Effect of Tirzepatide on Heart Failure in Type 2 Diabetes Mellitus and Obesity: A Systematic Review and Meta‐Analysis

ABSTRACT Aims This systematic review and meta‐analysis aimed to evaluate the effects of tirzepatide on heart failure in patients with type 2 diabetes mellitus (T2DM) and obesity. Materials and Methods An updated systematic search of the PubMed, Embase, The Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov databases for relevant studies, published from database inception to February 13, 2025, was performed using tirzepatide and heart failure‐related search terms. Results Eleven randomized controlled trials (RCTs) (funded by Eli Lilly and Co., Indianapolis, IN, USA) comprising 13,378 participants were included. Compared with placebo or other active glucose‐lowering drugs, tirzepatide had a neutral effect on the overall risk for heart failure (risk ratio [RR] 0.63 [95% confidence interval (CI) 0.35–1.13]), but the effect was neither statistically nor clinically meaningful (absolute risk reduction [ARR] 0.17%, number needed to treat [NNT] 588; Food and Drug Administration (FDA) minimal important difference [MID] 1.5%). The certainty of evidence was rated as moderate according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria ( p = 0.628; I 2 = 0.0%). Subgroup analysis revealed different pooled estimates for heart failure outcomes in the ≤ 58 years of age subgroup (RR 0.40 [95% CI 0.17–0.96]) compared with the > 58 years' subgroup (RR 0.86 [95% CI 0.39–1.90]) ( p for interaction = 0.201). Additionally, subgroup analysis comparing tirzepatide alone with tirzepatide in combination with other agents revealed different pooled estimates ( p = 0.661; I 2 = 0.0%), with an RR 0.43 (95% CI 0.20–0.88) and 2.25 (95% CI 0.51–9.87), respectively ( p for interaction = 0.05). Subgroup analyses stratified according to different doses of tirzepatide, baseline body weight, body mass index, fasting plasma glucose, glycated haemoglobin, T2DM, obesity, or overweight, and intervention time indicated no association between tirzepatide use and the risk for heart failure. Conclusions Tirzepatide had no overall effect on heart failure outcomes in patients with T2DM or obesity. However, among patients ≤ 58 years of age, tirzepatide yielded a 60% relative risk reduction (i.e., RR = 0.40), while in patients undergoing monotherapy, it yielded a 57% relative risk reduction (i.e., RR = 0.43). Results of this systematic review and meta‐analysis of RCTs support the safety of tirzepatide as a therapeutic option for the clinical management of T2DM or obesity. Trial Registration PROSPERO registration number, CRD42024620051