Cardiovascular and kidney outcomes of GLP-1 receptor agonists in adults with obesity: A target trial emulation study

Abstract

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide cardiovascular and renal benefits in type 2 diabetes, but their real-world effects in individuals with obesity without diabetes are unclear. This study aimed to evaluate the cardiovascular and kidney outcomes of GLP-1RAs versus other anti-obesity medications (AOMs) in adults with obesity.

Materials and methods: This target trial emulation used TriNetX electronic health records (July 2021-May 2025) to identify adults with obesity and no diabetes history who initiated GLP-1RAs (liraglutide, semaglutide, or tirzepatide) or other AOMs. Outcomes included major adverse cardiovascular events (MACE), major adverse kidney events (MAKE), all-cause mortality, mental health conditions, and safety outcomes. Propensity score matching (1:1) balanced baseline characteristics; Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: The study included 140 169 matched pairs of GLP-1RA and AOM initiators. Mean follow-up was 392 days for GLP-1RA users and 564 days for AOM users. Compared to AOMs, GLP-1RA use was associated with lower risks of MACE (HR, 0.76; 95% CI, 0.72-0.81), MAKE (HR, 0.64; 95% CI, 0.55-0.74), and all-cause mortality (HR, 0.49; 95% CI, 0.42-0.57). Mental health outcomes also improved, with reduced risks of depression (HR, 0.63), suicidal ideation/attempt (HR, 0.42), and substance use disorder (HR, 0.58). GLP-1RAs were not associated with increased risks of acute pancreatitis (HR, 1.17), hypoglycemia (HR, 1.08), or gastrointestinal symptoms (HR, 0.99).

Conclusions: Among adults with obesity but without diabetes, GLP-1RA use was associated with reduced cardiovascular, kidney, mortality, and mental health risks compared to other AOMs.

Keywords: GLP‐1 receptor agonists; anti‐obesity medication; major adverse cardiovascular events; major adverse kidney events.