Plain Language Summary
Systematic review and meta-analysis of RCTs examining whether GLP-1 RAs and tirzepatide reduce heart failure risk differently in obese versus non-obese patients with CVD or CKD (PROSPERO registered, January 2015–July 2025). Tests the hypothesis that obesity-mediated HF pathophysiology drives incretin therapy HF benefit. Identifies obesity as a treatment effect modifier for incretin therapy HF risk reduction—providing mechanistic insight that GLP-1 RA/tirzepatide HF benefits may be primarily mediated through weight loss and adiposity-driven pathophysiology rather than direct cardiac receptor effects.
Abstract
BACKGROUND: Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.
METHODS: This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015-July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.
RESULTS: A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84-0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84-0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83-0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78-1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89-0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85-0.96, P < 0.01) compared with placebo.
CONCLUSION: In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.
Authors
Zhang, Ju; Guan, Xiangfeng; Kong, Mowei; Xia, Meng; Yu, Yang; Zhang, Chunxiang