Diabetes player Senseonics unveiled topline results from a clinical investigation of its long-term continuous glucose monitoring implant, indicating “significant” accuracy.

From www. fiercebiotech.com
Nyhetsinfo
www red DiabetologNytt

The Precise II trial involved 90 adults with diabetes at 8 clinical centers and was conducted to assess the safety and efficacy of Senseonics’ Eversense continuous glucose monitoring system. It consists of a subcutaneously implanted sensor, a transmitter patch worn on the skin over the implant, and a mobile device.

The implant, a fluorescent polymer surrounded by a biocompatible material, is intended to last 90 days below the skin. It indicates changes in glucose levels by changing its light output. This change is signaled to the transmitter patch, which automatically sends alerts and alarms to a mobile device when the user’s blood glucose reaches preset low or high levels. While it requires twice-daily fingerstick calibration, Senseonics hopes to move away from that.

The topline results indicated strong accuracy for the 90-day period of continuous wear, posting a mean absolute relative difference (MARD) of 8.8% across the 400-400 mg/dL range when compared to YSI blood reference values, according to a statement.

“The early result shows that this system can be an important treatment option for our patients. Having a long lasting, 90-day CGM sensor that is safe and accurate will be a welcome addition to the diabetes community, as it will offer greater freedom of choice,” said principal investigator Dr. Mark Christiansen of Diablo Clinical Research, in the statement.

The company anticipates submitting a PMA filing within the next few months, with eyes on a U.S. launch pending approval. Eversense received a CE mark in May this year. At the time, Senseonics said it would start commercializing the device in Sweden.

- here's the statement

Senseonics Reports Topline Accuracy Results from U.S. Pivotal Study of Eversense CGM System.

Topline Accuracy of 8.8% MARD (Mean Absolute Relative Difference) over 90 Days.August 09, 2016 04:05 PM Eastern Daylight Time

 

GERMANTOWN, Md.--(BUSINESS WIRE)--Senseonics Holdings, Inc. (NYSE-MKT:SENS), a medical technology company focused on the development and commercialization of a long-term, implantable continuous glucose monitoring (CGM) system for people with diabetes, today announced topline results of the PRECISE II (A Prospective, Multicenter Evaluation of the Accuracy of a Novel Continuous Implanted Glucose Sensor) Clinical Investigation.

“The promising results and compelling accuracy data shown in the PRECISE II study represent a major milestone for the company”

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Results from the 90 adults with diabetes generated over 16,000 comparative glucose data points and demonstrated strong accuracy for the 90-day continuous wear period with a mean absolute relative difference (MARD) of 8.8% across the 40-400 mg/dL range when compared to YSI blood reference values.

According to the Principle Investigator, Dr. Mark Christiansen of Diablo Clinical Research, “The accuracy result is quite significant with the device. This was an important study and we are thankful to all the patients and clinics who participated. The early result shows that this system can be an important treatment option for our patients. Having a long lasting, 90-day CGM sensor that is safe and accurate will be a welcome addition to the diabetes community, as it will offer greater freedom of choice.”

The PRECISE II U.S. investigational device exemption trial enrolled 90 participants at eight clinical centers. The objective of the study was to determine the safety and effectiveness of the Eversense® CGM system over 90 days of continuous glucose sensor wear.

Participants in the study underwent unilateral (n=75) or bilateral sensor (n=15) insertions in the clinic and used the system’s smart transmitter and mobile app at home for the next 90 days. Sensor glucose readings were calculated prospectively. Calibration with a standard home blood glucose meter was performed twice a day but real-time glucose readings and trends were not made available to participants. Clinic visits were scheduled at approximately 30-day intervals in order to obtain lab reference glucose values for comparison with the sensor values and to evaluate hyperglycemic and hypoglycemic challenges in a controlled setting.

“The promising results and compelling accuracy data shown in the PRECISE II study represent a major milestone for the company,” said Tim Goodnow, PhD., CEO and President of Senseonics. “We are quite excited to complete the full analysis and report on other outcomes in the coming months. Pending FDA review and approval, we look forward to bringing this exciting technology to the U.S. market and to people with diabetes.”

Senseonics expects to submit its Pre-Marketing Approval (PMA) package to the U.S. Food and Drug Administration in the next few months. Subject to receiving FDA regulatory approval, Senseonics plans to initiate sales in the United States. The company currently markets the system under the brand name Eversense in select European countries.

About Senseonics

Senseonics Holdings, Inc. is a medical technology company focused on the design, development and commercialization of glucose monitoring products designed to help people with diabetes confidently live their lives with ease. Senseonics’ first generation continuous glucose monitoring (CGM) system, Eversense®, includes a small sensor, smart transmitter and mobile application. Based on fluorescence sensing technology, the sensor is designed to be inserted subcutaneously and communicate with the smart transmitter to wirelessly transmit glucose levels to a mobile device. After insertion, the sensor is designed to continually and accurately measure glucose levels. For more information on Senseonics, please visit www.senseonics.com.

 

Senseonics 

Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease:
national population based cohort study

From BMJ


Nyhetsinfo

Kommentar nederst från BT-expert prof Peter M Nilsson, Malmö

www red DiabetologNytt

ABSTRACT

Samuel Adamsson Eryd,1,2,3 So a Gudbjörnsdottir,1,2 Karin Manhem,2 Annika Rosengren,2,3 Ann-Marie Svensson,1 Mervete Mi araj,1 Stefan Franzén,1 Sta an Björck1

OBJECTIVES

To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.

DESIGN

Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years.

SETTING

861 Swedish primary care units and hospital outpatient clinics.

PARTICIPANTS

187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease.

MAIN OUTCOME MEASURES

Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for di erent levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates.

RESULTS

The group with the lowest systolic blood pressure (110-119 mm Hg) had a signi cantly lower risk of

non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% con dence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality.

CONCLUSIONS

Lower systolic blood pressure than currently recommended is associated with signi cantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment. 

Introduction

Several major hypertension guidelines have recently changed their recommended goal for systolic blood pressure in patients with diabetes.1-3 Instead of aiming for below 130 mm Hg, the current guidelines recom- mend below 140 mm Hg. The consequences of the changed guidelines are unknown.

Over the past 16 years, during which the previous rec- ommendations were in e ect, the average systolic blood pressure among Swedish primary care patients with type 2 diabetes has decreased by 15 mm Hg. In 2015, the average blood pressure of 300000 patients was 135/76 mm Hg.4 The overall excess risk of death among individuals with type 2 diabetes has fallen to a historically low 15%.5

The reason for the new blood pressure target was the lack of randomised studies with conclusive results to support the goal of below 130 mm Hg, together with information based on post hoc analyses of clinical trials and register studies.1 These observational studies have usually shown a J shaped relation between blood pres- sure and cardiovascular events, with an increased risk at the highest and lowest levels.

The relevance of this J curve phenomenon has been called into question given that observational studies of clinical trial data could be awed by uncontrolled con- founding—that is, major disease is a possible cause of low blood pressure.6 If so, the problem is exacerbated by the tendency of clinical trials to focus on patients at advanced stages of disease and an increased risk of car- diovascular events as a means of ensuring su cient statistical power and reasonable study size.

page1image44960

WHAT IS ALREADY KNOWN ON THIS TOPIC

Hypertension is one of the major risk factors for cardiovascular disease, and the management of hypertension is a high priority in the treatment of type 2 diabetes Recent hypertension guidelines have raised the target blood pressure for patients with diabetes from below 130 mm Hg to below 140 mm Hg because of a lack of conclusive randomised studies to support the lower goal, together with observational studies showing a J shaped relation between blood pressure and complications

WHAT THIS STUDY ADDS

Lower systolic blood pressure than currently recommended is associated with a signi cantly lower risk of cardiovascular events in patients with type 2 diabetes Adjustment for comorbidity, mainly by exclusion of patients with previous cardiovascular disease, eliminates the J curve relation between blood pressure and stroke, myocardial infarction, and coronary heart disease

The association between low blood pressure and increased mortality might be caused by concomitant disease rather than antihypertensive treatment

the bmj | BMJ 2016;354:i4070 | doi: 10.1136/bmj.i4070

Earlier studies based on the Swedish national diabetes register have also shown a tendency toward a J shaped relation between blood pressure and cardio- vascular disease in patients with type 2 diabetes. To ensure statistical signi cance, however, they included patients with previous cardiovascular disease. The reg- ister has grown substantially over the past decade, enabling appropriate selection of patients while still enabling su cient statistical power. To test our hypoth- esis that the J curve phenomenon is caused by concom- itant comorbidities, we examined the predictive value of systolic blood pressure at baseline for future cardio- vascular events among patients with type 2 diabetes after excluding those with a history of cardiovascular or other major disease. In addition, we used several methods to minimise uncontrolled confounding by other risk factors.

We aimed to compare the risk associated with a systolic blood pressure that meets current recommenda- tions with the risk of lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.  

Discussion

This observational study of 187106 individuals with type 2 diabetes who did not have previous cardiovascu- lar disease shows that those with systolic blood pres- sure lower than 120 mm Hg have a signi cantly lower long term risk of myocardial infarction, cardiovascular disease, and coronary heart disease than those with a systolic blood pressure of 130-139 mm Hg, which would meet the currently recommended goal.

Furthermore, we found no J shaped relation between systolic blood pressure and stroke, myocardial infarc- tion, or coronary heart disease. We did, however, nd a J shaped relation for both all cause mortality and heart 

failure. A secondary analysis showed that systolic blood pressure also exhibited a more or less a J shaped rela- tion with all studied outcomes when we included patients with previous disease. Accordingly, the J curve relation observed in real world data depends on patient selection and the extent to which comorbidity can be adjusted for.

The new goal of below 140 mm Hg for systolic blood pressure in patients with diabetes is based on several mainly observational studies.1-3 The European guide- lines highlight four studies as providing “supportive evidence” against reducing systolic blood pressure to below 130 mm Hg. The most often cited study is the ran- domised Action to Control Cardiovascular Risk in Dia- betes blood pressure trial (ACCORD BP), which failed to show any signi cant bene t for the primary composite cardiovascular endpoint from intensive antihyperten- sive treatment.12 The trial did, however, show that the risk of stroke was reduced by 40% in the group assigned to systolic blood pressure below 120 mm Hg. The rate of cardiovascular events was only half of that which had been expected when the study size was planned. The next two studies were post hoc analyses of clinical trials showing a J shaped relation between blood pressure and prognosis. Post hoc analysis of data from the Ongo- ing Telmisartan alone and in combination with the Ramipril Global Endpoint Trial (ONTARGET) showed that neither myocardial infarction nor cardiovascular death was related to baseline systolic blood pressure.13 Based on a subgroup analysis of patients with low blood pressure who experienced a cardiovascular event, the authors concluded that a higher baseline risk, rather than excessive reduction of blood pressure, was a key determinant of the J curve phenomenon.

A post hoc analysis of data from the International Verapamil SR/Trandolapril Study (INVEST), a compari- son of a β blocker and calcium antagonist based antihy- pertensive treatment strategy, showed that patients with systolic blood pressure below 130 mm Hg did not experience any favourable e ect compared with those with blood pressure of 130-140 mm Hg. Thus, the authors proposed a treatment goal of 130-139 mm Hg.14 In this study, however, patients with systolic blood pressure below 130 mm Hg had the least antihyperten- sive treatment, measured both as the number and dose of drugs. The nding indicates that lower blood pres- sure was not a treatment e ect but might have been caused by other disease.

The fourth highlighted study, NDR-BP-II, was an observational study of 53 553 individuals with type 2 diabetes that found a J curved relation between blood pressure and several cardiovascular complications.15 The national diabetes register has, however, grown con- siderably in size over the past decade, enabling appro- priate selection of patients while still ensuring su cient statistical power, as shown in the present study. While previous studies based on the diabetes register have included patients with a history of cardiovascular dis- ease, we have shown here that excluding them elimi- nates the J curve phenomenon for several, but not all, endpoints. Simple adjustment for these comorbidities in the regression models, as in the NDR-BP-II study, was not su cient to eliminate the J curve. These ndings strengthen the hypothesis that the J curve phenomenon is caused by more patients with comorbidities in the lowest blood pressure groups.

The results of the Systolic Blood Pressure Interven- tion Trial (SPRINT) have reset the debate about optimal levels.16 The randomised design for two di erent blood pressure targets was similar to the ACCORD BP study, but more than twice as many patients were included. Patients with diabetes, however, were excluded. SPRINT showed that the treatment goal of below 120 mm Hg was associated with much better outcomes than below 140 mm Hg. As discussed in a recent edito- rial, these two studies exhibit many similarities and point to the same conclusion—that is, that more inten- sive antihypertensive treatment than the current recom- mendation provides additional protection from cardiovascular events.17

Several recent reviews and meta-analyses have sum- marised the literature but arrived at di erent conclu- sions regarding the benefits of antihypertensive treatment below 140 mm Hg.6 18-21 We analysed the risk related to systolic blood pressure at baseline, regardless of whether it was due to antihypertensive treatment or uncontrolled confounding (concomitant disease, etc). We tried to minimise uncontrolled confounding in sev- eral ways. Firstly, we included only patients who had had diabetes for a year or more, which ensured ade- quate monitoring and treatment before baseline. Like the ACCORD and NDR-BP-II studies, we had an upper age limit and excluded patients aged ≥76 to minimise the impact of concomitant disease. We also excluded those with previous coronary heart disease, stroke, atrial brillation, cancer, or BMI <18, as well as the few with systolic blood pressure below 110 mm Hg, which was outside of the scope of the study. In addition, we used drug prescription data as markers for comorbidity and treatment intensity. Finally, missing data were imputed to preserve study size and maximise statistical power.

By selecting patients without previous reports of car- diovascular disease, we eliminated the J curve relation between blood pressure and stroke, myocardial infarc- tion, and coronary heart disease. Of concern, however, is that our adjustments did not eliminate the J curve rela- tion with total mortality. Worth noting is that the group with the lowest blood pressure also received the least antihypertensive treatment. We cannot therefore draw any conclusions about harmful e ects of intensive anti- hypertensive treatment. Patients in the group with the lowest blood pressure who died also had indications of more serious conditions, including a high rate of smok- ing and treatment with loop diuretics, spironolactone, and drugs for heart disease. They also had the highest rates of mortality from infection; diseases of the ner- vous, respiratory, and digestive systems; and external causes. Thus, this group would seem to include patients with a favourable prognosis, as well as a subgroup with complications that led to a high mortality rate. As the ONTARGET study concluded, the high mortality is probably more associated with high baseline risk rather than excessive reduction in blood pressure.13

Controlled clinical trials have the advantage of well de ned endpoints that can be examined when they appear and assessed in accordance with strict criteria in a blinded fashion, while the endpoints in observational studies, such as ours, rely on endpoints with varying degrees of accuracy. Data on stroke and myocardial infarction from the hospital discharge register are highly reliable.11 These diagnoses are usually based on a clinical evaluation on acute admission to hospital, which is highly important for ensuing treatment. The situation for our other endpoints, including heart fail- ure and total mortality, is di erent. Completeness of reporting and the date of onset are uncertain for heart failure, angina pectoris, and certain other cardiovascu- lar diagnoses, given that primary care data are not included in the hospital discharge register. It is evident from the drug prescription data that some patients who do not have previous diagnoses of major diseases use drugs that are indicated for cardiovascular complica- tions (spironolactone, furosemide, etc, and possibly β blockers as well). For causes of death, cardiovascular endpoints often appear together with other potentially fatal diagnoses, such as cancer, infection, or psychiatric problems. The cause of death register includes all deaths, regardless of whether they occurred in hospital or elsewhere. Fewer than 20% of death certi cates are based on autopsy reports.22 Furthermore, considerable discrepancies have been reported between certi cates and hospital discharge records.22 We believe that this di erence in the accuracy of outcome measurements explains the fact that the almost linear relation between systolic blood pressure and risk for the most well de ned endpoints was attenuated when we added less accurate and fatal endpoints. The J shaped relation was pronounced when the outcome was based solely on mortality data.

 

KOMMENTAR 

prof Peter M. Nilsson, Malmö

Ny observationsstudie från NDR anger association mellan lägre systoliskt blodtryck och lägre kardiovaskulär risk - betydelse för guidelines?

I en ny stor och välgjord observationsstudie från NDR har en författargrupp undersökt samband mellan systoliskt blodtryck (SBT) och risk hos patienter med typ 2 diabetes utan tidigare känd kardiovaskulär komplikation [1].

Resultatet anger sammanfattningsvis att man kunnat se linjära förhållanden mellan SBT och risk så att lägre observerat SBT associeras med lägre kardiovaskulär risk över hela skalan ner till 110 mmHg på ett monotont sätt utan s.k. J-kurva.

Enda undantaget var en ökad mortalitet som sågs vid SBT <120 mmHg men här kan det finnas störfaktorer som ev. skulle kunna påverka sambandet.

Studien är mycket stor och baseras på uppföljning av baslinje-SBT värden hos 187.106 patienter fria från kända tidigare komplikationer. Detta är i hög grad förväntade resultat och konfirmerar fynd i en klassisk observationell UKPDS publikation, också i BMJ (men ej citerad), som i princip angav samma observationella fynd, dock utan överrisk för mortalitet i det lägre SBT intervallet [2].

Tolkningen blir sammantaget att patienter med lägre blodtryck löper lägre risker, och det är ju välkommet  - men ingen stor nyhet. Det som gjorts i den nya studien är att man justerat för en rad störfaktorer, inklusive data från Läkemedelsregistret. Problemet är dock att man i detta register inte kan identifiera på vilken indikation som kardiovaskulärt aktiva läkemedel har givits och detta vållar problem. Vad man skulle önska, och av betydelse för nya guidelines, är separata analyser för just behandlade hypertoniker med DM2, en uppgift som kan fås från NDR och som tidigare använts [3]. Man kan hoppas att författarna vill återkomma med en sådan mer fokuserad analys.


Man ser i Tabell 1 att antalet antihypertensiva läkemedel är lägre ju lägre blodtryck patienterna har. Inte förvånande, men det innebär att de patienter som befinner sig i de lägre blodtrycksgrupperna INTE har behandlats dit, utan istället har ett naturligt lägre tryck. Rimligen är det väl så att dessa patienter har ett friskare kärlsystem vilket leder till både lägre tryck och mindre risk för CVD. Analyserna baserat på enskilda läkemedelsgrupper anger en del överraskningar, t.ex. överrisker vid användande av CCB, vilket inte stöds av fynd i RCT. Här kan finnas störsamband, t.ex. att gamla rökare kan tänkas få lungneutrala CCB vilket därmed kan markera överrisker.

Vid EASD i Munchen kommer det att vara en debatt om resultaten i SPRINT-studien (utan diabetespatienter) och ifall man ev. skulle kunna extrapolera fynden i SPRINT till att även gälla patienter med typ 2 diabetes. Debatten äger rum fredag den 16/9 med start 12:15.


Peter M Nilsson
Malmö

Referenser:
1. Adamsson Eryd S, Gudbjörnsdottir S, Manhem K, Rosengren A, Svensson AM,Miftaraj M, Franzén S, Björck S. Blood pressure and complications in individualswith type 2 diabetes and no previous cardiovascular disease: national populationbased cohort study. BMJ. 2016 Aug 4;354:i4070.
2. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD,Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospectiveobservational study. BMJ. 2000 Aug 12;321(7258):412-9.
3. Cederholm J, Gudbjörnsdottir S, Eliasson B, Zethelius B, Eeg-Olofsson K,Nilsson PM; NDR. Blood pressure and risk of cardiovascular diseases in type 2 diabetes: further findings from the Swedish National Diabetes Register (NDR-BP II). J Hypertens. 2012 Oct;30(10):2020-30.

 

Rekommenderat blodtrycksmål vid diabetes ifrågasätts

Socialstyrelsen höjde nyligen den rekommenderade blodtrycksgränsen för patienter med diabetes. Detta kan leda till att fler patienter drabbas av stroke eller hjärtinfarkt, visar en ny studie vid Sahlgrenska akademin. Den nya studien är världens hittills största i ämnet ochbaseras på data från Nationella Diabetesregistret.

I februari 2015 höjde Socialstyrelsen i sina riktlinjer för diabetesvård gränsen för systoliskt blodtryck (blodtrycket vid hjärtats sammandragning). Tidigare låg gränsen på 130 mm Hg och i de nya rekommendationerna höjdes den till 140 mm Hg. Den rekommenderade gränsen har betydelse för hur intensivt man behandlar patienter med blodtryckssänkande läkemedel.

Bakgrunden till den ändrade rekommendationen var forskning som tydde på att inte bara höga blodtrycksvärden, utan också värden under 130 mm Hg kunde leda till ökad sjuklighet i hjärtkärlsjukdomar.

Forskarna bakom den nya studien ifrågasätter nu detta. Deras studie visar ett linjärt samband mellan blodtryck och hjärtkärlsjukdom. Ju lägre blodtryck desto färre fall av stroke och hjärtinfarkt, alltså även på de lägsta nivåerna.

– Rekommendationerna att acceptera högre blodtryck hos patienter med diabetes tror vi är felaktiga. De kan leda till fler fall av stroke och hjärtinfarkt i patientgruppen, säger Staffan Björck, docent i njurmedicin vid Sahlgrenska akademin, Göteborgs universitet, och en av forskarna bakom studien.

Den nya studien bygger på data från Nationella Diabetesregistret, patientregistret och läkemedelsregistret. Den omfattar 187 000 patienter med diabetes typ 2, som i genomsnitt följts i fem år. Det finns en väsentlig skillnad i upplägget mellan den här studien och de studier som Socialstyrelsen baserar sina rekommendationer på. I den nya studien ingår inte patienter som redan drabbats av allvarliga sjukdomar.

– Det vi har sett i vår studie är att om vi tar bort individer med tidigare allvarlig sjuklighet då försvinner sambandet mellan lågt blodtryck och ökad risk för stroke och hjärtinfarkt, säger Samuel Adamsson Eryd, medicine doktor och försteförfattare till studien.

Till detta finns en naturlig förklaring.

– Lågt blodtryck kan bero på att man är allvarligt sjuk och har man med dessa patienter i en studie ser det ut som att lågt blodtryck ger mer hjärtkärlsjukdom, säger Staffan Björck.

I Sverige finns cirka 300 000 patienter med diabetes, men problemet med blodtrycksgränserna berör inte bara dem. Både europeiska och amerikanska expertorganisationer har höjt den rekommenderade gränsen till 140 mm Hg för systoliskt blodtryck. Eftersom den nya studien är mycket större än alla tidigare studier i ämnet har den betydelse för diskussionerna om blodtrycksgränser både i Sverige och utomlands.

Studien Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study publicerades i BMJ den 4 augusti.

Länk till artikel:http://www.bmj.com/content/354/bmj.i4070.long


Staffan Björck, docent vid Sahlgrenska akademin, Göteborgs universitet


Samuel Adamsson Eryd, medicine doktor och forskare vid Sahlgrenska akademin, Göteborgs universitet

Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease:
national population based cohort study

Samuel Adamsson Eryd,1,2,3 So a Gudbjörnsdottir,1,2 Karin Manhem,2 Annika Rosengren,2,3 Ann-Marie Svensson,1 Mervete Mi araj,1 Stefan Franzén,1 Sta an Björck1

page1image11432

ABSTRACT

OBJECTIVES

To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.

DESIGN

Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years.

SETTING

861 Swedish primary care units and hospital outpatient clinics.

PARTICIPANTS

187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease.

MAIN OUTCOME MEASURES

Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for di erent levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates.

RESULTS

The group with the lowest systolic blood pressure (110-119 mm Hg) had a signi cantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% con dence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality.

CONCLUSIONS

Lower systolic blood pressure than currently recommended is associated with signicantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment. 

http://www.bmj.com/content/351/bmj.h4612

The National Institute for Health and Care Excellence (NICE) has recommended tighter blood sugar control for patients with diabetes, to minimise the risk of long term vascular complications.

An updated NICE guideline on diagnosing and managing type 1 diabetes in adults recommends a target HbA1c level of 48 mmol/mol (6.5%) or less1: this is lower than the clinical guideline on type 1 diabetes published in 2014, which recommended an HbA1c target of less than 7.5% for prevention of microvascular disease and 6.5% or less in patients at increased risk of arterial disease.2

A target HbA1c target level of 48 mmol/mol (6.5%) or lower is also recommended in children and young people with type 1 or 2 diabetes to minimise the risk of complication

GUIDELINES
Diagnosis and management of type 1 diabetes in
adults: summary of updated NICE guidance
Stephanie A Amiel guideline development group chair, RD Lawrence professor of diabetic medicine1,
Nancy Pursey senior project manager 2, Bernard Higgins clinical director, consultant respiratory
physician 3, Dalia Dawoud health economist, lecturer 4, on behalf of the Guideline Development
Group
1Division of Diabetes and Nutritional Sciences, King’s College London, London, UK; 2National Clinical Guideline Centre, Royal College of Physicians,
London NW1 4LE, UK; 3National Clinical Guideline Centre, Royal College of Physicians, Newcastle upon Tyne Hospitals NHS Foundation Trust,
Newcastle upon Tyne, UK; 4National Clinical Guideline Centre, Royal College of Physicians, Faculty of Pharmacy, Cairo University, Cairo, Egypt


This is one of a series of BMJ summaries of new guidelines based on
the best available evidence; they highlight important recommendations
for clinical practice, especially where uncertainty or controversy exists.
Having type 1 diabetes reduces the life expectancy of adults in
the United Kingdom by as much as 13 years.1 Despite
incontrovertible evidence that good care reduces the risk of
complications such as blindness, renal failure, and premature
cardiovascular disease and death,2 as well as complications of
treatment such as severe hypoglycaemia,3 fewer than 30% of
UK adults with type 1 diabetes achieve current national
treatment targets for glucose control.4 The challenges of
managing type 1 diabetes do not lessen after the age of 18 years.
Since the publication of the 2004 National Institute for Health
and Care Excellence (NICE) guideline, new technologies to
achieve diabetic control have become available—for example,
insulin analogues, new glucose meters, and real time
subcutaneous continuous glucose monitoring systems. The
recent updated NICE guidance aims to support healthcare
professionals and adults with type 1 diabetes to use these
technologies optimally and to individualise targets and treatment
regimens for greater lifestyle flexibility, with clear advice on
education programmes, glucose monitoring, and insulin
preparations.
This article summarises the most recent recommendations from
NICE on the diagnosis and management of type 1 diabetes in
adults.5


Recommendations
NICE recommendations are based on systematic reviews of best
available evidence and explicit consideration of cost
effectiveness. When minimal evidence is available,
recommendations are based on the Guideline Development
Group’s experience and opinion of what constitutes good
practice. Evidence levels for the recommendations based on the
GRADE method6 are given in italics in square brackets.
Diagnosis
• Diagnose type 1 diabetes on clinical grounds:
-Ketosis
-Rapid weight loss
-Age of onset below 50 years
-Body mass index (BMI) below 25
-Personal or family history of autoimmune disease. (New
recommendation.)
• However, do not discount a diagnosis of type 1 diabetes
in people aged 50 years or more or those with a BMI of 25
or above. (New recommendation.)
• In any person of any age or BMI presenting with thirst and
excessive micturition in whom diabetes is suspected,
particularly those with weight loss or nausea, check random
blood glucose and blood or urinary ketones. The presence
of ketonuria or ketonaemia should raise suspicion of type
1 diabetes. Diabetic ketoacidosis (ketonaemia ≥3 mmol/L,
or >2+ ketonuria on strip testing; venous bicarbonate <15
mmol⁄L, or venous pH <7.3, or a combination thereof) is
a medical emergency.7 Lesser degrees of ketosis with
hyperglycaemia (>11 mmol/L) will probably also require
urgent institution of insulin therapy.
• Consider further investigation (measurement of C peptide
or diabetes specific autoimmune antibodies, or both) if
there are atypical features (age ≥50 years, BMI ≥25, slow
evolution of hyperglycaemia, or long prodrome) or

The bottom line
• Offer all adults with type 1 diabetes a structured education programme in self management of diabetes six to 12 months after diagnosis
or, if this was not achieved, at any time that is clinically appropriate and suitable for the person
• Support adults to aim for a target glycated haemoglobin 48 mmol/mol (6.5%) or lower, to minimise risk of vascular complications;
ensure that aiming for the target is not accompanied by problematic hypoglycaemia, and support four to 10 daily self monitoring blood
tests as routine
• Offer all adults daily basal-bolus insulin injection regimens, with twice daily insulin detemir as basal insulin therapy and rapid acting
insulin analogues injected before meals for mealtime insulin “boluses”
• Assess awareness of hypoglycaemia at least annually using a scoring system
How patients were involved in the creation of this article
Patients were involved at every stage of creating the guideline. Patient groups and individuals contributed to the scoping of the update and
at the consultation stage. Lay members were active in the Guideline Development Group, contributing to the formulation of the recommendations
summarised here, and were instrumental in setting the new treatment targets.
uncertainty exists about the type of diabetes. (New
recommendation.)
• [Based on evidence from cross sectional observational
studies and case series and the opinion of the Guideline
Development Group (GDG).]
Education and information
• Offer all adults with type 1 diabetes a structured education
programme in the self management of flexible insulin
therapy (for example the DAFNE (dose adjustment for
normal eating) programme8) six to 12 months after
diagnosis or at any time that is clinically appropriate and
suitable for the person, regardless of duration of type 1
diabetes. Such programmes aim to transfer skills of insulin
dose adjustment to the person with diabetes, enabling
diabetic control with minimal risk of acute complications
of therapy (diabetic ketoacidosis and hypoglycaemia)9 and
long term vascular complications (visual loss, renal failure,
nerve damage, and vascular disease),10 while allowing
flexibility of lifestyle and good quality of life.11 They fulfil
the requirements of structured therapeutic education, which
include evidence of the programme’s efficacy, a written
curriculum, delivery by trained educators, and a quality
assurance programme to ensure consistency and regular
audit of its outcomes.12 (New recommendation.)
• Provide an alternative of equal standard for those not able
to participate in group education and ensure that this
includes the components of structured therapeutic
education. (New recommendation.)
• Carry out a formal review of patients’ ability to manage
their insulin regimen annually, and their need for support
from healthcare professionals, including assessment of
their achievement of glucose targets, their freedom from
problematic hypoglycaemia, and the management of their
risk of complications. (Amended recommendation.)
• [Based on very low to moderate and high quality evidence
from randomised controlled trials (RCTs), the experience
and opinion of the GDG, and a cost-utility study with
potentially serious limitations and direct applicability.]
Dietary management and physical activity
• Offer carbohydrate counting training to adults with type 1
diabetes as part of structured education programmes. (New
recommendation.)
• [Based on very low to moderate quality evidence from
RCTs, observational studies, and the opinion of the GDG.]
• Offer dietary advice about matters other than blood glucose
control, such as weight control and cardiovascular risk
management, as indicated clinically. (New
recommendation.)
• [Based on the opinion and experience of the GDG.]
• Do not advise adults to follow a low glycaemic index diet
for blood glucose control. The GDG found no evidence of
benefit for glycaemic control, frequency of hypoglycaemia,
or quality of life. (New recommendation.)
• [Based on very low to low quality evidence from
randomised and non-randomised controlled trials.]
• Advise adults with type 1 diabetes that physical activity
can reduce their increased cardiovascular risk in the
medium and longer term.
• [Based on evidence from randomised and non-randomised
controlled trials and observational studies in the 2004
NICE guideline (GRADE assessment not performed).]
Blood glucose management
• Measure glycated haemoglobin (HbA1c) every three to six
months, or more often if blood glucose control might be
changing rapidly, and ensure that the result is available at
the time of consultation. (New recommendation.)
• Support adults with type 1 diabetes to aim for a target
HbA1c of 48 mmol/mol (6.5%) or lower to minimise the
risk of vascular complications. (New recommendation.)
• Agree an individualised target based on daily activities,
aspirations, likelihood of complications, comorbidities,
occupation, and history of hypoglycaemia. Most adults
should be supported to aim for the recommended target,
but adjust the numerical value in, for example, frail elderly
patients, and those with limited life expectancy or advanced
vascular complications. Take care to help people in
occupations with a high risk of accidents to avoid
hypoglycaemia; this can be achieved by good education
and, where indicated, use of newer technologies for insulin
delivery and glucose monitoring, although some people
may also need the target to be modified. (New
recommendation.)
• Ensure that aiming for the target is not accompanied by
problematic hypoglycaemia. (New recommendation.)
• [Based on evidence from RCTs, prospective case series
studies, cross sectional observational studies, and an
original economic analysis with potentially serious
limitations but direct applicability.]

Self monitoring of blood glucose
• Advise routine monitoring at least four times a day, before
each meal and before bed. (New recommendation.)
• Support self monitoring up to 10 times a day and enable
more than this if necessitated by the person’s lifestyle.
(New recommendation.)
• Advise patients to aim for a fasting plasma glucose of 5-7
mmol/L before breakfast; 4-7 mmol/L before meals at other
times of day, and, if patients chose to test after meals, 5-9
mmol/L at least 90 minutes after eating. Agree a bedtime
target that accounts for the time of the last meal. (New
recommendation.)
• [Based on low quality evidence from RCTs,
non-comparative observational studies, and an original
economic analysis with potentially serious limitations but
direct applicability.]
• Teach self monitoring skills at diagnosis and educate
patients to interpret and use the results, reviewing their
skills at least annually. (Amended recommendation.)
• Do not recommend routine use of sites other than the
fingertips for testing. (Amended recommendation.)
• Do not routinely offer real time continuous glucose
monitoring (use of subcutaneous sensors for measuring
glucose continuously), but consider it for patients willing
to use it at least 70% of the time if they are experiencing
problematic hypoglycaemia despite optimised use of insulin
(multiple daily injections of insulin or pump therapy) and
conventional monitoring. (New recommendation.)
• [Based on very low to moderate quality evidence from
RCTs, cost-utility studies with potentially serious
limitations and partial applicability, and an original
economic analysis with potentially serious limitations but
direct applicability.]
Insulin therapy
• Offer multiple daily insulin injection basal-bolus regimens,
rather than twice daily mixed insulin regimens. Such
regimens control endogenous glucose production with slow
acting insulins (“basal” insulin), to which fast acting insulin
“boluses” are added before a meal or snack. In flexible
therapy, doses of basal insulin are based on fasting glucose
readings and readings made five or more hours after eating;
doses for meal insulin are based on the current blood
glucose test result and the amount of carbohydrate the
patient plans to eat. All doses can be adjusted prospectively,
after reviewing the effectiveness of doses taken in the past
few days, or to accommodate exercise or other predicted
changes in insulin requirement. Bolus doses of fast acting
insulin can also be used to correct a glucose reading that
is over target.
• Do not offer newly diagnosed patients non-basal-bolus
regimens. (New recommendation.)
• Basal-bolus regimens include:
Basal insulin to control endogenous glucose production:
-Offer twice daily insulin detemir as basal insulin therapy
(New recommendation.)
-As an alternative, consider an existing regimen that is
delivering agreed glucose targets or once daily glargine or
detemir, if the twice daily regimen is not acceptable to the
patient
-Consider other regimens only if the above do not deliver
agreed targets (New recommendation.)
-For guidance on use of continuous subcutaneous insulin
(“pump”) therapy, refer to the NICE technology appraisal.13
(New recommendation.)
• [Based on very low to high quality evidence from RCTs, a
network meta-analysis, cost-utility studies with minor to
very serious limitations and partial or direct applicability,
and an original economic analysis with potentially serious
limitations and direct applicability.]
Bolus insulin to cover ingestion of food (primarily
carbohydrate):
-Offer rapid acting insulin analogues injected before meals
for mealtime insulin replacement (New recommendation.)
-Do not advise routine use of rapid acting insulin analogues
after meals. Delayed injection increases the risk of high
blood glucose immediately after eating (because the glucose
from the food is absorbed before the insulin is active) and
of late hypoglycaemia (because the insulin continues to
act after the food related glucose has gone) (New
recommendation.)
Respect the wishes of the patient in choosing a rapid acting
insulin. (New recommendation.)
• [Based on very low to moderate quality evidence from
RCTs and cost-utility studies with potentially serious
limitations and partial or direct applicability.]
Awareness and management of
hypoglycaemia
• Assess awareness of hypoglycaemia at least annually, using
a scoring system. For example, ask patients to rate their
awareness from 1 (always aware of their hypoglycaemia)
to 7 (never aware of their hypoglycaemia) and consider a
score of 4 or more to indicate impaired awareness with
high risk of severe hypoglycaemia.14
• Ensure that people with impaired hypoglycaemia awareness
receive structured education in flexible insulin therapy
using basal-bolus regimens, and offer additional education
around avoidance and treatment of hypoglycaemia if
needed. (New recommendation.)
• [Based on low quality evidence from observational studies
and the opinion of the GDG.]
• Avoid raising agreed blood glucose targets as a treatment
for impaired awareness of hypoglycaemia and reinforce
recommended targets if the person prefers lower ones.
(New recommendation.)
• First reinforce principles of structured education, then offer
“pump” therapy, and then offer real time glucose
monitoring if impaired awareness of hypoglycaemia
persists. (New recommendation.)
• [Based on very low to moderate quality evidence from
RCTs, cohort studies, and low quality case series.]
Overcoming barriers
Implementing the recommendations will require adequate
resourcing and training of the healthcare workforce to help
healthcare professionals and people with diabetes understand
the importance of glycaemic control; to deliver the mandated
structured education programmes in flexible insulin therapy; to
support glucose self monitoring; and to identify and help patients
who need additional support, including enhanced techniques of
insulin delivery and glucose monitoring (pumps and glucose
sensors). The aim is to help people achieve their targets for
glycaemic control and thereby reduce long term complications,
while avoiding asymptomatic, severe hypoglycaemia, and acute
emergencies, while also optimising quality of life. Solutions
may include creating skilled teams that can deliver education
and psychological support across wide geographical areas, and
greater use of communication technology in delivering
structured education “refresher” courses and accessing specialist
advice on regimen change. More effective monitoring for, and
treatment of, risk factors for long term complications also require
stronger engagement between primary and specialist care, ideally
with access to shared data systems.


Funding: NP, BH, and DD are employed by the Royal College of
Physicians, London at the National Clinical Guideline Centre, which is
commissioned and funded by NICE to develop clinical guidelines. No
authors received specific funding to write this summary.


1 Levin D, Looker HC, Lindsay RS, et al. Scottish Diabetes Research Network epidemiology
group; Scottish Renal Registry. Estimated life expectancy in a Scottish cohort with type
1 diabetes, 2008-2010. JAMA 2015;313:37-44.
2 Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, Zinman B,
et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term
mortality. JAMA 2015;313:45-53.
3 Elliott J, Jacques RM, Kruger J, et al. Substantial reductions in the number of diabetic
ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to
reduced costs after structured education in adults with type 1 diabetes. Diabet Med
2014;31:847-53.
4 National Diabetes Audit 2011-2012. Report 1: care processes and treatment targets.
2014. .www.hscic.gov.uk/catalogue/PUB12421/nati-diab-audi-11-12-care-proc-rep.pdf.
5 National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis
and management. (NICE guideline 17.) 2015. http://www.nice.org.uk/guidance/ng17.
6 What is GRADE? BMJ Clinical Evidence . http://clinicalevidence.bmj.com/x/set/static/ebm/
learn/665072.html.
7 Savage MW, Dhatariya KK, Kilvert A, et al; Joint British Diabetes Societies. Joint British
Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet Med
2011;28:508-15.
8 DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary
freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE)
randomised controlled trial. BMJ 2002;325:746.
9 Elliott J, Jacques RM, Kruger J, et al. Substantial reductions in the number of diabetic
ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to
reduced costs after structured education in adults with type 1 diabetes. Diabet Med
2014;31:847-53.
10 Kruger J, Brennan A, Thokala P, et al. The cost-effectiveness of the dose adjustment for
normal eating (DAFNE) structured education programme: an update using the Sheffield
type 1 diabetes policy model. Diabet Med 2013;30:1236-44.
11 Hopkins D, Lawrence I, Mansell P, et al. Improved biomedical and psychological outcomes
1 year after structured education in flexible insulin therapy for people with type 1 diabetes:
the UK DAFNE experience. Diabetes Care 2012;35:1638-42.
12 National Institute for Health and Care Excellence. Diabetes in adults quality standard.
2011. www.nice.org.uk/guidance/qs6/chapter/Introduction-and-overview.
13 National Institute for Health and Care Excellence. Continuous subcutaneous insulin
infusion for the treatment of diabetes mellitus. (Technology appraisal guideline 151.) 2008.
www.nice.org.uk/guidance/ta151.
14 Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with
type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994l;17:697-703.
15 Diabetes Control and Complications Trial Research Group. The effect of intensive treatment
of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
16 Hopkinson HE, Jacques RM, Gardner KJ, et al. Twice- rather than once-daily basal insulin
is associated with better glycaemic control in type 1 diabetes mellitus 12 months after
skills-based structured education in insulin self-management. Diabet Med 2015;8:1071-6.
Cite this as: BMJ 2015;351:h4188
© BMJ Publishing Group Ltd 2015
For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
BMJ 2015;351:h4188 doi: 10.1136/bmj.h4188 (Published 26 August 2015) Page 4 of 4
PRACTICE
Further information on the guidance
The National Diabetes Audit showed that targets for glycaemic control were not being met and that regional variations existed in the proportions of patients achieving
these targets, the use of currently available insulins, the availability of accredited structured education programmes, and the proportion of patients using insulin
pumps.4
Some recommendations in the updated guideline may seem aspirational but are necessary to improve clinical outcomes for adults with type 1 diabetes. The tighter
targets for glycaemic control require adequate resourcing and a culture shift in the health service, so that the workforce believes in the importance of achieving these
targets and can support people with diabetes to do so comfortably and safely. The National Institute for Health and Care Excellence (NICE) has developed an
educational tool for healthcare professionals.13 However, even where good structured education has been delivered,5 people may struggle to sustain the strategies
they have learnt.11 Techniques to help deliver sustainable behaviour change may be the key to greater long term success.12
Hypoglycaemia and fear of hypoglycaemia, as well as fear of weight gain, remain barriers to optimal insulin therapy. Yet the evidence is that structured education
programmes reduce severe hypoglycaemia risk even more than glycated haemoglobin (HbA1c).14 Technologies such as pumps and sensors can be beneficial and
their cost effectiveness enhanced if properly used within a care pathway that starts with structured education and adds these technologies as needed to people who
already know how to adjust insulin doses. This ensures that the technologies go first to people who need them most.
Services should document the proportion of patients achieving an HbA1c of 53 mmol/mol (7%) or lower (new recommendation). In the major randomised controlled
trial of intensified versus conventional insulin therapy in people with type 1 diabetes, this is the approximate HbA1c value that was associated with long term benefit
(fewer complications and reduced premature mortality).15 It should be noted that the target for control in this study was 42.6 mmol/mol (6.05%).
What’s new
• Reduction of the HbA1c target from 53 mmol/mol to 48 mmol/mol, with an audit standard of the proportion of people achieving 53 mmol/mol rather than 58
mmol/mol, based on evidence that achieved glycated haemoglobin is always higher than the target set15 4
• Twice daily detemir as the basal insulin regimen of choice, based on a network meta-analysis,5 audit data,16 and original economic analysis5 showing its
effectiveness and cost effectiveness, especially with structured education programmes
• Annual assessment of awareness of hypoglycaemia, based on growing recognition of the increased risk of severe hypoglycaemia in people with impaired
awareness
• More frequent daily routine glucose self monitoring with strips, based on evidence showing better glycated haemoglobin with increased self testing
• Appropriate use of continuous glucose monitoring
Methods
The updated guideline was developed in accordance with NICE guideline methodology (http://publications.nice.org.uk/the-guidelines-manual-pmg6). The Guideline
Development Group (GDG) included diabetologists, nurse and dietitian diabetes educators, patient representatives, a general practitioner, a chemical pathologist,
and a pharmacist, as well as the research and technical staff from NICE. It developed clinical questions and protocols a priori, undertook systematic literature searching,
appraised the evidence, and evaluated cost effectiveness of interventions through review of published evaluations and economic modelling. The quality of the evidence
was assessed using the GRADE methodology (www.gradeworkinggroup.org). The guideline was subject to a rigorous validation process, during which stakeholder
organisations were invited to comment. All comments were considered in producing the final version.
The guideline is available in three formats: a short version; a full version (including all evidence; www.nice.org.uk/guidance/ng17/evidence); and information for the
public for people with type 1 diabetes, their families and carers, and the general public (www.nice.org.uk/guidance/ng17/informationforpublic).
Implementation and costing tools have been developed and are available at the NICE website (www.nice.org.uk/guidance/ng17/resources.)
Further updates of the guidance will be produced as part of NICE’s guideline development programme.
Future research
The GDG prioritised these five research recommendations:
• What methods and interventions are effective in increasing the number of adults with type 1 diabetes who achieve the recommended HbA1c targets without
risking severe hypoglycaemia or weight gain?
• In adults who have chronically poor control of blood glucose levels, what is the clinical and cost effectiveness of continuous glucose monitoring technologies?
• What methods can increase the uptake of structured education programmes and improve their clinical outcomes (particularly achieving and sustaining blood
glucose control targets)?
• Could a risk stratification tool help set individualised HbA1c targets?
• In preventing and treating impaired awareness of hypoglycaemia, what are the most clinically and cost effective technologies (such as insulin pump therapy
or continuous glucose monitoring (or both); partially or fully automated insulin delivery; and behavioural, psychological and educational interventions)? How
are they best used?
 

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Novo Nordisk has given up on the GLP-1 drug as a treatment for Type 1 diabetes, at least for now. A blockbuster in the Type 2 form of the disease, Victoza fell short in a new late-stage trial as an add-on to insulin therapy.

Higher doses of the drug did cut blood sugar levels and helped patients lose weight, but they also boosted the risk of hypoglycemia, Novo said. The lowest dose failed to beat placebo at controlling blood sugar or triggering weight loss.

Together with the results of a previous Type 1 trial, the latest data underwhelmed Novo execs. The company "does currently not intend to submit an application to expand the label of Victoza for use in type 1 diabetes," Novo said in a statement.

Novo's Mads Krogsgaard Thomsen

"We are disappointed as we believed in the potential to provide people with type 1 diabetes with a new treatment option, and we will continue to invest in new treatment options for this group of people," said Mads Krogsgaard Thomsen, Novo's EVP and chief science officer.

From http://www.fiercepharmamarketing.com

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Press release

En internationell studie med mer än 7 000 deltagare visar att läkemedlet Jardiance minskar risken att drabbas av hjärt-kärlhändelser hos patienter med typ 2-diabetes. Runt hälften av alla dödsfall i patientgruppen orsakas av hjärt- kärlsjukdomar. De fullständiga resultaten presenteras den 17 september vid EASD-mötet, en stor europeisk diabeteskonferens, i Stockholm.

Patienterna i studien behandlades antingen med Jardiance (empagliflozin) plus standardbehandling för att sänka blodsocker, blodtryck och kolesterol, eller standardbehandling plus placebo. Patienterna följdes upp i genomsnitt drygt tre år. Resultaten visar att antalet hjärt-kärlhändelser, såsom hjärtinfarkt, stroke och död på grund av hjärt-kärlsjukdom, var färre hos dem som fick Jardiance som tillägg till standardbehandling.

De kompletta resultaten presenteras torsdagen den 17 september i Stockholm under EASD-konferensen som pågår 14-18 september. EASD står för European Association for the Study of Diabetes.

– Patienter med diabetes har en fördubblad risk att drabbas av stroke eller hjärtinfarkt varför det länge har varit angeläget att finna en behandling som minskar denna risk. Det här är den första studien i sitt slag på flera tusen patienter som visar att ett läkemedelsom sänker blodsockret även minskar patienternas risk att drabbas av hjärt-kärlhändelser. Dessa resultat kan därför få stor betydelse, men vi vet mer när vi sett de detaljerade resultaten som presenteras i Stockholm den 17 september, säger Mattias Wieloch, kardiolog och medicinsk rådgivare vid Boehringer Ingelheim.

Omkring 350 000 personer i Sverige beräknas ha diabetes typ 2 och mellan 10 och 20 procent av befolkningen över 65 år, enligt Diabetesförbundet.

Ulrika Edvinsson, pressansvarig, Boehringer Ingelheim AB
Charlotte Luderowski, medicinskt ansvarig, Boehringer Ingelheim AB

 

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Dexcom had put a bit of a Band-Aid on its mobile strategy--its prior smart device-compatible continuous glucose monitor required a separate worn transmitter and a dedicated handheld receiver.

But now the FDA has approved the first CGM system, dubbed G5, which connects an all-in-one adhesive sensor/transmitter combo directly to an app on a smart device.

The new system will launch in late September with initial compatibility with Apple's iOS; Android compatibility is slated for early next year. In the G5 iteration, there is no additional hardware to facilitate the wireless data transfer between the adhesive CGM and Dexcom's Share analytical and data sharing app, although the system can be used with a dedicated receiver instead of a smart device if the user opts to do so.

"Obviously there are a lot of moving parts to our commercial launch plans given this sooner-than-expected approval, and the financial ramifications, such as inventory adjustments and revenue recognition policies are being evaluated and will be discussed in detail on the Q3 2015 earnings call in early November," said Dexcom President and CEO Kevin Sayer in a statement.

The G5 system is a big leap forward in terms of simplicity and ease-of-use for diabetic patients. The FDA approved it for adults as well as children as young as two-years-old. Dexcom has always had an edge with younger patients, who are most receptive to cutting-edge technology and whose parents require a way to remotely monitor glucose levels. The G5, like its predecessor, the G4, enables the user to share blood glucose data with up to 5 recipients, which can include healthcare providers as well as parents and other relatives.

But CGMs typically still require twice-daily calibration via the traditional finger-stick method. Up next, Dexcom expects to start to untether its CGM from the finger stick--it expects the G6 version will require only one calibration finger stick daily and enable 10-day extended wear. It hopes to start pre-pivotal testing for that newest iteration later this year, with a pivotal study planned for shortly after and a launch planned for early 2017.

Dexcom is trying to encourage G5 adoption among its existing customers by offering a free upgrade to the G5 for those that have ordered the G4 Platinum with Share System since the start of August. In addition, it's offering a "low cost cash upgrade" to the G5 for all patients who remain under warranty for their existing Dexcom CGM system.

 

From FierceMedicalDevices

First and Only Fully Mobile CGM System Allows Adults and Children as young as 2 years old to Conveniently and Discreetly Monitor and Share Glucose Levels

SAN DIEGO--(BUSINESS WIRE)-- Dexcom, a leader in continuous glucose monitoring (CGM) for patients with diabetes, announced today that the U.S. Food and Drug Administration (FDA) has approved the Dexcom G5® Mobile Continuous Glucose Monitoring (CGM) System. With wireless Bluetooth® technology built into the device transmitter, the G5 Mobile CGM System is the first and only fully mobile CGM system approved by the FDA for both adults and children as young as 2 years of age that sends glucose data directly to a smartphone, freeing users from the need to carry a separate receiver. The new transmitter securely sends vital glucose information directly to an app on iOS-enabled devices for real-time diabetes management. Android applications will follow early next year. Like its predecessor, the G4 PLATINUM CGM with Share, users can also select up to five designated recipients, or "followers." These followers can remotely monitor a patient's glucose information and receive alert notifications from almost anywhere.

"Dexcom is rapidly advancing technology for continuous glucose monitoring devices to improve diabetes management. Since January, the company has introduced the G4 PLATINUM CGM with Share, apps to enable the first CGM on the Apple WatchTM and now the Dexcom G5® Mobile CGM. These advances are making diabetes management more convenient and flexible than ever before," stated Kevin Sayer, President and Chief Executive Officer of Dexcom. "We are excited for the promise this new technology holds for patients and caregivers."

About the Dexcom U.S. G5 Mobile Launch
The G5 Mobile system is anticipated to begin shipping in late September 2015.
All purchasers of a G4 Platinum with Share system from August 1, 2015, until the G5 Mobile system is shipped, will be eligible to receive a no-cost upgrade to the G5 Mobile system.
There will be a low cost cash upgrade to the G5 Mobile system for those patients who are still under warranty with their existing system.
"Obviously there are a lot of moving parts to our commercial launch plans given this sooner-than-expected approval, and the financial ramifications, such as inventory adjustments and revenue recognition policies are being evaluated and will be discussed in detail on the Q3-2015 earnings call in early November," remarked Sayer.

Enhanced Mobility and Flexibility
Available by prescription, the Dexcom G5 Mobile CGM System features the most accurate glucose sensor on the market while providing enhanced mobility and flexibility to view and share personal glucose data and trends. The only CGM with single digit MARD (Mean Absolute Relative Difference), the Dexcom G5 Mobile comes with the longest-wear sensor on the market and features customizable alerts and a built-in low glucose alarm (55 mg/dL alarm) to warn patients of highs and lows and how quickly they may be happening through a simplified mobile interface. Data from the Dexcom G5 Mobile can be integrated with Dexcom CLARITYTM, a Cloud-based reporting software, for personalized, easy-to-understand analysis of trends that may improve diabetes management.

Continuous glucose monitoring is considered the most significant breakthrough in diabetes management in the past 40 years.The traditional standard-of-care for glucose (blood sugar) monitoring has been a finger stick meter. CGM augments the use of glucose meters for the management of diabetes. Meters are still required to calibrate CGMs and for guidance in making therapy and meal decisions. CGM is important because, in addition to providing the glucose level, it provides the direction and rate of glucose change with the push of a button and alerts users when glucose is too low or too high.

From http://www.fiercemedicaldevices.com/

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Se tidigare inlägg på www.dagensdiabetes.se kring insulinpump 640G

Enligt företrädare för Medtronic idag har företaget begärt prövning hos Kammarrätten av beskedet om att inhibition av Läkemedelsverkets (LVs) beslut ej beviljats av Förvaltningsrätten. Kammarrätten har beviljat prövningstillstånd kring inhibition av beslutet i väntan på utslag i ärendet. Senast om en vecka ska företaget inge yttrande till Kammarrätten. LV har redan inkommit med sitt yttrande. Därefter väntas beslut från Kammarrätten inom förhoppningsvis relativt kort tid. 

Utredare vid Medicinsk Teknik på LM anger idag att myndigheten i nuläget vill avvakta Kammarrättens beslut och avböjer press release eller att gå ut med info på sin www sida. Detta uppges vara de rutiner som LV normalt liksom nu har. 

I dagsläget kan nya Medtronics Minimed 640 G i Sverige för närvarande ej levereras.

De flesta diabetesmottagningar har i brist på annan information beslutat, att pumpen kan användas men att bolusguiden stängs av. Alla patient-användare är i flertalet fall redan kontaktade via telefon eller vid extra besök för information hur man stänger av bolusguiden i pumpen.  Information om orsaken ges med uppgift om problem i time-out funktion i display. Åtgärden om information journalförs.

Så här gör man. 1) Gå in i menyn, 2) välj insulininställning 3) välj bolus wizard stäng av och röd markering visas 4) Nu går det inte att räkna kolhydrater eller få förslag på korrigeringsdos. Denna uträkning får nu göras manuellt 

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» Den snabbt växande mängden medicinsk programvara och digital utrustning inom både forskningsinriktad och rutinmässig vård har blivit en veritabel utmaning för Läkemedelsverket och resten av världens läkemedelsmyndigheter.
– Vi ser en fullständig explosion av hälso- och vårdrelaterade appar som finns tillgängliga för allmänheten att ladda ned från till exempel Google Play och Appstore.Utmaningen för oss på Läkemedelsverket är att försöka bidra till att de nya tjänsterna och produkterna inom digital hälsa är så säkra som möjligt att använda, säger Mats Artursson, utredare och inspektör på Läkemedelsverket, till Läkemedelsmarknaden.


Läkemedelsverket deltar i nätverket International Medical Device Regulatos Forum, IMDRF, som försöker harmonisera de nationella regelverken för medicinteknik.
– Myndigheter, läkemedelsbolagen och medtechbolagen verkar på en alltmer globaliserad hälso- och sjukvårdsmarknaden. Därför har vi allt att vinna på att harmoniserade regelverk för tillsyn gäller över hela världen, säger Mats Artursson.


För några år sedan blev det alltmer uppenbart att de befintliga regelverken släpade efter den tekniska utvecklingen med till exempel växande användning av mobilt internet. IMDRF har därför sedan 2013 varit inriktad på att ta fram globala riktlinjer för hur industrin och myndigheterna ska definiera medicinsk programvara.
Utvecklingen inom framför allt mobilt internet går snabbt.
– Jag närmast dränks av frågor från tillverkare av appar, som undrar om deras produkt ska betraktas som medicinteknik och därför behöver CE-märkning eller någon form av tillstånd. Bara för tre fyra år sedan fick vi ytterst sällan den typen av förfrågningar, säger Mats Artursson.


I dag finns cirka 100 000 appar som tillverkarna anser vara avsedda för hälso- och sjukvårdsområdet. Appar, annan program- och hårdvara tas fram i rask takt för att möta det växande behovet av kostnadsbesparande automatisering av vård och hemsjukvård, för tidig upptäckt av sjukdomar och för monitorering av till exempel läkemedelsbehandling.
 

En viktig uppgift för Läkemedelsverket och de övriga i IMDRF är att öka utvecklares och tillverkares medvetenhet om de särskilda säkerhets- och valideringskrav som ställs på applikationer och hårdvara inom hälso- och sjukvården.
– Det blir inte juste konkurrens på marknaden om vissa smiter undan sitt säkerhetsansvar. Det vill vi förhindra genom att anpassa regelverken, informera och genom att bedriva ”signalspaning” för att hitta lösningar som inte håller måttet. Sedan kan vi behöva statuera exempel, säger Mats Artursson.


Den tyska läkemedelsmyndigheten statuerade ett exempel genom att återkalla en app som användes för administrering av diabetesbehandling. Appens bristande funktion innebar att den kunde uppmana användaren att ta en felaktig dos insulin. 

VÄRLDENS LÄKEMEDELSMYNDIGHETER SKA NU DEFINIERA MEDICINSKA APPAR

Under hösten ska det globala nätverket International Medical Device Regulatos Forum, IMDRF, presentera en samling dokument som ska öka patientsäkerheten vid användningen av den snabbt växande floran av appar och andra digitala tjänster och produkter inom hälso- och sjukvården.
Under sommaren har Läkemedelsverket varit värd i Uppsala för ett möte där representanter för IMDRF arbetade med dokumentet.
– Vi som arbetar inom världens läkemedelsmyndigheter beskriver i dokumentet hur medicinsk programvara kan defineras, hur vi vill att tillverkarna ska resonera när de beskriver programvarans avsedda användningen och utifrån det kan göra en riskklassificering, säger säger Mats Artursson, utredare och inspektör på Läkemedelsverket, till Läkemedelsmarknaden.


Riskklassificeringen baseras bland annat på om programvaran är avsedd för användning i hemmet eller på en utsatt plats som en akutmottagning.
Mats Artursson betonar att IMDRF har en grundläggande positiv inställning till den snabba utveckling som digitalisering och programvaruutveckling driver fram inom både den forskningsinriktade och den mer rutinmässiga hälso- och sjukvården.


– Men in på området digital hälsa kommer nu helt nya aktörer som inte har kunskap och erfarenhet av de höga krav som ställs på säkerhet och tillförlitlighet inom läkemedel, medtech och hälso- och sjukvården. De är ofta mycket kompetenta i sin verksamhet, men måste lära sig mer om framför allt riskhantering, säger Mats Artursson.
Bland de nya aktörerna finns till exempel spelutvecklare, som nu alltså börjar konkurrera med de traditionella utvecklarna och tillverkarna av till exempel inbyggda IT-system i hälso- och sjukvården. 

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Nyhetsinfo

www red DiabetologNytt

Läkemedelsverket, LV, kan hålla fast vid sitt krav på företaget Medtronic från den 31 juli att återkalla samtliga insulinpumpar av modellen MiniMed 640G. Förvaltningsrätten i Uppsala avslog i fredags Medtronics begäran om att LV:s beslut skulle frysas tills domstolen fattat ett beslut i frågan. 

 

Produkten har belagts med marknadsförbud på grund av ett programvarufel i den så kallade Bolusguiden. 

Programvarufelet i MiniMed 640G innebär att patienten riskerar att ge sig själv en felaktig dos insulin (bolusdos), vilket kan resultera i att blodsockervärdet ändras till en så låg eller hög nivå att patientens hälsotillstånd allvarligt försämras.

Medtronics analyser visar att risken att skada ska uppstå är mindre än en på miljonen. 

 

LV skriver följande yttrande i ett följebrev till förvaltningsrätten:

MiniMed 640G insulinpump introducerades av Medtronic i Sverige under 2015. Enligt FSCA-rapporten FA 640 (field safety corrective action) har Medtronic upptäckt två risker:

 

1. Då pumpens Bolusguide kalkylerar värden överskridande pumpens programmerade maximala bolusstorlek tas föråldrade data inte bort i pumpens informationsfönster (popup notification window – no time out).

2. Föråldrad varningsinformation för högt/lågt blodsocker tas inte bort i pumpens informationsfönster (alert notification window – no time out).

 

En grupp läkare skriver i ett yttrande från Medtronic till Läkemedelsverket att de anser att myndighetens beslut saknar medicinsk förankring. De skriver bland annat:

 

”Sammanfattningsvis anser vi att risken för patienten med felaktiga insulindoser och följder av dessa med nuvarande skärmfunktion är lägre än risken med att återkalla denna pump med denna pump med de funktioner som bara finns i MiniMed 640G med tanke på en klart ökad hypoglykemirisk.”

 

Från www.lakemedelsvarlden.se

 

Nyhetsinfo

www red DiabetologNytt

 
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