N Engl J MedHeart & CardiovascularRCTDecember 18, 2025

Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.

Nicholls SJ, Pavo I, Bhatt DL, Buse JB, Del Prato S, Kahn SE, Lincoff AM, McGuire DK, Miller D, Nauck MA, Nishiyama H, Nissen SE, Sattar N, Weerakkody G, Wiese RJ, Zinman B, Zoungas S, Basile J, Davies MJ, Giorgino F, Kellerer M, Ji L, Varkonyi T, Menon V, Broder JC, Herschtal A, D'Alessio D, SURPASS-CVOT Investigators

View on PubMed DOI: 10.1056/NEJMoa2505928

Key Finding

Tirzepatide performed just as well as dulaglutide in preventing heart attacks, strokes, and cardiovascular deaths in 13,165 diabetes patients, with 12.2% versus 13.1% experiencing these major events.

What This Study Found

Think of this study as a head-to-head race between two diabetes medications to see which better protects the heart. Tirzepatide is like a dual-engine car - it targets two hormone receptors (GLP-1 and GIP) simultaneously, while dulaglutide is a single-engine vehicle targeting just GLP-1. The researchers wanted to know if the dual-engine approach could match or beat the proven single-engine in preventing heart disasters. They followed over 13,000 people with diabetes and existing heart disease for several years, like monitoring two groups of drivers on a dangerous highway. The finish line was reaching a major cardiovascular event - heart attack, stroke, or death from heart problems. In the tirzepatide group, 801 out of 6,586 people (12.2%) crossed this unwanted finish line, compared to 862 out of 6,579 (13.1%) in the dulaglutide group. The difference was small but meaningful - tirzepatide proved it could run just as well as the established champion, with a hint it might even be slightly better.

Statistics Decoded

Hazard ratio of 0.92 (95.3% CI: 0.83-1.01): This means tirzepatide users had about 8% lower risk of cardiovascular events than dulaglutide users - like comparing two groups where one has 92 events for every 100 in the other group. The confidence interval crossing 1.0 means we can't be completely certain tirzepatide is better. P=0.003 for noninferiority: This is like flipping heads 300 times in a row - virtually impossible by chance alone, confirming tirzepatide is at least as good as dulaglutide. P=0.09 for superiority: This is like flipping heads 11 times in a row - unlikely but not rare enough to prove tirzepatide is definitively better. The 1.05 noninferiority margin means tirzepatide could be up to 5% worse and still be considered 'good enough' - it easily beat this bar.

Why This Matters

This gives doctors and patients a new option that works just as well as proven cardiovascular-protective diabetes drugs, with the added bonus of tirzepatide's superior weight loss and blood sugar control from previous studies. For the millions with diabetes and heart disease, this confirms they can choose tirzepatide without sacrificing heart protection.

Original Abstract

Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and 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. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point 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). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).