Double-blind, randomized clinical trial assessing the efficacy and safety of early initiation of sitagliptin during metformin uptitration in the treatment of patients with type 2 diabetes: The CompoSIT-M study.

AIMS: To characterize the glycaemic efficacy and safety of initiation of the dipeptidyl peptidase-4 inhibitor sitagliptin during metformin dose escalation in people with type 2 diabetes (T2D) not at glycated haemoglobin (HbA1c) goal on a sub-maximal dose of metformin. MATERIALS AND METHODS: Study participants with HbA1c ≥58 mmol/mol and ≤97 mmol/mol (≥7.5% and ≤11.0%) while on 1000 mg/d metformin were randomized to sitagliptin 100 mg once daily or placebo. All were to uptitrate metformin to 2000 mg/d. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is superior to placebo when initiated during uptitration of metformin in reducing HbA1c at week 20. [ClinicalTrials.gov Identifier: NCT02791490, EudraCT: 2015-004224-59] RESULTS: A total of 458 participants (mean HbA1c 71.1 mmol/mol [8.7%], T2D duration 6.3 years) were treated. After 20 weeks, the least squares (LS) mean changes from baseline in HbA1c were -12.1 mmol/mol (-14.0, -10.1) (-1.10% [-1.28, -0.93]) and -7.6 mmol/mol (-9.6, -5.6) (-0.69% [-0.88, -0.51]) with sitagliptin and placebo, respectively; the between-group difference in LS mean changes from baseline HbA1c was -4.5 mmol/mol (-6.5, -2.5) (-0.41% [-0.59, -0.23]); P < 0.001. The likelihood of having HbA1c <53 mmol/mol (<7.0%) at week 20 was higher in the sitagliptin group than in the placebo group in the overall population (relative risk 1.7, P = 0.002) and in those with a baseline HbA1c ≥69 mmol/mol (≥8.5%) (relative risk 2.4, P = 0.026). There were no notable differences between groups with regard to adverse events overall, hypoglycaemia events, changes in body weight or other safety variables. CONCLUSION: In participants not at HbA1c goal on a sub-maximal dose of metformin, addition of sitagliptin at the time of metformin dose uptitration improved glycaemic response and HbA1c goal attainment, with similar safety and tolerability, compared to metformin uptitration alone.

A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.

BACKGROUND: Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that is approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval of omarigliptin in the United States, the clinical development program included a cardiovascular (CV) safety study. Subsequently, a business decision was made not to submit a marketing application for omarigliptin in the United States, and the CV safety study was terminated. Herein we report an analysis of data from that early-terminated study. METHODS: In this randomized, double-blind study, 4202 patients with T2DM and established CV disease were assigned to either omarigliptin 25 mg q.w. or matching placebo in addition to their existing diabetes therapy. A Cox proportional hazards model was used to summarize the primary endpoint of time to first major adverse CV event (MACE, the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) and the analysis of first event of hospitalization for heart failure (hHF). RESULTS: The median follow-up was approximately 96 weeks (range 1.1-178.6 weeks). The primary MACE outcome occurred in 114/2092 patients in the omarigliptin group (5.45%; 2.96/100 patient-years) and 114/2100 patients in the placebo group (5.43%; 2.97/100 patient-years), with a hazard ratio (HR) of 1.00 (95% confidence interval [CI] 0.77, 1.29). The hHF outcome occurred in 20/2092 patients in the omarigliptin group (0.96%; 0.51/100 patient-years) and 33/2100 patients in the placebo group (1.57%; 0.85/100 patient-years), with an HR of 0.60 (95% CI 0.35, 1.05). After 142 weeks, the least-squares mean difference (omarigliptin vs. placebo) in glycated hemoglobin levels was -0.3% (95% CI -0.46, -0.14). The numbers of patients with adverse events, serious adverse events or discontinued from study medication due to adverse events were similar in the omarigliptin and placebo groups. CONCLUSIONS: In this CV safety study of patients with T2DM and established CV disease, omarigliptin did not increase the risk of MACE or hHF and was generally well tolerated. Trial registration ClinicalTrials.gov: NCT01703208. Registered 05 October 2012.