Findings for iGlarLixi versus BIAsp 30 confirmed in groups of people with type 2 diabetes with different biomedical characteristics.

AIM: To report prespecified and post hoc analyses of the SoliMix dataset exploring the impact of baseline participant characteristics on the original SoliMix study outcomes, to enable informed treatment choices for people with different biomedical characteristics. METHODS: SoliMix (EudraCT 2017-003370-13) compared once-daily iGlarLixi (a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist lixisenatide) with twice-daily BIAsp 30 (30% insulin aspart and 70% insulin aspart protamine). In this analysis, the original primary outcomes of noninferiority of iGlarLixi versus BIAsp 30 in terms of glycated haemoglobin (HbA1c) change and superiority in terms of body weight change, together with change in basal insulin dose and hypoglycaemia outcomes, were investigated by baseline age, duration of diabetes, insulin dose, HbA1c level, body mass index (BMI), and renal function. RESULTS: No evidence of difference in comparative treatment effect was detected across baseline age, duration of diabetes, insulin dose, HbA1c level, BMI and renal function subgroups for any endpoint (all heterogeneity P > 0.05), except American Diabetes Association Level 2 hypoglycaemia event rate when stratified by insulin dose (P = 0.011), which may be a chance difference given multiple testing and the small numbers of Level 2 events. CONCLUSIONS: Treatment effects of iGlarLixi were consistent irrespective of baseline HbA1c, insulin dose, BMI, age, duration of diabetes and renal function, supporting the use of iGlarLixi as an efficacious and well-tolerated treatment option in people with type 2 diabetes with a wide range of biomedical characteristics.

Insulin therapy development beyond 100 years.

The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin peptides or by chemical insulin mimetics. Some of the problems of prospective unregulated absorption of insulin into the circulation from subcutaneous depots might be overcome with glucose-responsive insulins. Approaches to these problems could be modification of the peptide by adducts, or the use of nanoparticles or insulin patches, which deliver insulin according to glucose concentration. Some attention has been paid to targeting insulin preferentially to different organs, either by molecular engineering of insulin, or with adducts. But all these approaches still have problems in even beginning to match the responsiveness of physiological insulin delivery to metabolic requirements, both prandially and basally. As would be expected, for all these technically complex approaches, many examples of abandoned development can be found. Meanwhile, it is becoming possible to change the duration of action of subcutaneous injected insulin analogues to act even more rapidly for meals, and towards weekly insulin for basal administration. The state of the art of all these approaches, and the barriers to success, are reviewed here.

Efficacy and safety of iGlarLixi versus IDegAsp: Results of a systematic literature review and indirect treatment comparison.

AIM: To assess the efficacy and safety of iGlarLixi, a fixed-ratio combination of basal insulin glargine 100 U/mL and lixisenatide (glucagon-like peptide-1 receptor agonist) versus IDegAsp, a co-formulation of basal insulin degludec 100 U/mL with rapid-acting insulin aspart. MATERIALS AND METHODS: A systematic literature search of randomized controlled trials (RCTs) was performed. Outcomes from eligible RCTs were compared by an indirect treatment comparison using a Bayesian framework. Subanalyses of Japanese and international trials were performed. RESULTS: Eight RCTs (duration 26-30 weeks) were included. Mean difference in HbA1c change with iGlarLixi exceeded that for IDegAsp: -0.64 (95% credible interval -1.01, -0.28) %-units (-7.0 [-11.0, -3.1] mmol/mol) for all trials, -0.39 (-0.55, -0.23) %-units (-4.3 [-6.0, -2.5] mmol/mol) for international, and -0.88 (-1.11, -0.64) %-units (-9.6 [-12.1, -7.0] mmol/mol) for Japanese trials. HbA1c target achievement (<7.0%-units [<53 mmol/mol]) was greater for iGlarLixi in all trials (odds ratio 2.50 [1.06, 5.56]) and Japanese trials (2.17 [1.27, 3.70]), but not in international trials (2.17 [0.42, 11.11]). Analyses suggesting differences in mean postmeal self-measured plasma glucose were significantly lower by 1.0-2.0 mmol/L (18-36 mg/dL) with iGlarLixi in all analyses. Bodyweight change was more favourable (1-2 kg) for iGlarLixi versus IDegAsp for all analyses (P < 0.05). Comparisons of hypoglycaemia were inconclusive owing to differences in definitions between studies. Adverse events were more frequent with iGlarLixi because of gastrointestinal intolerance. CONCLUSIONS: iGlarLixi appears to offer clinical benefit in glucose control and bodyweight change in people needing both basal and meal-time intervention.

Efficacy and safety of iGlarLixi versus IDegLira in adults with type 2 diabetes inadequately controlled by glucagon-like peptide-1 receptor agonists: a systematic literature review and indirect treatment comparison.

AIMS: To estimate the relative treatment effect between the fixed-ratio combinations iGlarLixi and IDegLira (glucagon-like peptide 1 receptor agonist with basal insulin) in people with type 2 diabetes inadequately controlled on a glucagon-like peptide 1 receptor agonist. MATERIALS AND METHODS: A systematic literature review of randomized controlled trials followed by an indirect treatment comparison was performed to compare the efficacy and safety of the available fixed-ratio combinations. Main outcomes were glycated haemoglobin (HbA1c) change and target achievement [<6.5% and <7.0% (<48 and <53 mmol/mol)], fasting plasma glucose, self-monitored plasma glucose, body weight, and incidence and rate of hypoglycaemia. RESULTS: From 4850 abstracts screened, 78 qualified for full-text article review and two randomized controlled trials were included. Baseline characteristics were similar in the two studies. The mean difference at 26 weeks between IDegLira and iGlarLixi was -0.36 (95% credible intervals -0.58, -0.14) % [-3.9 (-6.3, -1.5) mmol/mol] for HbA1c and -1.0 (-1.6, -0.4) mmol/L for fasting plasma glucose. No significant differences were found in HbA1c target attainment, preprandial or postprandial self-monitored plasma glucose, or body weight change. Formal comparisons of hypoglycaemia were limited by differences in definitions between the studies: in non-sulphonylurea users, incidence was 28% for IDegLira ('confirmed' at ≤3.1 mmol/L); for iGlarLixi, incidence was 9% ('documented symptomatic' at <3.0 mmol/L). CONCLUSIONS: Results of this indirect treatment comparison using two studies suggest iGlarLixi and IDegLira appear to offer similar benefits for HbA1c target achievement. However, the findings suggest differences in other glycaemia results and hypoglycaemia, which may reflect differences in study design and titration approaches.

Hypoglycaemia risk with insulin glargine 300 U/mL compared with glargine 100 U/mL across different baseline fasting C-peptide levels in insulin-naïve people with type 2 diabetes: A post hoc analysis of the EDITION 3 trial.

The relationship between baseline fasting C-peptide (FCP) and glucose control was examined in insulin-naïve people with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs commencing basal insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) in the absence of sulfonylurea/glinides. Participants with FCP measurement from the EDITION 3 trial (n = 867) were stratified according to baseline FCP (≤0.40, >0.40-1.20, >1.20 nmol/L); 11.0%, 70.9% and 18.1% contributed to each group. Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 26 weeks. Glycaemic control (HbA1c, FPG) at 26 weeks was similar in each FCP group between insulins. However, end-of-study insulin dose was greater with higher FCP for both insulins. More people with lower baseline FCP experienced hypoglycaemia with both insulins, but with numerically lower incidence for Gla-300 versus Gla-100 across all FCP groups for all definitions (time periods and levels) of hypoglycaemia. This suggests that Gla-300 might be particularly advantageous for people who are at higher risk of hypoglycaemia.

Commencing insulin glargine 100 U/mL therapy in individuals with type 2 diabetes: Determinants of achievement of HbA1c goal less than 7.0.

AIMS: To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Post-hoc pooled analysis of 16 randomized, treat-to-target trials involving individuals with T2DM inadequately controlled with oral anti-hyperglycaemic drugs (n = 3415) initiated on once-daily insulin glargine 100 U/mL (Gla-100). Clinical outcomes were assessed by HbA1c response at 24 weeks and individuals were classified as "good responders" with HbA1c <7.0% (<53 mmol/mol) or as "poor responders" with HbA1c ≥7.0% (≥53 mmol/mol). Univariable and multivariable stepwise logistic regression analyses were performed to identify predictive factors for attaining HbA1c <7.0%. RESULTS: Lower levels of baseline HbA1c, fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG), higher body mass index (BMI), shorter diabetes duration and male sex were associated with a good glycaemic response, but not age or baseline C-peptide levels. Gla-100 dose (U/kg) was highest in the poor-responder group, which had the fewest hypoglycaemia episodes. Univariable analysis for achievement of HbA1c <7.0% confirmed these observations. Multivariable analysis retained baseline HbA1c, body weight, BMI, sex, 2-hours PPG and diabetes duration as predictors of a good response. Continued use of sulfonylureas, hypoglycaemia and change in body weight were indicative of poor response. CONCLUSIONS: Baseline HbA1c was the strongest determinant for achieving target HbA1c <7.0% by supplementary Gla-100 therapy, while sex and BMI were also useful indicators. However, age and C-peptide levels at baseline did not predict glycaemic response to the introduction of basal insulin.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naïve at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4).

AIMS: Insulin glargine 300 U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla-100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM). METHODS: EDITION 4 was a 6-month, multicentre, randomized, open-label phase 3 study. People with T1DM who completed the 6 months continued randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6 months. RESULTS: Among 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, -0.13 to 0.17]) %-units [0.2 (-1.5 to 1.9) mmol/mol]), to a mean of 7.86 %-units (62.4 mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12 months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning group than in the Gla-300 evening group (difference, -0.25 [-0.47 to -0.04] %-units [-2.7 (-5.2 to -0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla-300 than with Gla-100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups. CONCLUSIONS: In T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day.

Three-year data from 5 HARMONY phase 3 clinical trials of albiglutide in type 2 diabetes mellitus: Long-term efficacy with or without rescue therapy.

AIMS: Diabetes therapies that provide durable glycaemic control for people with type 2 diabetes mellitus (T2DM) are needed. We present efficacy results of albiglutide, a glucagon-like peptide-1 receptor agonist, in people with T2DM over a 3-year period. METHODS: Five of the 8 HARMONY phase 3 trials, comparing albiglutide with other therapies or placebo across a spectrum of clinical care, lasted for a preplanned 3years. Participants with uncontrolled hyperglycaemia who met predetermined criteria could receive rescue medication. The ability to remain on study medication without needing additional rescue was an efficacy measure. Glycaemic measures and body weight were analysed in 2 populations: those who remained rescue-free and all participants. RESULTS: Participants (n=3132) were randomised to albiglutide or comparator. A greater proportion of participants who received albiglutide remained rescue-free (55-71%) compared with placebo (35-51%; p<0.001 to p=0.002). The proportion of rescue-free participants with albiglutide did not differ from glimepiride or insulin glargine, was higher than with sitagliptin (p=0.013), and lower than with pioglitazone (p=0.045). At 3years, albiglutide was associated with clinically significant reductions in hyperglycaemia (eg, rescue-free participants: HbA1c -0.52% [SE0.11] to -0.98% [0.12]; -5.7mmol/mol [1.2] to -10.7mmol/mol [1.3] and all participants: HbA1c -0.29% [0.11] to-0.92% [0.13]; -3.2mmol/mol [1.2] to -10.1mmol/mol [1.4]). Albiglutide was also associated with modest reductions in body weight vs pioglitazone, glimepiride, and insulin glargine, which were associated with weight gain. CONCLUSION: These 3-year efficacy data support long-term use of albiglutide in the management of people with T2DM. ClinicalTrials.gov NCT00849056, NCT00849017, NCT00838903, NCT00838916, NCT00839527.

Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?

The overall impact of glucose lowering on vascular complications and major clinical outcomes, including mortality, in type 2 diabetes is still an open issue. While intensive glucose control has undoubted benefit for microvascular end points, the relationship between glucose-lowering approaches and reduced incidence and/or progression of macrovascular complications is less clear. This review article will discuss the effect of glucose lowering per se as well as the effects of specific glucose-lowering therapies on vascular outcomes in type 2 diabetes. The role of lifestyle changes on cardiovascular outcomes will be also addressed. Recent analyses from large cardiovascular outcome studies (ACCORD, ADVANCE, and VADT) provide new information on factors that modulate the impact of intensive glucose lowering on outcomes, helping to identify the specific clinical characteristics of the patients receiving the intervention that would show a better response. While several studies on cardiovascular outcomes with diabetes drugs are available, they do not clearly highlight a benefit from using a specific medication or will require additional evidence, as for the sodium-glucose cotransporter 2 blockers.

Efficacy and Safety of Flexible Versus Fixed Dosing Intervals of Insulin Glargine 300 U/mL in People with Type 2 Diabetes.

BACKGROUND: Insulin glargine 300 U/mL (Gla-300) has a more constant and prolonged action profile than insulin glargine 100 U/mL and in clinical studies is associated with similar glycemic control but less hypoglycemia. Whether its effects are altered by variability of injection time was examined in two 3-month substudies. MATERIALS AND METHODS: Eligible participants completing 6 months of optimized treatment with Gla-300 in EDITION 1 (n = 109) and EDITION 2 (n = 89), having a mean hemoglobin A1c (HbA1c) level of 7.3 % (SD 1.0 %), were randomized (1:1) to groups advised to increase variability of between-injection intervals to 24 ± up to 3 h or to maintain fixed 24-h intervals for 3 months. Changes of HbA1c level and other efficacy and safety measures were assessed. RESULTS: In the fixed-dosing group, 64% of participants reported all intervals within the 23-25-h range, compared with 15% of those advised flexible dosing. In the fixed- and flexible-dosing groups, 12% and 41%, respectively, of between-injection intervals were outside the 23-25-h range, and 2% and 16%, respectively, were outside the 21-27-h range. Least squares mean between-group difference in HbA1c change from baseline was 0.05 % (95% confidence interval [CI], -0.13 to 0.23); for fasting plasma glucose, 2.7 mg/dL (95% CI, -9.0 to 14.4); and for daily basal insulin dose, 0.00 U/kg (95% CI, -0.02 to 0.03). Frequencies of hypoglycemia and adverse events did not differ between groups. CONCLUSIONS: The efficacy and safety of Gla-300 demonstrated in EDITION 1 and EDITION 2 are maintained in substudies when the insulin was injected up to 3 h before or after the usual time of administration.

Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors' Expert Forum.

As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors' Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease.

New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4).

OBJECTIVE: Insulin therapy in type 1 diabetes still provides suboptimal outcomes. Insulin glargine 300 units/mL (Gla-300), with a flatter pharmacodynamic profile compared with insulin glargine 100 units/mL (Gla-100), is an approach to this problem. RESEARCH DESIGN AND METHODS: People with type 1 diabetes, using a mealtime and basal insulin regimen, were randomized open-label to Gla-300 or Gla-100 and to morning or evening injection, continuing the mealtime analog, and followed for 6 months. RESULTS: Participants (n = 549) were a mean age of 47 years and had a mean duration of diabetes of 21 years and BMI of 27.6 kg/m(2). The change in HbA1c (primary end point; baseline 8.1%) was equivalent in the two treatment groups (difference, 0.04% [95% CI -0.10 to 0.19]) (0.4 mmol/mol [-1.1 to 2.1]), and Gla-300 was thus noninferior. Similar results with wider 95% CIs were found for morning and evening injection times and for prebreakfast self-measured plasma glucose (SMPG) overall. Results were also similar for Gla-300 when morning and evening injection time was compared, including overlapping 8-point SMPG profiles. Hypoglycemia did not differ, except for the first 8 weeks of the study, when nocturnal confirmed or severe hypoglycemia was lower with Gla-300 (rate ratio 0.69 [95% CI 0.53-0.91]). Hypoglycemia with Gla-300 did not differ by time of injection. The basal insulin dose was somewhat higher at 6 months for Gla-300. The adverse event profile did not differ and was independent of the Gla-300 time of injection. Weight gain was lower with Gla-300. CONCLUSIONS: In long-duration type 1 diabetes, Gla-300 provides similar glucose control to Gla-100, with a lower risk of hypoglycemia after transfer from other insulins, independent of time of injection, and less weight gain.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

AIMS: It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. METHODS: People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. RESULTS: Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. CONCLUSION: Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen.

Predictors of HbA1c over 4 years in people with type 2 diabetes starting insulin therapies: The CREDIT study.

AIMS: To identify factors associated with glucose control, as measured by HbA1c over 4 years, in people with type 2 diabetes starting insulin therapy. METHODS: CREDIT, an observational cohort study, collected data semi-annually over 4 years, on people with type 2 diabetes starting any insulin, in 311 centres in 12 countries; 2803 people had data on HbA1c during follow-up. Multivariable backward regression analysis selected characteristics associated with glycaemic control from a limited number of candidate variables. RESULTS: Before starting insulin therapy, HbA1c was 9.3% (78 mmol/mol) and decreased to 7.6% (60 mmol/mol) after 1 year, and changed little after that. Insulin dose increased from 0.21 U/kg to 0.36 U/kg at 1 year, and then by 0.10 U/kg over the next 3 years. Body weight increased by 2.0 kg in the first year and increased little thereafter. Poorer glycaemic control over the 4 years was mainly determined by the HbA1c before starting therapy, after accounting for the other statistically significant associated variables in multivariable analysis: higher BMI, younger age, longer diabetes duration, more glucose-lowering drugs, using basal insulin alone, higher insulin dose and female sex. At 4 years, a higher current insulin dose was the characteristic most strongly associated with a higher concurrent HbA1c. CONCLUSIONS: HbA1c at the start of insulin therapy was the characteristic most predictive of later HbA1c, after accounting for other variables associated with HbA1c. This may provide some justification for earlier insulin introduction to improve glucose control to target.

Cancer and bone fractures in observational follow-up of the RECORD study.

AIMS: The RECORD study evaluated the effects of rosiglitazone on cardiovascular outcomes. A 4-year observational follow-up was added to the study to monitor the occurrence of cancer and bone fractures. We present the cancer and bone fracture data aggregated across the main study and its observational follow-up. METHODS: RECORD was a multicentre, open-label trial in people with type 2 diabetes on metformin or sulfonylurea monotherapy randomly assigned to addition of rosiglitazone (n = 2,220) or to a combination of metformin and sulfonylurea (n = 2,227). At the end of the main study, patients stopped study drug and were invited to enter the observational follow-up during which glucose-lowering treatment was selected by the patient's physician. Serious adverse events of cancer and serious and non-serious events of bone fracture were recorded. The study is registered with ClinicalTrials.gov, number NCT00379769. RESULTS: Of the 4,447 patients comprising the intent-to-treat population, 2,546 entered the observational follow-up (1,288 rosiglitazone, 1,258 metformin/sulfonylurea) and added 9,336 patient-years experience to the main RECORD study, making an aggregate of 33,744 patient-years. Based on the totality of follow-up, malignancies were reported in 179 of 2,220 patients (8.1 %) in the group originally randomised to rosiglitazone and in 195 of 2,227 patients (8.8 %) in the group allocated metformin/sulfonylurea [relative risk, RR, 0.92 (95 % CI 0.76-1.12)]. More patients reported bone fractures in the rosiglitazone group (238, 10.7 %) than in the metformin/sulfonylurea control [151, 6.8 %; RR 1.58 (1.30-1.92)]. For women, the corresponding figures were rosiglitazone 156 (14.5 %), metformin/sulfonylurea 91 (8.5 %), RR 1.71 (1.34-2.18), and for men, the corresponding figures were rosiglitazone 82 (7.2 %), metformin/sulfonylurea 60 (5.2 %), RR 1.37 (0.99-1.90). Potentially high-morbidity fractures (hip, pelvis, femur, and spine) occurred in the same number of patients (31, 1.4 %) in the two treatment groups. CONCLUSIONS: We conclude that data from a 4-year observational follow-up, combined with the main RECORD study data, do not suggest an increased risk of cancer in patients randomised to rosiglitazone combination use compared with those randomised to metformin/sulfonylurea. Consistent with the main study, rosiglitazone is associated with an increased risk of peripheral bone fracture in women, and probably in men, but the combined data do not suggest an increase in potentially high-morbidity (hip, pelvis, femur, and spine) fractures.