Identification of Subpopulations Exhibiting the Greatest Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide-1 Receptor Agonists—A Combined Analysis of Large Cardiovascular Outcome Trials

Abstract

BACKGROUND: By combining the results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major cardiovascular events (MACE) and identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.

METHODS: Three multicenter, randomized, double-blind, placebo-controlled CVOTs of long-acting GLP-1 RAs were included: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering). The primary endpoint was three-point MACE (i.e., CV death, non-fatal myocardial infarction, and non-fatal stroke). Overall effect estimates were calculated as hazard ratios (HRs) and 95% confidence intervals (CIs) using the random-effects model; pre-defined subgroup analyses were performed.

RESULTS: Overall, significant risk reductions in MACE (relative risk [RR]: 0.88 [95% CI: 0.81-0.97]) and CV death (RR: 0.85 [95% CI: 0.75-0.95]) were observed. Subgroup analysis indicated significant racial differences in this CV benefit (P for test of difference < 0.001). Risk reductions were observed in subjects of black race (RR: 0.78 [95% CI: 0.60-0.99]) and Asians (RR: 0.35 [95% CI: 0.09-1.32]). However, post-hoc analysis using Bonferroni correction revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with subjects of white race (P < 0.0001).

CONCLUSIONS: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in diabetic study populations, and racial difference in the CV benefit was observed. The existence of extra CV benefit in Asians and the underlying mechanisms should be investigated in the future.

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