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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Verma reported receiving research grants and personal fees from Boehringer Ingelheim and Eli Lilly and Company during the conduct of the study; receiving personal fees from AstraZeneca, Janssen, Merck, Novartis, and Sanofi during the conduct of the study; receiving grants and personal fees from Amgen and Boehringer Ingelheim; receiving grants from Bristol-Myers Squibb; and receiving personal fees from Bayer, LivaNova, Servier, and Valeant outside the submitted work. Dr Bain reported receiving research grants from Healthcare and Research Wales (Welsh Government) and Novo Nordisk; receiving other research and infrastructure support from Healthcare and Research Wales (Welsh Government); receiving honoraria from Boehringer Ingelheim, Eli Lilly and Company, Merck, Novo Nordisk, and Sanofi; and having ownership interest in Glycosmedia (diabetes online news service). Dr Buse reported receiving grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the American Diabetes Association; receiving grants and nonfinancial support from Novo Nordisk during the conduct of the study; receiving grants, nonfinancial support, and other support from AstraZeneca, Eli Lilly and Company, GI Dynamics, Intarcia Therapeutics, Lexicon, Novo Nordisk, Orexigen, Sanofi, Takeda, and vTv Therapeutics; receiving grants and other support from Dexcom; receiving nonfinancial and other support from Adocia, Elcelyx Therapeutics, MannKind, Mellitus Health, Senseonics, Shenzhen High Tide, Stability Health, and Zafgen; receiving grants from GlaxoSmithKline, Johnson & Johnson, Medtronic, Scion Neurostim, and Theracos; receiving other support from Dance Biopharm, Fractyl, Metavention, NovaTarg, and PhaseBio; receiving personal fees from Cirius Therapeutics, CSL Behring, and Neuroimmune AG; being a consultant to Neurimmune AG; and holding stock options in Mellitus Health, PhaseBio, and Stability Health. Dr Idorn reported being a full-time employee at Novo Nordisk A/S. Dr Rasmussen reported being a full-time employee at Novo Nordisk A/S; being a significant stockholder in Novo Nordisk; and having a patent to PCT/EP2017/054977 issued. Dr Ørsted reported being a full-time employee at and holding stocks and shares in Novo Nordisk. Dr Nauck reported receiving grants and personal fees from Novo Nordisk during the conduct of the study; receiving grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, and Merck, Sharp, & Dohme outside the submitted work; receiving personal fees from Fractyl and Menarini/Berlin Chemie outside the submitted work; and receiving grants from Novartis and Intarcia/Servier outside the submitted work.

Figures

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).