Abstract 4371746: Comparative Study of Cardiovascular Safety of GLP-1 Receptor Agonists Across Indications: A Meta-Analysis of Randomized Controlled Trials in Type 2 Diabetes and Obesity

Background: Cardiovascular disease is a leading cause of death globally, with type 2 diabetes (T2DM) and obesity as major contributors.GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in patients with T2DM.More recent evidence suggests similar benefits in obese individuals without diabetes.However, no meta-analysis has directly compared cardiovascular safety of GLP-1 RAs between diabetic and non-diabetic populations. Hypothesis: We hypothesized that GLP-1 receptor agonists reduce cardiovascular events irrespective of baseline glycemic status,with comparable benefit in individuals with and without T2DM. Methods: We conducted a meta-analysis of randomized controlled trials comparing GLP-1 receptor agonists with placebo in adults with T2DM or obesity without diabetes.Eligible trials reported major adverse cardiovascular events and related outcomes,were phase 3 or 4,parallel-group,placebo-controlled,and conducted between 2008 and 2025.A systematic search of PubMed,Embase,and ClinicalTrials.gov was performed.The primary outcome was MACE; secondary outcomes included cardiovascular death,myocardial infarction,stroke,and heart failure hospitalization.Data were pooled using random-effects models and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated.Subgroup analyses were performed based on glycemic status.Risk of bias was assessed using Cochrane RoB 2 tool. Results: Seven RCTs were included (N = 69,433).GLP-1 RAs significantly reduced MACE (HR 0.84; 95% CI,0.79–0.89,p < 0.001).Risk reductions were consistent in both diabetic (HR 0.85; 95% CI,0.80–0.91) and non-diabetic populations (HR 0.80; 95% CI, 0.72–0.89),with no statistically significant difference between glycemic subgroups (p= 0.37).GLP-1 RAs also significantly reduced all-cause mortality (HR 0.90), hospitalization for heart failure (HR 0.90),cardiovascular death (HR 0.88),non-fatal myocardial infarction (HR 0.89), and non-fatal stroke (HR 0.82),with consistent effects across trials.A dose-response pattern suggested that higher doses are associated with greater cardiovascular risk reductions. Conclusion: GLP-1 RAs reduced major cardiovascular events in both T2DM and obesity without diabetes.The similar efficacy across indications supports a paradigm shift toward broader therapeutic use of GLP-1 RAs as cardioprotective agents in high-risk individuals regardless of glycemic status and underscores the need for updated clinical guidelines inclusive of non-diabetic populations.