopathy, nephropathy and neuropathy [149]. Patients in the intensively treated group were introduced to three or more insulin injections per day -- or insulin pump treatment -- in contrast to the conventional treatment group which had one or two daily insulin injections. Glycemic goal was to achieve blood glucose levels as close to normal as possible. Out of the 1,441 included patients 726 were included in a primary prevention (no retinopathy, urinary albumin excretion rate <40 mg/24 hrs), while the remaining 715 in a secondary prevention (mild or non-proliferative retinopathy and urinary albumin excretion rate <200 mg/24 hrs) cohort [149].

The outcome of this landmark study showed a significant lowering of HbA1c levels in the intensively treated group as compared to the control group (55 mmol/mol vs. 76 mmol/mol IFCC standard [corresponding to 7.2 % vs. 9.1 % DCCT standard]), accompanied by a relative risk reduction of 76 % (primary prevention) and 54 % (secondary prevention) regarding the progression rate of retinopathy 44. The relative risk reduction for progression of peripheral neuropathy was 60 % and 54 % for nephropathy . These very impressive  improvements were, however (and perhaps not so surprisingly), accompanied by an increased risk of severe hypoglycemia in the intensive treatment group (62 vs. 19 episodes per 100 patient years) [144].

A later analysis, at study entry, in DCCT subjects (age 13 to 17 years) demonstrated in the primary prevention cohort that intensive insulin treatment decreased the relative risk of retinopathy by 53 %, while in the secondary prevention cohort the relative risk reduction for progression in retinopathy was 70 % [150]. In this sub-study with adolescent patients, the risk of severe hypoglycemia was three times higher in the intensive insulin therapy group. Another report showed that levels of HbA1c, both at study entry and during DCCT completion, were positively correlated to the risk of retinopathy progression [151]. The first evaluation of macrovascular events demonstrated no statistically significant differences, although the absolute numbers were higher in the conventional treatment group [152]. Risk factors for CVD, such as dyslipidemia were improved in the intensive treatment group, but -- as expected -- weight gain was also significantly greater.

The EDIC study was a multicenter observational study designed to follow up the DCCT cohort [153], and 96 % of the original DCCT patients agreed to participate. After DCCT was ended, all patients were offered the intensive treatment regimen. As a result, two years later, 95 % of the former intensive treatment group and 69 % of the conventional treatment group were treated according to the intensive treatment regimen. Despite this, HbA1c levels converged between the groups and were no longer statistically significantly different between the two groups over the five years of EDIC [154], and have been remained similar with a mean HbA1c level of approximately 64 mmol/mol for both groups [155].

As a marker of atherosclerosis, cIMT was measured 3 times during the EDIC study, at base­line and at years 6 and 12 [156]. 1,229 individuals from the DCCT/EDIC cohort were followed-up regarding cIMT measurements. After 6 years, the cIMT was significantly greater among study subjects compared to age- and sex-matched non-diabetics; also the progression in cIMT was greater for those with conventional insulin treatment compared to the group receiving intensive insulin treatment during DCCT. cIMT progression also positively correlated with age, sBP levels, smoking, LDL/HDL-cholesterol ratio and urinary albumin excretion rate, all known risk factors for CVD [157]. On the other hand, the 12-year follow-up analysis showed no difference in cIMT progression between the two DCCT groups from years 6 to 12 [156].

The DCCT/EDIC 13-year follow-up study revealed a lower number of macrovascular complications in the intensified insulin treatment group [99]. The relative risk reduction in mortality and morbidity CVD was 57 % [99]. It was also demonstrated that a 10 % reduction in levels of HbA1c, during the DCCT, was accompanied by a 20 % decreased relative risk of subsequent CVD events [99]. These salutary effects on macrovascular complications in the intensively insulin-treated group were suggested not to be driven by differences in levels of HbA1c, blood lipids, blood pressure or pharmacological treatment (although more patients in the conventional group had beta blockers). Authors speculated that the earlier 6.5 years of intensified insulin treatment, which substantially decreased HbA1c levels, contributed to these long-term effects [99]. Now, nearly 30 years after DCCT commenced, 1,429 of the original study subjects have been followed up, demonstrating a modest, although statistically significant, difference in all-cause mortality rate in favor of those previously randomized to initial intensive insulin replacement therapy compared with conventional glycemic treatment [22].

2.8      Stockholm diabetes intervention study (SDIS)

The DCCT and SDIS studies both demonstrated almost identical results, i.e. that early intensive insulin treatment can postpone or prevent microvascular complications in type 1 diabetes patients [44, 144]. The treatment effects were, by any standard, very impressive.

The SDIS was initiated by the late Dr. Per Reichard in 1982 in order to investigate whether intensive insulin therapy could reduce the incidence of microvascular complications in type 1 diabetes patients in Sweden [44]. One hundred and two patients were randomly assigned to receive either intensified conventional treatment (ICT) or standard treatment (ST) for a period of 7.5 years. Inclusion criteria were type 1 diabetes (diagnosed before the age of 31, and requiring insulin treatment within one year), no or non-proliferative retinopathy, and normal urinary albumin excretion rate and glomerular filtration rate. Exclusion criteria were pro­liferative or photo-coagulated retinopathy and known drug or alcohol abuse. The treatment regimen in the ICT group consisted of four daily injections of insulin while the majority in the ST group received two daily injections of insulin. Patients were evaluated regarding microvascular complications after approximately 18 months [158], 3 and 5 years of study start [159, 160], and at the end of the study [44]. A 10-year follow-up was also made with respect to mortality and treatment side effects [44, 158-161].

The results were strikingly similar with the DCCT findings (published a few weeks later), with a significantly lower mean level of HbA1c 54 mmol/mol (DCCT 7.1%) in the intensive treatment group, as compared to 70 mmol/mol (DCCT 8.5%) in the conventional treatment group, and a corresponding reduced risk of severe retinopathy, nephropathy and neuropathy in the intensified insulin treated group. During the SDIS, four patients died in the intensive treatment group and three in the conventional treatment group and -- as in the DCCT -- a three-fold higher incidence of serious hypoglycemia was noted in the intensive treatment group, and a borderline significant weight gain [162].

In the 10-year follow-up of SDIS, the glycemic control was still significantly better in the intensive treatment group despite the fact that the randomization had ceased and treatments were individualized. However, even at this late time point, the microvascular complications were even more prevalent in the conventionally treated group [44, 158-161].

Although the number of participants in SDIS was relatively few and the study primarily was designed (and statistically powered) to study microvascular complications, some sub-studies (after 7.5 years) were nonetheless performed to evaluate any differences in macrovascular complications between the two groups. Fifty nine of the subjects were tested for risk markers of CVD such as flow mediated vasodilatation in the brachial artery (an established surrogate marker for endothelial dysfunction), cIMT, arterial wall stiffness calculated and the carotid arteries scanned for plaques [163]. The results showed a better outcome for the previously intensively treated group with thinner cIMT and less stiff arteries. Moreover, among all participants, patients with lower levels of HbA1c had less stiff arteries and a better endothelial function [163].

2.9      Glycemic memory

Although the mean HbA1c converged between the two treatment groups in DCCT soon after study end, the effect of the diverging treatment intensity during the trial continued to cause more complications in the previously conventionally treated group [99, 154, 155]. This phenomenon was later on described as a glycemic memory. The same phenomenon was observed in the UK Prospective Diabetes Study (UKPDS), studying newly diagnosed type 2 diabetes individuals [148]. In the DCCT/EDIC trial, this glycemic memory effect has remained over the years, as was recently demonstrated for both microvascular [164, 165] and macrovascular complications [22, 166].

One suggested mechanism behind the purported glycemic memory is epigenetic alterations, i.e. non-hereditary modifications gene expression efficacy by for instance methylation without affecting the underlying genomic sequence [167]. Epigenetic modifications can also be caused by alterations in the environment [168] and by exercise. Experimental models have demonstrated that a high-glucose environment causes alterations in epigenetic post-translational histone modification affecting inflammation and vascular complications [169, 170]. Indeed, it was recently demonstrated that epigenetic histone modification is involved in the glycemic memory in study subjects from the DCCT/EDIC cohort trial [171].

2.10   Revascularization in type 1 diabetes

Established CHD is a strong risk factor for recurrent events, especially if combined with diabetes [172]. Coronary artery bypass grafting (CABG) is, together with percutaneous coronary intervention (PCI), currently the methods of choice for interventional coronary revascularization therapy in CHD. Patients with known or previously undiagnosed diabetes constitute a large proportion of the CHD population, up to 25 % [173]. This figure is even further increased if subjects with pre-diabetes (i.e. impaired glucose tolerance) are included. Revascularization surgery for patients with multivessel CHD is a common procedure. Patients with diabetes and established CHD often have more disseminated and aggressive atherosclerosis and are at much higher risk of developing major adverse CVD events and death than those without diabetes [174-177].

The outcomes of most studies have favored CABG over PCI as the preferred type of intervention, not least in diabetic subjects since they (as mentioned above) often have multi-vessel disease [178]. A recent meta-analysis, based on eight studies including some 300,000 subjects, also found outcome in favor of CABG compared to PCI [179]. In the Bypass Angioplasty Revascularization Investigation (BARI) trial, a randomized controlled trial comparing CABG and PCI was conducted and patients were followed for 5.4 years.  As compared to CABG, an initial choice of PCI did not significantly compromise five-year survival [180]. However, in a sub-analysis of diabetic patients (not specified by the protocol), the five-year survival rate was significantly increased in patients randomized to CABG [180].

In the Strategies For Multivessel Revascularization in Patients with Diabetes (FREEDOM) trial, the hypothesis of CABG being more favorable than the introduction of PCI with drug-eluting stents among diabetes patients for long-term outcome was tested [181]. The five year event rates of all-cause mortality, non-fatal myocardial infarction and non-fatal stroke were all significantly lower in the CABG group compared to PCI [181]. The stroke frequency, on the other hand, was higher in the CABG group, being consistent with many other studies and demonstrated in a recent meta-analysis of 19 RCTs with 10,944 subjects [182]. The higher rate of stroke has been suggested to be caused by more extensive coronary artery disease, perhaps being typical for diabetes patients.

 

3       Hypothesis

In this thesis, the following hypothesises were tested. First (Study I), we hypothesized that young type 1 diabetes individuals have more signs of atherosclerotic development, measured by means of cIMT as a surrogate marker, and that they are more insulin resistant compared to subjects of a matched healthy control group. Second (Study II-III), despite the fact that SDIS was not statistically powered to address macrovascular complications, we hypothesized that the unusually long duration of this study may compensate for the relatively small number of study subjects, and that differences in macrovascular outcomes between groups might there­fore be possible to detect. Moreover, we also hypothesized that glycemic memory, or rather the earlier intensive insulin therapy, may explain the putative differences in outcomes between those groups. Since numerous studies have demonstrated a shorter longevity and an increased risk of CVD related mortality in type 1 diabetes, as compared to non-diabetic subjects, we hypothesized (Study IV) an increased risk of death in type 1 diabetes individuals, vs. non-diabetic subjects, after CABG.

4       AIMS

Briefly, these projects focus on macrovascular complications in individuals with type 1 diabetes in different settings. It started out with the aim to investigate early signs of athero­sclerotic lesions in adolescent and young adult type 1 diabetes patients. Thereafter, the individuals, previously randomized to receive either intensive insulin replacement therapy or standard treatment in the SDIS cohort were studied with regard to all-cause mortality, mortality/morbidity in CVD, diabetic nephropathy, and ischemic foot ulcer. The last project was aiming at exploring the outcome of macrovascular complications in type 1 diabetes patients undergoing CABG and to compare the incidence of such complications with type 2 diabetes patients and non-diabetics.

The specific aims of this work were:

  • To investigate early signs of atherosclerotic lesions, measured by using cIMT as a surrogate marker, and their relation to insulin sensitivity in young type 1 diabetes individuals.
  • To compare skin microvascular function in the foot and time to first hospitalization for ischemic foot ulcer in patients from the two groups in the SDIS.
  • To compare the incidence of all-cause mortality between patients from the two SDIS cohorts. The secondary aim was to compare these two groups in terms of incidence in CVD events, i.e. myocardial infarction and stroke, and in diabetic nephropathy.
  • To compare long-term survival in patients with either type 1 diabetes or type 2 diabetes with that of non-diabetic subjects following CABG.

 

5       Methods

5.1      Study Patients

5.1.1     Study I

In this study, 20 adolescent and young adult type 1 diabetes patients were recruited from the diabetes outpatient clinic at Sachs’ Children and Adolescent Hospital. Twenty healthy peers (aged 14-20 years) were also invited by means of visiting schools in the same area as our patients and constituted a matched control group. Inclusion criteria (diabetes group) were: known type 1 diabetes, diabetes duration > 1 year, and age 14–20 years.

5.1.2     Study II and III

In previously published papers, 112 patients from four diabetes clinics in the greater metro­politan Stockholm area were initially invited to participate in SDIS. One hundred and two patients (91 %) met the inclusion criteria and were enrolled from September 1982 to March 1984. The participants were followed for 7.5 years and thereafter the randomization ceased.

In 1995, all the remaining SDIS participants (n=96) were invited to an investigation of skin microcirculation by means of iontophoresis. Seventy two patients (ICT=35 vs. ST=37) agreed and were enrolled. These 72 individuals constitute the study population in Study II (Figure 1).

The study population in study III consists of the 102 participants originally recruited to the SDIS in the early 1980´s (Figure 2).

 

 

 

 

 

 

 

 

 

 

 

 

 

Assessed for eligibility in SDIS (n=121)

 

Declined to participate (n=19)

Original SDIS cohort randomized 1982-1984 (n=102)

 

Intensive conventional insulin treatment ICT (n=48)

Conventional insulin treatment ST (n=54)

SDIS randomization ended 1990 after mean 7.5 years, seven patients died (ICT=4, ST=3). Six patients participated only partially

(n=96) 

SDIS Ionotphoresis study 1995          Invited to participate (n=96)

 

Study III n=102                                          Longitudinal observational study         

Primary outcome all-cause mortality and composite mortality from MI, stroke and ESRD 

Observation time 1996-2011

Declined to participate (n=17) excluded for other reason (n=7)

Former ICT patients participating (n=35)

Former ST patients participating (n=37)

 

Study II (n=72)                                                        Longitudinal observation study                                                                     Primary outcome hospitalization for ischemic foot ulcer Observation time 1996-2011

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2 Flow chart outlining the original Stockholm Diabetes Intervention Study, the timing of iontophoresis, study II and III.

5.1.3     Study IV

The study population consisted of all persons, in total 39,235 patients, who underwent primary isolated non-emergency CABG in Sweden between 2003 and 2013. Patients were obtained from the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) register.

5.2      Study protocols

5.2.1     Study I

This was a cross-sectional study. After a 12 hours overnight fast, blood test were drawn for analyses of blood lipids, creatinine and HbA1c. BMI, waist circumference, and blood pressure were also measured. Thereafter a hyperinsulinemic euglycemic clamp was performed to measure insulin sensitivity. After the clamp procedure, cIMT was measured with high-resolution ultrasonography.

5.2.2     Study II and III

Patients in the ICT group received extra education, including how to use self blood glucose tests several times daily. They had continuous tutoring by telephone and scheduled visits to the diabetology outpatient clinic every 2nd month. The ST patients were instructed how to use self blood glucose tests. They received no extra education and only discussed the treatment at regular visits to the outpatient clinic every four months. Glycemic control was measured by means of HbA1c levels every four months for all participants. The treatment regimen in the ICT group consisted of four daily injections of insulin, usually a pre-meal fast acting human insulin (Actrapid®) combined with long acting (Monotard®) insulin. The majority in the ST group received two daily injections of insulin, usually a mixed insulin (Mixtard 30/70®). The glycemic goal was to improve glycemia to achieve an HbA1c level < 52 mmol/mol (DCCT: 6%). Seven and a half years after the first inclusion into the SDIS, the randomization ceased and both the ICT and ST patients continued visiting the attending diabetologist according to the standard diabetes care at the time. The ST patients were now given advice on how to further improve their insulin replacement therapy in order to improve their HbA1c levels. Ten years after the randomization, 71 % of ST group and 89 % of the ICT group were treated with at least three daily insulin injections [161].

Study II was a prospective follow-up study (Figure 2). Seventy two patients from the original SDIS cohort were evaluated regarding skin microcirculation with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine (ACh) [endothelial-dependent vasodilatation], sodium nitroprusside (SNP) [endothelial-independent vasodilatation], and capsaicin [C-nociceptive-dependent vasodilatation]. HbA1c levels were prospectively collected from 1990-1995 and tested for association with skin microcirculation. The cohort was then followed up as described in study III until the 31st of December 2011 and primary outcome was defined as the first recorded hospitalization for ischemic foot ulcer.

Study III was a longitudinal and observational study (Figure 2). Primary outcome was all-cause mortality, mortality in stroke, myocardial infarction and kidney failure and secondary outcomes were morbidity in myocardial infarction, stroke and ESRD. For the period January 1996 to December 2011, outcome data were extracted from the Swedish Death Register and the Swedish National Inpatient Register (IPR). Patients’ medical records were obtained from Melior® and Take Care® as well as data from the Swedish national registry of diabetes (NDR). HbA1c, lipid profile, blood pressure, microalbuminuria, smoking habits and use of acetyl salicylic medications, antihypertensive and lipid lowering agents were collected and the latest available data (2011) was recorded. Mean HbA1c levels were also analyzed for the entire period from 1996-2011. 

5.2.3     Study IV

Study IV was an observational, nation-wide population-based cohort study. Baseline characteristics were obtained from the SWEDEHEART register, and further expanded by cross-linking the data with information from the Swedish Cause of Death Register (CDR), the National Inpatient Register (IPR), the NDR, the Swedish Renal Register, and socioeconomic data from Statistics Sweden at the Swedish National Board of Health and Welfare (Figure 3). The type of diabetes was obtained from NDR. The definition of type 1 diabetes was onset of diabetes before the age of 30 years and treatment with insulin only. Type 2 diabetes was defined as diabetes treated with diet or oral hypoglycemic agents alone, or age 40 years or older at onset and treated with insulin alone or in combination with oral hypoglycemic agents. All persons not included in the NDR were defined as non-diabetic. The data were censored at the time of death or at the end of the follow-up period (March 24, 2014), whichever occurred first.

 

The SWEDEHEART Register          All persons who underwent primary isolated non-emergency CABG in Sweden 2003-2013

Final data-set for analyses                                               n=39 235 patients underwent CABG 2003-2013

  • 725 (1.8%) with type 1 diabetes
  • 8208 (21.2%) with type 2 diabetes
  • 8170 (21%) women
  •  

The Swedish National Diabetes Register (NDR)

The Swedish Renal Register

The Swedish Cause of Death Register (CDR)

The Swedish National Inpatient Register (IPR)

Socioeconomic data from Statistics Sweden

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 3 Flow Chart comprising data collection in study IV

5.3      Study outcome

5.3.1     Study I

Primary endpoint was defined as mean group difference in cIMT and its association to insulin sensitivity (measured by glucose infusion rate) obtained from the clamp. Secondary endpoints were to explore the association between BMI, waist circumference, sBP, triglycerides, HDL-cholesterol, HbA1c on one hand, and the measurements of cIMT and cross-sectional intima-media area (CIMA), on the other hand.

5.3.2     Study II

Primary outcome was the time to first hospitalization for ischemic foot ulcer, defined by ICD discharge codes in the IPR and confirmed by adjucating medical records with reference to the diagnostic criteria for ischemic foot ulcer, defined as ongoing foot ulcer together with ankle–brachial index <0.9 and/or toe pressure <50 mmHg. Secondary outcomes were to explore changes in skin microvascular circulation, measured by laser Doppler flowmetry, after topical administration of ACh, SNP and capsaicin, by means of iontophoresis technique and its association to which group study participants were randomized to in the original SDIS study.

5.3.3     Study III

The primary outcome was all-cause mortality and a composite mortality from myocardial infarction, stroke and ESRD. The secondary outcomes were morbidity (disease-free survival) from CVD complications, i.e. myocardial infarction and stroke, or ESRD.

5.3.4     Study IV

The primary outcome was all-cause mortality. Secondary outcome measures were CVD death and any major adverse coronary event (MACE), defined as a combination of hospital stay for myocardial infarction, heart failure, stroke or need of revascularization, either by PCI or CABG.

5.4      Routine Biochemical analyses

In study I, the local clinical chemistry laboratory was used for analyses of HbA1c, blood lipids, hsCRP, and plasma/urine creatinine levels. All the tests were drawn in the morning before the clamp. Blood glucose levels taken during the clamp were determined by the glucose oxidase method with a glucose analyzer (2300 STAT PLUS; Yellow Springs Instruments, Yellow Springs, OH, USA). Serum insulin and C-peptide levels were analyzed locally by an immunometric method with monoclonal antibodies (Modular E 170, Roche Diagnostics Scandinavia, Stockholm, Sweden).

In SDIS, HbA1c levels were measured in both groups at study entry, after 6 months and then approximately at every 4 months. Mean HbA1c levels were calculated for the whole 7.5 year period in the original study, as well as between 1990 and 1995 in the 10-year follow-up. In our follow-up period from 1996-2011 (study II-III), analyses of HbA1c and total cholesterol levels were performed by the local clinical chemistry laboratory whenever each participant had their routine visits.

5.5      Hyperinsulinemic clamp

The hyperinsulinemic euglycemic clamp is considered to be the gold standard method for determining insulin sensitivity [183]. The aim of the clamp is to increase the plasma insulin concentration level and maintain this until steady-state (usually 120 minutes). To avoid hypoglycemia, and to keep the blood glucose concentration at a constant level, a variable glucose infusion is given. The high plasma insulin concentration is estimated to cause a halt in liver glucose production so that in the “steady-state” condition endogenous glucose production is suppressed and the glucose infusion rate during steady-state equals the net tissue glucose utilization which mirrors the tissue insulin sensitivity (Figure 4).

 

Figure 4 Outline of the hyperinsulinemic euglycemic clamp

 

In summary, one intravenous needle was inserted into the antecubital vein on the left arm and a second one, in a retrograde fashion, on the back of the right hand. The hand was kept warm with an electric device for intermittent sampling of arterialized venous blood. In the left arm needle, human Actrapid insulin (40 mU/m2 NovoNordisk A/S, Copenhagen, Denmark) was infused along with 20 % dextrose (Fresenius Kabi, Stockholm, Sweden). Blood glucose samples were taken from the right hand vein catheter every 5 minutes and the rate of dextrose infusion was adjusted to achieve a blood glucose level of 5.0 mmol/l through the 120 minute clamp. Whole-body insulin sensitivity (Si) was measured as glucose infusion rate (GIR), calculated from the amount of dextrose infused during the last 30 min of the clamp and expressed as mg/kg/min. The glucose clamp-derived index of Si [Si index; in (10-4 dl/kg/ min)/(μU/ml)] was calculated from the GIR, corrected for body weight, during the final 30 min as follows: Si index = GIRss/Gss x ΔIss, where GIRss is the steady state GIR (mg/min), Gss is the steady state blood glucose concentration (mg/dl), and Iss is the difference between basal and steady state plasma insulin concentrations (μU/ml). This calculation is assumed to correct for differences in prevailing, individual glucose and insulin concentrations.

5.6      Carotid Intima-media thickness

Measurement of cIMT is a well-accepted method used in estimating atherosclerotic changes in large vessel walls [184]. It has been used in both adult, childhood and adolescent populations [185] and to assess impact from various chronic illnesses [184, 186].

In our study, the left and right carotids were examined, by one operator, using a Siemens Acuson Sequoia™ 512 Ultrasound System (Mountain View, CA, USA) with an 8 MHz linear array transducer. The subjects head was tilted in order to get the common carotid artery (CCA) just proximal to the bulb placed horizontally across the screen. Magnified pictures were frozen incidentally with the R wave on the electrocardiogram. The cIMT was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in the far wall (Figure 4). Lumen diameter was defined as the distance between the leading edge of the intima-lumen echo of the near wall and the leading edge of the lumen-intima echo of the far wall. The distal part of the CCA, 5–10 mm proximal to the carotid bulb, was used for measurements of cIMT and lumen diameter (Figure 5). The computer system calculated the average intima-media thickness and lumen diameter of the analyzed section. CIMA was calculated using the formula [(lumen diameter + 2 x IMT)/2]2 x 3.14 - (lumen diameter/2)2 x 3.14]. All measurements were performed by one operator, blinded to all other data, using an automated computerized analyzing system. The computer system calculated the average cIMT and lumen diameter of the analyzed section. As cIMT of multiple measurements is most widely used, it was chosen as our primary end point measurement.

 

Figure 5 cIMT measurement of the common carotid artery intima media layer, area indicated by square.CCA= common carotid artery; ICA= internal carotid artery; ECA= external carotid artery

5.7      HbA1c

Glucose in the blood binds irreversibly to the hemoglobin in the erythrocytes, thus creating glycated hemoglobin, i.e. HbA1c. HbA1c remains glycated during the erythrocyte’s whole life span and therefore reflects average glycemia during the past six to eight weeks prior to the sample time [187]. HbA1c is firmly established as a tool for evaluating both clinical interventions and scientific investigations.

During the eighties and nineties, different countries had different HbA1c standardization programs, i.e. the National Glycohemoglobin Standardization Program (NGSP) in the U.S., using the DCCT HPLC method as reference method and the Mono S ion exchange chromatography designated as the comparison method in Sweden [188]. Generally, the Mono S method readouts are 1.1 % (in absolute differences) lower than the DCCT method readouts. IFCC initiated a standardization of HbA1c, leading to an agreement to use the units of mmol/mol as an international standard [188]. Hence, this method of measuring HbA1c is used by the laboratories in Sweden since 2011. Still, the mmol/mol and DCCT % HbA1c units are applied parallel in reports and medical journals and in the ADA recommendations 2015 only the DCCT % is used [7]. To convert HbA1c results from NGSP (% HbA1c) and IFCC (mmol/mol), the equation (NGSP = [0.09148 x IFCC] + 2.152) can be used.

HbA1c analyses have been done with a HPLC method which is considered to be a “gold standard” technology. During the SDIS, the HPLC method switched to a Mono S HPLC as a reference method for measuring HbA1c [189].

In study II–III, HbA1c measurements for most of the study participants were analyzed at Karolinska University Laboratory. During the time of our follow-up (1996-2011), IFCC have introduced a change in reference method for calibration of HbA1c [190].

5.8      eGFR

To estimate glomerular filtration rate, as a measure of kidney function, eGFR based on measurements of creatinine levels is a valid and widely used method. Contemporary cal­culation for eGFR is (eGFR = 170 x [Pcr]-0.999 x [Age]-0.176 x [0.762 if patient is female] x [1.180 if patient is black] x [serum urea nitrogen concentration SUN (mg/dL)]-0.170 x [Alb]+0.318). This equation is based on data from the Modification of Diet in Renal Disease (MDRD) Study [191]. Briefly, there are five stages defining chronic kidney disease based on eGFR; stage 1 (> 90), 2 (60-89), 3 (30-59), 4 (15-29) and 5 (< 15 ml/min/1.73 m2), representing normal, mildly reduced, moderately reduced, severely reduced kidney function and very severely reduced/end-stage renal disease, respectively (from the 2012 update of the Kidney Disease Outcomes Quality Initiative, Clinical Practice Guideline for Diabetes and Chronic Kidney Disease) [192].

5.9      Iontophoresis and ankle-brachial index

Iontophoresis is an established method by which a small applied electrical field is used to facilitate the rate of penetration of drugs into accessible tissues, such as skin (Figure 6). In combination with laser Doppler flowmetry, the technique enables access to the microvascular bed and, by applying vasoactive substances, makes measurements of changes in cutaneous blood flow amenable. 

 

Figure 6 Principle of Iontophoresis system

 

A probe holder for combined single-point iontophoresis and blood flow measurement was fixed on the dorsum of the right foot. Skin blood flow at a depth of approximately 1 mm was registered by laser Doppler flowmetry technique (Periflux, Perimed, Stockholm, Sweden). Basal flow was calculated as an average of flow for 10 seconds during the last minute before the start of iontophoresis. Blood flow after administration of drugs was defined as the average blood flow for the 10 seconds with the maximal flow following the stimulation. Results are given as the change in blood flow for each of the vasoactive substances used, calculated as a ratio between the maximum blood flow after stimulation and basal flow, and presented as arbitrary perfusion units (PU). The chamber holder was filled with 2 % (wt/vol) ACh (Dispersa Hettlingen, Zürich, Switzerland) solution in de-ionized sterile water. Iontophoresis was performed with a 0.20 mA current for 15 s and repeated with a longer stimulation time (30 s) and maximal stimulation of 60–120 s. At a different site on the same foot, and not simultaneously, 2 % (wt/vol) SNP (Nipride, Hoffman-La Roche, Basel, Switzerland) and 2 % (wt/vol) capsaicin (Sigma-Aldrich, St. Louis, MO, USA) in solutions in de-ionized sterile water were iontophoresed at 0.5 mA to obtain a dose–response curve with the same time points as followed previously. For the ACh we used an anodal current, while for the SNP and the capsaicin we used a cathodal current. The investigator and the interpreter of the results were blinded to the former allocation of the individual patient.

5.10   National Registers

THE SWEDISH NATIONAL CAUSE OF DEATH REGISTER AND INPATIENT REGISTER                                                                                                                             

The CDR and the Swedish National IPR were initiated in 1964 by the Swedish National Board of Health and Welfare. It became mandatory for all county councils to report to the register from 1984 and attained national coverage in 1987. Today, more than 99 % of all somatic and psychiatric hospital discharges are registered in the IPR. From 2001, the register also includes outpatient visits from specialized private and public caregivers.

The diagnostic validity for myocardial  infarction, stroke and renal failure in the register has been shown to be more than 90 % provided it was the principal cause of hospitalization [193-195]. A drawback is that, as of today, primary care is not covered in the IPR. On the other hand, people with type 1 diabetes are routinely followed in special care units at the hospitals in Sweden. The IPR drop-out rate for 2007 has been estimated to less than one percent but changes in the country’s hospital organization make it difficult to estimate the drop-out rate particularly in the areas concerning psychiatric and geriatric care. A quality control of the data reported to the IPR is routinely performed. The control includes ascertainment that compulsory variables, i.e. personal registration number (unique for all Swedish citizens), hospital, and main diagnosis are reported. The validity of all variables is tested and if the data is obviously incorrect it is corrected and is sent back to the liable unit for approval.

THE SWEDISH NATIONAL REGISTER OF DIABETES                                            

The Swedish national register of diabetes (Nationella diabetesregistret, NDR) was initiated in 1996 by the Swedish Society for Diabetology. Today, virtually all type 1 diabetes patients are included in the register [196].

SWEDEHEART                                                                                                                     

The Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) register includes all patients who have underwent coronary angiography, percutaneous coronary intervention, or cardiac surgery or were cared for at any cardiac intensive care unit in Sweden since 1992 [197]. Agreement between information in the register and the medical records was reported to be between 93 % and 97 % [197].

THE SWEDISH RENAL REGISTER                                                                                

The Swedish Renal Register is a national health data registry for patients on maintenance for renal replacement therapy [198]. Every patient with chronic renal insufficiency starting dialysis treatment or receiving a kidney transplant should be reported to the register, and all dialysis and transplant units in Sweden report to the register. Reporting of patients is virtually 100 %.

STATISTICS SWEDEN                                                                                                

Statistics Sweden (Statistiska Centralbyrån) provides up-to-date information in a variety of areas, i.e. education, household economy and living conditions and is one of Europe’s leading statistical agencies [199].

 

5.11   Statistical methods

5.11.1 Study I

Student’s t test was used for comparison between study groups if parameters were normally distributed; otherwise Mann Whitney test was used. Test of normality was conducted with Kolmogorov-Smirnov and Shapiro Wilks test. McNemar’s and sign tests were used for dichotomous variables. Spearman test was used for the correlation data. A stepwise multivariate regression analysis was used for further testing associations between cIMT (dependent) and group (explanatory) regarding atherosclerotic risk factors (Si, BMI, waist circumference, sBP, triglycerides, HDL-cholesterol) and HbA1c. All risk factors were included and successively excluded in a stepwise order, starting with Si.

5.11.2 Study II and III

In study II, comparisons between treatment groups were made with the Mann–Whitney U test. Contingency tables were analyzed using the χ2 test. Associations were determined with linear univariable and multiple regression analysis. The measurements of skin microcirculation for each of the vasoactive substances used (ACh, SNP and capsaicin) were log transformed in order to achieve normality and then studied in the regression analyses for predefined factors collected at the time of the iontophoresis: age, duration of diabetes, HbA1c, smoking, sBP, and severe microvascular complications (i.e. retinopathy, nephropathy and neuropathy). Time to first hospitalization for ischemic foot ulcer was analyzed using the Kaplan–Meier method, and differences between ICT and ST groups tested with the logrank test.

In study III, comparisons between the treatment groups were made with a two-sided unpaired Student’s t test or Mann–Whitney’s U-test, depending on distribution according to the Kolmogorov–Smirnov and Shapiro–Wilk tests. Categorical data were analyzed using the χ2-test. Time to death for all-cause mortality and mortality in myocardial infarction and stroke (composite outcome), as well as time to first hospitalization for cardiovascular events, i.e. myocardial infarction and stroke, or ESRD, were all analyzed using the Kaplan–Meier method and differences between ICT and ST tested with logrank test.

5.11.3 Study IV

Patient characteristics were described using frequencies and percentages for categorical variables, and means and standard deviations for continuous variables. Cox regression was used to estimate the risk of all-cause mortality or a combined end point (all-cause mortality or hospital stay for myocardial infarction, heart failure, stroke, or repeat revascularization) in patients with type 1 and type 2 diabetes in a comparison with reference patients without diabetes. Crude and multivariable adjusted hazard ratios (HRs) were calculated and co­variates used in the final multivariable model were age, sex, BMI, eGFR, ESRD, hyper­tension, dyslipidemia, PAD, prior PCI, chronic pulmonary disease, stroke, prior myocardial infarction, heart failure, atrial fibrillation, left ventricular ejection fraction, EuroSCORE  (i.e. a method of calculating predicted operative mortality for patients undergoing cardiac surgery taking patient risk factors into consideration) [200, 201], alcohol consumption, birth region, education, marital status, off-pump CABG, number of grafts and type of graft.

6       Ethical Considerations

All four study protocols are in full agreement with the declaration of Helsinki. In study I, all participating adolescents and young adults, as well as the parents of those below18 years of age, gave written informed consent before inclusion. In study II, all participants in the iontophoresis study gave their written informed consent before inclusion. All four study protocols were approved by the local ethics committees (Reference numbers: 04-867/4, 2009/623-32, 2014/1878-32/4; 92-74, 189/95, 2012/829-31/4, 2012/1852-32, 2012/829-31/4, 2012/1852-32, 2009/1667-31/1, 2013/1382-32).

 

7        Results

7.1      Study I

Seven of the type 1 diabetes individuals were treated with insulin pump and 13 with multiple daily injections, having a mean insulin dose of 0.84 and 0.94 U/kg/day, respectively. There was no difference in HbA1c between those treated with insulin pump and those with insulin injections (68 vs.77 mmol/mol, n.s.). As expected, glucose homeostasis differed between the study groups; however, there were no significant differences in BMI, waist circumference, blood pressure or in lipid profile between groups. Mild retinopathy was found in seven diabetes individuals and moderate in one. Statistical analysis showed a significant correlation between diabetes duration and retinopathy (β=0.65, p<0.001).

The assessment of cIMT showed that the type 1 diabetes individuals had a significantly increased cIMT (0.52±0.1 vs. 0.47±0.1 mm, p<0.01) and CIMA (9.92±0.8 vs. 8.94±1.3 mm2, p<0.01), compared to their healthy peers. There was no difference in carotid lumen diameter between the study groups. Type 1 diabetes individuals were significantly more insulin resistant, demonstrated by a significantly lower GIR (5.0±2.1 vs. 7.1±2.2 mg/kg/min, p<0.01) compared to the non-diabetic group. Also, the glucose clamp-derived index of insulin sensitivity (Si index; adjusting for insulin concentration during clamp) was correspondingly lower in the diabetes group compared to the non-diabetic group (10.2±6.7 vs. 14.8±5.7 [(10-4 dl/kg/min)/(μU/ml)], p<0.05), demonstrating that different plasma levels of insulin were not accounting for differences in insulin sensitivity.

 

14

12

10

8

6

4

2

0

 

Figure 7 Association between cIMT and insulin sensitivity in diabetes individuals and controls

 

In the Spearman analysis for all 40 studied subjects, insulin sensitivity was negatively correlated with cIMT (r=−0.40, p<0.01), whereas waist circumference was positively correlated with cIMT (r=0.34, p=0.03). No such correlations were observed for the other risk factors of atherosclerosis, i.e. BMI, sBP, triglycerides, low HDL-cholesterol levels, or for HbA1c.

The association between Si and cIMT for each group is given in Figure 7. When introducing all the atherosclerotic risk factors in a multivariate regression model, with cIMT (dependent) and group (explanatory), Si abolished the significant association between cIMT and group, with no such effects for the other factors. Whenever the Si factor was excluded -- but including one or more of the other risk factors in multivariate analyses -- the association between cIMT and group was, again, statistically significant. Moreover, adjustment for insulin concentration in the model did not change the results (r=0.02, p=0.07), suggesting that insulin infusion during the clamp was not a confounder.

Explanatory

 

β

p

Included

 

All factors

 

0.07

<0.01

Excluded (stepwise in order)

 

Si

0.08

  0.11

Waist circumference

0.09

  0.03

BMI

0.10

<0.01

sBP

0.09

  0.01

Triglycerides

0.08

<0.01

HDL-cholesterol

0.08

<0.01

HbA1c

0.05

<0.01

Table 1 Stepwise regression analysis of explanatory factors between

cIMT (dependent) and group (controls and type 1 diabetes)

 

7.2      Study II

Seventy-two patients participated in the iontophoresis study, 35 from the former ICT group and 37 from the former ST group. All 72 were followed up until the end of our follow-up in 2011. Group characteristics for the ICT and ST groups revealed no statistically significant differences, except for a more frequent use of anti-hypertensive treatment in the ST group (Table 2). The incidences of nephropathy and retinopathy were significantly lower in the ICT group at the time of iontophoresis; this is in accordance with the previously published results from the SDIS [44]. The SDIS baseline levels of HbA1c did not differ between study groups at the time of randomization for the entire cohort of 102 individuals (ICT 76 mmol/mol vs. ST 79 mmol/mol, n.s.) or vs. the 72 patients included in the current study (ICT 76 mmol/mol vs. ST 79 mmol/mol, n.s.).

 

 

 

 

 

 

 

 

Characteristic

SDIS iontophoresis (1995)

End of follow-up (2011)

 

ICT

ST

ICT

ST

n (women/men)

35 (21/14)

37 (22/15)

32 (19/13)

27 (16/11)

Age (years)

42 (28–63)

42 (31–63)

56 (45–80)

58 (49–69)

Duration of diabetes (years)

28 (19–45)

27 (19–39)

44 (36–61)

44 (37–56)

BMI (kg/m2)

24 (19–30)

24 (19–30)

25 (18–36)

25 (17–34)

Current cigarette smokers (n)

14

9

5

4

Blood pressure (mmHg)

  Systolic

  Diastolic

 

135 (100–170)

77 (60–100)

 

135 (100–175)

75 (60–95)

 

130 (105–160)

70 (58–85)

 

135 (120–170)

70 (60–90)

HbA1c (mmol/mol)

57 (40–79)

68** (41–96)

63 (51–90)

67 (41–98)

HbA1c (%)

7.4 (5.8–9.4)

8.4** (5.9–10.9)

7.9 (6.8–10.4)

8.3 (5.9–11.1)

Total cholesterol (mmol/l)

4.5 (2.7–7.4)

5.1 (2.9–6.6)

Nephropathy (n)

2

8*

Retinopathy (n)

11

24**

Peripheral neuropathy (n)

5

10

Insulin dose (U kg body weight−1 day−1)

0.7 (0.5–0.9)

0.7 (0.4–1.0)

0.6 (0.4–1.2)

0.6 (0.3–1.0)

Anti-hypertensive medication (n)

13

25*

Lipid-lowering agent (statin) (n)

16

12

Anti-platelet therapy (n)

12

14

Table 2 Group characteristics for study II *p<0.05, **p<0.01 and ***p<0.001

 

At the time of iontophoresis, levels of HbA1c were lower in the ICT group, 57 mmol/mol (minimum– maximum 40–79 mmol/mol) compared with the ST group, 68 mmol/mol (41–96 mmol/mol, p<0.01). During the 20 year follow-up from 1996 to 2010 and in 2011, HbA1c levels were similar between the groups. There were no significant differences in total cholesterol levels at any point during our follow-up period from 1996 to 2011. Cholesterol was not measured in the original SDIS study.

During the median 28 years of follow-up, 13 patients developed ischemic foot ulcer. Three patients out of 35 in the ICT group with a median follow-up of 29 years developed an ischemic foot ulcer during follow-up, compared with ten out of 37 in the ST group with a median follow-up of 28 years (logrank test p=0.035),  figure 8.

 

Figure 8 Ischemic foot ulcer disease-free survival. Dashed line, ICT group; Solid line, STgroup

 

At time of the iontophoresis, the basal skin microcirculation blood flow rates did not differ between groups (ICT 4.5 PU [1.6–13.9 PU] vs. ST 5.9 PU [2.1–20.0 PU], p=0.33). As expected, the healthy participants showed a higher skin microcirculation in response to all vaso­active substances tested compared with the diabetes patients regardless of former randomization. During the iontophoresis, skin microcirculation blood flow was higher in the ICT group compared with the ST group for all three vasoactive substances applied: ACh 8.1 (4.6-24.7) vs. 5.3 (1.7-21.4) PU, p=0.004; SNP 8.1 (2.2-20.1) vs. 5.6 (2.3-19.2) PU, p=0.031; capsaicin 5.0 (1.7-22.9) vs. 3.4 (1.5-8.4) PU, p=0.005, respectively. The differences between groups were already evident during the shortest stimulation time (15 s) when ACh or SNP were applied, and with the second shortest stimulation time (30 s) during iontophoresis with capsaicin-induced vasodilatation. ABI did not differ between study groups (ICT 1.1 PU [1.0–1.2 PU] vs. ST 1.1 PU [0.8–1.3 PU], p=0.54).

In the linear regression analysis against skin microcirculation results (for the maximal stimulation), a negative association was noted between mean levels of HbA1c (1990–1995) and vasodilatation induced by ACh (b=−0.02, p<0.01) and capsaicin (b=−0.02, p=0.03), with a borderline association with SNP-induced vasodilatation (b=−0.01, p=0.052). There was also a negative association between severe retinopathy and ACh-induced vasodilatation (b=−0.23, p=0.047). By using the other two time points, i.e. 15 s and 30 s, in the linear regression analysis the results did not change. In the linear multiple regression analyses adjusting for age, duration of diabetes, smoking, sBP and severe microvascular complications, with the vasoactive substances (ACh, SNP and capsaicin) as dependent variables and HbA1c as the explanatory factor, HbA1c was independently associated with vasodilatation induced by ACh (b=−1.48, p<0.01) and capsaicin (b=−1.45, p<0.01), but not by SNP (b=−0.87, p=0.07).

7.3      Study III

At the end of the present follow-up, observational study group characteristics showed no statistically significant differences, except for a significantly higher use of anti-hypertensive treatment in the ST group (Table 3). There were no study subjects lost to follow-up, nor were there any missing data at year 2011.

 

 

 

 

 

 

 

 

Characteristics

 

 

SDIS Start

(1982-1984)

SDIS End

(1990)

End of follow-up

(2011)

ICT

ST

ICT

ST

ICT

ST

n (women/men)

48 (26/22)

54 (28/26)

42 (21/21)

47 (25/22)

41 (20/21)

39 (20/19)

Age (years)

30±8

32±7

37±7

39±8

57±8

59±7

Duration of diabetes (years)

18±6

16±4

25±4

23±4

45±6

44±4

BMI (kg/m2)

22.6±2.1

22.8±2.2

22.5±1.9

22.8±2.7

25.2±4

25.1±4

Current cigarette smokers, n

25

27

15

21

6

7

Blood pressure (mmHg)

 

 

 

 

 

 

  Systolic

129±14

133±15

127±13

132±15

130±15

133±15

  Diastolic

77±7

79±7

78±7

78±7

70±8

72±9

HbA1c (mmol/mol)

80±16

79±13

54±7

68±11

68±10

67±16

HbA1c (%)

9.5±1.3

9.4±1.4

7.1±0.7

8.5±0.7***

8.4±1.0

8.3±1.4

GFR (ml min-1)

122±19

126±21

109±19

110±27

89±24

91±29

Insulin dose (U/kg/day)

0.73±0.21

0.75±0.22

0.73±0.19

0.71±0.21

0.66±0.24

0.62±0.25

Anti-hypertensive medication, n

(ACEi or ARB-II), n

11

(10)

17

(14)

22

(20)

33*

(31)

Lipid-lowering agent (statin), n

19

25

Anti-platelet therapy, n

29

21

Table 3 Group characteristics for study III *p<0.05, **p<0.01 and ***p<0.001

 

During the median 28 years of follow-up, 22 persons died, 7 in the ICT group compared with 15 in the ST group (logrank test p = 0.15), figure 9a. Age did not differ at baseline in people who died in the ICT group 36 ± 3 years vs. the  ST group 32 ± 8 years, p= 0.23. Three persons died from cancer, i.e. one male person from the ICT group died from a brain tumour and two female persons from the ST group died from a pancreatic tumour and a breast tumour, respectively. For the predefined cause-specific mortality composite endpoint, i.e. myocardial infarction, stroke and ESRD, there were no significant differences between groups, logrank test p= 0.28, figure 9b.

One person in the ICT group compared with seven in the ST group developed ESRD (logrank test p= 0.047), figure 9c. Although the chronic kidney disease stage classifications did not differ between groups, two persons (both in the ST group) out of seven who developed ESRD had a kidney replacement procedure (both persons were on dialysis and had an eGFR < 15 ml/min/1.73m2 prior to the transplant). The duration of diabetes before ESRD in all eight persons of both groups was 37 ± 7 years. The diabetes duration for the person in the ICT group before dialysis was 33 years. All people who developed ESRD died during the follow-up. The mean survival time after the start of dialysis for all persons (both groups) was 28 ± 40 months. The primary causes of death for the ESRD people were: ESRD (two in the ST group), myocardial infarction (four in the ST group) and stroke (one person from both groups).

Eleven persons in the ICT group compared with 17 in the ST group developed myocardial infarction and/or stroke, logrank test p= 0.4, figure 9d.

 

 

 

a. b.

c.  d.

Figure 9 Kaplan–Meier curves showing Cumulative Incidence in SDIS from time of randomization until sensor date (31st December 2011) for: (a) all-cause mortality (logrank, p= 0.15), (b) composite mortality endpoint, i.e. MI, stroke and ESRD (logrank, p= 0.28), (c) ESRD events in (logrank p= 0.047) and (d) non-fatal cardiovascular events, i.e. MI and/or stroke (logrank  = 0.4). Dashed line, ICT group; solid line, ST group.

 

7.4      Study IV

In total 39,235 patients with a mean age of 67 years were included, of whom 21 % (8,170) were women. There were 23 % (8,933) patients with diabetes, of whom 1.8 % (725) had type 1 diabetes and 21 % (8,208) had type 2 diabetes. Patients with type 1 diabetes were more likely to be younger, female, and have diabetes nephropathy, PAD or heart failure in comparison with patients with no diabetes or type 2 diabetes.

The mean follow-up time was 5.9 years, comprising 230,085 person-years. In total, 17 % (6,765/39,235) patients died: 17 % with no diabetes, 21 % (152) with type 1 diabetes, and 19 % (1,549) with type 2 diabetes. The age-adjusted Kaplan–Meier estimated survival curve in the 39,235 patients who underwent CABG in Sweden from 2003-2013 is shown in Figure 10.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 10 The crude incidence rate of death in patients with no diabetes, type

1 diabetes, and type 2 diabetes was 28 (95% CI 27–29), 39 (95% CI 33–45),

and 33 (95% CI 31–35) per 1000 person-years, respectively.

 

 

Figure 11 After 5 years of surgery survival was 89%, 85%, and 89%, respectively.

 

After multivariable adjustment, the HR (95 % CI) for death was 2.04 (1.72–2.42) in patients with type 1 diabetes and 1.11 (1.05–1.18) in patients with type 2 diabetes, compared with patients without diabetes. When analyzing death and MACE as a composite outcome, the associations found were similar to those for death alone, with nearly a doubling of risk in patients with type 1 diabetes and only a small increase in risk in patients with type 2 diabetes (Figure 11). In a subset of patients with type 1 and type 2 diabetes (n=8,933), we found that there was a significantly higher risk for all-cause mortality in type 1 diabetes (HR 1.70 [1.40-2.06]). In 99.6 % (8,899/8,933) of these patients, information regarding preoperative HbA1c level and diabetes duration was available. When HbA1c levels and duration of disease were added to the multivariable model, the risk for all-cause mortality in type 1 diabetes compared with type 2 diabetes was slightly attenuated (HR 1.44 [1.14-1.80]).The patients with type 1 diabetes had a longer duration of disease (mean 40.8 vs. 9.6 years). The adjusted risk of death was similar among men and women with type 1 diabetes: HR 1.83 (1.45–2.30) and HR 2.17 (1.66–2.84), respectively. In type 2 diabetes, the absolute risk of death was higher in women than in men (22 % vs. 18 %). After adjustment for confounders, the relative risks for death and MACE were similar for both men and women with type 2 diabetes.

8       General Discussion

The main findings of this thesis are that throughout life, and in different populations and concepts, type 1 diabetes renders the affected person a significantly increased risk of macrovascular complications. Adolescents and young adults with type 1 diabetes have signs of early atherosclerotic development, as reflected by increased thickening of the intima-media layer of the carotid artery walls concomitant with insulin resistance. Long term follow-up of intervention with earlier intensive insulin treatment, improving glycemic control, seems to exert a favorable impact on the outcome in future macrovascular complications, as well as for diabetes nephropathy. Also, type 1 diabetes individuals have a dire outcome after CABG interventions compared to type 2 diabetes and non-diabetes individuals in the same situation.

 

Insulin resistance and markers of atherosclerosis (cIMT)

 

There are other studies that have examined the influence of insulin sensitivity on cIMT, of which some [202-204], but not all [205], have found an association. Not only insulin resistance, but clustering of metabolic factors such as hyperglycemia, hypertension and dyslipidemia have all been demonstrated as risk factors involved in the progression of cIMT [206, 207]. In our study, levels of HbA1c did not correlate with cIMT, which is in line with a previous Finnish study [208], in which diabetes duration, LDL-cholesterol and sBP all were associated to the increased cIMT [208]. In contrast, other studies demonstrate that the progression of cIMT largely is explained by differences in HbA1c [156, 209], and that diabetes duration, sBP and BMI, rather could add to the risks for the increment in cIMT [210]. In the DCCT/EDIC trial, cIMT was significantly higher in all study subjects compared to a matched control group during the first six years [157]. Progression of cIMT was associated with age, blood pressure, smoking, blood lipids, microalbumiuria and levels of HbA1c [157]. Also the progression of cIMT was greater for those with conventional insulin treatment, compared to the group with earlier intensive treatment during DCCT [157]. The discrepancy between our study and others, in terms of lack of association between glycemic control and cIMT, may possibly be explained by cohort size, age and diabetes duration [208, 209].

 

Whether cIMT is a useful marker to predict CVD is not yet established. However, the Association for European Pediatric Cardiology Working Group on Cardiovascular Prevention suggests that cIMT might be a useful tool to use in adjuvance in high risk groups [184].

 

Glycemic control and the progression of macrovascular disease

SDIS and DCCT clearly demonstrated that intensified insulin treatment and improved glycemic control retards microvascular complications in type 1 diabetic patients [43, 44]. The two trials share many features regarding population and study protocol, as well as the timing. Although the DCCT cohort was 15 times larger than SDIS, the primary results on macro­vascular complications were borderline significant [43]. Later follow-ups in DCCT/EDIC were on the other hand undisputable in the favor of intensified insulin replacement therapy in preventing CVD events [22, 99].

We found in our SDIS follow-up study that the previously intensified insulin-treated individuals had significantly fewer ischemic foot ulcers and ESRD events. Although, all-cause mortality, composite mortality (myocardial infarction, stroke and ESRD), CVD mortality or CHD and stroke events did not differ statistically between groups, all the out­comes point in the same direction, i.e. with fewer cases in the previous ICT group. One can argue that these findings might purely be by chance. SDIS was a small cohort and therefore underpowered and never designed to study macrovascular outcome. On the other hand, previous reports from the SDIS cohort have demonstrated that markers of atherosclerosis can be halted by intensified insulin treatment [163].

In contrast to the DCCT/EDIC cohort, the former SDIS participants have solely been followed in a routine clinical setting. The DCCT/EDIC protocol may influence the approach to signs and symptoms so that they may be more thoroughly followed-up regarding long-term complications compared to type 1 diabetes patients in general, e.g. a selection bias. The concordant results between our follow-up SDIS and the DCCT/EDIC may strengthen the assumption that the DCCT/EDIC findings are representative for every day routines for type 1 diabetes patients in general. The long-term perspective of nearly three decades in SDIS also strengthens our findings. Very recently, long-term follow-up data from the DCCT/EDIC trial demonstrated an inverse correlation between earlier intensive insulin treatment and all-cause mortality [22].

Even though the rates of diabetes-related complications have substantially declined over the last decades, there is still a large burden of the disease [15] and in fact higher for type 1 diabetes individuals compared to type 2 [211]. One explanation for this might simply be owing to the duration of the disease. An average duration of 45 years, as observed in SDIS, substantially increases the risk of complications. The same goes for the findings after CABG intervention where the type 1 diabetes patients had more than 30 year longer diabetes duration compared to their type 2 diabetes counterparts. Here the type 1 diabetes individuals had twice the mortality risk compared to type 2 diabetics [212]. The former were also more likely to have diabetic nephropathy, PAD and heart failure, thus having more advanced macrovascular co-morbidity.

Glycemic control and microvascular function

The earlier ICT group in SDIS had better skin microcirculation for all three substances used in the iontophoresis procedure, compared to the ST group. Except for long-standing hyper­glycemia, no other differences in risk factors believed to affect microcirculation were observed between the two groups after multiple regression analysis. Only levels of HbA1c were associated with endothelial-dependent (ACh-induced) and C-nociceptive-dependent (capsaisin-induced) skin microvascular blood flow, but not with non-endothelial dependent (SNP -nduced). C-nociceptive-nerve fibers stimulate the release of vasoactive substances, e.g. bradykinin, which in turn improve the ACh-induced endothelial function [213]. Development of foot ulcers in patients with diabetes is common with serious implications, including leg amputations [214]. The majority of leg amputations are caused by PAD in combination with skin infection [66]. Still, microvascular disturbances and progressive neuropathy most often precede the development of foot ulcers [215]. Therefore, the ionto­phoresis results align very well with this and, as our treatment groups do not differ in risk factors other than glycemic control, it suggests that the increased long term propensity for foot ulcer development may to a large extent be caused by hyperglycemia-induced deterioration in skin microcirculation.

Glycemic control and diabetes nephropathy                                                                        

We found that intensive insulin treatment for an average of 7.5 years was associated with significantly lower incidence of ESRD compared with individuals randomized to standard insulin treatment in the SDIS cohort. Since there were multiple secondary outcomes and no correction was made for multiplicity, this result should be interpreted with some caution.  

It was demonstrated in the DCCT and SDIS that intensive insulin therapy halted the progression of diabetes nephropathy [44, 144]. Impairment of GFR is the unified common pathway for renal failure, i.e. ESRD. Diabetic nephropathy, including ESRD, clearly adversely impacts the mortality rate [24, 25], which was also observed in the SDIS follow-up study where patients had a mean survival rate of only 28 months after the start of dialysis. Undisputedly, glycemic control at today’s recommended levels can protect from and halt the development of diabetic nephropathy, which in turn impacts the risk of future macro­vascular complications. Interesting and promising findings from the DCCT/EDIC study indicate that sustained reversal of diabetic nephropathy is amenable and primarily seems associated to lower HbA1c and antihypertensive treatment, mainly with Renin-Angiotensin inhibitors [83]. These findings are hopeful and provide impetus for continuous efforts in early improvement in glycemic control and treatment of albuminuria and hypertension [121, 122].

 

Adverse effects of improvement in glycemic control

There is a relationship between hypoglycemia and CVD mortality in type 1 diabetes [142]. In our studies, we did not investigate hypoglycemic events in association to macrovascular complications. However, both the DCCT and the SDIS trials recognized increased incidence of severe hypoglycemia in the intensively insulin-treated groups [43, 44]. Earlier follow-up studies from these trials have not shown any differences in cognitive function [133, 161]. In contrast to this, cross-sectional studies have demonstrated some detrimental impact of severe hypoglycemia on cognitive function in type 1 diabetes individuals [216, 217].

Obesity is a risk factor for the progression of subclinical atherosclerosis into overt macro­vascular complications. However, we did not observe any changes in weight or BMI at follow-up in the SDIS. Others have expressed concerns regarding weight gain as a result of intensified insulin treatment [132]. In the DCCT/EDIC trial, it was demonstrated that patients with the largest weight gain (both DCCT intensive and conventional treatment subjects) had a greater cIMT at both year 1 and 6 [133].

Glycemic memory                                                                                                                  

The long-term outcomes from the SDIS, may suggest a role for glucose memory, in which the 7.5 years of diverging glycemic control between treatment groups eventually vanished [163, 218]. The DCCT/EDIC and the UKPDS findings of a persistent effect of intensified anti-hypergycemic treatment on the development of macroangiopathy are more or less unequivocal today [22]. Also, an increasing number of experimental studies where a high glucose environment can cause alterations in epigenetic post-translational modifications -- for example affecting inflammation and vascular complications [169, 170] -- offer mechanistic insights into this phenomenon. Similar findings from the DCCT/EDIC cohort suggest such mechanisms to be at least part of the explanation behind the glycemic memory [171].

 

One main finding from the DCCT/EDIC studies has been that elevation of HbA1c, both at study entry and during the randomized treatment period, is associated with the risk of progression of complications [151]. It was also recently suggested that levels of HbA1c, very early from the onset of type 1 diabetes, i.e. already in children and adolescents, may predict the risk of developing complications later on [219], indicating a strong and early need for rigorous metabolic control.

9       Conclusions

Throughout the work with the thesis, the over-arching goal has been to describe diabetes complications as a continuum gradually developing in a life-time perspective. We have found in our studies on type 1 diabetes that:

  • Adolescent and young adult type 1 diabetes individuals show early signs of atherosclerosis compared to a matched control group. The marker of atherosclerosis identified (cIMT) is associated to insulin resistance.
  • Earlier intensive insulin treatment and improvement of glycemic control preserve skin microcirculation and seem to exert a favorable impact on incidence of foot ulcers in a long-term perspective.
  • Earlier intensive insulin treatment also seems to have a favorable impact on incidence in diabetes nephropathy in a long-term perspective.
  • Type 1 diabetes individuals have a poorer outcome after CABG intervention compared to type 2 diabetics and non-diabetics in the same situation.

 

 

10  Study limitations

Study I was an explorative study with no power analysis conducted. Also, since this study was cross-sectional no conclusions can be made regarding causal relationship between cIMT and insulin resistance. The SDIS cohort was small and was not primarily designed for analyses of macrovascular complications. In study III, no correction was made for multiple comparisons. The results from the CABG follow-up study are only applicable for this intervention as no data were analyzed regarding PCI. On the other hand, CABG is today considered the treatment of choice in patients with diabetes.

11  Future perspectives       

In the DCCT/EDIC trial, excessive weight gain as a result of intensified insulin treatment was a cause for concern [133]. I believe there is a need to explore treatment regimens for handling unsatisfactory glycemic control and weight gain, and to further explore the role of adjuvant type 1 diabetes treatment that traditionally has been traditionally been targeting type 2 diabetes,  metformin [220], incretin-based therapy [221]. Also, sodium glucose transporter-2 (SGLT2) inhibitors has gained interest [222], but in the light of recent reports on development of ketoacidosis during treatment in type 1 diabetes patients the safety needs to be better evaluated [223].Some of these anti-diabetic agents may even have beneficial effects on the vasculature beyond glucose control [224].

In conjunction with this, the impact of insulin resistance and possible gender differences in development of long-term CVD complications in type 1 diabetes individuals would be interesting to investigate. One such example would be to investigate whether eGDR could predict CVD events in type 1 diabetes individuals.

A recent publication by Steineck et al. present a register based study from Swedish NDR data with more than 18000 type 1 diabetes patients followed-up for a mean of 6.8 years [225]. Here the adjusted hazard ratio for fatal CHD and CVD were significantly lower in the group using insulin pump treatment compared to patients using multiple injections. The author’s suggest mechanisms for these findings to be more stable blood glucose with lower frequency of hypoglycemia episodes and hyperglycemic periods. Another aspect worth considering might be the influence of treatment mode on blood glucose variability and its effect on endothelial function and repair.

Continuous glucose monitoring systems offer more sophisticated control of diabetes management, especially if used in combination with insulin pump therapy, i.e. sensor augmented pump therapy [226]. In Sweden the use is common in children and adolescents with diabetes but less so in adults, although increasing. Internationally, recommendations slowly change towards more active use of these techniques in adults as well [227]. As the use of continuous glucose monitoring systems and insulin pump therapy are more expensive, compared to self-monitoring of glucose and treatment with multiple daily injections, there is a need for studies evaluating effects on treatment satisfaction and long term complication development [228, 229].  The resent introduction of the Flash-Glucose-Monitoring FGM Libre® emphasizes the need for evaluation even further as it is more affordable and user friendly but does not offer the ability to directly monitor glucose fluctuations during sleep and alert patients and care-givers to avoid severe hypoglycemia episodes,  something the other continuous glucose monitoring-systems does [230].

Since type 1 diabetes individuals have an increased risk of adverse outcomes after CABG [212] , one obvious issue to address is whether preoperative treatments could predict CVD events or death after such a procedure. It would also be of great interest to investigate whether hypoglycemia or glucose variability, or variability of glycemic control may predict CVD events or death after CABG in type 1 diabetes individuals.

Recent analyses by the DCCT/EDIC group [231] confirmed the previous findings of lack of impact of severe hypoglycemia on cognition. They instead found an association between high levels of HbA1c and mild cognitive dysfunction. Microvascular complications, smoking, hypertension and increased levels of HbA1c are all risk factors affecting cognition and psychomotor function [232]. Microvascular complications, associated with chronic hyper­glycemia, may affect cerebral microvasculature causing structural and functional impairment [233, 234]. These issues need to be further studied

12  Svensk Sammanfattning

Risken att insjukna eller avlida i hjärt- och kärlsjukdom i förtid är betydligt större för personer med typ 1 diabetes jämfört med personer utan diabetes. Utveckling av mikroangiopati och tecken på makrovaskulära komplikationer föregår insjuknandet. Stockholm diabetes intervention study (SDIS) och, något senare, den amerikanska DCCT/EDIC studien visade redan 1993 mycket tydligt att tidig intervention med intensifierad insulinbehandling minskade de mikrovaskulära komplikationerna DCCT/EDIC studien har senare också visat motsvarande resultat med minskad risk för makrovaskulära komplikationer, vilket föreslås orsakas av ett glykemiskt minne.


Denna avhandlings syfte har varit att (studie I) undersöka om ungdomar och unga vuxna med typ 1 diabetes har tecken på ateroskleros, mätt som carotis intima-media tjocklek (cIMT) och hur detta relaterar till deras insulinkänslighet. Vidare har vi (studie II) analyserat mikrocirkulationen i huden på foten och om resultatet associerar till tiden till första inläggning på grund av ischemiskt fotsår. Vi har också studerat om utfallet skiljer sig mellan de båda tidigare studiegrupperna i SDIS som genomgick intensiv insulinbehandling eller standardbehandling med insulin under 7.5 år. Vi har också genomfört en långtidsuppföljning (studie III) där vi studerat incidensen i död oavsett orsak, död i hjärt- och kärlsjukdom eller terminal njursvikt liksom insjuknande i hjärt- och kärlsjukdom, dvs. hjärtinfarkt, stroke och terminal njursvik i de båda studiegrupperna i SDIS kohorten . Slutligen har vi (studie IV) undersökt långtidsöverlevnaden efter genomgången koronar bypass kirurgi (CABG) mellan personer med typ 1 diabetes, typ 2 diabetes och personer utan diabetes genom att samköra data från SWEDEHEART-registret och nationella diabetesregistret. Utfall var dö oavsett orsak, död i hjärt- och kärlsjukdom samt insjuknande i hjärt- och kärlsjukdom, dvs. hjärtinfarkt, hjärtsvikt, stroke och behov av revaskularisering.          

I studie I hade ungdomarna med typ 1 diabetes signifikant ökad cIMT tillsammans med en mindre insulinkänslighet jämfört med ungdomarna utan diabetes. I en multivariat regressionsanalys var cIMT associerat till insulinkänsligheten. I studie II drabbades 13 patienter av ischemiska fotsår under den 28 år långa uppföljningen. Blodflödesförändringen i hudens mikrocirkulation var större hos den tidigare intensivbehandlade gruppen än hos den standardbehandlade gruppen. Blodsockerkontrollen mätt med HbA1c associerade till graden av endotelberoende kärlvidgning och kapsaisin-inducerad kärlvidgning.. Under 28 års uppföljning i studie III, avled 22 personer. Vi fann ingen signifikant skillnad mellan studiegrupperna avseende död oavsett orsak, död i hjärt- och kärlsjukdom eller terminal njursvikt eller insjuknande i hjärt- och kärlsjukdom . En person i den intensivbehandlade gruppen och sju i standardbehandlingsgruppen insjuknade i terminal njursvikt. HbA1c skilde sig inte åt mellan grupperna under de sista 16 åren av uppföljningstiden. I studie IV var genomsnittliga uppföljningstiden 5.9 år. Totalt avled 6765 av 39235 patienter som genomgått CABG: 17 % utan diabetes, 21 % med typ 1 diabetes och 19 % med typ 2 diabetes. Risken för död oavsett orsak var dubbelt så stor för patienter med typ 1 diabetes som för patienter med typ 2 diabetes. Risken att avlida var lika stor för män och kvinnor med typ 1 diabetes.

Ungdomar med typ 1 diabetes visar mer tidiga tecken på aterosklerosutveckling och är mindre insulinkänsliga än jämnåriga utan diabetes. Tidigare intensivbehandlade typ 1 diabetiker från SDIS studien förefaller ha en gynnsammare prognos vad gäller utvecklingen av ischemiskt fotsår och terminal njursvikt i jämförelse med de som fick standardbehandling. Detta trots att gruppernas blodsockerkontroll varit likvärdiga under de sista 16 åren av uppföljningen.  Patienter med typ 1 diabetes som genomgått koronarkärlskirurgi har mycket sämre långtidsöverlevnad jämfört med personer med typ 2 diabetes.

 

13  Acknowledgements

I could not have written this thesis without various contributions from so many people.

First of all, I want to express my gratitude towards my supervisors Thomas Nyström, Svante Norgren and Kerstin Jensen-Urstad. I have learned a great many things from our many discussions through the years.

I owe special thanks to Thomas, my main supervisor. Your expertise in research in general and diabetes in particular have been invaluable. You have firmly guided me through this project with your constructiveness and great enthusiasm. I am filled with admiration of your generosity towards me and of your compassion. No one could ask for a better teacher.

To Svante, for your constant encouraging and willingness to assist and for sharing insights in your scientific knowledge. The free fatty acids are waiting for us.

I also want to thank Kerstin for sharing your great expertise with me and for, calmly, pointing me in the right directions.

I also want to thank my co-writers for all their efforts during this project. Particularly Carina Ursing for having saved Per Reichards material and for sharing it with me and Marina Donner for the fantastic work on constructing the SDIS cohort database.

Lotta Larsson and Christina Häll for your enthusiasm and expertise guiding me and our young patients through the clamp-investigations

Lina Benson for sharing your knowledge in the mysteries of statistics with me.

My deepest gratitude towards Margareta Pihl, Anders Britz and Urban Rosenqvist for sharing invaluable information on the SDIS patients and insights into Per Reichards work.

My warmest thanks to Gunnar Lilja, my mentor, for being encouraging and helpful and for putting my research in perspective.

Also, I want to express my gratitude towards Per Sandstedt, Eva Berggren-Broström and Gerd Lärfars for your support and for giving me the opportunity to pursue this project and to Eva Östblom for your constant support and encouraging.

I also owe many thanks to my colleagues.

Anna Wennberg, my dearest friend, for watching over me and supporting me at all times. Our walks and endless discussions have been invigorating. Please, keep on LOL.

To Jan Engvall, Josephine Haas, Joakim Beermann and Ulrika Käck for your good humor, kind support and for taking care of all the patients. To Agneta Uusijärvi, for our talks.

To Anna Lindholm Olinder for inspiring me to continue with this project and for valuable input. 

I am also grateful to Monica, Margareta, Lotta and Katarina and the rest of the diabetes team for covering for me and for giving me space to finish this project. I owe you one.

Finally, I owe many thanks my family. To my parents Solveig och Per for their never ending love and support. To my sister, Maria, and to Lena and Pelle for your constant support. To PO, it looks as I will have some time to spend in the future, let’s take that long walk.

To my dear wife Charlotte. Without you this would not have been possible. I love you very much. To you and to Paula, my daughter, for being the two most important persons in my life.

 

In memory of Per Reichard 1950-2002 and Anna Kernell 1945-2010


I am also grateful for receiving grants from the Childhood Diabetes Foundation, The Samariten Foundation and Svenska diabetesstiftelsen

 


 

 

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179.     Efird, J.T., et al., Long-Term Mortality of 306,868 Patients with Multi-Vessel Coronary Artery Disease: CABG versus PCI. Br J Med Med Res, 2013. 3(4): p. 1248-1257.

180.     Investigators, B., Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. N Engl J Med, 1996. 335(4): p. 217-25.

181.     Farkouh, M.E., et al., Strategies for multivessel revascularization in patients with diabetes. N Engl J Med, 2012. 367(25): p. 2375-84.

182.     Palmerini, T., et al., Risk of stroke with coronary artery bypass graft surgery compared with percutaneous coronary intervention. J Am Coll Cardiol, 2012. 60(9): p. 798-805.

183.     DeFronzo, R.A., J.D. Tobin, and R. Andres, Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol, 1979. 237(3): p. E214-23.

184.     Dalla Pozza, R., et al., Intima media thickness measurement in children: A statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology. Atherosclerosis, 2015. 238(2): p. 380-387.

185.     Raitakari, O.T., et al., Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA, 2003. 290(17): p. 2277-83.

186.     Kavey, R.E., et al., Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation, 2006. 114(24): p. 2710-38.

187.     Jeffcoate, S.L., Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med, 2004. 21(7): p. 657-65.

188.     John, W.G., et al., HbA1c standardisation: history, science and politics. Clin Biochem Rev, 2007. 28(4): p. 163-8.

189.     Philcox, J.C., M.R. Haywood, and A.M. Rofe, Hemoglobin A1c by HPLC with the Pharmacia Mono S HR 5/N cation-exchange column: influence of sample protein load on optimal chromatographic conditions. Clin Chem, 1992. 38(8 Pt 1): p. 1488-90.

190.     Jeppsson, J.O., et al., Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med, 2002. 40(1): p. 78-89.

191.     Levey, A.S., et al., A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med, 1999. 130(6): p. 461-70.

192.     National Kidney, F., KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis, 2012. 60(5): p. 850-86.

193.     Ludvigsson, J.F., et al., External review and validation of the Swedish national inpatient register. BMC Public Health, 2011. 11: p. 450.

194.     Appelros, P. and A. Terent, Validation of the Swedish inpatient and cause-of-death registers in the context of stroke. Acta Neurol Scand, 2011. 123(4): p. 289-93.

195.     Ragnarson Tennvall, G., J. Apelqvist, and M. Eneroth, The inpatient care of patients with diabetes mellitus and foot ulcers. A validation study of the correspondence between medical records and the Swedish Inpatient Registry with the consequences for cost estimations. J Intern Med, 2000. 248(5): p. 397-405.

196.     Gudbjornsdottir S, C.J., Eliasson B, and Nilsson PM, Result Report NDR 1996–2005. 2006, Swedish Board of Health,Socialstyrelsen, Stockholm, Sweden.

197.     Harnek, J., et al., The 2011 outcome from the Swedish Health Care Registry on Heart Disease (SWEDEHEART). Scand Cardiovasc J, 2013. 47 Suppl 62: p. 1-10.

198.     Toppe, C., et al., Renal replacement therapy due to type 1 diabetes; time trends during 1995-2010--a Swedish population based register study. J Diabetes Complications, 2014. 28(2): p. 152-5.

199.     (ESGAB), E.S.G.A.B., Eurostat Peer Reviow Report 2014. 2014.

200.     Nashef, S.A., et al., Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery. Eur J Cardiothorac Surg, 2002. 22(1): p. 101-5.

201.     Roques, F., et al., Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg, 1999. 15(6): p. 816-22; discussion 822-3.

202.     Cardellini, M., et al., Carotid artery intima-media thickness is associated with insulin-mediated glucose disposal in nondiabetic normotensive offspring of type 2 diabetic patients. Am J Physiol Endocrinol Metab, 2007. 292(1): p. E347-52.

203.     Fujiwara, S., et al., Arterial wall thickness is associated with insulin resistance in type 2 diabetic patients. J Atheroscler Thromb, 2003. 10(4): p. 246-52.

204.     Jarvisalo, M.J., et al., Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation, 2001. 104(24): p. 2943-7.

205.     Dengel, D.R., et al., Gender differences in vascular function and insulin sensitivity in young adults. Clin Sci (Lond), 2011. 120(4): p. 153-60.

206.     Tzou, W.S., et al., Increased subclinical atherosclerosis in young adults with metabolic syndrome: the Bogalusa Heart Study. J Am Coll Cardiol, 2005. 46(3): p. 457-63.

207.     Magnussen, C.G., et al., Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, and type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study. Circulation, 2010. 122(16): p. 1604-11.

208.     Jarvisalo, M.J., et al., Carotid artery intima-media thickness in children with type 1 diabetes. Diabetes, 2002. 51(2): p. 493-8.

209.     Dalla Pozza, R., et al., Subclinical atherosclerosis in diabetic children: results of a longitudinal study. Pediatr Diabetes, 2010. 11(2): p. 129-33.

210.     Dalla Pozza, R., et al., The effect of cardiovascular risk factors on the longitudinal evolution of the carotid intima medial thickness in children with type 1 diabetes mellitus. Cardiovasc Diabetol, 2011. 10: p. 53.

211.     de Ferranti, S.D., et al., Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation, 2014. 130(13): p. 1110-30.

212.     M, H., et al., Long-Term Prognosis in Patients With Type 1 and 2 Diabetes Mellitus After Coronary Artery Bypass Grafting. J Am Coll Cardiol, 2015. 65(16): p. 1644–52.

213.     Schramm, J.C., T. Dinh, and A. Veves, Microvascular changes in the diabetic foot. Int J Low Extrem Wounds, 2006. 5(3): p. 149-59.

214.     Prompers, L., et al., Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia, 2008. 51(5): p. 747-55.

215.     Adler, A.I., et al., Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers. Diabetes Care, 1999. 22(7): p. 1029-35.

216.     Wredling, R., et al., Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia, 1990. 33(3): p. 152-7.

217.     Lincoln, N.B., et al., Effect of long-term glycemic control on cognitive function. Diabetes Care, 1996. 19(6): p. 656-8.

218.     Jensen-Urstad, K., P. Reichard, and M. Jensen-Urstad, Decreased heart rate variability in patients with type 1 diabetes mellitus is related to arterial wall stiffness. J Intern Med, 1999. 245(1): p. 57-61.

219.     Samuelsson, U., I. Steineck, and S. Gubbjornsdottir, A high mean-HbA1c value 3-15 months after diagnosis of type 1 diabetes in childhood is related to metabolic control, macroalbuminuria, and retinopathy in early adulthood--a pilot study using two nation-wide population based quality registries. Pediatr Diabetes, 2014. 15(3): p. 229-35.

220.     Liu, C., et al., Efficacy and safety of metformin for patients with type 1 diabetes mellitus: a meta-analysis. Diabetes Technol Ther, 2015. 17(2): p. 142-8.

221.     Issa, C.M. and S.T. Azar, Possible role of GLP-1 and its agonists in the treatment of type 1 diabetes mellitus. Curr Diab Rep, 2012. 12(5): p. 560-7.

222.     Tahrani, A.A., A.H. Barnett, and C.J. Bailey, SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol, 2013. 1(2): p. 140-51.

223.     Peters, A.L., et al., Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care, 2015. 38(9): p. 1687-93.

224.     Eriksson, L. and T. Nystrom, Antidiabetic Agents and Endothelial Dysfunction - Beyond Glucose Control. Basic Clin Pharmacol Toxicol, 2015.

225.     Steineck, I., et al., Insulin pump therapy, multiple daily injections, and cardiovascular mortality in 18,168 people with type 1 diabetes: observational study. BMJ, 2015. 350: p. h3234.

226.     Langendam, M., et al., Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev, 2012. 1: p. CD008101.

227.     Amiel, S.A., et al., Diagnosis and management of type 1 diabetes in adults: summary of updated NICE guidance. BMJ, 2015. 351: p. h4188.

228.     2013, T., Kunskapsunderlag: Insulinpump och kontinuerlig glukosmätning-TLV2013. http://www.tlv.se/Upload/Medicinteknik/Kunskapsunderlag_insulinpumpcgm.pdf. 2013.

229.     2013-04., S.a.-r.n., Kontinuerlig subkutan glukosmätning vid diabetes. http://www.sbu.se/201304.

230.     Bailey, T., et al., The Performance and Usability of a Factory-Calibrated Flash Glucose Monitoring System. Diabetes Technol Ther, 2015. 17(11): p. 787-94.

231.     DCCT/EDIC, et al., Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med, 2007. 356(18): p. 1842-52.

232.     Jacobson, A.M., et al., Biomedical risk factors for decreased cognitive functioning in type 1 diabetes: an 18 year follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. Diabetologia, 2011. 54(2): p. 245-55.

233.     Ferguson, S.C., et al., Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia. Diabetes, 2003. 52(1): p. 149-56.

234.     Biessels, G.J., I.J. Deary, and C.M. Ryan, Cognition and diabetes: a lifespan perspective. Lancet Neurol, 2008. 7(2): p. 184-90.

 

 

 

 

 

 

 

 

Almedalen Program Diabetes 4-7/7
Nyhetsinfo
www red DiabetolopgNytt

– Var finns ersättningsmodellerna som ger mer hälsa för pengarna?

I samarbete med Dagens Medicin Agenda arrangerar seminarium under Almedalsveckan, onsdagen den 6 juli kl.11:40-12:40. Plats: Burmeisters Bakficka, Tage Cervins gata 8, Dagens Medicin Agenda Vårdtorg.

Sjukvården ropar efter bättre och innovativa lösningar för att möta hälso- och sjukvårdens utmaningar med åldrande population och stigande kostnader. Dagens ersättningsmodeller kritiseras för att vara alltför trubbiga och snarare motverka än stimulera till nytänkande och användning av de möjligheter som digitaliseringen och andra smarta, tekniska lösningar ger, vilket i sin tur hämmar tillgången till ny teknik för patienterna. Hur ser framtidens ersättningsmodeller ut, för att skapa mer värde för insatta resurser? Hur skapar vi ersättningsmodeller som stimulerar i stället för vara ett hinder för utveckling? Hur kan ersättningssystemen uppmuntra mer jämlik vård över hela landet? Hur ska ersättningssystemen anpassas efter behoven i olika delar av hälso- och sjukvården? Hur kan olika aktörer samverka för att finna bättre lösningar för vårdens utmaningar och ge bättre hälsa för pengarna?

Medverkande: 

Georg Engel, chef för vårdinformatik och ersättningsmodeller, Stockholms läns landsting, Per-Erik Gustafsson, överläkare, hjärtkliniken, Länssjukhuset i Gävle, Daniel Forslund (L), innovationslandstingsråd, Stockholms läns landsting, Anders Lönnberg (S), regeringens nationella life science samordnare, Ann Söderström, hälso-och sjukvårds­direktör, Västra Götalandsregionen, Heidi Stensmyren, ordförande, Läkarförbundet, Marie Aabö, vd, Medtronic Sverige.

Twitter: #värdebaseradvård

Välkommen! Om inte ledningen tar sitt ansvar – måste diabetespatienterna rösta med fötterna?

Arrangör:
Nationella diabetesregistret, Novo Nordisk
Dag:
4/7 2016 09:30 - 10:15
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
Vid Stora Torget
 
Beskrivning av samhällsfrågan

Alla patienter med diabetes har rätt att få vård utifrån bästa tillgängliga kunskap – men svensk diabetesvård är långt ifrån jämlik. På vilket sätt påverkar ledningens engagemang och intresse diabetesvårdens resultat? Och vilken roll har patienterna i förbättringsarbetet? 

Utökad beskrivning av samhällsfrågan

Diabetesvårdens kvalitet varierar över landet visar färsk statistik från Nationella Diabetesregistret, NDR, som i år fyller 20 år. Totalt sett har diabetesvården blivit bättre på det mesta under de här två decennierna. Men fortfarande skiljer det både i behandlingspraxis och medicinska resultat mellan olika vårdgivare. Studier har visat att kvaliteten i diabetesvården ökar om ledningen är engagerad och intresserad. Andra framgångsfaktorer är till exempel lättillgängliga riktlinjer och regelbunden återkoppling till enheterna. Verktygen finns – vad krävs för att de också ska användas? Blir det patienterna som kommer att axla rollen som förändringsmotor? I NDR finns en funktion som gör det möjligt för profession och patienter att jämföra diabetesvården på olika enheter. Inom kort ska även patienternas åsikter inkluderas i registret via enkäter. Vilka konsekvenser får detta för framtidens diabetesvård?

Medverkande: 
  • Soffía Guðbjörnsdóttir, adjungerad professor, registerhållare, Nationella Diabetesregistret
  • Tony Holm, samordnare, regionala kunskapsstyrningsgruppen i Uppsala-Örebro sjukvårdsregion
  • Fredrik Löndahl, ordförande, Diabetesförbundet
  • Göran Hägglund, moderator
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Ja
Sökord:
diabetes, jämlik vård, Kvalitetsregister, Personcentrerad vård, Värdebaserad vård
Sidvisningar:
69


Varför diskrimineras patienter med fetma och övervikt i sjukvården?

Arrangör:
Riksförbundet HOBS- Hälsa oberoende av storlek, Novo Nordisk
Dag:
4/7 2016 11:00 - 11:30
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
Vid Stora Torget
 
Beskrivning av samhällsfrågan

Personer med fetma och övervikt riskerar sämre sjukvård på grund av fördomar och okunskap bland vårdpersonalen. Varför upplever denna patientgrupp sig mindre värd i vården? Vad behöver göras för att situationen ska förbättras?

Utökad beskrivning av samhällsfrågan

Samstämmig forskning visar att många patienter som lider av fetma och övervikt upplever ett ovärdigt bemötande i hälso- och sjukvården. Man känner sig misstrodd, förnedrad och skuldbelagd. På grund av detta avstår många från att söka vård, trots en ökad risk att drabbas av följdsjukdomar som typ 2-diabetes, vissa cancerformer, högt blodtryck och hjärtinfarkt. Riksförbundet HOBS - hälsa oberoende av storlek arbetar för motverka den diskriminering och stigmatisering som man upplever förekommer inom hälso- och sjukvården. ”Ett bra bemötande är en förutsättning för hållbar hälsa. Vi vill bli bemötta som människor, inte som feta personer”, betonar förbundet. Under seminariet ger Riksförbundet HOBS exempel på hur patienter med fetma och övervikt bemöts i vården idag. Tillsammans med panelen diskuteras varför denna patientgrupp riskerar att diskrimineras och vad som krävs för att situationen ska förbättras.

Medverkande: 
  • Monica Andreasson, förbundsordförande, HOBS
  • Jenny Vinglid, generalsekreterare, HOBS
  • Lars-Torsten Larsson, chef, avdelningen för kunskapsstyrning för hälso- och sjukvården, Socialstyrelsen
  • Jonas Andersson (L), regionråd, ordförande i hälso- och sjukvårdsutskottet, Västra Götalandsregionen
  • Ingrid Bengtsson-Rijavec, hälso- och sjukvårdsdirektör, Region Skåne
  • Björn Eliasson, professor, Sahlgrenska Universitetssjukhuset, Göteborg
  • Göran Hägglund, moderator
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Nej
Sökord:
Bemötande, diabetes, Diskriminering, fetma, övervikt
Sidvisningar:
59

Life Science – så blir Sverige ett attraktivt investeringsland

Arrangör:
Novo Nordisk
Dag:
4/7 2016 12:15 - 13:00
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Ämnesområde 2:
Näringsliv
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
Vid Stora Torget
 
Beskrivning av samhällsfrågan

Utvecklingen inom Life Science är av stor betydelse för Sveriges ekonomi och för människors hälsa. Hur kan samverkan mellan näringslivet, akademin och sjukvården fördjupas? Vad krävs för att ytterligare stärka Sveriges position inom området? Regeringens nationella samordnare ger sin syn på saken.

Utökad beskrivning av samhällsfrågan

Tillståndet inom svensk Life Science utreds just nu av regeringens nationella samordnare Anders Lönnberg. Uppdraget är att ta reda på vad som krävs för att sektorn (det vill säga läkemedel, bioteknik och medicinteknik) ska utvecklas till att bli världsledande inom området. Regeringen betonar att Life Science-sektorn är av stor betydelse för Sveriges ekonomi, för näringslivets utveckling, forskning och innovation, samt för människors hälsa både i Sverige och globalt. Utredningen ska lämna sin rapport i januari 2017. Förhoppningarna är stora – det finns bland annat högt ställda förväntningar att arbetet ska resultera i ökade anslag till forskningen. Under seminariet kommer Anders Lönnberg att berätta om de iakttagelser som gjorts så här långt. Några konkreta åtgärdsförslag kommer också att presenteras. Vad säger företrädare för näringslivet, professionen, akademin och politiken om hans slutsatser? Är utredningen inne på rätt spår? Tar vi tillvara på den potential som finns

Medverkande: 
  • Anders Lönnberg (S), regeringens samordnare inom life science
  • Göran Ando, styrelseordförande, Novo Nordisk
  • Anders Henriksson (S), landstingsråd Landstinget i Kalmar län, 1:e vice ordförande Sveriges Kommuner och Landsting
  • Karin Båtelson, ordförande, Sjukhusläkarna
  • Martin Ingvar, professor, Karolinska institutet
  • Göran Hägglund, moderator
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Kontaktperson 2:
Rolf Danielsson, Market Access and Public Affairs Manager, Novo Nordisk, 0706388998, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Ja
Sökord:
diabetes, forskning näringsliv, Forskningsfinansiering, Innovation, Life science
Sidvisningar:
119

Jämlik vård för kroniskt sjuka patienter – centraliserad eller decentraliserad vård?

Arrangör:
Nationella diabetesteamet, Novo Nordisk
Dag:
4/7 2016 13:45 - 14:30
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
Vid Stora Torget
 
Beskrivning av samhällsfrågan

Svenska kvalitetsregister visar att behandlingsresultaten för personer med kroniska sjukdomar varierar över landet. Hur ska vården organiseras för att blir mer jämlik? Ska primärvården förstärkas eller ska vården av kroniskt sjuka patienter, till exempel med diabetes, bli mer centraliserad?

Utökad beskrivning av samhällsfrågan

De flesta patienter med kroniska sjukdomar har idag sin vårdkontakt i primärvården, till exempel merparten av landets 450 000 diabetiker. Nationella diabetesregistret visar dock på stora skillnader i behandlingsresultaten mellan olika vårdenheter. Göran Stiernstedt – som på regeringen uppdrag utrett hur resursutnyttjande i hälso- och sjukvården ska bli effektivare – anser att vården av kroniskt sjuka måste koordineras bättre och mer utgå från patientens behov. Han betonar att den enskilt viktigaste åtgärden för att minska ojämlikheten i hälsa är att förstärka primärvården. Hur ska hälso- och sjukvården organiseras i framtiden? Ska primärvårdens kompetens förstärkas ytterligare, till exempel genom certifierade diabetesmottagningar som i Region Skåne? Eller ska det istället byggas upp särskilda specialistenheter/sjukhus, så kallade Center of Excellence?

Medverkande: 
  • Göran Stiernstedt, regeringens tidigare utredare av en effektiv vård
  • Magnus Kåregård, medicinsk rådgivare, Novakliniken, Skåne
  • Ulrika Elmroth, Svensk förening för allmänmedicin, projektledare, Sveriges Kommuner och Landsting
  • Stefan Lamme (M), ledamot regionfullmäktige, 2:e vice ordförande beredningen för framtidens sjukvård, Region Skåne
  • Mona Landin-Olsson, professor, ordförande Svensk förening för diabetologi
  • Fredrik Löndahl, ordförande, Diabetesförbundet
  • Göran Hägglund, moderator
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Nej
Sökord:
diabetes, jämlik vård, Kroniska sjukdomar, Organisation, Sjukvårdsutveckling
Sidvisningar:
71

Allt fler svenskar är feta eller överviktiga – hur ska det sluta?

Arrangör:
Riksförbundet HOBS- Hälsa oberoende av storlek, Björn Eliasson, Novo Nordisk
Dag:
4/7 2016 15:15 - 16:00
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
 
 
Beskrivning av samhällsfrågan

Sverige är ett av de länder i Europa där fetman ökar snabbast. Nära hälften av befolkningen har i dag fetma eller övervikt. Om 15 år kommer två av tre svenskar att vara feta eller överviktiga. Hur bryter vi den oroande trenden?

Utökad beskrivning av samhällsfrågan

Övervikt och fetma (obesitas) är en av våra största folkhälsoutmaningar. I Sverige har antalet överviktiga nästan fördubblats under de senaste 20 åren. Fetma utgör en riskfaktor för att drabbas av flera olika sjukdomar, däribland typ 2-diabetes. Enligt WHO är fetma en av de fem främsta riskfaktorerna för förlorade friska levnadsår. Arbete pågår runt om i landstingen och regionerna för att ta fram vårdprogram för prevention och behandling av patienter med övervikt och fetma. Nyligen gav också regeringen Folkhälsomyndigheten och Livsmedelsverket i uppdrag att föreslå insatser för bättre matvanor och ökad fysisk aktivitet. I samband med detta konstaterade folkhälsominister Gabriel Wikström: ”Vi måste göra mer. Det här kommer annars innebära ett enormt lidande för enskilda individer men också enorma samhällskostnader.” Vad behöver göras för att vända den oroande utvecklingen? Behövs nya metoder och verktyg - och kanske också lagstiftning? Vem tar ansvaret?

Medverkande: 
  • Björn Eliasson, professor, Sahlgrenska Universitetssjukhuset, Göteborg
  • Anna Starbrink (L), ordförande hälso- och sjukvårdsstyrelsen, Stockholms läns landsting
  • Lars-Torsten Larsson, chef avdelningen för kunskapsstyrning för hälso- och sjukvården, Socialstyrelsen
  • Ingrid Bengtsson-Rijavec, hälso- och sjukvårdsdirektör, Region Skåne
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Ja
Sökord:
diabetes, fetma, Folkhälsa, samhällskostnader, övervikt
Sidvisningar:
79

Vad krävs för en diabetesvård i världsklass?

Arrangör:
Nationella diabetesteamet, Novo Nordisk
Dag:
4/7 2016 16:45 - 17:30
Evenemangskategori:
Seminarium
Evenemangstyp:
Seminarium
Ämnesområde:
Vård och omsorg
Språk:
Svenska
Plats:
Södra kyrkogatan 11
Platsbeskrivning:
Vid Stora Torget
 
Beskrivning av samhällsfrågan

Om Sveriges diabetiker ska få en jämlik vård i världsklass måste patienterna erbjudas de senaste innovationerna, både vad gäller mediciner och tekniska hjälpmedel. För att uppnå detta vill olika diabetesföreträdare att statens styrning på området blir tydligare. Vilka åtgärder är viktigast?

Utökad beskrivning av samhällsfrågan

I ”Blå boken” från 2014 beskriver Nationella diabetesteamet vad som behöver göras för att möta de krav och lösa de problem som finns inom svensk diabetesvård. Nu – två år senare - tar man nästa steg och publicerar en ny bok i samband med Världsdiabetesdagen i november. Den nya ”Röda boken” ersätter inte den blå, utan fokuserar istället på en viktig fråga i diabetesvården, nämligen hypoglykemier (lågt blodsocker). I dagens diabetesvård pressas blodsockret till allt lägre nivåer, men regleringen är inte enkel. Det finns en risk att blodsockret blir alltför lågt, ett potentiellt livshotande tillstånd. Under seminariet ges en försmak av innehållet i den kommande boken. I debatten diskuteras även hur de medicinska resultaten och livskvaliteten kan förbättras med hjälp av nya läkemedel och tekniska innovationer. Den övergripande frågan för debatten är: ”Vad krävs för att vi ska uppnå en jämlik diabetesvård i världsklass?”.

Medverkande: 
  • Olivia Wigzell, generaldirektör, Socialstyrelsen
  • Mona Landin-Olsson, professor, ordförande, Svensk förening för diabetologi
  • Anders Åkesson (MP), regionråd, Region Skåne
  • Hans Karlsson, chef, avdelningen för vård och omsorg, Sveriges Kommuner och Landsting
  • Fredrik Löndahl, ordförande, Diabetesförbundet
  • Göran Hägglund, moderator
Kontaktperson 1:
Magnus Barkstedt, Market Access and Public Affairs Director, Novo Nordisk, 0705568200, Den här e-postadressen skyddas mot spambots. Du måste tillåta JavaScript för att se den.
Tillgänglighet
 Miljödiplomerat
Förtäring
Nej
Sökord:
diabetes, hjälpmedel, jämlik vård, livskvalitet, läkemedel
Sidvisningar:
80

DAGENS MEDICINS VÅRDTORG 2016

Dagens Medicins Vårdtorg i Almedalen 2016

Dagens Medicins Vårdtorg är mötesplatsen för sjukvårdsdebatten under politikerveckan i Almedalen 2016. Med start måndag morgon den 4 juli ger Dagens Medicin Agenda plats för seminarier, debatter och utfrågningar om sjukvårdens viktigaste framtidsfrågor tillsammans med andra aktörer i sjukvården. 

 

Dela:

Alla våra seminarier går också att se i efterhand på DM-Play. I väntan på årets Almedalsvecka kan du se fjolårets sändningar från Dagens Medicins Vårdtorg.

Preliminärt program 

  •  

    MÅNDAG 4 JULI 8.00-8.30

    Frukost-tv med aktuell debatt och intervjuer: Framtidens sjukvård - bit för bit.

    Varje morgon bjuder vi in aktuella makthavare från sjukvården till en direktsänd frukostdebatt på Dagens Medicins Vårdtorg för diskussion om vårdfrågorna i nyhetsflödet. Följ oss i direktsändning eller se reprisen på DM-Play

  •  

    MÅNDAG 4 JULI 9.00-9.50

    Kan svensk sjukvård öka produktiviteten med 40 procent? Vem ska få del av överskottet?

    Akutsjukhus i Finland är 40 procent mer effektiva än svenska, enligt en ny studie vid Karolinska Institutet. Mer och bättre vård för pengarna, mindre stress och högre löner för personalen samtidigt som kostnaderna sjunker. Är detta möjligt i Sverige?

    Thomas Berglund, vd, Capio, Sveneric Svensson, medicinsk chef, Capio, Heidi Stensmyren, ordförande, Läkarförbundet, Marie-Louise Forsberg-Fransson, regionråd (S), Region Örebro län, Agneta Jansmyr, regiondirektör, Region Jönköpings län.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #dmagenda

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Arrangeras av Dagens Medicin Agenda i samarbete med Capio.

  •  

    MÅNDAG 4 JULI 10.20-11.10

    Vänta inte! Framtidens sjukvård är redan här.

    Med digitala verktyg kan vi redan i dag ta reda på vad medborgare, patienter och medarbetare behöver för att kunna ta ansvar för sin hälsa.

    Johan Assarsson, vd, Inera, Hans Winberg, generalsekreterare Leading Health Care, Göran Modin, affärsområdeschef, primärvård och rehabilitering, Praktikertjänst, Sofia Palmquist, vice vd, Capio St Göran, Peder Hofman-Bang och Hanna Emami, ICQuality.

    Läs mer

    Moderator: Mikael Nestius, vd, Dagens Medicin.
    Twitter: #vänta inte #dmagenda

    Efter seminariet bjuder vi på fika.

    Arrangeras av Dagens Medicin Agenda och IC Quality.

    APPEN VÅRD I ALMEDALEN

    Politikerveckan i Almedalen har växer för varje år och erbjuder i år över 350 seminarier inom ämnet vård och omsorg.För snabb och enkel navigering bland utbudet har ICQuality tagit fram en app som guidar och håller dig uppdaterad kontinuerligt. Via appen guidar vi dig till de mest intressanta vårdseminarierna och här hittar du även Dagens Medicins rapportering från Almedalen.

    Läs mer om appen här

  •  

    MÅNDAG 4 JULI 11.40–12.30

    När vet vi mer om kvinnor med spridd bröstcancer?

    I dag lever över 5 500 kvinnor med spridd bröstcancer i Sverige, en grupp som växer i takt med att överlevnaden förbättras. Med ett nationellt register går det att jämföra den vård som ges över hela landet och säkerställa att den är jämlik. När blir det verklighet?

    Elizabeth Bergsten Nordström, ordförande, BRO, Bröstcancerföreningarnas Riksorganisation, Henrik Lindman, överläkare, onkologkliniken, Akademiska sjukhuset i Uppsala, Dag Larsson (S), ordförande SKL:s sjukvårdsdelegation, oppositionslandstingsråd, Stockholms läns landsting, Anders Åkesson (MP), regionråd, Region Skåne, Gunilla Gunnarsson, samordnare för regionala cancercentrum i samverkan, SKL, Maria Ekholm, överläkare, onkologkliniken, länssjukhuset Ryhov, Jönköping, Lars Franksson, value and innovation manager, Roche.

    Läs mer

    Moderator: Mikael Nestius, vd, Dagens Medicin.
    Twitter: #spriddcancer #dmagenda.

    Efter seminariet bjuder vi på lunch.

    Seminariet arrangeras av Dagens Medicin Agenda i samarbete med BRO, Bröstcancerföreningarnas Riksorganisation samt Roche.

  •  

    MÅNDAG 4 JULI 13.20–14.10

    Kroniskt sjuka – eller kroniskt friska? Kan vi sikta högre?

    Patienter med kronisk sjukdom har kroniska svårigheter i kontakterna med sjukvården. Sju av tio har aldrig diskuterat behandlingsmål med sin läkare och endast fyra av tio har en behandlingsplan. Många har problem med otillräcklig effekt av sin behandling, trots tillgång till nya moderna läkemedel. Ett exempel är patienter med reumatism – en av de största patientgrupperna med kroniska sjukdomar.

    Sofia Ernestam, registerhållare, Svensk Reumatologis Kvalitetsregister, SRQ, Dag Larsson (S), ordförande i sjukvårdsdelegationen, SKL, landsstingsråd, Stockholms läns landsting, Jonas Andersson (L), regionråd, ordförande i hälso- och sjukvårdsutskottet, Västra Götalandsregionen, Ingrid Lennerwald (S), ordförande i beredningen för framtidens sjukvård, Region Skåne, Suzanne Ahlqvist, styrelse­ledamot, Reumatikerförbundet, Stina Björkqvist, patient med reumatism.

    Läs mer

    Moderator: Maja Florin, chef, Dagens Medicin Agenda.
    Twitter: #kronisktfrisk #dmagenda.

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Seminariet arrangeras av Dagens Medicin Agenda i samarbete med Lilly.

  •  

    MÅNDAGEN 4 JULI 15:30-16:50

    Här skapas värdet av digital teknik i den svenska vården

    Digitala tekniker, som redan finns tillgängliga, har potential att i grunden förändra vårdsystemet i Sverige. En ny analys av 14 tillämpningsområden visar att en systematisk digitalisering i kombination med nya arbetssätt kan möjliggöra en hållbar utveckling för den svenska hälso- och sjukvården.

    Mårten Blix, tidigare sekreterare Framtidskommissionen, Institutet för näringslivsforskning, Oscar Boldt Christmas, McKinsey, Charlotte Brogren, generaldirektör, Vinnova, Daniel Forslund (L), innovationslandstingsråd, Stockholms läns landsting, Pia Hardy, McKinsey, Josefin Landgård, grundare, KRY, Filippa Reinfeldt, ansvarig för business development och public affairs, Aleris,Inger Ros, ordförande, Riksförbundet Hjärt-lung, , Sara Öhrvall, senior rådgivare, MindMill Network.

    Läs mer

    Moderator: Mikael Nestius, vd, Dagens Medicin.
    Twitter: #dmagenda

    Efter seminariet bjuder vi på mingel med tillbehör.

    Arrangeras av Dagens Medicin Agenda och McKinsey.

  •  

    TISDAG 5 JULI 8.00-8.30

    Frukost-tv med aktuell debatt och intervjuer: Framtidens sjukvård - bit för bit.

    Varje morgon bjuder vi in aktuella makthavare från sjukvården till en direktsänd frukostdebatt på Dagens Medicins Vårdtorg för diskussion om vårdfrågorna i nyhetsflödet. Följ oss i direktsändning eller se reprisen på DM-Play

     

  •  

    TISDAG 5 JULI 9.00–9.50 

    Kronisk cancer – vem tar ansvar för patienten?

    Fler än 60 000 personer får varje år i Sverige cancer. Alla botas inte, men nya effektiva läkemedel, gör det möjligt för patienter att leva hemma längre med god livskvalitet. Istället för bot eller död, blir cancer en kronisk sjukdom. Hur vi ser på framtiden för cancerdrabbade som överlevare?

    Katarina Johansson, ordförande, Nätverket mot cancer, Pehr Lind, verksamhetschef, onkologkliniken, Landstinget Sörmland, Dag Larsson (S), ordförande i sjukvårdsdelegationen SKL, landstingsråd, Stockholms läns landsting, Cecilia Widegren (M), socialpolitisk talesperson, riksdagsledamot, socialutskottet, Roger Henriksson, professor, chef, Regionalt cancercentrum Stockholm Gotland, Emma Spak, ordförande, Sylf, Sveriges yngre läkares förening, Ulrika Elmroth, vice ordförande, SFAM, Svensk förening för allmänmedicin.

    Läs mer

    Moderator: Mikael Nestius, vd, Dagens Medicin.
    Twitter: #kroniskcancer, #dmagenda.

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Arrangeras av Dagens Medicin Agenda i samarbete med Nätverket mot cancer.

  •  

    TISDAG 5 JULI 10.20-11.10

    Patienten som kompass när vi styr mot värdebaserad vård

    DEL 1 - Tre olika vägar mot samma mål

    Tre universitetssjukhus berättar varför värdebaserad vård är en central strategi och en viktig förutsättning för att erbjuda vård som ger störst nytta för patienterna. Hur skapar man bästa vård med utgångspunkt från patientens behov? Vilka fördelar har uppnåtts och vad återstår?

    Medverkande: Hans-Olov Hellström, biträdande sjukhusdirektör, Akademiska sjukhuset, Morten Kildal, överläkare och ansvarig för värdebaserad vård, Akademiska sjukhuset, Andreas Ringman Uggla, produktionsdirektör och operativ chef, Karolinska universitetssjukhuset, Anna Göjeryd Ulander, sektionschef strategisk styrning och stöd, Karolinska universitetssjukhuset, Ali Khatami, kvalitetsdirektör, kvalitetsutveckling och patientsäkerhet, Sahlgrenska universitetssjukhuset, Barbro Edén, överläkare, medicinskt ansvarig inom värdebaserad vård, Sahlgrenska universitetssjukhuset, Anna-Lena Sörenson (S), vice ordförande, socialutskottet.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #vbv #dmagenda

    Efter seminariet bjuder vi in till mingel med fika.

    Seminariet arrangeras av Dagens Medicin Agenda, Akademiska sjukhuset, Karolinska Universitetssjukhuset samt Sahlgrenska Universitetssjukhuset.

  •  

    TISDAG 5 JULI 11.40-12.40

    DEL 2 - Patienten som partner när vi förbättrar vården

    Patienter och profession berättar och reflektera om sina erfarenheter och resultatet av samarbetet med sjukhusen. Arbetet med värdebaserad vård i tre olika patientflöden presenteras. Patienterna kommer från grupperna mycket för tidigt födda barn, förstföderska med spontan förlossningsstart i fullgången tid samt prostatacancer.

    Eva Johansson, patientprocessledare för värdebaserad vård prostatacancer, Akademiska sjukhuset, Thore Eklund, patientrepresentant, värdebaserad vård, prostatacancer, Akademiska sjukhuset, Boubou Hallberg, patientflödeschef, neonatologen, Karolinska Universitetssjukhuset, Karl Rombo, Prematurförbundet, Karolinska universitetssjukhuset. Anna-Karin Ringqvist, verksamhetsutvecklare och processledare för värdebaserad vård för normalförlossning, Sahlgrenska universitetssjukhuset Liselotte Bergqvist, verksamhetsutvecklare och processledare för värdebaserad vård för normalförlossning, Sahlgrenska universitetssjukhuset, Emma Johansson, patient, förstföderska, Sahlgrenska universitetssjukhuset.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #vbv #dmagenda

    Efter seminariet bjuder vi på lättare lunch.

    Seminariet arrangeras av Dagens Medicin Agenda, Akademiska sjukhuset, Karolinska Universitetssjukhuset samt Sahlgrenska Universitetssjukhuset.

  •  

    TISDAG 5 JULI 13.20–14.10

    Bättre strokevård – är sjukvården redo att dra ur proppen?

    Hur kan organisationen av strokevården i Sverige förbättras för att få jämlik och bättre tillgång till bästa behandling? Vilken infrastruktur på nationell och regional nivå behövs för att patienter med svår stroke ska komma till rätt sjukhus i rätt tid?

    Gabriel Wikström, sjukvårdsminister (s), socialdepartementet, Nils Wahlgren, professor, överläkare, Karolinska Universitetssjukhuset, Olivia Wigzell, generaldirektör, Socialstyrelsen, Lise Lidbäck, ordförande, Neuroförbundet, Anna Starbrink, sjukvårdslandstingsråd (L), Stockholms läns landsting, Anders Henriksson, landstingsråd (S), vice ordförande Sveriges Kommuner och Landsting, Landstinget i Kalmar, Malin Blixt, enhetschef, TLV, Stefan Persson, undersköterska, Skånes universitetssjukhus, med egen erfarenhet som strokepatient.

    Läs mer

    Moderator: Maja Florin, chef, Dagens Medicin Agenda.
    Twitter: #stroke #dmagenda

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Arrangeras av Dagens Medicin Agenda i samarbete med Medtronic och Neuroförbundet.

  •  

    TISDAG 5 JULI 14.40–15.30

    Goda grannar – vad kan Sveriges tre bästa sjukhus lära av varandra?

    Sveriges tre bästa sjukhus ligger alla i sydöstra sjukvårdsregionen med Östergötland, Jönköping och Kalmar i de tre kategorierna universitetssjukhus, mellanstora och mindre sjukhus. Hur jobbar de vidare tillsammans för att behålla den positionen även i framtiden?

    Mats Uddin, regiondirektör, och Johanna Zechel, ungt råd, Region Östergötland, Krister Björkegren, landstingsdirektör, och Ragnhild Holmberg, hälso- och sjukvårdsdirektör, Landstinget i Kalmar, Agneta Jansmyr, regiondirektör, och Lotta Larsdotter, primärvårdsdirektör, Region Jönköpings län.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin
    Twitter: #bastasjukhus #dmagenda

    Efter seminariet bjuder vi på fika.

    Arrangeras av Dagens Medicin Agenda i samarbete med Landstinget i Kalmar, Region Östergötland och Region Jönköpings län.

  •  

    TISDAG 5 JULI 16.00–16.50

    Helikopterperspektiv på akutsjukvården – räddar vi fler liv och sparar pengar?

    Den helikopterbaserade akutsjukvården är underutvecklad i Sverige, jämfört med våra grannländer. Frågan har stötts och blötts i flera utredningar, men utvecklingen går trögt, trots att det finns stöd för att ambulanshelikoptrar räddar liv och att vården är kostnadseffektiv.

    Anna-Lena Sörenson (S), riksdagsledamot, vice ordförande, socialutskottet, Fredrik Larsson (M), landstingsråd, Landstinget i Värmland, Börje Wennberg (S), landstingsråd, Landstinget i Uppsala län, Jonas Andersson (L), regionråd, Västra Götalandsregionen, Hans Karlsson, chef för avdelningen för vård och omsorg, Sveriges Kommuner och Landsting, Tobias Kjellberg, hälso- och sjukvårds­direktör, Landstinget i Värmland, Joacim Linde, ordförande, Svensk förening för läkare i prehospital akutsjukvård, Mikael Gellerfors, medicinsk forskningschef, Svensk Luftambulans.

    Läs mer

    Twitter: #räddaliv #dmagenda
    Moderator: Mikael Nestius, vd Dagens Medicin.

    Efter seminariet bjuder vi in till mingel med lättare förfriskningar.

    Arrangeras av Dagens Medicin Agenda i samarbete med Landstinget i Värmland och Svensk Luftambulans.

  •  

    ONSDAG 6 JULI 8.00-8.30

    Frukost-tv med aktuell debatt och intervjuer: Framtidens sjukvård - bit för bit.

    Varje morgon bjuder vi in aktuella makthavare från sjukvården till en direktsänd frukostdebatt på Dagens Medicins Vårdtorg för diskussion om vårdfrågorna i nyhetsflödet. Följ oss i direktsändning eller se reprisen på DM-Play

     

  •  

    ONSDAG 6 JULI 9.00–9.50

    Den nya temasjukvården – framtidens modell för framtidens patient

    En ny modell för framtidens universitetssjukhus skapas nu på Karolinska Universitetssjukhuset. Den nya tematiska organisationen följer patientens resa genom vården, en förändring som lägger grunden för att utveckla en högspecialiserad sjukvård i toppklass.

    Melvin Samsom, sjukhusdirektör, och Andreas Ringman-Uggla, produktionsdirektör, operativ chef, Karolinska Universitetssjukhuset, Daniel Forslund, innovationslandstingsråd (L), Stockholms läns landsting, Hans Karlsson, chef för avdelningen för vård och omsorg, SKL, Britt-Marie Ahrnell, sjukvårdsdebattör, anhörig, Emma Spak, ordförande, Sveriges yngre läkares förening, Sineva Riberio, ordförande, Vårdförbundet.

    Läs mer

    Twitter: #temavård #dmagenda
    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Arrangeras i samarbete med Karolinska Universitetssjukhuset.

  •  

    ONSDAG 6 JULI 10.20–11.10

    Leva livet med diabetes – får hjärtat vara med?

    Vilka konkreta förändringar måste vi göra i dag för att patienter med diabetes ska få minskad risk att drabbas av komplikationer av sin sjukdom? Vad har patienterna, vården och samhället att vinna på om behandlingsmålen vid typ-2 diabetes nås? 

    Carl Jan Granqvist, krögare, vinkännare, Mona Landin-Olsson, ordförande, Svensk förening för diabetologi, Magnus Löndahl, överläkare, Skånes universitetssjukhus, Lund, Fredrik Löndahl, ordförande, Diabetesförbundet, Christoffer Bernsköld (S), regionråd, Region Östergötland, Anna Starbrink (L), sjukvårdslandstingsråd, Stockholms läns landsting.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #leva livet #dmagenda

    Efter seminariet bjuder vi på fika.

    Seminariet arrangeras av Dagens Medicin Agenda i samarbete med Boehringer Ingelheim och Svensk förening för diabetologi.

  •  

    ONSDAG 6 JULI 11.40–12.30

    Var finns ersättningsmodellerna som ger mer hälsa för pengarna?

    Dagens ersättningsmodeller kritiseras för att vara alltför trubbiga och snarare motverka än stimulera till nytänkande och innovation. Hur ser framtidens ersättningsmodeller ut, som skapar mer värde för insatta resurser?

    Georg Engel, chef för vårdinformatik och ersättningsmodeller, Stockholms läns landsting, Per-Erik Gustafsson, överläkare, hjärtkliniken, Länssjukhuset i Gävle, Daniel Forslund (L), innovationslandstingsråd, Stockholms läns landsting, Anders Lönnberg (S), regeringens nationella life science-samordnare, Ann Söderström, hälso-och sjukvårds­direktör, Västra Götalandsregionen, Heidi Stensmyren, ordförande, Läkarförbundet, Marie Aabö, vd, Medtronic Sverige.

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #värdebaseradvård #dmagenda

    Efter seminariet bjuder vi på lunch.

    Arrangeras av Dagens Medicin Agenda i samarbete med Medtronic.

  •  

    ONSDAG 6 JULI 13.20-14.20

    Digitaliseringen: Hur kommer hälso- och sjukvården se ut om tio år?

    Patienter, anhöriga och medarbetare i sjukvården ställer allt högre krav på vårdens tillgänglighet och informationsförsörjning. Vården står inför en digital transformation där behovet av korrekt information vid rätt tillfälle är stort. Vad måste vi konkret göra för att uppnå ett optimalt integrerat sjukvårdssystem, från förebyggande hälsovård, via sjukvård, till vård i hemmet? Är sjukvården redo för transformationen? Vem driver på och vem genomför?

    Stefan Vlachos, tillförordnad verksamhetschef Innovationsplatsen, Karolinska universitetssjukhuset, Hans-Olof Hellström, biträdande sjukhusdirektör Akademiska sjukhuset, Jeroen Tas, CEO of Philips Connected Care and Health Informatics and European CIO of the Year 2014, Ann Söderström, hälso- och sjukvårdsdirektör, Västra Götalandsregionen, med flera. 

    Läs mer

    Moderator: Christina Kennedy, chefredaktör, Dagens Medicin.
    Twitter: #framtidenssjukvård #dmagenda

    Efter seminariet bjuder vi på kaffe med tillbehör.

    Arrangeras av Dagens Medicin i samarbete med Philips Health Systems.

     

  •  

    ONSDAG 6 JULI 14.40–15.30

    Kan vi ge en minnesvärd vård vid Alzheimers sjukdom?

    Samhällets kostnader för demensvård, där Alzheimers sjukdom står för den största delen, uppgår redan i dag till det hisnande beloppet 63 miljarder kronor. Det överstiger kostnaderna för cancer, stroke och hjärt-kärlsjukdomar tillsammans. Om prognoserna stämmer ökar antalet drabbade kraftigt när fyrtiotalisterna når 80-årsåldern. Vad är det värt med tidig diagnostik och vad kan tidig behandling av Alzheimers sjukdom medföra – för patienterna, deras familjer och för landsting respektive kommuner?

    Anders Wimo, professor i geriatrisk allmänmedicin, Karolinska Institutet, Göran Stiernstedt, regeringens utredare av en effektiv vård, seniorkonsult, Rud Pedersen, Peter Graf, vd, Vårdbolaget Tiohundra, Anders Henriksson (S), landstingsråd Landstinget i Kalmar län, Ella Bohlin (KD), barn- och äldrelandstingsråd, Stockholms läns landsting, Liselotte Jansson, generalsekreterare, Alzheimerfonden.

    Läs mer

    Moderator: Maja Florin, chef, Dagens Medicin Agenda.
    Twitter: #alzheimers #dmagenda

    Efter seminariet bjuder vi på fika.

    Seminariet arrangeras av Dagens Medicin Agenda i samarbete med Lilly.

  •  

    ONSDAG 6 JULI 16.00-16.50 

    Världsbäst på data - men till vilken nytta? 

    Real world evidence handlar om att följa upp och analysera data över hur läkemedel och behandlingar fungerar i verkligheten och i praktiken. Sverige är ett av de länder som är världsbäst på patientdata - men hur använder vi den egentligen för att förbättra för patienter och för sjukvården? Kan vi öka patientnyttan, effektivisera läkemedelsanvändningen och skapa kostnadsbesparingar med real world evidence? Vilka hinder finns det och finns det några eventuella risker?

    Daniel Forslund (L), innovationslandstingsråd, Stockholms läns landsting, Ragnar Linder, chef, RWES and HEOR Norden, IMS Health, Tobias Nilsson, ledningsstöd, koncernstab hälso- och sjukvård, Västra Götalandsregionen, Margareta Haag, vice ordförande, Nätverket mot cancer, med flera.

    Moderator: Jonny Sågänger, redaktör Nyhetsbrev Läkemedelsmarknaden och Digital Hälsa.
    Twitter: #realworldevidence #dmagenda

    Seminariet arrangeras av Dagens Medicin Agenda i samarbete med IMS Health.

  •  

    TORSDAG 7 JULI 8.30-10.00 

    Big data in little Sweden 2020 - kvalitetsregistrens framtida betydelse

    Vad händer med de svenska kvalitetsregistren? Vem äger data - patienten, professionen landstingen staten? Hur använder och tillgodogör vi oss den data som finns på nätet, till exempel Patient like me? Hur bedriver vi den kliniska forskningen och registerforskningen framgent?

    Anna Nilsson Vindefjärd, generalsekreterare Forska!Sverige, Anders Lönnberg, regeringens samordnare inom life science, Karolina Antonov, chefsstrateg, LIF, Patrik Sundström, programansvarig för e-hälsa, SKL, Sofia Ernestam, registerhållare SRQ samt patientföreträdare.

    Läs mer

    Moderator: Boel Mörck, vice ordförande Svensk Reumatologisk Förening.
    Twitter: #reumatism

    Frukost serveras från kl 8.00.

    Arrangeras av Svensk Reumatologisk Förening, Forska!Sverige och SRQ.



 
 

Recensioner på uppdrag av DiabetologNytt

Nyhetsinfo

wwww red DiabetologNytt

 

Recension av ”Bara en tanke – din guide till villkorslöst välmående

av Dennis Westerberg, föreläsare och världsförbättrare, coach samt artist

Förlag: Soderpalm Publishing (Andra upplagan) 2016

Pris: 261 kr

”Du befinner dig alltid endast en tanke från glädje, ro och harmoni. Nästa tanke kan vara just den som gör dig sagolikt lycklig”, står det på omslaget.

Där står också att Dennis Westerberg utnämnts till 2015 år föreläsare av SAJ AB. Jag har aldrig lyssnat till honom men föreställer (tänker!) mig att han är en person med karisma som kan trollbinda sin publik, få dem att sucka med honom och skratta med honom, att de verkligen gillar och känner igen det han säger. Det står på nätet om honom att han guidar individer till nya insikter, insikter som ger omedelbar förändring. Mer detaljerat lär han oss ”helt nya sätt” att se på sinnet, medvetandet och tänkandet så att stress, van-trivsel, ångest, ilska, tvångstankar m.m. kan försvinna. Simsalabim!

Problemet är boken. Jag har svårt för tjocka böcker som tuggar om allt för att få till de många hundra sidorna. Jag har lika svårt för ”kompendieböcker”, de som inte har någon språklig estetik, inte gör läsandet njutbart, utan mest bankar in vissa omkväden. Denna bok tillhör den senare kategorin.

För mig är detta ett manus till en föreläsning, inte litteratur. Här finns t.o.m. kursiverat orden som bör betonas (och de är många – det gäller ju att trumma in sitt budskap!) och var pauserna skall läggas…..Jag har svårt att motivera mig till att läsa hela boken, men har ju lovat redaktören en recension…. Skizzerna i boken lättar upp det redan lätta.

Det blir för mig så tjatigt att jag från att ha tänkt titeln ”Bara en tanke” går över till ”Bara en tanke” och sedan glider mina tankar iväg……”Tomma tunnor skramlar mest”….””Oj, vad tanken skramlar där i tunnan”… Jag förvandlas från en positivt nyfiken recensent till en felsökande kritiker. För att föra fram sitt budskap på ett lättläst sätt gör Westerberg många förenklingar och ibland blir det felaktigt.

”Lånta fjädrar”- uttrycket dyker också upp hos mig, för det skaver att Westerberg inte någon gång hänvisar till ACT (Acceptance and Commitment Therapy”):s grundare Steven C. Hayes, eller någon annan inom den tredje vågens KBT, då han så tydligt tagit sina tankar från dem (och faktiskt har en avdelning med referenslitteratur). Hayes har klarare än de flesta ”tjatat” om att ”En tanke är bara en tanke” och inte verkligheten. Hayes har naturligtvis inte patent på den idén, men han är den som skarpast introdu-cerat detta mantra inom terapin och skapat en teoretisk ram ”Relational Frame Theory”. I stället för Westerbergs bok föreslår jag att du läser någon av Heyes böcker, t.ex.: ”Sluta grubbla börja leva,” Natur och Kultur 2007. Men alla tycker inte som jag, annars hade ”Bara en tanke” inte tryckts i en andra upplaga!

Eller – varför inte läsa något helt annat? Lyfta blicken lite grand. Sjukvården tar emot flera nya patientgrupper, människor som flytt från t.ex. Somalia, Syrien, Eritrea eller Afghanistan och gatubarn från Marocko. Kan vi förstå dem bättre? Kunskap om dessa kulturer kan fås på många sätt. Sommaren brukar inbjuda till läsning av skönlitteratur och det är ett utmärkt sätt att skapa sig en bild av andra länders liv och leverne!

Afrikanska kontinenten ståtar ju med fyra Nobelpristagare sedan mitten av 80-talet: Woyle Soyinka (Nigeria), Naguib Mahfouz (Egypten), Nadine Gordimer  och J.M. Coetzee (båda Sydafrika). Många, många har också älskat ”En halv gul sol” av Chimamanda Ngozu Adichie (Nigeria/Biafra) liksom Khaled Hosseinis (Afghanistan)böcker.

 

BRA SOMMARLÄSNING

Här följer några andra alternativ:

- Somalia:Kartor” av Nuruddin Farah är första delen i en trilogi. Författaren, som sedan länge lever i exil, var nyligen i Sverige. Han omtalas som en möjlig blivande Nobelpris-tagare. Magiskt skickligt berättande, där vi samtidigt får ta del av intressanta fakta, vilka smidigt smygs in.

I ”Förlorade själar” av Nadifa Mohamed, lånar författaren blicken från tre somaliska kvinnor.

- Syrien; ”Resa in i tomheten. En berättelse från Syrien”  av Samar Yazbek har fått många positiva recensioner – själv hade jag svårt att ta mig in i den. Kände att jag kunde för lite om landet. Men bedöm själva!

Kanske är den lättare att ta till sig om man först läst t.ex. ”Drömmen om Damaskus” av Aron Lund?

- Eritrea:Vägen till frihet” av Feven  Tekle & Raffaele Masto, en kvinnas flyktberättelse.

Något helt annat: ”Agent 72” av  Embaye Teages Afewerki – en thriller om en syrisk kommandosoldat som förklädd till egyptisk journalist reser till  Eritrea för att mörda landets president.

- Afghanistan:Till Afghanistan kommer Gud bara för att gråta – berättelsen om Shirin-Gol” av Siba Shakib, som egentligen är dokumentärfilmare.

Nyhetsankaret Lasse Bengtsson har skrivit ett antal artiklar från sin tid i Afghanistan; ”Afghanistan – om en yttre och inre resa”.

- Marocko:”Kalifens hus” av Tahir Shah, en bitvis dråplig, biografi om kulturkrockar.        ”Det nakna brödet”, självbiografi av Muhammed Shukri. Denna bok har varit svartlistad i Marocko bl.a. p.g.a. den svåra misär som skildras. Men kan kanske få oss att förstå varför dessa gatubarn drar hit?

Kanske vill vi också ta till oss hur nyinvandrade andra ser på oss, vi som bott i Sverige i några, kanske många generationer?

- ”Väldigt sällan fin” av Sami Said. Boken har två delar; I den första följer vi Noha och hans äventyr i Linköping  - i den andra far han med sin familj tillbaka till födelselandet Eritrea. Kulturkrockarna skildras på ett skarpsynt och stundom roande sätt, trots Nohas plågade själ.

- Antologin ”Sverige – en (o)besvarad kärlekshistoria” med redaktörerna Lejla Hastor        (född i Bosnien Hercegovina) och Nirvin Yosef (född i Syrien), båda uppvuxna i Sverige, båda statsvetare, har tagit ett helt annat grepp. De har samlat texter från sexton kvinnor med erfarenheter av dubbla identiteter. Dessa berättar om sin längtan att passa in, hur de kämpar för att finna en identitet och hur de hanterar okunniga frågor. Författarnas åldersspan är snävt; 29 – 38 år, vilket man bör vara medveten om när man läser boken. De kom till Sverige när de var 1-3-4-5-6-9-10-15-16-18 år, från Algeriet, Bosnien, Colombia, Eritrea, Irak, Iran, Libanon, Ryssland/Kurdiska bergen, Syrien, Turkiet eller Zambia/Uganda,  samtliga är nu mycket välutbildade och med ordet i sin makt. Detta är en mycket läsvärd bok som ger upphov till självreflektion hos läsaren. Men en fråga skulle jag vilja sända tillbaka till skribenterna; Varför ta så illa vid sig av frågan ”Var kommer du från – egentligen?” Jag kan förstå irritationen att ofta ställas inför den, men vad skulle hända om det i stället sågs som startpunkten på ett fördjupat och intressant ömsesidigt givande och tagande av information, både av känslomässig och faktainriktad art?

En sak är säker: Varierad och ögonöppnande läsning väntar!

Marie Insulander

Leg. psykolog, specialist i klinisk psykologi

Leg. psykoterapeut, handledarutbildad

 

New Diabetes Prevention Program Data Indicates Physical Activity Helps Prevent Type 2 Diabetes, Independent of Weight Loss

From ADA Nyhetsinfo SA

www red DiabetiologNytt

  Physical activity, independent of weight loss, may help to prevent or delay type 2 diabetes in people who are at high risk for diabetes, according to new follow-up data from the landmark Diabetes Prevention Program (DPP) study, presented today in the President’s Oral Session at the American Diabetes Association’s 76th Scientific Sessions® at the Ernest N. Morial Convention Center in New Orleans. 

 

The DPP[1] was primarily supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of National Institutes of Health.  Published in 2002, the study found that lifestyle changes, including moderate weight loss and increased physical activity, reduced the chance of developing type 2 diabetes by 58 percent over three years in overweight people with prediabetes. 

 

Study participants were randomized to one of three groupslifestyle interventionmetformin or placebo. Both lifestyle and metformin substantially reduced the risk of developing type 2 diabetes, with the lifestyle intervention more effective than metformin. Participants in the lifestyle intervention arm of this multi-center study received an intensive behavioral intervention composed of nutrition and physical activity with the two goals of being physically active for a minimum of 150 minutes per week, and achieving a weight loss of 7 percent. 

 

Due to the success of the lifestyle intervention, all participants were provided a modified version of the intervention and asked to participate in the DPP Outcomes Study (DPPOS), also supported by NIDDK. Despite the fact that everyone beginning the DPPOs had been offered the lifestyle intervention, the DPPOS demonstrated that the lifestyle arm maintained a significantly lower cumulative diabetes incidence than the other two groups, which could not be explained by differences in weight loss.

 

The current study is a 12-year follow-up of the subgroup of 1,793 participants (93% of eligible cohort; n for lifestyle = 589; metformin =599; and placebo =605) who were part of a DPP ancillary study in which they were asked to wear an activity monitor for one week. The interviewer-administered Modifiable Activity Questionnaire was used to track physical activity (PA) yearly, and diabetes status was determined by annual oral glucose tolerance and semi-annual fasting plasma glucose tests. 

 

The researchers found that in all three treatment groups, diabetes incidence was lower for participants who were more physically active, regardless of changes in weight. Specifically, there was a 2 percent decrease in diabetes incidence (HR 0.98 [0.97, 0.99]P<0.0001for each 6 MET-hours/week increase (roughly 1.5 more hours/week of activity equivalent to a brisk walk).

 

Cumulative physical activity levels were highest in the lifestyle intervention group (P=0.003, in a mixed model of PA over the entire study), and the incidence of type 2 diabetes was lowest in the lifestyle intervention arm.

 

The reduction in type 2 diabetes risk was greatest for participants who were least active at baseline (reporting fewer than 150 minutes of physical activity per week) compared to those who met the 150-minutes per week goal (5% decrease, n=728; HR 0.95 [0.93, 0.97]; P<0.0001).

 

These current results show that physical activity, over an average of 12 years, decreased the chances of developing diabetes even after considering any changes in weight.  This protective effect was greater in those who were less active at baseline. They also suggest that the lower development of diabetes across the entire study in those that took part in the lifestyle arm of the study may be partially explained by improvement in physical activity levels as well as weight loss,” said one of the lead investigators, Andrea M. Kriska, PhD, MS, Professor, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health.

 

“Until now, the importance of physical activity in preventing diabetes development in the DPP was thought to be due to its role in achieving weight loss and weight maintenance; however, it was not considered a strong key factor alone,” Kriska continued.

 

 “It is very important for health care professionals to look beyond their high-risk patients weight,and also consider their physical activity levels, when discussing strategies to prevent progression to type 2 diabetes.”

 

 
 
 

Diabetesläkemedlet Jardiance minskar risken för njursjukdom vid typ 2-diabetes 

Nyhetsinfo

www red DiabetologNytt

Press release

Lars Weiss, Överläkare Med Dr vid njurmedicinska kliniken Centralsjukhuset Karlsta

  • Nya resultat från studien EMPA-REG OUTCOME publiceras idag i The New England Journal of Medicine (1) Jardiance är det enda diabetesläkemedlet som har visat minskad risk för kraftig njurfunktionsförsämring och dialys, utöver den blodsockersänkande effekten (1) 
  • Tidigare resultat ifrån samma studie visade att Jardiance minskade risken att dö i hjärt-kärlsjukdom med 38 procent (2) 

Nya data visar att behandling med diabetesläkemedlet Jardiance (empagliflozin) minskar risken att utveckla eller förvärra njursjukdom med 39 procent jämfört med placebo hos patienter som har både typ 2-diabetes och hjärt-kärlsjukdom. 

– Dessa resultat är viktiga ur ett kliniskt perspektiv med tanke på att 150-200 patienter med typ 2-diabetes påbörjar dialysbehandling varje år i Sverige. Dialys innebär stor påverkan på patienternas livskvalitet och dessutom är det en hög kostnad för samhället, då dialysbehandling kostar cirka 800 000 kronor per år och patient, säger Lars Weiss, överläkare Med Dr vid njurmedicinska kliniken Centralsjukhuset i Karlstad.

Detta är första gången ett diabetesläkemedel har kunnat visa minskad risk för grav njurfunktionsförsämring hos patienter med typ 2-diabetes och hjärt-kärlsjukdom, utöver den effekt som uppnås av blodsockersänkningen i sig. När patienterna i studien gavs Jardiance i tillägg till standardbehandling (andra läkemedel mot diabetes och hjärtsjukdom) och sedan jämfördes med dem som fick placebo (verkningslöst medel) i tillägg till standardbehandling så rapporterades följande (1): 

  • 55 procent färre patienter påbörjade dialysbehandling 
  • 44 procent färre patienter fick försämrad njurfunktion mätt som en dubblering av nivåerna av kreatinin – en slaggprodukt som ansamlas i kroppen om inte njurarna förmår att rena blodet tillräckligt väl (en fördubbling av kreatinin innebär ungefär en halvering av njurfunktionen). 
  • 38 procent färre patienter utvecklade höga nivåer av äggviteämnet albumin i urinen, (makroalbumineri) vilket ökar risken för både njursvikt som kräver dialys samt för hjärt-kärlsjukdom. 

– Det här är väldigt viktigt. Det här är det enda diabetesläkemedel som hittills visats kunna förskjuta dialysstart och förskjuta en kraftig försämring av njurfunktionen. Hittills har detta endast visats med läkemedel som påverkar blodtrycket, säger Lars Weiss. Jag skulle välkomna studier på patienter utan hjärt-kärlsjukdom för att se om samma goda effekt i njurarna kvarstår.

Dessa nya data är en fördjupad analys av EMPA-REG OUTCOME-studien som redan tidigare visat att Jardiance avsevärt minskar risken för död hos patienter som har typ 2-diabetes och hjärt-kärlsjukdom. (2)

30 - 40 procent av alla patienter med typ 2-diabetes kommer med tiden att drabbas av någon form av njurskada. (3) Nedsatt njurfunktion innebär även en ökad risk för hjärt- kärlsjukdom och död.

Antalet allvarliga biverkningar och biverkningar som ledde till att patienterna avbröt behandlingen, var likartat hos patienterna, oavsett om de hade eller inte hade nedsatt njurfunktion när studien inleddes. Dödsfall till följd av njursjukdom var sällsynt och inträffade endast hos tre patienter (0,1 procent) som behandlades med Jardiance och ingen som behandlades med placebo.

Studien har finansierats av Boehringer Ingelheim och publiceras i New England Journal of Medicinesamtidigt som den presenteras vid American Diabetes Association (ADA) 76:e Scientific Sessions i New Orleans.

Charlotte Luderowski, medicinsk rådgivare diabetes, Boehringer Ingelheim 
 

FAKTA EMPA-REG OUTCOME

EMPA-REG Outcome är en randomiserad, dubbelblind, placebokontrollerad studie med över 7 000 patienter från 42 länder. Resultaten visar att patienter med typ 2-diabetes som behandlas med läkemedlet Jardiance (empagliflozin) som tillägg till standardbehandling löper en signifikant minskad risk att dö på grund av hjärt-kärlsjukdom, samt för död oavsett orsak jämfört med placebo (overksamt medel). Patienterna som hade både typ 2-diabetes och hjärt-kärlsjukdom följdes i snitt under drygt tre år. 

Jardiance (empagliflozin) minskar njurarnas upptag av blodsocker (glukos) från urinen, genom att blockera effekten av ett transportprotein (natrium-glukos-kotransportör. Därmed försvinner mer glukos ur kroppen med urinen och blodsockernivån sjunker.

Patienterna i studien fick antingen en daglig dos Jardiance (4 687) eller placebo (2 333). Alla fick samtidigt standardbehandling för att sänka blodsocker, blodtryck och kolesterol. Syftet var att jämföra hur många i respektive grupp som dog i någon hjärt-kärlsjukdom eller drabbades av icke dödlig hjärtinfarkt eller stroke under studiens gång.(2)

Referenser

(1) Wanner C. et al. Empagliflozin and Progression of Kidney Disease in Type 2 diabetes Doi: 10.1056/NEJMoa1515920

(2) Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 10.1056 (2015) (Last accessed: May 2016)
a) Primärt kombinerat effektmått med RRR14 % (p=0,04), ARR 1,6%

(3) Afghahi H et al. Nephrol Dial Transplant 2010. Doi: 10.1093/ndt/gfg/535

NEW ORLEANS — A program that combines in-person and online training significantly reduced impaired hypoglycemia awareness and also decreased hypoglycemia-related stress and episodes of severe hypoglycemia, researchers announced at the American Diabetes Association (ADA) 2016 Scientific Sessions on June 12.

From www.medscape.com

Nyhetsinfo

www red DiabetologNytt

"HypoAware" was designed by researchers at VU University Medical Center, the University of Amsterdam, the Netherlands. It is a "retooling" of Blood Glucose Awareness Training (BGAT), traditionally delivered in six to eight weekly in-person workshops. The Dutch researchers shortened the program to three workshop-type group sessions of 2.5 hours each and created two online modules, for a program that lasts 4 weeks.

"We aimed to make it brief, light, and attractive," said Frank J Snoek, PhD, chair of the department of medical psychology at VU University Medical Center.

The program delivered promising results in a pilot study, so the researchers conducted a cluster-randomized controlled trial at eight outpatient centers. Patients with both type 1 and type 2 diabetes were randomized to either care as usual or usual care plus HypoAware.

At 6 months after the training, HbA1c was unchanged, but episodes of severe hypoglycemia had been reduced by 35% to 37% in the intervention group. Impaired hypoglycemia awareness was decreased by 62%, and hypoglycemia-related stress was reduced by 20% to 30%, said Dr Snoek, who presented his data here.

"I think we can be really pleased with the outcomes of this very brief intervention," he told attendees. Dr Snoek said that while it was not completely straightforward to contrast HypoAware with results seen with BGAT, HypoAware "compares reasonably well."

The educational pathway — and psychological components of disease management — identified by BGAT were confirmed with HypoAware, he noted.

"It's very much about understanding your body, it's about awareness, it's about understanding your own risky behaviors, as well as communicating with your environment."

Asked to comment, Danielle M Hessler, MD, assistant professor of family community medicine, at the University of California, San Francisco School of Medicine, called the reduction in hypoglycemia and increased awareness of symptoms "very powerful."

It "was a very nice intervention that shows this hybrid of leveraging some technology but also interfacing with the patient at the same time," Dr Hessler told 

She said it would be useful to find out more about the revisions the Dutch researchers made to BGAT and how it might be integrated with training in the United States.

Number Needed to Treat Is Less Than One 

In the trial, patients at four clinics were randomized to receive HypoAware, and those at four other clinics received usual care. The mean age of patients was 52, and two-thirds were female.

Of the patients, 121 had type 1 diabetes and 14 had type 2. The mean disease duration was 28 years, and 104 patients had experienced episodes of impaired hypoglycemia awareness.

Forty-seven patients (34%) said they were very worried about hypoglycemia.

The researchers followed up with patients at 2, 4, and 6 months after the study began and estimated rate ratios (RR) and odds ratios (OR) with 95% confidence intervals (CI).

Intention-to-treat analyses were corrected for baseline outcomes, diabetes duration, treatment, HbA1c, and episodes of severe hypoglycemia in the preceding 2 years.

The relative risk of episodes of severe hypoglycemia (defined as requiring help from others) without medical intervention for those getting HypoAware was 0.65 (95% CI, 0.37–1.15; P = .139).

For episodes that required medical interference, the RR was 0.63 (95% CI, 0.19–2.15; = .462). For impaired hypoglycemia awareness, the RR was 0.38 (95% CI, 0.15–0.95; P = .038).

"If you were to translate into numbers needed to treat, to prevent one episode you'd need to expose 0.7 patients to our intervention," said Dr Snoek.

The study did have some limitations, he said, including that the fact that it had relatively mild inclusion criteria and a short duration of follow-up. The researchers will soon be examining 12-month data to see whether the findings hold for that longer duration, he noted..

American Diabetes Association 2016 Scientific Sessions; June 12, 2016; New Orleans, Louisiana. Abstract 285-OR/285

The National Institute of Health and Care Excellence (NICE), UK, has recommended that SGLT-2 inhibitors on the UK market can be used earlier in patients with diabetes.

From www.diabetesincontrol.com

Nyhetsinfo www red DiabetologNytt

The new guidanceallows the drugs to be used first-line for people who cannot tolerate metformin, and in whom sulfonylureas or Actos (pioglitazone) are not considered appropriate. More importantly, the recommendations put the SGLT-2 inhibitors on par with another newer class of diabetes drug — DPP-4 inhibitors such as MSD’s Januvia (sitagliptin) and AstraZeneca’s Onglyza (saxagliptin).  The guidance applies to Johnson & Johnson’s Invokana (canagliflozin), AstraZeneca’s Farxiga (dapagliflozin) and Boehringer Ingelheim/Eli Lilly’s Jardiance (empagliflozin).

Previously, NICE guidance only backed use of the drugs in combination with metformin, either alone or in combination with a sulfonylurea or insulin, but now the recommendations allow clinicians “the freedom to prescribe SGLT-2 inhibitors when they feel it is appropriate.”  

While the growth of the SGLT-2 inhibitor class has been held back somewhat by safety concerns such as ketoacidosis, data published last year on Jardiance showing it was able to lower cardiovascular risk — the first diabetes drug to do so — has reinforced confidence in the class. — Recommendation positions Invokana, Farxiga and Jardiance as first-line treatments

A recent survey, along with an OCR statement, reiterate the importance of organizations understanding healthcare application security measures. 

 

As more covered entities and business associates continue to implement mobile options, healthcare application security is an increasingly critical aspect to overall data security.

From www.healthiit.security.com launched inn time during the ADA

Nyhetsinfo

www red DiabetologNytt

OCR warns healthcare application security critical for third-party apps

If a recent survey is any indication, organizations should take particular care when it comes to cloud-based applications, as over one-quarter of such apps were found to be risky. 

CloudLock’s Q2 2016 Cloud Cybersecurity Report found that 27 percent of third-party apps are classified as high risk.

There has also been a huge increase in apps from 2014 to 2016, growing from 5,500 to nearly 160,000 in that time frame.

There is a real danger in Shadow IT, according to the report summary, which is when employees utilize applications without IT approval. 

“As more and more organizations adopt cloud platforms, new Shadow IT risk vectors are coming into play in the form of connected third-party apps,” the report’s authors explained. “These apps are authorized using corporate credentials, demand extensive permission sets, and communicate with corporate SaaS platforms via OAuth connections.”

For the survey, application risk was measured across access scopes, community trust ratings, and application threat intelligence. 

Of all the apps granted access to corporate systems in 2016, 27 percent were classified as high risk by security teams, while 58 percent were listed as medium-risk and just 15 percent were low-risk.

CloudLock graph of percent of installs by risk

As previously mentioned, the number of third-party apps has greatly increased in recent years. Since 2014, the number of third-party application installations has increased 11 times, while there has been a 19 percent increase in the last three months alone, according to the report. 

“Over the past two years, the number of apps per average organization has increased from 130 to 733,” wrote the report’s authors. “There are even organizations with more than 18,500 applications, all with the potential to become backdoors through which hackers can easily infiltrate their environments.”

CloudLock graph of third-party app install growth

In terms of healthcare application security, the report found that 28 percent of third-party apps utilized by healthcare providers were deemed high-risk by IT teams. Fifty-six percent were listed as medium-risk, while just 16 percent were considered low-risk apps. 

The Department of Health and Human Services (HHS) Office for Civil Rights (OCR) is also taking note of potential third-party application risk, releasing a document on how organizations should review their apps.

Third-party application software is designed to work within operating systems, OCR explained, as well as help users complete tasks on computers and other devices. However, recent research shows that while a majority of companies use third-party applications or software, less than 1 in 5 organizations has performed third-party software verification.

“Covered Entities and Business Associates should define the criteria they are willing to accept for safe third-party applications, including open source and public domain applications,” OCR urged. “Applications should meet the corporate standards set by the entities and also satisfy compliance requirements, and entities should test against these criteria.”

Healthcare organizations should also install the necessary software patches or the most updated version of an app, the statement warned. Even so, these patches should be assessed before deployment to ensure they do not inadvertently put a system at risk. 

Finally, OCR encouraged organizations to review any software license agreements, which can also be referred to as an end-user license agreement (EULA). OCR specifically cited recommendations from the United States Computer Emergency Readiness Team (US-CERT). 

“Software license agreements are legal binding agreements that can have restrictions on how the software can be used; the agreements can require entities to agree to certain conditions when using the software, and can also limit their ability to sue for damages,” OCR stated. 

According to US-CERT, facilities should review the software EULA before installing any software. Additionally, organizations need to be aware of any firewall prompts when they are installing software, as it should be verified that the software requires changes to your firewall settings for normal operation.

It will also be beneficial for organizations to familiarize themselves with a company, and review that company’s EULA “with added scrutiny.” 

Dig Deeper:

NEW ORLEANS -- Dogs may be good at sniffing out some types of cancer, but that skill doesn't appear to transfer to detecting hypoglycemic events, according to research presented here.

From www.medpage.com

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Diabetic dog alerts had a low sensitivity and positive predictive value (PPV), reported Evan Los, MD, of Oregon Health & Science University in Portland, and colleagues.

When the trained dog issued an alert to a hypoglycemic event in a patient with type 1 diabetes, these alerts were only "timely" -- defined as within 10 minutes before or up to 30 minutes after a diabetic event -- a little over a third of the time (36%).

When comparing dog alerts with continuous glucose monitoring (CGM), of the 30 hypoglycemic events detected by both the CGM and the dog, the CGM alerted to these events by a clinically significant median of 22 minutes ahead of the dog. The CGM detected the threshold for hypoglycemia 73% of the time, they said in a presentation at the American Diabetes Association annual meeting.

In addition, because of inappropriate alerts, the PPV of a dog alert for hypoglycemia was 12%. The false-positive rate was high -- dogs that alerted 16-20 times a week led to a mean false positive rate of 14.5 times per week, the authors reported.

"Published literature regarding diabetes alert dogs is limited to case reports, retrospective surveys, and in vitro evaluation of dogs not reflecting real-life use," Los told. "Still, patients are utilizing them and clinicians are without much guidance when asked the question: 'What about diabetes alert dogs?'"

Diabetes alert dogs undergo rigorous training, starting with obedience and socialization, as well as scent training. For the latter, they are trained based on a cotton swab of sweat from a human companion during a hypoglycemic event. The training takes 6-24 months to complete, but there is no universal competence test for dogs.

This is the first controlled study of the reliability of diabetes alert dogs to hypoglycemia in their diabetic companions under real-life conditions, Los said. His group examined eight patients (the youngest was 4-years-old) who had both a diabetes alert dog and a blinded CGM. Dog alerts were recorded in a diary and those were compared with capillary blood glucose (CBG) and CGM downloads.

Hypoglycemia was defined as CBG and/or CGM <70 mg/dL. The patients reported impressions of dog reliability and reasons for obtaining a diabetes alert dog.

While the dogs' performance compared with CGM was lackluster, their human companions reported being happy with their performance. Dog owners self-reported as very satisfied (8.9 of 10 on a Likert scale) and largely confident (7.9 of 10) in their dog's ability to detect hypoglycemia. The latter was cited by the study participants as the reason for having a diabetes alert dog.

The rate of dog alerts during hypoglycemia were 3.2 times greater (95% CI 2.0-5.2) than during euglycemia. However, the first sign of hypoglycemia was the CGM (70%), followed by the dog (19%), followed by a patient's symptoms (12%).

Study limitations included the small sample size, short duration of the study, and the fact that the dogs were different breeds and different ages, and from different trainers. The most reliable dog in the sample had completed 24 months of dog training, suggesting that dog skills diminish over time and may require re-training.

Los said that if someone has an alert dog and finds it beneficial, he wouldn't tell them to get rid of the animal because it is identifying more hypoglycemia than not having a dog at all.

"This is not the final word on whether trained dogs might be helpful for patients with diabetes," Los told. "There may be other benefits not assessed by this study that are important such as having a positive partner in the daily management of a chronic disease."

 

This study was supported by the Helmsley Trust.

Los disclosed no relevant relationships with industry.

NEW ORLEANS — Pioglitazone halved the progression to diabetes in people with insulin resistance and cerebrovascular disease, new data from the Insulin Resistance Intervention after Stroke (IRIS) trial show.

From www.medscape.com

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The new findings from the 5-year study were presented June 14 by Silvio E Inzucchi, MD, as part of the president's oral abstract session here at the American Diabetes Association (ADA) 2016 Scientific Sessions.

The main IRIS finding — that pioglitazone reduced by a significant 24% the risk for recurrent stroke or myocardial infarction (MI) in people with insulin resistance, no frank diabetes, and a recent history of stroke or transient ischemic attack — were presented earlier this year at the International Stroke Conference 2016 and simultaneously published in the New England Journal of Medicine. 

In the new analysis, progression to diabetes — a prespecified secondary end point of IRIS — occurred in 3.8% of the 1939 individuals randomized to 45 mg/day of pioglitazone compared with 7.7% of the 1937 receiving placebo, a significant 52% reduction in the time to diabetes onset (< .0001).

The difference was driven primarily by the reduction in patients at highest risk, including those with prediabetes and the greatest degrees of insulin resistance and metabolic syndrome.

The prevention of diabetes and secondary stroke seen together in IRIS is "the first time [both have been] shown in one trial with one drug, although they are not necessarily linked," Dr Inzucchi told 

But this isn't the first time pioglitazone has been shown to reduce the risk of type 2 diabetes, he stressed. In 2011, the Actos Now for Prevention of Diabetes (ACT NOW) study demonstrated a 72% reduction in the conversion rate from impaired glucose tolerance to type 2 diabetes. And a recent look at those patients showed that pioglitazone's protective effect persists at least a year after they stop taking it.

Pioglitazone also previously showed cardiovascular benefit in the 2005 PROactive trial, with a significant 16% reduction in death, MI, and stroke, although it failed to show a statistically significant reduction in the composite primary end point of major adverse cardiac events (MACE).

In August 2012, the US Food and Drug Administration approved the first generic version of pioglitazone.

In Connecticut, it now costs less than $10 a month, approximately 100-fold less than some of the newer oral and injectable type 2 diabetes drugs, Dr Inzucchi pointed out during a press conference held to discuss the findings during the ADA meeting.

"Pioglitazone is the only oral type 2 diabetes drug with clear antiatherosclerosis effects.…Should the role of this inexpensive, generic medication in type 2 diabetes management be reassessed?" he wondered.

Also, he said, "Should the neurology community consider the potential role of pioglitazone for secondary stroke prevention?"

Ralph A DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center, San Antonio, and ACT NOW lead author, believes the time is right to take another look at pioglitazone.

"IRIS was very impressive.…Believe me, if you have a stroke, you should be on that drug. I would think we ought to change our practice of treating stroke," he said in an interview during the ADA meeting.

And regarding the new IRIS data, Dr DeFronzo said: "I think pioglitazone, particularly in lower doses is an ideal drug for prevention of diabetes," adding, "Personally, I think it is the second-best drug for treating people with diabetes."

But Will Safety Concerns Trump Benefit? 

Pioglitazone's use has waned in recent years, due primarily to concerns about the well-supported risk of heart failure generally with the thiazolidinedione (TZD) class of drugs, and the less well-clarified possible risk for bladder cancer specifically with pioglitazone. Studies continue to volley between an increased bladder cancer risk and no risk, and the issue remains controversial.

Weight gain and edema are also common side effects with TZDs generally, and an increased risk for fractures has also been reported.

In IRIS, there was no increased risk for incident cancer with pioglitazone (6.9% vs 7.7%, P = .29) or heart failure (2.6% vs 2.2%, P = .35), but bone fractures did occur at a significantly higher rate with the drug (5.1% vs 3.2%, P < .01). The lack of significance for heart failure was probably due to the study's exclusion of patients with heart failure at baseline and aggressive protocols for managing patients who developed edema during the trial, Dr Inzucchi noted.

Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, told Medscape Medical News that he believes pioglitazone's safety issues, particularly the fracture risk, deserve serious consideration.

"I think that there are a lot of good things about the TZDs and certainly the PROactive study suggested that in that patient population, pioglitazone was safe and, at least, as judged by secondary end points, might possibly have benefit in terms of preventing MACE.…But, I think the bone fractures are really a very substantial risk from a quantitative point of view, particularly with chronic use of the drug."

Previous data suggest about a 3-year time lag to increase in fractures in men and about 1-year delay in women. That, combined with the heart-failure risk, "is important to take into consideration as one judges the benefit/risk profile of the drug," particularly in the context of prevention, Dr Taylor said.

"We've been aware of the bone-fracture issue for years with the TZDs. It is a concern and we don't understand it that well, so it is difficult to make recommendations as to how to prevent them from happening."

Dr Inzucchi said that the additional risk of fractures is about one for every 100 patients using the drug for 1 year, "so it's not a large signal. One might think that preventing a stroke or an MI is more important, but that depends on several factors, including how severe the fracture vs the stroke/MI is.

"In IRIS we did not see a hip-fracture signal, which is gratifying. Nonetheless it needs to be incorporated into decision making with the patient."

Diabetes Prevention 

In IRIS, at baseline, about 42% of the 3876 total patients had impaired fasting glucose (IFG) of 100 to 125 mg/dL (as defined by the American Diabetes Association), while 14% met the World Health Organization/International Diabetes Federation IFG criteria (110–125 mg/dL), and two-thirds had HbA1clevels of 5.7% or greater. Just over half had at least three components of the metabolic syndrome.

At 1 year, fasting plasma glucose was reduced significantly in the pioglitazone group (from 98.2 to 95.1 mg/dL) but remained unchanged in the placebo group (< .0001 for between-group difference). Homeostasis model assessment of insulin resistance (HOMA-IR) also dropped significantly with pioglitazone compared with placebo (P < .0001).

Over an average 4.8 years, there was a 3.9% absolute risk reduction in progression to diabetes with pioglitazone compared with placebo (hazard ratio, 0.48), with greater risk reductions seen among those meeting the ADA definition of IFG at baseline (8.5% vs 0.8%), those with baseline HbA1c 5.7% or greater compared with below (5.6% vs 1.0%), and HOMA-IR 4.6 or above vs below (6.3% vs 1.4%).

Dr Inzucchi told "My belief is that the diabetes community must readjudicate the role of pioglitazone based on these data. It is an extremely cost-effective drug."

However, press briefing moderator Ann Albright, PhD, director of the division of diabetes translation at the US Centers for Disease Control and Prevention, Atlanta, Georgia, made a plea for clinicians not to forget about lifestyle when aiming to help at-risk patients to avoid developing diabetes.

"From our perspective at CDC, the use of medications is clearly a decision that the patient and their clinician needs to discuss. They should be considered tools in the armamentarium that people should be able to call upon, but even if you pursue those, lifestyle is still the foundation."

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

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Christoph Wanner, M.D., Silvio E. Inzucchi, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Maximilian von Eynatten, M.D., Michaela Mattheus, Dipl. Biomath., Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D., and Bernard Zinman, M.D., for the EMPA-REG OUTCOME Investigators*

June 14, 2016DOI: 10.1056/NEJMoa1515920

BACKGROUND

Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium–glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.

 

METHODS

We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.

 

RESULTS

Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001).

Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%.

Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group.

There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.

 

CONCLUSIONS

In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)

Ny milstolpe i forskningen om typ 2-diabetes

Patienter med typ 2-diabetes och hög risk för hjärt-kärlsjukdom fick minskad sådan risk om de behandlades med läkemedlet liraglutid som härmar effekten av tarmhormonet GLP-1. Det visar en ny studie i New England Journal of Medicine, skriver Carl-Magnus Hake www.dagensmedicin.se

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– Resultatet är så bra man kan förvänta sig. Redan nu används det här läkemedlet lite mer i klinisk praxis än vad som anmodas i nationella riktlinjer. Det här resultaten kan nog ytterligare stärka liraglutids roll i behandlingen, säger Mona Landin-Olsson, professor och överläkare vid Skånes universitetssjukhus i Lund samt ordförande i Svensk förening för diabetologi.  

Det har länge varit svårt att visa att glukossänkande behandling också motverkar den förhöjda kardiovaskulära risken vid typ 2-diabetes. Men på kort tid har framför allt två studier ändrat på den bilden.

I september 2015 presenterades studien Empa-reg som visade att den så kallade SGLT-2-hämmaren empagliflozin (Jardiance) minskade risken för hjärt-kärlhändelser och förtidig död bland patienter med hög kardiovaskulär risk.

Och nu kommer ett liknande resultat för GLP-1-analogen liraglutid (Victoza) i studien Leader som totalt omfattade 9 340 patienter.

Efter i snitt 3,8 års behandling hade 13 procent av deltagarna som lottats till liraglutid drabbats av någon händelse i det primära effektmåttet, vilket omfattade kardiovaskulär död samt icke-dödlig stroke eller hjärtinfarkt. . Motsvarande siffra i placebogruppen var 14,9 procent.

Även andelen dödsfall oavsett orsak var lägre för dem som fått liraglutid: 8,2 jämfört med 9,6 procent. 

Den vanligaste anledningen till att patienter avbröt behandling med liraglutid var mag-tarmbiverkningar.

Överlag är resultaten övertygande och studien är välgjord. Ett möjligt frågetecken är dock att fler patienter som fick liraglutid uppnådde målet för det långsiktiga blodsockret HbA1c. Det kan möjligen förklara en del av skillnaderna i utfall mellan grupperna, snarare än specifika skillnader i verkningsmekanism, säger Mona Landin-Olsson.

Även Peter M Nilsson, professor i klinisk kardiovaskulär forskning vid Lunds universitet, ser positivt på studien.

– Detta är en milstolpe i behandlingsforskningen vid typ 2-diabetes. Liksom andra väsentliga resultat från stora randomiserade studier tror jag den kommer att påverka behandlingsriktlinjer, säger han.

Peter M Nilsson poängterar att resultaten gällde för patienter som bedömts ha hög risk för hjärt-kärlsjukdom, huvudsakligen för att de redan drabbats av sådan sjukdom.  

– Troligen kan man inte utan vidare extrapolera resultaten till ”vanliga” typ 2-diabetespatienter. Och det är viktigt eftersom liraglutid också lanseras som viktminskande behandling och många patienter med typ 2-diabetes är obesa, säger han.

Ytterligare ett frågetecken är att patienter som inte tålde behandlingen sållades bort innan studien började.

– Det kan ge en falsk bild av att behandlingen var mer tolerabel i studien än i verkligheten, säger Peter M Nilsson.

Den statistiska säkerställda skillnaden i det primära effektmåttet i studien drevs huvudsakligen av en gynnsam effekt på kardiovaskulär död. Förekomsten av icke-dödlig hjärtinfarkt och stroke var lägre i liraglutidgruppen men inte statistiskt säkerställt så, jämfört med kontrollgruppen. Även förekomsten av sjukhusinläggningar på hjärtsvikt var icke-signifikant lägre i liraglutidgruppen. 

Deltagarna i studien hade alla otillräckligt kontrollerat blodsocker och var över 50 år med minst en kardiovaskulär sjukdom. Alternativt kunde de vara över 60 år och ha någon annan kardiovaskulär riskfaktor.  

Bakom undersökningen står ett internationellt forskarlag som presenterar resultaten på den amerikanska diabeteskongressen ADA i New Orleans.

Forskarna jämför resultaten i den aktuella studien med dem för empagliflozin i Empa-reg. Slutsatsen är att effekterna i Empa-reg kom tidigare än i Leader, något forskarna spekulerar kan bero på att empagliflozin mer kan ha en positiv effekt på hemodynamiken medan liraglutid eventuellt skulle kunna ha en mer direkt effekt på aterosklerosutveckling. 

Forskarna jämför också med flera andra liknande studier av läkemedel mot typ 2-diabetes där man dock inte sett