Cardiovascular outcomes of glucagon-like peptide-1 receptor agonists in patients without obesity: a systematic review and meta-analysis of randomized controlled trials

Glucagon-like peptide-1 receptor agonists (GLP1-RAs) improve cardiometabolic health in patients with obesity and/or type 2 diabetes mellitus. However, their role in cardio protection in individuals without obesity (BMI < 30 kg/m²) remains unclear. This study aimed to determine whether GLP1-RAs reduce cardiovascular events in individuals without obesity.

A systematic review and meta-analysis of RCTs evaluating GLP1-RAs in obese (BMI ≥ 30 kg/m²) and non-obese (BMI < 30 kg/m²) individuals was conducted. The analyzed outcomes included major adverse cardiovascular events (MACE), cardiovascular (CV) death, and heart failure hospitalization (HFH). Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. The study was conducted according to a prespecified protocol registered in PROSPERO (CRD4201287112).

Twelve RCTs comprising 91,167 participants were included. BMI subgroup population counts were available in 10 of the 12 included trials. In patients without obesity, GLP1-RAs significantly reduced MACE (HR = 0.81 [0.72–0.90]; p = 0.0002) and CV death (HR = 0.80 [0.70–0.91]). No significant effect was observed in HFH (HR = 1.00 [0.68–1.47]). There was no evidence of effect modification by BMI for MACE (p = 0.53), CV death (p = 0.49), or HFH (p = 0.50).

GLP1-RAs reduce MACE and CV death in individuals irrespective of the obesity status. These findings support expanding GLP1-RA use beyond weight management to broader cardiometabolic prevention, though long-term data in healthy weight and lower-risk populations are warranted.