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

BackgroundOmarigliptin 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.MethodsIn 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).ResultsThe 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.ConclusionsIn 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 2012Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0593-8) contains supplementary material, which is available to authorized users.

Reappraisal on pharmacological and mechanical treatments of heart failure

“…A secondary analysis of HF and related outcomes with linagliptin versus placebo in CARMELINA, a cardiovascular outcomes trial that enrolled participants with T2DM and atherosclerotic cardiovascular disease and/or kidney disease, demonstrated that linagliptin did not affect the risk of HHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous LVEF [150]. A multicentre, double-blind, randomized, placebo-controlled, parallel group, phase III study that assigned 4202 patients with T2DM and established cardiovascular disease indicated that omarigliptin did not increase the risk of cardiovascular death, nonfatal MI, nonfatal stroke or HHF and was generally well tolerated [151].…”

“…Omarigliptin: Gantz et al [151] AF ENGAGE AF-TIMI 48 [154], HF-ACTION [155], PARADIGM-HF/ATMOSPHERE [156], TOPCAT [157], ARISTOTLE [158], AATAC [159], CASTLE-AF [160], GENETIC-AF [163] MR MITRA-FR [165,166], COAPT [167] Hyperkalemia Patiromer: PEARL-HF [170], AMETHYST-DN [171], Patiromer-204 [172] Lokelma: Stephen et al [173], DIALIZE [174], ZS-005 [175] CSA SERVE-HF [177], Ponikowski et al [178], Pilot [179], Zhang et al [180] us to design trials to test whether a borderline EF is a signal of potential benefit from therapy targeting HFrEF and HFpEF simultaneously [186]. To date, a high-quality clinical trial specifically designed for HFpEF is still lacking, whether it is pharmacotherapy or device-based therapy.…”

FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

“…However, the requirement to assess each new antihyperglycaemic medication in at least one largescale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe. Figure 1), [2][3][4][5][6][7][8][9][10][11][12][13][14][15] and several others are ongoing. In addition, one comparative insulin trial has also been completed.…”

Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo

“…We identified 14 randomized cardiovascular outcome trials (CVOT) which met the inclusion criteria and were included in the meta-analysis, yielding a total of 128,149 patients. The antidiabetic drugs were a dipeptidyl peptidase 4 (DPP-4) inhibitor: saxagliptin, alogliptin, sitagliptin, omarigliptin, linagliptin [12][13][14][15][16], an analogue of human glucagon-like peptide 1 (GLP-1): lixisenatide, liraglutide, semaglutide, exenatide, albiglutide [17][18][19][20][21][22] or an inhibitor of sodium-glucose cotransporter 2 (SGLT-2): empagliflozin, canagliflozin, dapagliflozin [23][24][25]. In all these trials, other therapy for the management of the patient's diabetes was at the discretion of the responsible physician.…”

“…Table 1 lists the characteristics of the individual trials. In 5 trials, patients needed to have a history of cardiovascular disease to be included [13,15,17,22,23]. In the other 8 trials, eligible patients had either established cardiovascular disease or associated cardiovascular risk fac-DOI: 10.1159/000506004 tors.…”