Tirzepatide, a dual agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, has demonstrated superior glycemic control and greater weight reduction compared with GLP-1 receptor agonists alone in patients with type 2 diabetes. Dulaglutide, a GLP-1 receptor agonist, has established cardiovascular benefits in this population. However, the cardiovascular effects of tirzepatide relative to dulaglutide remain unknown.
We conducted a multicenter, active-comparator–controlled, double-blind, randomized noninferiority trial (SURPASS-CVOT). Patients with type 2 diabetes and established atherosclerotic cardiovascular disease were assigned in a 1:1 ratio to receive once-weekly subcutaneous tirzepatide (titrated to a maximum dose of 15 mg) or dulaglutide (1.5 mg). The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (three-component major adverse cardiovascular events [MACE-3]). Noninferiority of tirzepatide to dulaglutide was declared if the upper boundary of the 95.3% confidence interval for the hazard ratio was less than 1.05; superiority was tested if noninferiority was met (upper boundary <1.00).
A total of 13,126 patients underwent randomization (mean age 64.5 years; 34% women). The median follow-up was 5.3 years. A primary endpoint event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P=0.003 for noninferiority; P=0.09 for superiority). Key secondary cardiovascular outcomes, including individual components of the composite, showed consistent trends favoring tirzepatide, though not reaching statistical significance for superiority. Rates of death from any cause and hospitalization for heart failure were similar between groups. Adverse event profiles were comparable overall, with higher rates of gastrointestinal events (nausea, vomiting, diarrhea) in the tirzepatide group, consistent with the class effects of incretin-based therapies. Discontinuation due to adverse events was slightly higher with tirzepatide.
In patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior, but not superior, to dulaglutide for the reduction of major adverse cardiovascular events. Both treatments confirmed cardiovascular safety in this high-risk population, with tirzepatide providing similar protection to an established GLP-1 receptor agonist with proven cardiovascular benefit. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.)
