Zhang Ju, Guan Xiangfeng, Kong Mowei, Xia Meng, Yu Yang, Zhang Chunxiang
Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan 646000, China.
Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan 646000, China.
Metabolism. 2026 Feb;175:156433. doi: 10.1016/j.metabol.2025.156433. Epub 2025 Nov 8.
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.
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.
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.
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.
