We aimed to estimate the cardiovascular (CV) benefit of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) without a history of CV disease (CVD) (primary CVD prevention). We searched MEDLINE and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) and Epistemonikos for systematic reviews (up to July 4, 2025). We included RCTs of patients with T2D comparing a GLP-1 RA to placebo using a CV or renal primary outcome. 11 drug manufacturer-funded trials (77 419 participants) were included. We used version 1 of the Cochrane risk of bias tool. Our primary analysis was the pooled estimate of the treatment effect in primary CVD prevention. Outcomes of interest were major adverse cardiovascular events (MACE, primary outcome), all-cause mortality, CV mortality, myocardial infarction, stroke, and serious adverse events (secondary outcomes). Only 26% of participants were primary CVD prevention patients. The pooled estimates of treatment effect for primary CVD prevention were not significant for the primary outcome, MACE (pooled HR 0.88, 95% CI 0.74 to 1.05, based on eight trials, n=16 672), and all secondary outcomes. The certainty of the evidence was rated as low due to trials’ risk of bias and imprecision. Our review was limited to subgroup analyses of aggregated data from studies not powered for primary prevention alone. Current evidence is insufficient to establish CV benefits of GLP-1 RAs in T2D without a history of CVD, and dedicated primary prevention trials are needed.
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