Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Glargine (Gan & Lee Glargine) Compared With Originator Insulin Glargine (Lantus) in Patients With Type 1 Diabetes After 26 Weeks Treatment.

OBJECTIVE: To compare the immunogenicity, safety, and efficacy of Gan & Lee insulin glargine (GL Glargine) with that of the originator insulin glargine (Lantus) in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase 3, multicenter, randomized, open-label, equivalence study. Five hundred seventy-six subjects with T1DM were randomized 1:1 to receive either GL Glargine or Lantus treatment for 26 weeks. The primary end point was the percentage of subjects in each treatment group who developed treatment-induced anti-insulin antibody after baseline and up to visit week 26, which was evaluated using a country-adjusted logistic regression model. The study also compared the changes in glycated hemoglobin, and adverse events including hypoglycemia. RESULTS: The percentage of subjects positive for treatment-induced anti-insulin antibody by Week 26 was 25.8% in the GL Glargine treatment group and 25.3% in the Lantus treatment group, with a 90% confidence interval (-5.4, 6.5) of the difference in proportions that fell completely between the similarity margins (-11.3, 11.3). The least squares mean difference between treatment groups for changes in glycated hemoglobin was -0.08 (90% confidence interval: -0.23, 0.06), and the other immunogenicity and safety profiles were comparable. CONCLUSION: GL Glargine demonstrated similar immunogenicity, efficacy, and safety compared to Lantus over 26 weeks in patients with T1DM.

Risk of clinically relevant hypoglycaemia in patients with type 2 diabetes self-titrating insulin glargine U-100.

AIMS: We evaluated risk factors for clinically relevant hypoglycaemia (blood glucose <3 mmol/L) in patients with type 2 diabetes during insulin glargine self-titration. Data were from two clinical trials in which patients were able to improve glycaemic control by self-titration of insulin glargine using a simple algorithm. MATERIALS AND METHODS: We performed post hoc analyses of pooled treatment groups from each of two Phase 3 studies comparing LY2963016 with LANTUS: ELEMENT-2 (double-blind) and ELEMENT-5 (open label). Clinically relevant hypoglycaemia was analysed by category of HbA1c (<7%, 7%-8.5%, >8.5%) at Week 12 (titration period) and at Week 24 (overall study), and by subgroups of age (<65, ≥65 years) and previous insulin use (naïve or not). RESULTS: In the ELEMENT-2 study (N = 756), there were no overall differences in rate or incidence of hypoglycaemia among HbA1c categories. In the ELEMENT-5 study (N = 493), patients with HbA1c greater than 8.5% had a lower rate and incidence of hypoglycaemia throughout the study compared to those in the lower HbA1c categories. In both studies, patients 65 years of age or older, compared to those less than 65 years, had a higher rate and incidence of hypoglycaemia during the titration phase, had lower baseline HbA1c, and experienced smaller increases in dose, with no differences in HbA1c post baseline. The rate and incidence of hypoglycaemia was similar between naïve patients and patients previously using basal insulin, across all levels of glycaemic control. With the exception of the older subgroup, hypoglycaemia rates were similar during titration and maintenance periods. CONCLUSION: Our results support broader use of self-titration algorithms for patients with type 2 diabetes.

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.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, baseline A1C 6.8%-8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS: Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS: Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.

Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial.

BACKGROUND: Basal insulin therapy does not stop loss of ß-cell function, which is the hallmark of type 2 diabetes mellitus, and thus diabetes control inevitably deteriorates. Insulin degludec is a new, ultra-longacting basal insulin. We aimed to assess efficacy and safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes mellitus. METHODS: In this 52 week, phase 3, open-label, treat-to-target, non-inferiority trial, undertaken at 123 sites in 12 countries, we enrolled adults (aged ≥18 years) with type 2 diabetes mellitus and a glycated haemoglobin (HbA(1c)) of 7·0-10·0% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs). We randomly allocated eligible participants in a 3:1 ratio to receive once-daily subcutaneous insulin degludec or glargine, stratified by previous insulin regimen, via a central interactive response system. Basal insulin was titrated to a target plasma glucose concentration of 3·9-<5·0 mmol/L self-measured before breakfast. The primary outcome was non-inferiority of degludec to glargine measured by change in HbA(1c) from baseline to week 52 (non-inferiority limit of 0·4%) by ANOVA in the full analysis set. We assessed rates of hypoglycaemia in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00972283. FINDINGS: 744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58·9 years [SD 9·3], diabetes duration 13·5 years [7·3], HbA(1c) 8·3% [0·8], and fasting plasma glucose 9·2 mmol/L [3·1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA(1c) decreased by 1·1% in the degludec group and 1·2% in the glargine group (estimated treatment difference [degludec-glargine] 0·08%, 95% CI -0·05 to 0·21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11·1 vs 13·6 episodes per patient-year of exposure; estimated rate ratio 0·82, 95% CI 0·69 to 0·99; p=0·0359), as were rates of nocturnal confirmed hypoglycaemia (1·4 vs 1·8 episodes per patient-year of exposure; 0·75, 0·58 to 0·99; p=0·0399). Rates of severe hypoglycaemia seemed similar (0·06 vs 0·05 episodes per patient-year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups. INTERPRETATION: A policy of suboptimum diabetes control to reduce the risk of hypoglycaemia and its consequences in advanced type 2 diabetes mellitus might be unwarranted with newer basal insulins such as degludec, which are associated with lower risks of hypoglycaemia than insulin glargine. FUNDING: Novo Nordisk.

Comparing the effects of insulin glargine and thiazolidinediones on plasma lipids in type 2 diabetes: a patient-level pooled analysis.

BACKGROUND: The prevalence of dyslipidaemia and the risk of cardiovascular disease are elevated in patients with type 2 diabetes. This analysis compared the effects of insulin glargine versus thiazolidinediones (TZDs) on lipid profiles. METHODS: Patient-level data were pooled from two randomized clinical studies. The population included 552 men and women aged >18 years, diagnosed with type 2 diabetes for at least 6 months, on metformin and/or sulphonylurea, and with A(1C) ≥7.5% and <12.0% at screening. Lipid outcome measures included change from baseline in lipid levels [low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, triglycerides, and free fatty acids] and attainment of lipid goals for LDL-C, non-HDL-C, and triglycerides. RESULTS: Both insulin glargine and TZDs improved lipid profiles from baseline values. Compared with TZDs, treatment with insulin glargine led to 7.9% greater reduction in LDL-C (p < 0.0003), 7.5% greater reduction in non-HDL-C (p < 0.0001), and 7.8% greater reduction in total cholesterol (p < 0.0001), whereas the HDL-C increase with TZD was 7.6% greater than that with insulin glargine (p < 0.0001). The percentage of patients attaining the lipid goals was comparable between insulin glargine and pioglitazone, but lower for rosiglitazone. Insulin glargine improved glycaemic control more than TZDs; however, insulin glargine caused more hypoglycaemia. Treatment with TZDs caused more weight gain and peripheral oedema. CONCLUSION: These findings suggest that the favourable effects of insulin glargine on plasma lipid profiles should be considered among the advantages of treatment with insulin glargine as they are for TZDs.

Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults.

Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.

Impact of Simultaneous Versus Sequential Initiation of Basal Insulin and Glucagon-like Peptide-1 Receptor Agonists on HbA1c in Type 2 Diabetes: A Retrospective Observational Study.

INTRODUCTION: When and how to intensify treatment in patients with type 2 diabetes (T2D) not achieving glycated hemoglobin (HbA1c) targets with oral antidiabetic drugs (OADs) in clinical practice remains a matter of clinical preference. This pilot study was conducted using the retrospective observational data from such patients to evaluate the impact on HbA1c of three treatment sequences: simultaneous initiation of basal insulin (BI) and a glucagon-like peptide-1 receptor agonist (GLP-1 RA; Cohort 1); BI followed by GLP-1 RA initiation within a 90-day timeframe (Cohort 2); or BI followed by GLP-1 RA initiation beyond 90 days (Cohort 3). METHODS: Data from the regional US electronic medical records database, Research Action for Health Network (REACHnet), were extracted for all patients with T2D aged ≥ 18 years who had encounter dates between January 2011 and August 2017 and ≥ 1 HbA1c laboratory value(s) < 90 days before BI initiation and ≥ 2 HbA1c laboratory values within 1 year after BI initiation and who met the inclusion criteria for GLP-1 RA initiation set for Cohorts 1, 2, or 3. The primary endpoints were the proportion of patients achieving HbA1c < 7.0%, which was estimated via Kaplan-Meier analysis, and change in HbA1c within 12 months. RESULTS: Overall, 869 patients were analyzed, of whom 109 were in Cohort 1, 301 in Cohort 2, and 459 in Cohort 3. Baseline HbA1c was 10.3 ± 2.1, 10.3 ± 2.0, and 10.2 ± 2.1% for these three cohorts, respectively. Statistically significantly more patients in Cohort 1 than in Cohort 3 achieved HbA1c < 7.0% (33.4 vs. 20.9%, respectively; p = 0.0186). Mean observed reductions in HbA1c at 12 months were - 1.7% (Cohort 1), - 1.5% (Cohort 2), and - 1.3% (Cohort 3). CONCLUSIONS: Simultaneous initiation of BI and GLP-1 RA achieves glycemic control more effectively than sequential initiation of BI with GLP-1 RA added beyond 90 days.

Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight.

OBJECTIVE: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for <10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in. RESULTS: Adjusted for duration of run-in, the mean ± SD change in HbA1c was -0.65 ± 0.02% (-7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, -0.48 ± 0.02% (-5.2 ± 0.2 mmol/mol) when the dose was unchanged, and -0.23 ± 0.07% (-2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P < 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894). CONCLUSIONS: Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control.

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin.

Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0-9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were -0.3% (-0.4, -0.2), -0.4% (-0.5, -0.3) and -0.4% (-0.5, -0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks.

A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes.

OBJECTIVE: This trial compared the efficacy and safety profiles of the insulin analogues detemir and glargine as the basal insulin component of a basal-bolus regimen in patients with type 2 diabetes mellitus (T2DM) who were being treated with oral antidiabetic drugs (OADs) or insulin with or without OADs. METHODS: This was a multinational, 52-week, openlabel, parallel-group, noninferiority, treat-to-target trial. Patients with a diagnosis of T2DM for > or = 12 months who had been receiving an OAD or insulin, with or without OADs, for > 4 months were randomized in a 2:1 ratio to receive detemir or glargine. According to the approved labeling, detemir could be administered once or twice daily, and glargine was administered once daily. Insulin aspart was given at mealtimes. Insulin secretagogues and a-glucosidase inhibitors were discontinued at study entry, and existing OADs were continued. Doses of detemir and glargine were titrated to achieve a prebreakfast (and predinner for detemir administered twice daily) plasma glucose target of < or = 6.0 mmol/L. Patients monitored their plasma glucose levels before breakfast and dinner on the 3 days before each of 13 scheduled visits, recorded their insulin doses on 1 of these 3 days, and recorded their 10-point self-monitored plasma glucose (SMPG) at baseline and after 24 and 52 weeks. The primary efficacy end point was glycosylated hemoglobin (HbA(1c)) at 52 weeks; secondary efficacy end points included changes in fasting plasma glucose (FPG), postprandial plasma glucose, insulin doses, and weight change at 52 weeks. Safety end points included the frequency of hypoglycemia and adverse events (AEs). RESULTS: The intention-to-treat population included 319 patients (58.0% male, 42.0% female; 78.4% white; mean age, 58 years; mean weight, 92.8 kg; mean duration of diabetes, 13.6 years). At study entry, 46.1% of patients were receiving insulin and > or = 1 OAD, 35.4 were receiving insulin only, and 18.5% were receiving > or = 1 OAD only. At 52 weeks, there was no significant difference between detemir and glargine in terms of mean HbA(1c) (7.19% and 7.03%, respectively; mean difference, 0.17% [95% CI, -0.07 to 0.40]) or the mean decrease in HbAlc from baseline (-1.52% and -1.68%). The reduction in HbA(1c) was not significantly affected by whether detemir was administered once or twice daily. There were no significant differences between groups in terms of mean FPG (7.05 and 6.68 mmol/L) or the mean change in FPG from baseline (-2.56 and -2.92 mmol/L; mean difference, 0.36; 95% CI, -0.26 to 0.99). The overall shape of the 10-point SMPG profiles was not significantly different between groups. Mean weight gain at 52 weeks was significantly lower with detemir than with glargine (2.8 vs 3.8 kg; mean difference, -1.04; 95% CI, -2.08 to -0.01; P < 0.05). Doses of basal and prandial insulins at the end of the study were not significantly different between groups. Major hypoglycemic episodes were reported by 4.7% and 5.7% of patients in the respective treatment groups. There was no significant difference in the risk of hypoglycemia between groups. The proportion of patients with AEs and the number of AEs per patient were comparable between groups (185/214 patients [86.4%] reporting 743 AEs and 88/105 patients [83.8%] reporting 377 AEs). CONCLUSIONS: when used as indicated as part of a basal-bolus regimen in patients with T2DM who had previously received other insulin and/or OAD regimens, detemir was noninferior to glargine in its effects on overall glycemic control. Both basal insulins were associated with clinically relevant reductions in hyperglycemia. Both were well tolerated, with no significant difference in the frequency of hypoglycemia or AEs.

Low-dose rosiglitazone in patients with insulin-requiring type 2 diabetes.

BACKGROUND: The objective was to compare the efficacy and safety of adding low-dose rosiglitazone (2 or 4 mg/d) to insulin therapy vs continued insulin monotherapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with insulin therapy alone. METHODS: In this 24-week, double-blind study, 630 individuals with type 2 diabetes mellitus that was inadequately controlled with insulin therapy alone were randomized to treatment with rosiglitazone (2 or 4 mg/d) or placebo in combination with ongoing insulin therapy. The dosage of insulin therapy could be adjusted at the investigator's discretion if required for hypoglycemia or additional glycemic control. RESULTS: The addition of rosiglitazone (2 or 4 mg/d) to insulin therapy significantly decreased mean glycated hemoglobin concentrations compared with placebo plus insulin (-0.3% [P=.02] and -0.4% [P<.001]) and compared with baseline (-0.6% and -0.8% [both P<.001]) after 24 weeks. The addition of 2 or 4 mg/d of rosiglitazone significantly decreased the C-reactive protein level (vs baseline: -22.0% [P<.001] and -34.2% [P<.001]; vs placebo: -22.2% [P=.003] and -32.0% [P<.001]) and fibrinogen (vs baseline: -10.5% and -12.0% [both P<.001]; vs placebo: -7.9% [P=.002] and -7.6% [P=.004]), while 4 mg/d of rosiglitazone significantly reduced matrix metalloproteinase 9 levels (vs baseline: -17.1% [P=.007]; vs placebo: -23.3% [P<.001]). The adverse event profile, including incidence of hypoglycemia and edema, was similar between treatment groups, and most adverse events were mild to moderate in intensity. CONCLUSIONS: The addition of low-dose rosiglitazone to insulin therapy is an effective and well-tolerated treatment option for patients with type 2 diabetes mellitus who continue to have poor glycemic control despite administration of exogenous insulin as monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054782.

Similar Efficacy and Safety of Basaglar® and Lantus® in Patients with Type 2 Diabetes in Age Groups (< 65 Years, ≥ 65 Years): A Post Hoc Analysis from the ELEMENT-2 Study.

INTRODUCTION: To compare efficacy and safety of Basaglar® [insulin glargine 100 units/mL; LY insulin glargine (LY IGlar)] to Lantus® [insulin glargine 100 units/mL; SA insulin glargine (SA IGlar)] in older (≥ 65 years) or younger (< 65 years) patients with type 2 diabetes (T2D). METHODS: This subgroup analysis of a phase 3, randomized, double-blind, multinational, 24-week study compared LY IGlar and SA IGlar on several clinical efficacy (change in glycated hemoglobin (A1c), basal insulin dose, weight) and safety outcomes (incidence of adverse events, insulin antibodies, hypoglycemia incidence and rates) in patients either ≥ 65 or < 65 years. RESULTS: Compared with patients aged < 65 years (N = 542), patients aged ≥ 65 years (N = 214) had a significantly longer duration of diabetes; lower baseline A1c and body weight; and body mass index; and were more likely to report prestudy SA IGlar use. Compared to patients < 65 years, patients ≥ 65 years needed a lower basal insulin dose and experienced lower body weight gain. There were no significant treatment-by-age interactions for the clinical efficacy and safety outcomes, indicating that there was no differential treatment effect (LY IGlar vs SA IGlar) for patients ≥ 65 years vs those < 65 years. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. CONCLUSIONS: LY IGlar and SA IGlar exhibit similar efficacy and safety in patients with T2D who are ≥ 65 years and in those < 65 years. TRIAL REGISTRATION: ClinicalTrials.gov trial registration: NCT01421459. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim.

Plain language summary available for this article.The aim of this phase 3 clinical study was to compare the efficacy and safety of two drugs, Basaglar^® (LY IGlar) and Lantus (SA IGlar), in patients with type 2 diabetes that were either 65 years of age and/or older or younger than 65 years of age. This study ran for 24 weeks. The factors used to measure efficacy were changes in glycated hemoglobin (A1c), insulin dose, and weight. The safety outcomes were incidence of adverse events, incidence and levels of insulin antibodies, and the incidence and rate of low blood sugar. Compared with patients less than 65 years of age (N = 542), patients 65 years of age and older (N = 214) had diabetes for a significantly longer time period; had a lower baseline A1c, body weight, and body mass index; and were more likely to report that they used SA IGlar prestudy. Compared to patients less than 65 years of age, patients equal to or older than 65 years of age showed significantly smaller increases in insulin dose and body weight. There were no significant treatment-by-age interactions for the efficacy and safety outcomes, indicating that there was no difference in treatment effect (LY IGlar vs SA IGlar) for patients equal to or older than 65 years of age vs those less than 65 years of age. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. LY IGlar and SA IGlar have similar efficacy and safety in patients with T2D who are equal to or older than 65 years of age and in those less than 65 years of age.

Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study.

INTRODUCTION: This study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. METHODS: This phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1c ≥ 7.0% and ≤ 9.0% on stable metformin ≥ 1500 mg/day 1:1:1 to ertugliflozin 15 or 5 mg once-daily (QD), or glimepiride (titrated from 1 mg QD). The primary hypothesis was that ertugliflozin 15 mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment difference < 0.3%). RESULTS: Mean baseline HbA1c of randomized patients (N = 1326) was 7.8%. Mean and median doses of glimepiride were 3.0 mg/day throughout the study. At week 52, the least squares mean change (95% CI) from baseline in HbA1c was - 0.6% (- 0.7, - 0.5), - 0.6% (- 0.6, - 0.5), and - 0.7% (- 0.8, - 0.7) in the ertugliflozin 15 mg, ertugliflozin 5 mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15 mg and glimepiride of 0.1% (- 0.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups. CONCLUSIONS: Ertugliflozin 15 mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01999218.

Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.

BACKGROUND: Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas. METHODS: 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848. FINDINGS: 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness. INTERPRETATION: These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

Basal insulin or premix analogue therapy in type 2 diabetes patients.

BACKGROUND: We sought to compare the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) given twice daily with once-daily insulin glargine in patients with type 2 diabetes beginning insulin therapy and who did not use thiazolidinediones, which are contraindicated with insulin in the European Union, in a subpopulation (N=157) of the INITIATE study. METHODS: At baseline, HbA(1c) was >/=8.0% on >/=1000 mg/day metformin alone or in combination with other oral antidiabetic drugs (OADs; e.g. sulphonylurea or alpha-glucosidase inhibitors). Metformin was adjusted up to 2550 mg/day and other OADs were discontinued. Starting insulin doses were subsequently adjusted weekly for 26 weeks by algorithm-directed titration. RESULTS: The proportion of patients achieving a HbA(1c) below 7.0% at 28 weeks was greater with BIAsp 30 than with insulin glargine (65% vs 41%, P=0.003). The mean reduction in HbA(1c) was greater for BIAsp 30 than for insulin glargine: -2.89+/-1.6% vs -2.46+/-1.6%, respectively (P=0.035). Postprandial glucose increments were lower for the BIAsp 30 group after breakfast (P=0.003) and dinner (P=0.033); post-lunch values were not significantly different. No major hypoglycemic episodes were recorded. Nocturnal hypoglycemia was reported by 25% of subjects in the BIAsp 30 group and by 10% in the insulin glargine group (P=0.021). Weight gain was 5.6+/-4.6 and 3.0+/-4.3 kg (P=0.0004) for BIAsp 30 and insulin glargine, respectively. CONCLUSIONS: BIAsp 30, given twice daily in combination with metformin, was more effective than insulin glargine, given once daily in combination with metformin, at controlling blood glucose in insulin-naïve patients with type 2 diabetes, but was associated with increased weight gain and minor hypoglycemic events.

Evolution of a pulmonary insulin delivery system (Exubera) for patients with diabetes.

Many patients with diabetes fail to meet recommended glycemic goals regardless of the recognition of optimal glycemic control as a key component for improving clinical outcomes and quality of life in patients with diabetes. Patient- and physician-related barriers to the adoption of insulin therapy include fear and anxiety about injecting insulin, concerns about side effects, and personal health beliefs in regard to the use of insulin. There is an unmet need for an alternative insulin therapy that provides optimal glycemic control, is well tolerated, and improves patient adherence. Of the several inhaled insulin devices that are in various stages of development, the Exubera (INH) formulation is the first to be approved for use in the United States and in Europe. Exubera is a novel, rapid-acting inhaled human insulin formulation that has been developed for prandial insulin use. Clinical studies have shown that INH consistently improves glycemic control, in combination with longer-acting subcutaneous (SC) insulin regimens in patients with type 1 or type 2 diabetes, or is used to supplement or replace oral antidiabetic therapy in patients with type 2 diabetes. INH has demonstrated long-term safety and tolerability, with a risk for hypoglycemia similar to that of SC insulin, and no clinically meaningful changes in pulmonary function have been noted with its use. Patients treated with INH in clinical studies reported high levels of satisfaction with treatment, and many patients with diabetes choose inhaled insulin when it is offered as a treatment option. Taken together, these findings suggest that INH represents an important new development in the treatment of diabetes that may improve glycemic control in many patients with diabetes.

Where Are We Now? A Clinicians' Guide to the Use of Follow-On Insulin for Patients with Diabetes.

Insulin has been used as a standard treatment for patients with diabetes for almost 100 years. Over time, advances in insulin development have improved its pharmacologic properties. (Online access: http://courses.elseviercme.com/t2dm/666). Most recently, the US Food and Drug Administration approved a novel, follow-on basal insulin agent, with more expected to be commercially available in the near future. With the imminent availability of follow-on basal insulin agents, clinicians need to be aware of the potential benefits and concerns in order to facilitate informed decision making and to provide the best possible advice and guidance to their patients with diabetes. This program will review how follow-on insulin products are developed, manufactured, and receive regulatory approval; evaluate clinical trial data for new and emerging follow-on basal insulin agents; and provide practical information and guidance on how they may be incorporated into clinical practice. While it is unknown how follow-on basal insulins will affect patient outcomes, they have the potential to increase access to treatment among patients with diabetes and reduce healthcare costs.