From Gold Study
Marcus Lind, MD, PhD; William Polonsky, PhD; Irl B. Hirsch, MD; Tim Heise, MD; Jan Bolinder, MD, PhD;
Sofia Dahlqvist; Erik Schwarz, MD, PhD; Arndís Finna Ólafsdóttir, RN; Anders Frid, MD, PhD; Hans Wedel, PhD; Elsa Ahlén, MD; Thomas Nyström, MD, PhD; Jarl Hellman, MD
 
JAMA Continuous Glucose Monitoring vs Conventional Therapy for Glycemic Control in Adults With Type 1 Diabetes Treated With Multiple Daily Insulin Injections
The GOLD Randomized Clinical Trial
 
ABSTRACT
IMPORTANCE The majority of individuals with type 1 diabetes do not meet recommended glycemic targets.
 
OBJECTIVE Toevaluatetheeffectsofcontinuousglucosemonitoringinadultswithtype1 diabetes treated with multiple daily insulin injections.
 
DESIGN,SETTING,ANDPARTICIPANTS Open-labelcrossoverrandomizedclinicaltrial conducted in 15 diabetes outpatient clinics in Sweden between February 24, 2014, and June 1, 2016 that included 161 individuals with type 1 diabetes and hemoglobin A1c (HbA1c) of at least 7.5% (58 mmol/mol) treated with multiple daily insulin injections.
 
INTERVENTIONS Participantswererandomizedtoreceivetreatmentusingacontinuous glucose monitoring system or conventional treatment for 26 weeks, separated by a washout period of 17 weeks.
 
MAINOUTCOMESANDMEASURES DifferenceinHbA1cbetweenweeks26and69forthe2 treatments. Adverse events including severe hypoglycemia were also studied.
 
RESULTS Among161randomizedparticipants,meanagewas43.7years,45.3%werewomen, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, −0.43% [95% CI, −0.57% to −0.29%] or −4.7 [−6.3 to −3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia.
 
CONCLUSIONSANDRELEVANCE Amongpatientswithinadequatelycontrolledtype1diabetes treated with multiple daily insulin injections, the use of continuous glucose monitoring compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects.
 
TRIALREGISTRATION clinicaltrials.govIdentifier:NCT02092051
 
Background
Intensive insulin therapy resulting in good glycemic con- trol has been shown to prevent and reduce the progres- sion of diabetes-related complications in patients with type 1 diabetes.1 Today, intensive glycemic control is generally achieved through multiple daily insulin injections or continu- ous subcutaneous insulin infusions through an insulin pump.2 Regular self-measured capillary blood glucose values have been crucial to optimal insulin dosing for good glycemic control.3-5
In recent years, continuous glucose monitoring (CGM) has become an option for optimal insulin dosing and other activities.6 The advantages of CGM include providing continu- ous feedback on estimated glucose values and illustrating glu- cose trends. CGM systems include a subcutaneous sensor with a transmitter attached and continuous reporting of glucose lev- els and trends to the patient by a handheld monitor.
 
Data from clinical trials of CGM have been mixed regard- ing its effect on glycemic control.7 Such trials have, for example, consisted only of patients with the following characteristics: (1) continuous subcutaneous insulin infusions; (2) initiated CGM and continuous subcutaneous insulin infusions simulta- neously; or (3) included patients with both multiple daily insu- lin injections and continuous subcutaneous insulin infusions.7-10 Post hoc findings have also been mixed, in that glycemic control appears to differ when CGM is combined with either multiple daily insulin injections or continuous subcutaneous insulin infusions.8-10 Although the majority of adults with type 1 dia- betes in the United States and Europe are treated with multiple daily insulin injections, to our knowledge, clinical trials evalu- ating CGM vs conventional therapy in persons treated with mul- tiple daily insulin injections have not been performed.
 
The aim of this study was to analyze the effect of CGM on glycemic control, hypoglycemia, well-being, and glycemic vari- ability in individuals with type 1 diabetes treated with mul- tiple daily insulin injections.
 
Discussion
In this crossover study of persons with type 1 diabetes treated with multiple daily insulin injections, CGM was associated with a mean HbA1c level that was 0.43% (4.7 mmol/mol) less than conventional treatment. Moreover, glycemic variability was re- duced by CGM. Subjective well-being and treatment satisfac- tion were greater during CGM than conventional therapy.
The population evaluated in the current study differs to a great extent from earlier clinical trials of CGM.7-10,25,26 The cur- rent study aimed to include a more general population of per- sons with type 1 diabetes. In contrast to earlier trials, the cur- rent study had no upper limit of HbA1c for inclusion, which includes the group of patients with the greatest excess mortality27,28 and the highest risk of diabetic levels and diabetic complications.
ment options for reducing HbA1c in these patients is of great concern. Baseline HbA1c was also high (8.7%) in the current population, and not only was mean HbA1c reduced but fewer patients also had very high HbA1c levels during CGM therapy.
Also in contrast to earlier CGM-studies,7-10,25,26 the current trial had no limit on the number of self-measurement of blood glu- cose patients were required to perform for inclusion. Patients who do not perform self-measurement of blood glucose regularly have higher HbA1c levels.4 Despite the availability of free glucose me- ters and test strips in Sweden, less than 50% of patients perform self-measurement of blood glucose according to guidelines (>4 times/d). Hence, evaluating alternative glucose monitoring strat- egies for these patients is also important. In the present study, pa- tients performed self-measurement of blood glucose less during CGM than conventional therapy (2.7 vs 3.7 measurements/d).
When used in connection with an insulin pump, CGM may ease adjusting insulin doses with respect to observed CGM patterns.2 Certain processes in the pump can also be guided by CGM information, such as halting the insulin infusion during a rapid decline in glucose.26 Conversely, most adults with type 1 diabetes are treated with multiple daily insulin injections.29 Therefore, novel complementary treatment strategies are needed on a broad level. In the intervention/control sequence, HbA1c re- verted back to prestudy levels during the washout period (Figure 2), indicating that there was no carry-over effect. In ac- cordance with earlier findings,9 these results also suggest that the effectiveness of CGM depends on uninterrupted use during multiple daily insulin injections treatment. Our study in- creases knowledge in the field of type 1 diabetes in reporting that CGM may be a beneficial option for multiple daily insulin injec- tions–treated patients with respect to HbA1c levels.
A novel feature of this trial is a more comprehensive inves- tigation of psychosocial variables, which are now recognized as a high priority in clinical diabetes guidelines.30 To our knowledge, this trial is the first to demonstrate a significant improvement in subjective well-being and treatment satisfaction in adults using CGM in comparison with conventional therapy. The positive effect on well-being is consistent with previous studies that have shown a significant effect due to CGM on the physical component subscale of the SF-36 (Short Form Health Survey).10,31 In total, these psychosocial benefits may be at least partially due to the sig- nificant HbA1C improvement,32 as well as to the reduction in time spent in hypoglycemia. Indeed, less time in hypoglycemia is known to be associated with better quality of life33,34 and a lower risk of severe hypoglycemia.35,36 Furthermore, hypoglycemic con- fidence improved during CGM therapy, but it should be inter- preted with greater caution since this was an exploratory endpoint. Of note from a safety perspective, there were numerically more severe hypoglycemic episodes (5 vs 1) during conventional compared with CGM therapy. In addition, 7 severe hypoglycemia events occurred during the washout period of 4 months when pa- tients used conventional therapy.
 
This study had a number of limitations. First, 19 patients (approximately 12.0%) had no follow-up data in the second treat- ment period and were not included in the primary analysis. Gen- erally, in a parallel-group study, this can lead to an imbalance between groups. However, in the current study, patients served as their own controls and thus no such problem existed. It has therefore been proposed that the full analysis set population should be used in crossover studies as the main analysis.37 In ad- dition, with the crossover design, it can be determined whether results are going in the same direction during the first treat- ment period from a parallel design perspective. Sixteen of the 19 patients who had no follow-up data in the second treatment period had HbA1c data during the first follow-up period. Among these patients, those with CGM had a 1.0% decrease in HbA1c, whereas those with conventional therapy had an increase of 0.1%. There were more patients treated with CGM than conven- tional therapy who discontinued treatment during the first treat- ment period. This was due to patients wanting to continue CGM and therefore not completing the study while receiving conven- tional therapy in the second period and also due to patients ex- periencing device-related problems (Figure 1).
 
A second limitation is that the study could not be blinded and hence patients were aware of the intervention. It cannot be excluded that this, to some extent, could have influenced the treatment effect. Although the current reduction in HbA1c may be clinically important, other treatment alternatives are needed for persons with type 1 diabetes to obtain good glyce- mic control on a broad level. In addition, the current results are restricted to patients with HbA1c of at least 7.5%.
 
Conclusions
Among patients with inadequately controlled type 1 diabetes treated with multiple daily insulin injections, the use of CGM compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects.
 
Adult patients with type 1 diabetes who use multiple daily insulin injections had a significant reduction in HbA1c levels with continuous glucose monitor (CGM) versus usual care, according to researchers.
 
There was a -0.6% mean change in A1c levels after 24 weeks of using a CGM compared with usual care (95% CI, -0.8% to -0.3%, P<0.001), reported by Roy W. Beck, MD, PhD, of the Jaeb Center for Health Research in Tampa, Fla., and colleagues.
Usual care was defined as self-monitored blood glucose testing for a minimum of four times per day, they reported in the Journal of the American Medical Association.
 
A separate Swedish study, also in JAMA, also reported benefits with CGM in a similar patient population but at 26 weeks.
In an accompanying editorial, Mayer B. Davidson, MD, of the Charles R. Drew University of Medicine and Science in Los Angeles, stated both studies were important in analyzing the benefits of CGM with self-monitoring of blood glucose.
The majority of patients with type 1 diabetes use daily insulin injections and adjust insulin administration based on preprandial and postprandial self-monitored blood glucose values," Davidson noted.
Real-time CGM "has the potential to improve diabetes control by limiting hyperglycemia, decreasing episodes of hypoglycemia, lowering glucose variability ... and enhancing patient satisfaction with glycemic treatment," he added.
 
End of JAMA Citation
____________________
 
From www.medpagetoday.com
DIAMOND Trial
Beck's group recruited adults (mean age 48) with type 1 diabetes, using daily insulin injections, from 24 endocrinology practices, and randomly assigned them to the CGM intervention (n=105) or the usual care control group (n=53). The CGM group used a Dexcom G4 Platinum CGM System, which measured glucose levels every 5 minutes. Data collected at baseline, 12, and 24 weeks on 147 participants was included in the statistical analysis.
 
Women made up 44% of the study population. The mean baseline HbA level was 8.6%, and the median duration of diabetes was 19 years (interquartile range 10-31 years). Almost all of the participants (98%) completed the study.
The authors reported a 1.1% mean reduction in A1c levels in the CGM group after 12 weeks versus 0.5% in the control group. After 24 weeks, the CGM group had a 1.0% mean reduction in A1c levels versus 0.4% in the control group (P<0.001 for both).
 
Duration of hypoglycemia nearly decreased by half among the CGM group, averaging 43 minutes per day (IQR 27-69) compared to 80 min per day (IQR, 36-111) in the usual care group (P=0.002).
 
No cases of diabetic ketoacidosis were reported, but severe hypoglycemia occurred in two participants from each group.
Beck told MedPage today that a previous project -- the Type 1 Diabetes Exchange, a registry including over 30,000 individuals with type 1 diabetes -- found CGM was only utilized in about 6% of patients using insulin injections.
"We wanted to do a clinical trial to determine whether CGM would be beneficial for patients with type 1 diabetes using insulin injections, with the expectation that if the results were positive that this would lead to greater use of CGM and better diabetes outcomes," he explained.
 
"Prior to conducting the trial, we did not know whether patients not using an insulin pump would be willing to wear a CGM sensor on a daily or near-daily basis long term since, unlike pump users, injection users are not accustomed to wearing a device," Beck added. "Additionally, we did not know how much CGM would be beneficial even if worn every day. Pump users have far greater flexibility in adjusting their insulin delivery in response to CGM glucose readings than do injection users."
Nonetheless, the volume of CGM use among participants was surprisingly high, comparable to what previous studies have reported among pump users, he said.
 
Among the CGM group, median use was 7.0 days/week (IQR, 7.0-7.0) before 24 weeks, which dropped slightly to 6 or more days/week for 93% of participants during month 6. Only 2% of participants discontinued use before 24 weeks.
The study had some limitations. The authors pointed out that the results may not apply to individuals with type 1 diabetes who are younger than 26 years or have HbA levels outside the range of 7.5% to 9.9%. The results also should not be applied to individuals with type 2 diabetes who receive multiple daily injections of insulin, they cautioned.
 
GOLD Trial
Individuals with uncontrolled type 1 diabetes using multiple daily insulin injections had lower HbA1c levels when using CGM versus convention treatment, reported Marcus Lind, MD, PhD, of the Diabetes Outpatient Clinic at Uddevalla Hospital in Sweden, and colleagues
The randomized clinical GOLD trial found individuals using a CGM with multiple daily insulin injections had an average A1c of 7.92% (180.7 mg/dL) versus 8.35% (193.9 mg/dL) with conventional treatment (mean difference -27.4 mg/dL, 95% CI -31.6 to -23.2 mg/dL, P<0.001). Levels were measured at baseline and weeks 4, 13, and 26.
The mean age of the 161 participants from 15 diabetes clinics was 43.7, and 45.3% were women, with a mean HbA of 8.6%. A total of 142 participants had follow-up data in both treatment periods. Participants were assigned to the CGM group (n=82), which used the same system as the DIAMOND trial, or the conventional treatment group (n=79), which involved self-monitored blood glucose testing.
A total of 142 participants were included in the statistical analysis. Following the 26-week intervention period, all participants were included in a 17-week washout period, during which they all used conventional treatment.
Nineteen secondary endpoints of psychosocial variables were also assessed, "which are now recognized as a high priority in clinical diabetes guidelines," according to the authors.
Variables reaching statistical significance included improved overall well-being among the CGM group, measured by the WHO-5 questionnaire (66.1 versus 62.7, P=0.02). The CGM group also reported less hypoglycemia fear, measured by the Hypoglycemia Confidence Questionnaire scale (3.40 versus 3.27, P<0.001). The Diabetes Treatment Satisfaction Questionnaire status version found the CGM group had higher treatment satisfaction versus conventional treatment (30.21 versus 26.62, P<0.001).
The authors suggest the improvement in the psychosocial variables may be a result of the "significant HbA1c improvement, as well as to the reduction in time spent in hypoglycemia," among the CGM group.
During the first phase of the trial, one CGM user and five control participants experienced severe hypoglycemia, while seven participants experienced severe hypoglycemia during the washout period.
The study had some limitations including a lack of blinding so patients were aware of the intervention, which may have influenced treatment effects.
 
'Several Caveats'
Davidson warned that "there are several caveats regarding the findings and the generalizability of the results."
Lastly, he also warned against generalizing the results of the studies to patients with type 2 diabetes.
Beck told MedPage Today that his group has conducted two follow-up studies, one of which analyzed the benefits of CGM use among type 2 diabetes patients using insulin, while the other assessed the benefit of insulin pump therapy among the same participant group from the DIAMOND trial.
Both follow-up studies will be presented at the Advanced Technologies and Treatments for Diabetes meeting in Paris in February, he said.
 
Click here for a 2016 consensus statement on CGM from thee American Association of Clinical Endocrinologists and American College of Endocrinology
https://www.aace.com/files/guidelines/PrePrintContinuousGlucoseMonitoring.pdf
 
The DIAMOND trial was funded by Dexcom. Beck disclosed relevant relationships with Dexacom and Abbott Diabetes Care. Co-authors disclosed multiple relevant relationships with industry including Dexacom, Medtronic, Novo Nordisk, Lexicon, Sanofi, AstraZeneca; Eli Lilly, and Janssen.
 
The GOLD trial was supported by theNU Hospital Group, Trollhättan and Uddevalla, Sweden.
 
Svensk kommentar Hans Jönsson
 
CGM och sprutor
25 januari, 2017
 
Idag råder inga tvivel om nyttan en kontinuerlig blodglukosmätare, CGM, gör. Precisionen på dem är idag god och de förlänger liv, sparar pengar genom bättre kontroll och därmed minskade senkomplikationer på sikt och inte minst, de ger livskvalitet. Det sistnämnda är för oss med sjukdomen oerhört väsentligt men också en utmaning att förmå någon utan sjukdomen att förstå. Dessa hjälpmedel gör oss inte friska, det är inget botemedel, men vi känner oss mindre sjuka och mer fria.
 
Nästan alla studier som gjorts med CGM görs med kombinationen insulinpump och CGM. Antalet studier med CGM har eskalerat sista åren då tekniken förbättrats, kostnaden sänkts, förståelsen blivit bättre från flera håll och därmed har fler fått tillgång till hjälpmedlen.
 
Om CGM har jag skrivit en mängd gånger, inte minst den analys jag gjorde om förskrivningen i hela landet förra året, första gången vi kunde se skillnader mellan landsting. Här är ett par av de artiklar jag skrivit; 1, 2 och 3.
 
Nu har två mycket intressanta studier publicerats, som gjorts på personer som haft CGM och injektioner med sprutor. Detta är inte minst intressant eftersom majoriteten av Sveriges vuxna med typ 1 diabetes har sprutor. Förskrivningen av insulinpump har ökat sista åren men jag kunde i min artikel ovan, där jag även inkluderade insulinpump, visa att 24% av vuxna T1D har insulinpump. Tittar man på NDR (4) visar de 22%, så i paritet med min data. Det innebär således att ca 76% av vuxna T1D har sprutor. Både studierna har publicerats i JAMA, en gjord i USA och en i Sverige. Först den svenska som är utförd av Marcus Lind med kollegor, extremt välgjord studie.
 
SVENSK STUDIE MED CGM OCH INSULINSPRUTOR
Studien har pågått mellan februari 2014 och juni 2016, oerhört bra med en longitudinell studie. De rekryterade 161 vuxna med typ 1 diabetes med ett HbA1c om minst 58 mmol (snitt 70 mmol) utan övre gräns (mycket bra), snittålder 44 år och snittduration 22 år. Av de 161 personerna så fullföljde 142 studien.
 
Studiens frågeställning var:
Vid studiens start fick patienterna ha ”dold” CGM i två veckor, dvs de fick inte själva se värdena. I början av varje testperiod användes denna metod igen i två veckor, samt i två av de avslutande veckorna med CGM. Detta för att kunna jämföra standardavvikelse (i praktiken glukosvariabilitet), se tid i hypoglykemi/hyperglykemi etc, mot patienten själv. Samtliga använde Dexcom G4. Patienterna delades upp i två grupper där den ena bar CGM och hade insulinsprutor, den andra traditionella blodglukosmätare och insulinsprutor. Detta pågick i 26 veckor, sedan skiftade grupperna efter en paus om 17 veckor. Så här såg det ut över tid:
 
Med CGM var HbA1c efter 26 veckor motsvarande i vår standard 63 mmol, vs 68 hos de med traditionell mätning. Detta är en otroligt viktig skillnad, och för de som möjligen tror att det ”bara är 5 mmol” så kan detta vara avgörande över tid för risken att drabbas av senkomplikationer (se mer om detta nedan). Denna skillnad syntes i båda grupperna som hade CGM intressant nog, se nedan bild. Man ser tydligt var skiftet är mellan CGM och traditionell mätning, och deltagarna ”skiftar plats”. Man ser också att de som hade CGM första perioden i tiden mellan, månad 6-10, gick tillbaka till nivån motsvarande HbA1c de hade vid start. De som då fick CGM sänkte HbA1c motsvarande grupp 1:
 
Deltagarna fick även svara på frågor om livskvalitet, trygghet, rädsla för hypoglykemier etc, och givetvis upplevdes förbättringar på allt detta då de hade CGM. Detta är exceptionellt viktiga parametrar som jag skrev i början, och dessa fynd stöds av tidigare studier. Nedan är resultatet på studiens syften;
 
Deltagarna bar CGM i snitt 88% av tiden, ett fåtal hade den mindre än 70% av tiden och på dessa syntes ingen uppenbar minskning av HbA1c. Standardavvikelsen var 2,75 med CGM vs 3,66 utan (dvs jämfört med de som hade CGM men inte kunde se värdena, otroligt viktigt och intressant att jämföra detta). Tiden i hypoglykemi, här definierat under 3,9 mmol, var 38% med CGM vs 40%.
 
Forskarna skriver som avslutning att deltagarna i studien inte hade begränsningar för tester med stickor, och menar att de som helt förlitar sig på CGM generellt har högre HbA1c än de som kontrollmäter med stickor. CGM ger bättre HbA1c, mindre glukosvariabilitet, bättre välmående och livskvalitet, mindre hypoglykemier och rädsla för detta. Gör med andra ord enorm nytta. Observera att det trots teorier om att svängningar ökar risken för komplikationer inte kunnat visas i en enda studie ännu, däremot tiden som spenderas i hyperglykemi, höga värden, ökar risken för komplikationer. Viktigt budskap.
Studien som abstrakt, bilderna kommer från fulla versionen som jag har men inte kan publicera 5.
 
AMERIKANSK STUDIE MED CGM OCH INSULINSPRUTOR
Denna studie finns bara lite data från, jag har ännu inte tillgång till annat än abstraktet nedan. 158 deltagare med typ 1 diabetes, snittålder om 48 år, genomsnittlig duration 19 år, HbA1c vid start motsvarande 70 mmol. De bar CGM i 24 veckor, HbA1c sänktes i snitt med 6 mmol, i paritet med den svenska studien och fullkomligt ovärderligt. Tid under 3,9 mmol var häften för gruppen som hade CGM vs den utan, otroligt bra resultat. Studien 6.
 
SUMMERING
Forskarna bakom både studierna skriver att mer forskning behövs, vilket gäller allt inom diabetes. Tillika tycker jag personligen som läser allt att de är överdrivet ödmjuka då vi idag och särskilt senaste tre åren har så mycket data som påvisar nyttan av vad CGM och tekniska hjälpmedel gör för kontrollen på kort sikt samt risker på både kort och lång sikt. Dessa studier adderas till tidigare och är linje med dem, även om båda dessa nya är med insulinsprutor.
Typ 1 diabetes är en allvarlig, lynnig, kronisk och obotlig sjukdom, med få garantier. Det finns ingen nivå av kontroll eller HbA1c som ger 100% säkert skydd mot både akuta och långsiktiga komplikationer, men det finns med tekniska hjälpmedel möjlighet att förbättra chanserna radikalt. Det är inget botemedel fortsatt.
 
Den enormt uppmärksammade VISS-studien från Linköping (7) samt den longitudinella DCCT/EDIC-studien, som har en mängd publikationer under 25 år och ligger till grund för all diabetesbehandling globalt sedan länge (8 och 9) har visat kraftigt minskade komplikationer och mortalitet vid välkontrollerad typ 1 diabetes. Skillnaden mellan dessa två studier (DCCT/EDIC är i praktiken flera studier i en) är att VISS inte hade ett selektivt urval av deltagarna, DCCT/EDIC hade möjligen lite mer motiverade patienter. Jag kommer framöver skriva mer om dessa och andra studier.
 
Vi vet idag att risken inte är obefintlig men mycket lägre om vi kommer ner under 60 i HbA1c, det finns dock ingen nivå där vi är säkra och pressar vi oss för lågt ökar risken för problem med akuta hypoglykemier, neurologiska komplikationer, det kan påverka hjärnan och hjärtat. Tekniken är givetvis fantastisk men det är inget botemedel. Vi kan inte heller förlita oss på den till 100%, och både hypoglykemier och hyperglykemier inträffar fortsatt, liksom allvarliga incidenter och säkerligen tyvärr dödsfall pga akut lågt blodsocker, och ketoacidos. Chanserna förbättras dock radikalt om vi får de hjälpmedel som de facto existerar.
 
Referenser
 
 
 
http://jamanetwork.com/journals/jama/articleabstract/2598770http://care.diabetesjournals.org/content/38/2/308https://pdfs.semanticscholar.org/ba81/fbee15d437392bec7fac5738a31f1709c225.pdfhttp://care.diabetesjournals.org/content/39/8/1378.1)
 
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