Effect of Liraglutide on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Polyvascular Disease: Results of the LEADER Trial

Abstract

atherosclerosis ◼ diabetes mellitus, type 2 ◼ glucagon-like peptide 1 ◼ liraglutide ◼ myocardial infarction T he presence of polyvascular disease, defined as atherosclerosis involving >1 distinct vascular territory, is a strong, independent predictor of cardiovascular events.[1][2][3][4] In the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), 5 the human glucagon-like peptide 1 analog liraglutide reduced cardiovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk.In this post hoc analysis of LEADER, we evaluated the effects of liraglutide stratified by a number of atherosclerotic vascular territories (coronary, cerebrovascular, and peripheral).LEADER (ClinicalTrials.gov,NCT01179048) was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk (median follow-up, 3.8 years).5 The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (major adverse cardiovascular events [MACE]).The key secondary expanded outcome (expanded MACE) also included hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure.The ethics committee or institutional review board at each participating center approved the trial protocol.Patients provided informed consent.Cardiovascular outcomes were prospectively adjudicated by an independent, blinded event adjudication committee.Atherosclerotic vascular territories included coronary (myocardial infarction, ≥50% coronary artery stenosis, percutaneous coronary intervention or coronary artery bypass graft surgery, angina pectoris, or asymptomatic ischemia), cerebrovascular (stroke, transient ischemic attack, ≥50% intracranial or carotid artery stenosis), and peripheral (≥50% peripheral artery stenosis) arteries.Information was extracted from patients' baseline medical history.Risk groups were determined by number of vascular territories involved: polyvascular disease as ≥2, single vascular disease as 1, and a group with no documented atherosclerotic cardiovascular disease (ASCVD).The hazard ratios (HRs) comparing risk groups were calculated using a Cox proportional hazards model with treatment and risk group as factors.The treatment effect of liraglutide versus placebo within risk groups was estimated by using the Cox proportional hazards regression model with treatment, risk group, and the interaction of both as factors.In LEADER, 6775 patients (72.5%) had documented ASCVD.In patients with ASCVD, 1536 (23%) had a baseline history of polyvascular disease, and 5239 (77%) had single vascular disease.For the total population, the distribution of vascular territory involvement is shown in the Figure (A).In brief, 5364 patients (57.4%) had a history of coronary artery disease, 1968 (21.1%) had cerebrovascular disease, 1184 (12.7%) had peripheral artery disease, and 2565 (27.5%) had no documented ASCVD.At baseline, in patients with polyvascular disease versus single vascular disease, mean age±SD was higher (65.1±7.7 versus 63.5±7.3