Journal Article

Comparative efficacy of tirzepatide and glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes: a systematic review and network meta-analysis

Mancini, G.B. John, Seth, Jayant, Shokravi, Arveen

2026

Overview

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used therapies for cardiovascular risk reduction in type 2 diabetes (T2D). With the emergence of the SURPASS-CVOT trial, tirzepatide (a dual GIP/GLP-1 receptor agonist) has entered the therapeutic landscape; however, its comparative effect on cardiovascular outcomes compared to placebo and individual GLP-1RAs remains undefined. Methods We conducted a systematic review and frequentist network meta-analysis (NMA) of RCTs enrolling adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular (CV) risk. Eligible RCTs evaluated tirzepatide or GLP-1RAs and reported major adverse cardiovascular events (MACE), CV mortality, all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke. A class-level NMA was conducted to estimate the incremental benefit of tirzepatide and GLP-1RAs over placebo, and an agent-level NMA was conducted to explore differences between tirzepatide and individual GLP-1RA agents. Subgroup analyses, including established cardiovascular disease populations, and leave-one-out sensitivity analyses were performed. Results Eleven trials met inclusion criteria (10 GLP-1RA trials and 1 tirzepatide trial [SURPASS-CVOT]). In the class-level analysis, tirzepatide significantly reduced MACE (HR 0.79, 95% CI 0.69–0.91), CV mortality (HR 0.77, 95% CI 0.66–0.90), all-cause mortality (HR 0.74, 95% CI 0.65–0.83), non-fatal MI (HR 0.77, 95% CI 0.61–0.97), and non-fatal stroke (HR 0.79, 95% CI 0.64–0.97) compared to placebo. Formal statistical comparisons between tirzepatide and the GLP-1RA class could not be performed within the constraints of the NMA; however, point estimates across outcomes numerically favored tirzepatide compared with placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo (HR 0.81, 95% CI 0.70–0.94) and lixisenatide (HR 0.79, 95% CI 0.65–0.97). Subgroup and sensitivity analyses did not substantially change point estimates. Conclusion Among adults with T2D and established ASCVD or high CV risk, class-level analysis demonstrated that tirzepatide significantly reduced the risk of cardiovascular events compared to placebo; at the agent-level, tirzepatide demonstrated comparable efficacy to individual GLP-1RAs. These findings suggest that tirzepatide provides cardiovascular benefit at least comparable to established GLP-1RAs, supporting its emerging role in cardiovascular risk reduction in T2D. Graphical abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Agonists / Angiology / Arteriosclerosis / Bias / Biomarkers - blood / Cardiology / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - diagnosis / Cardiovascular Diseases - mortality / Cardiovascular Diseases - prevention & control / cardiovascular outcomes / Cerebral infarction / Clinical trials / Confidence intervals / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - diagnosis / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - mortality / GLP-1 receptor agonists / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide-1 Receptor - metabolism / Glucagon-Like Peptide-1 Receptor Agonists / Heart attacks / Heart Disease Risk Factors / Humans / Hypoglycemic Agents - adverse effects / Hypoglycemic Agents - therapeutic use / Incretins - adverse effects / Incretins - therapeutic use / Kidney diseases / Medicine / Medicine & Public Health / Meta-analysis / Metabolism / Mortality / Myocardial infarction / Peptides / Placebos / Randomized Controlled Trials as Topic / Risk Assessment / Sensitivity analysis / Stroke / Systematic review / tirzepatide / Tirzepatide - adverse effects / Tirzepatide - therapeutic use / Treatment Outcome / type 2 diabetes