Occurence of First and Recurrent Major Adverse Cardiovascular Events With Liraglutide Treatment Among Patients With Type 2 Diabetes and High Risk of Cardiovascular Events: A Post Hoc Analysis of a Randomized Clinical Trial

Abstract

Importance: After the occurrence of nonfatal cardiovascular events, recurrent events are highly likely. Most cardiovascular outcomes trials analyze first events only; extending analyses to first and recurrent (total) events can provide clinically meaningful information.

Objective: To investigate whether liraglutide is associated with reduced first and recurrent total major adverse cardiovascular events (MACE) compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events.

Design, setting, and participants: This post hoc analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized, double-blind, clinical trial included data from patients with type 2 diabetes who had established or were at high risk for cardiovascular disease at 410 sites in 32 countries from August 2010, to December 2015. Data analysis was performed from August 15, 2016, to July 5, 2019.

Interventions: Patients were randomized 1:1 to receive liraglutide (up to 1.8 mg per day) or placebo, both with standard care, for 3.5 to 5.0 years.

Main outcomes and measures: Assessed outcomes were MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), expanded MACE (primary MACE plus coronary revascularization and hospitalization for heart failure or unstable angina pectoris), and the individual end points.

Results: The 9340 LEADER trial participants (6003 [64.3%] male; mean [SD] age, 64.3 [7.2] years) experienced 1605 total MACE (1302 first and 303 recurrent events; median follow-up, 3.8 years [range, 0-5.2 years]). Patients who experienced any MACE were older (1 MACE: mean [SD] age, 65.6 [8.0] years; >1 MACE: 65.7 [7.9] years) and had diabetes for longer duration (1 MACE: mean [SD] duration, 13.4 [8.3] years; >1 MACE: 14.4 [8.7] years) compared with patients without MACE (mean [SD] age, 64.1 [7.1] years; mean [SD] duration, 12.7 [7.9] years). Fewer first and recurrent MACE occurred in the liraglutide group (n = 4668; 608 first and 127 recurrent events) than in the placebo group (n = 4672; 694 first and 176 recurrent events). Liraglutide was associated with a 15.7% relative risk reduction in total MACE (hazard ratio [HR], 0.84; 95% CI, 0.76-0.93) and a 13.4% reduction in total expanded MACE (HR, 0.87; 95% CI, 0.81-0.93) compared with placebo. For most individual cardiovascular end points, liraglutide was associated with lower risk vs placebo.

Conclusions and relevance: These results suggest that liraglutide treatment is associated with reduced total MACE compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events. This analysis supports the findings of an absolute benefit of liraglutide treatment with respect to the overall burden of cardiovascular events in this high-risk patient population.

Trial registration: ClinicalTrials.gov identifier: NCT01179048.

Figure 1.. Total First and Recurrent Cardiovascular Events During the LEADER Trial

Analysis included the total number of randomized patients in the liraglutide group (n = 4668) and in the placebo group (n = 4672). Hazard ratios (HRs) (95% CIs) for recurrent events were calculated using the pooled treatment effects across event numbers of 2 or more from the Prentice-Williams-Peterson model. A, The 3-point composite end point included time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. First events: HR, 0.87 (95% CI, 0.78-0.97); recurrent events: HR, 0.85 (95% CI, 0.67-1.07). B, The 6-point composite end point included the 3-point major adverse cardiovascular event end points plus coronary revascularization and hospitalization for heart failure or unstable angina pectoris. First events: HR, 0.88 (95% CI, 0.81-0.96); recurrent events: HR, 0.97 (95% CI, 0.87-1.07).

Figure 2.. Mean Total Major Adverse Cardiovascular Events per Patient During the Trial Period

Mean cumulative function estimated using the Nelson-Aalen nonparametric method. The number needed to treat to avoid 1 event was based on the mean cumulative function at 3 years without accounting for competing risk. Dashed lines indicate liraglutide or placebo with competing risk. The P value was calculated for no treatment difference in the mean cumulative function with competing risk. The 3-point composite end point included time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (number needed to treat at 3 years: 43 patients). The 6-point composite end points included the 3-point MACE end points plus coronary revascularization and hospitalization for heart failure or unstable angina pectoris (number needed to treat at 3 years: 23 patients).