Diabetes News

American Diabetes Association 75th Annual Scientific Sessions (ADA 2015), one of the largest diabetes-specific meetings in the world, took place 5–9 June 2015 in Boston (MA, USA). The meeting brought together over 18 000 attendees from 130 countries (approximately 50% were from outside the US). The largest international contingents were Denmark, Japan, China, Canada, and Germany. Some of the most prominent data presented at ADA 2015 were the primary results from the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) and Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) cardiovascular outcomes trials (CVOTs). In TECOS, the CVOT for Merck's (Whitehouse Station, NJ, USA) dipeptidyl peptidase (DPP) 4 inhibitor Januvia (sitagliptin), the hazard ratio (HR) for the primary composite cardiovascular endpoint (cardiovascular death, non-fatal myocardial infarction [MI], non-fatal stroke, or hospitalization for unstable angina) was 0.98 (95% confidence interval [CI] 0.89–1.08). The secondary cardiovascular composite (cardiovascular death, non-fatal MI, or non-fatal stroke) was also neutral (HR 0.99; 95% CI 0.89–1.10). Results for all individual components of the primary composite, and for all-cause mortality, were also neutral, as were the results for hospitalization for heart failure (HR 1.00; 95% CI 0.83–1.20). There were no significant differences between groups in the rates of pancreatic adverse events. Of the 24 prespecified subgroup analyses for the primary composite endpoint, the only one to produce a non-neutral result was body mass index (BMI), which demonstrated a modest but significant (P = 0.03) interaction in favor of sitagliptin in obese patients. Other factors, including age, sex, race, geographic region, history of heart failure, blood pressure, smoking, medications, baseline HbA1c, and diabetes duration, had no significant effect on the results. Results from ELIXA, the CVOT for Sanofi's (Paris, France) glucagon-like peptide-1 (GLP-1) agonist Lyxumia (lixisenatide), were also consistently neutral. The HR for the primary composite cardiovascular endpoint (cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina) was 1.02 (95% CI 0.89–1.17). The results were also neutral for heart failure hospitalization (HR 0.96; 95% CI 0.75–1.23) and all-cause death (HR 0.94; 95% CI 0.78–1.13). No subgroup analyses deviated from neutrality for the primary outcome. There were very modest average reductions in weight (0.7 kg) and systolic blood pressure (0.8 mmHg) with lixisenatide, with no effect on heart rate for most of the trial following a transitory 1 b.p.m. increase over the first few weeks. There was a slight attenuation in the rise in albuminuria over time (24% increase over 2 years with lixisenatide vs 34% with placebo; P < 0.01), but there was no significant change in estimated glomerular filtration rate (eGFR). Nausea and vomiting were more common with lixisenatide (odds ratio [OR] 8.4; 95% CI 4.8–15.9), and just under 5% of patients on lixisenatide discontinued the trial because of gastrointestinal side effects. This drove a modest imbalance in overall adverse events (OR 1.3; 95% CI 1.1–1.5), although severe adverse events were balanced (OR 0.9; 95% CI 0.8–1.0). There were no significant differences in the rates of pancreatitis or pancreatic cancer. Dr John Buse (University of North Carolina, Chapel Hill, NC, USA) presented strong results from the Dual Action of Liraglutide and Insulin Degludec (DUAL) V Phase 3b trial comparing Novo Nordisk's (Bagsvaerd, Denmark) Xultophy (insulin degludec/liraglutide) with Sanofi's Lantus (insulin glargine). The study randomized 557 patients with type 2 diabetes (T2D) already on Lantus and metformin to either intensify their Lantus therapy or switch to Xultophy. After 26 weeks, Xultophy led to a 1.8% reduction in HbA1c from a baseline of 8.4% to 6.6%; Lantus intensification led to a 1.1% reduction in HbA1c from 8.2% to 7.1%. The treatment difference of 0.6% was significant (P < 0.001). Xultophy also achieved a >3 kg weight benefit compared with Lantus (1.5 kg weight loss from baseline). Xultophy led to 57% fewer episodes of confirmed hypoglycemia (P < 0.001) and an 83% reduction in nocturnal hypoglycemia (P < 0.001). There were also improvements in quality of life metrics, and 5.5-fold more patients achieved an HbA1c below 7% without hypoglycemia and weight gain with Xultophy versus Lantus. The incidence of nausea was <4% throughout the trial; more subjects in the Xultophy group experienced adverse events (58% vs 51%), but there were fewer severe adverse events with Xultophy than Lantus. The conference featured several presentations of Phase 3 data for Lilly's (Indianapolis, IN, USA) novel basal insulin peglispro. The Study in Participants With Type 1 Diabetes Mellitus (IMAGINE-1) trial in patients with type 1 diabetes (T1D) found a 0.37% statistically superior HbA1c reduction with peglispro versus Lantus that mostly persisted out to 78 weeks, with concomitant reductions in fasting glucose, inter-day fasting plasma glucose variability, weight (2 kg benefit at 26 weeks), and nocturnal hypoglycemia (36% reduction after 26 weeks). However, the reduction in nocturnal hypoglycemia was counteracted by a significant 29% increase in total hypoglycemia and severe hypoglycemia (15% vs 8% out to 78 weeks). Triglycerides were significantly elevated, and there were increases in liver enzymes and liver fat, although there were no cases of Hy's Law. In the Study in Patients With Type 2 Diabetes Mellitus (IMAGINE-2) trial, which enrolled insulin-naïve patients with T2D, peglispro also produced statistically superior HbA1c reductions (difference of 0.3% after 52 weeks) versus Lantus. Peglispro also produced less nocturnal hypoglycemia and weight gain, but it resulted in higher serum triglyceride levels (18 mg/dL difference) and higher liver alanine aminotransferase (ALT) levels (6 IU/L difference) compared with Lantus. The presenter noted that a magnetic resonance imaging (MRI) substudy showed no increase in liver fat with peglispro but a reduction with Lantus, that there were no cases of Hy's Law, and that the ALT changes could reflect hepatic adaptation rather than injury. Dr Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX, USA) presented results from the Phase 3 Study to Evaluate ITCA 650 for the Treatment of Type 2 Diabetes (FREEDOM-1) trial (n = 460) for Intarcia's (Boston, MA, USA) implantable exenatide mini-pump ITCA 650. The mean HbA1c reduction for the overall ITCA 650 group was 1.4% at the end of the trial, and the placebo-adjusted efficacy was approximately 1.1%. A prespecified secondary analysis of efficacy by concomitant therapy found that patients not on a sulfonylurea had greater HbA1c reductions from baseline to Week 39 (1.7% from baseline; approximately 1.4% placebo-adjusted) than those on a sulfonylurea (1.2% from baseline; approximately 0.9% placebo-adjusted). In terms of efficacy, the higher 60 µg/day dose was modestly superior to the 40 µg/day dose without a significant safety or tolerability sacrifice. ITCA 650 produced 2% placebo-adjusted weight loss from baseline at the higher dose. Composite outcome analyses showed that ITCA 650 helped more patients achieve a ≥1% HbA1c reduction plus a >5% weight reduction (21% and 17% with the two ITCA 650 doses vs 6% with placebo). Dr Yasuo Terauchi (Yokohama City University, Yokohama, Japan) presented full-year results from the Comparison of a New Formulation of Insulin Glargine With Lantus Both in Combination With Oral Antihyperglycemic Drug(s) in Japanese Patients With Type 2 Diabetes (EDITION JP 2) study, which randomized 241 patients with T2D on basal insulin plus oral medications to either Sanofi's Lantus XR (insulin glargine U300) or Lantus (insulin glargine U100). At 1 year, both groups experienced comparable HbA1c reductions from baseline of approximately 0.3% from a baseline of 8%. The average daily dose of Lantus XR was 20% higher (0.36 vs 0.30 units/kg per day), and the annualized rate of confirmed or severe hypoglycemia was significantly lower with Lantus XR: 36% less (95% CI 6%–56% less) at any time of the day, and 59% less (95% CI 8%–82% less) nocturnally. Lantus XR produced a 0.7 kg mean weight loss versus a 0.5 kg weight gain with Lantus. Dr Jun Yang (Lilly Suzhou Pharmaceuticals, Shanghai, China) presented results from a 26-week study with predominantly Asian participants with T2D (n = 165) who were randomized to either Lilly's once-weekly GLP-1 agonist Trulicity (dulaglutide) or Lantus in combination with metformin and/or a sulfonylurea. The findings showed that Trulicity led to greater reductions in HbA1c with weight loss and less hypoglycemia. Specifically, HbA1c reductions from a baseline of 8.4% were 1.7% for the 1.5 mg dose of Trulicity, 1.3% for the 0.75 mg dose of Trulicity, and 1.2% for Lantus. The proportion of patients who reached target HbA1c levels (<7%) was 65% with 1.5 mg Trulicity, 54% with 0.75 mg Trulicity, and 41% with Lantus. Both doses of Trulicity were associated with weight loss: 1.5 kg with the 1.5 mg dose and 0.9 kg with the 0.75 mg dose from a mean baseline of 78 kg. In contrast, the Lantus group gained 1.0 kg. On the safety front, 18% of patients experienced hypoglycemia with Trulicity compared with 29% with Lantus. Trulicity was well tolerated, although it led to more gastrointestinal side effects than Lantus: 9% of the Trulicity 1.5 mg group and 5% of the 0.75 mg group experienced nausea compared with 1% of the Lantus group.

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