Cardiovascular Efficacy of Tirzepatide Versus GLP-1 Receptor Agonists: A Network Meta-Analysis

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated cardiovascular non-inferiority versus dulaglutide in SURPASS-CVOT (NEJM 2025). However, no network meta-analysis (NMA) has formally compared tirzepatide against selective GLP-1 receptor agonists (GLP-1 RAs) on 3-point major adverse cardiovascular events (MACE). We conducted an NMA to synthesize all available RCT evidence and derive indirect head-to-head comparisons. Methods: We systematically searched PubMed, Embase, and Cochrane CENTRAL from inception through March 2026 for randomized cardiovascular outcome trials (CVOTs) evaluating tirzepatide or GLP-1 RAs versus placebo or active comparators in adults with type 2 diabetes (T2DM) or obesity with established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk. Primary outcome: 3-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke). A random-effects NMA was performed using the DerSimonian-Laird method. Indirect comparisons used the Bucher method—heterogeneity assessed by I 2 and Cochran's Q. Risk of bias assessed with Cochrane RoB 2.0. PRISMA-NMA 2020 reporting guidelines were followed. Results: Eight RCTs encompassing 184,926 patients (mean follow-up 3.1 years) were included: SURPASS-CVOT, SELECT, SUSTAIN-6, PIONEER-6, LEADER, REWIND, AMPLITUDE-O, and HARMONY OUTCOMES. All trials were double-blind and placebo- or active-controlled. Pooled analysis demonstrated a significant 14% relative risk reduction in MACE with GLP-1 RA/tirzepatide versus comparator (HR 0.86; 95% CI 0.80-0.92; p<0.001; I2=23%). In indirect comparison versus placebo, tirzepatide reduced MACE by 28% (HR 0.72; 95% CI 0.55-0.94) and semaglutide by 20% (HR 0.80; 95% CI 0.72-0.90). Indirect head-to-head NMA showed comparable MACE efficacy between tirzepatide and semaglutide (HR 1.06; 95% CI 0.95-1.18). Benefit was consistent in T2DM (HR 0.84; 0.78-0.91), obesity without T2DM (HR 0.80; 0.72-0.90), and prior heart failure (HR 0.79; 0.70-0.88). Low heterogeneity across all analyses (I2=23%). Conclusions: Both tirzepatide and GLP-1 receptor agonists significantly reduce 3-point MACE versus comparators. Tirzepatide demonstrated a numerically greater absolute risk reduction than placebo (28% vs 20%), though an indirect head-to-head comparison showed similar efficacy to semaglutide. These findings provide a comprehensive comparative framework to guide clinical decision-making in patients with obesity, T2DM, and established ASCVD awaiting a prospective head-to-head cardiovascular outcome trial.