Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events

Abstract

BackgroundThe cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).MethodsPre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥12 weeks’ duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks’ duration, 8778 subjects) were also analyzed.Results5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55–1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43–2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68–1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.ConclusionsLinagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

Cardiovascular benefits of the newer medications for treating type 2 diabetes mellitus

“…In a pooled analysis of randomized trials in T2DM patients comparing linagliptin to either placebo or an active comparator medication, linagliptin was not associated with an increased CV risk (37). The 27% increased risk of HF hospitalization with the DPP-4 inhibitor saxagliptin as observed in the SAVOR-TIMI 53 trial was not replicated in the EXAMINE or the TECOS trials with alogliptin and sitagliptin, respectively (38).…”

“…Although the DPP-4 inhibitors extend the actions of endogenous incretins, they appear to have diverse actions on other inflammatory and metabolic pathways which could have negated the CV protective role of prolonging GLP-1 activity. However, DPP-4 inhibitors were proven to be safe from a CV standpoint based on the available recent data despite concerns regarding increased HF risk prompting the issue of FDA warnings (30,32,33,(36)(37)(38).…”

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

“…The DPP-4 inhibitors, otherwise known as the gliptins, are generally considered to have a neutral effect on weight. 58,59 Cardiovascular safety…”

Cardiovascular safety of type 2 diabetes medications: Review of existing literature and clinical implications

“…120 Another recent study has suggested that, according to a pooled analysis of trials, linagliptin is not associated with increased CV risk versus active comparators or placebo in patients with T2DM. 121 Currently there are other ongoing randomized clinical trials comparing DPP-4i versus placebo added to conventional therapy in patients with T2DM. The CArdiovascular safety and renal microvascular outcomE study with LINAgliptin in patients with T2DM (CARMELINA), lasting till 2018, has been designed to assess the long-term impact on CV morbidity, mortality and renal function of treatment with linagliptin.…”