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

Abstract

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.

Keywords: Antihyperglycemic agent; Dipeptidyl peptidase-4; Incretin; MK-3102.

Figures

Fig. 1

Study design; T2DM type 2 diabetes, CV cardiovascular, AHA antihyperglycemic agent, MF metformin, PIO pioglitazone, AGI alpha-glucosidase inhibitor, SGLT2i sodium–glucose co-transporter 2 inhibitor, SU sulfonylurea, q.w. once weekly, R randomization

Fig. 2

Kaplan–Meier plot of time to first major adverse cardiac event in the intention-to-treat population

Fig. 3

Forest plot of the hazard ratios for major adverse cardiac events (MACE) and other cardiovascular (CV) endpoints [CV-related death, fatal and nonfatal (FNF) MI, FNF stroke, and all-cause mortality]

Fig. 4

Changes from baseline in HbA1c over time; filled circle omarigliptin 25 mg q.w., open circle placebo