Tirzepatide was noninferior to dulaglutide among patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), with respect to the primary composite outcome of cardiovascular death, myocardial infarction (MI) or stroke, according to the double-blind, noninferiority SURPASS-CVOT trial published Dec. 17, 2025, in NEJM.

This active-comparator-controlled study, conducted by Stephen J. Nicholls, MBBS, PhD, FACC, et al., screened 16,979 patients diagnosed with T2D and ASCVD. After screening, which occurred from May 29, 2020 through June 27, 2022, 6,586 patients were assigned to the tirzepatide group and 6,579 to the dulaglutide group. The mean age of participants was 64 years and 29% were women. Additionally, the mean BMI was 33, mean glycated hemoglobin level was 8% and mean diabetes duration was 15 years.

Patients were randomized 1:1 to a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg). Of note, tirzepatide was initiated at a dose of 2.5 mg and increased by 2.5 mg every four weeks.

The primary endpoint was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio, and an upper limit of <1.00 indicated superiority of tirzepatide.

After a median follow-up of four years, results showed a primary endpoint occurred in 12% and 13% of the tirzepatide and dulaglutide groups, respectively (hazard ratio, 0.92; p=0.003 for noninferiority; p=0.09 for superiority). Although more gastrointestinal adverse events occurred in the tirzepatide group, the incidence of adverse events between the two groups was similar.

The authors note several limitations of their trial, including the exclusion of a placebo group, limited diversity of the global patient population and imbalances between the treatment groups.

"Additional analyses will be required to determine the contribution of different metabolic effects of tirzepatide and dulaglutide to the observed cardiovascular outcomes," write Nicholls and colleagues. "These metabolic effects are factors that can be considered when clinicians and patients decide on the use of glucose-lowering therapies."