Key result
Incretin mimetics cut 3P-MACE by ~15% vs placebo, independent of weight loss magnitude.
Why the study?
The study aimed to evaluate whether body weight loss induced by incretin mimetic therapy is associated with reductions in 3P-MACE, individual cardiovascular outcomes, and mortality, and to estimate the overall cardiovascular effects of incretin mimetics compared with placebo.
Does body weight loss induced by incretin mimetic therapy reduce three-point major adverse cardiovascular events (3P-MACE), individual cardiovascular outcomes, and mortality in adults with and without diabetes?
Meta-Analysis (n=97,199)
Placebo-controlled randomized trials
Does body weight loss induced by incretin mimetic therapy reduce three-point major adverse cardiovascular events (3P-MACE), individual cardiovascular outcomes, and mortality in adults with and without diabetes?
Answers are grounded in this paper and cite their sources.
While incretin mimetics significantly reduce 3P-MACE, heart failure hospitalization, and mortality across 16 trials, trial-level magnitude of weight loss does not significantly correlate with the degree of cardiovascular risk reduction.
AIMS: The primary aim was to evaluate, using aggregate-data meta-regression, whether body weight loss induced by incretin mimetic therapy is associated with reductions in three-point major adverse cardiovascular events (3P-MACE), individual cardiovascular outcomes and mortality. A secondary aim was to estimate the overall cardiovascular effects of incretin mimetics compared with placebo. METHODS: A systematic review of placebo-controlled randomized trials was conducted using MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. Eligible trials reported cardiovascular hazard ratios (HRs) and weight changes. The primary analysis was an aggregate-data meta-regression, with the prespecified moderator defined as the placebo-adjusted percentage weight difference at the latest reported follow-up time point. Standard meta-analysis was performed to estimate overall treatment effects. RESULTS: Sixteen randomized trials including 97 199 participants with and without diabetes were analysed. Meta-regression showed no statistically significant association between greater body weight loss and treatment HRs for 3P-MACE, cardiovascular or all-cause mortality, myocardial infarction, stroke and hospitalization for heart failure (HHF). These findings do not establish an individual-level or causal relationship. Meta-analysis showed significant reductions in 3P-MACE (15%), cardiovascular mortality (13%), all-cause mortality (12%), myocardial infarction (14%), stroke (13%) and HHF (10%). CONCLUSION: Greater trial-level placebo-adjusted body weight loss was not significantly associated with lower treatment HRs for the cardiovascular and mortality outcomes examined, including 3P-MACE and HHF. These findings do not exclude an individual-level contribution of weight loss to cardiovascular benefit or establish causality. Individual-participant-level analyses are needed to clarify the relationship between weight loss and cardiovascular outcomes.
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Skelin et al. (2026) conducted a meta-analysis in Participants with and without diabetes (n=97,199). Incretin mimetic therapy vs. Placebo was evaluated on Three-point major adverse cardiovascular events (3P-MACE) (15% reduction). Incretin mimetics reduced 3P-MACE by 15% vs placebo, though trial-level weight loss was not significantly associated with lower cardiovascular HRs.
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