The First Incretin Head-to-Head on the Heart: SURPASS-CVOT

Two GLP-1-class drugs were matched directly in more than 13,000 patients. The result settles a question cardiologists had carried for years.

For a long time, doctors could say GLP-1 drugs protect the heart but could not say which protects it most, because no one had run two against each other in a dedicated outcomes trial. SURPASS-CVOT did exactly that — the first head-to-head cardiovascular outcomes trial of two incretin therapies.

Published in The New England Journal of Medicine in December 2025, it pitted tirzepatide, the newer dual GLP-1/GIP agonist, against dulaglutide, an older GLP-1 drug already proven to reduce cardiovascular events.

The design and the population

Investigators led by Stephen J. Nicholls, with Deepak Bhatt among the authors, screened nearly 17,000 patients and assigned 13,299 adults with type 2 diabetes and established atherosclerotic cardiovascular disease to weekly tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), in a 1:1 double-blind design. Mean age was 64, mean BMI 33, and average diabetes duration 15 years.

Choosing dulaglutide as the comparator was the clever, demanding part. Because dulaglutide already has proven heart benefit, matching it implies benefit against a hypothetical placebo — without denying anyone effective treatment. The trade-off is that tirzepatide had to clear a high bar rather than an easy one.

What the trial found

Over a median of four years, the primary endpoint — cardiovascular death, heart attack, or stroke — occurred in 12.2% of the tirzepatide group and 13.1% of the dulaglutide group. That yielded a hazard ratio of 0.92, meeting the prespecified criterion for non-inferiority (p=0.003). The push for outright superiority fell just short: the 95.3% confidence interval ran to 1.01, and the superiority p-value was 0.09.

Beyond the primary endpoint, the signals leaned tirzepatide’s way. All-cause mortality was lower — 8.6% versus 10.2%, a hazard ratio of 0.84 that did reach statistical significance. Tirzepatide also delivered larger improvements in A1C, weight, blood pressure, lipids, and kidney function. Gastrointestinal side effects and treatment discontinuation were somewhat higher: 13.3% stopped tirzepatide for adverse events, against 10.2% for dulaglutide.

Reading the result honestly

This was a non-inferiority trial, and that framing is everything. Tirzepatide did not have to beat dulaglutide; it had to prove it was at least as good on hard cardiovascular outcomes, and it did, while outperforming on nearly every metabolic measure. The mortality finding is genuinely encouraging, though the trial’s hierarchy of statistical testing stops short of letting it be called a superiority claim for heart events.

The authors flag real limitations: no placebo group, a global population with limited diversity, and some imbalance between arms. Good trials say what they cannot prove.

What it means

For patients with type 2 diabetes and heart disease, the practical takeaway is solid. Tirzepatide now carries dedicated cardiovascular evidence of its own, not borrowed from its GLP-1 predecessors, alongside its edge on weight and glucose. SURPASS-CVOT also models something the field needs more of: head-to-head trials that tell clinicians not just whether a drug works, but how it stacks up against the best alternative.

The era of comparing these drugs only through separate, non-overlapping trials is ending. This is what direct evidence looks like.

Frequently asked questions

Does tirzepatide protect the heart? SURPASS-CVOT showed tirzepatide was at least as effective as dulaglutide — a drug with proven cardiovascular benefit — at preventing heart attacks, strokes, and cardiovascular death in people with type 2 diabetes and existing heart disease. All-cause mortality was also lower on tirzepatide.

Is tirzepatide better than dulaglutide for the heart? For hard cardiovascular events, tirzepatide met non-inferiority but fell just short of statistical superiority (p=0.09). It did outperform dulaglutide on weight, blood sugar, blood pressure, lipids, and kidney measures, and on overall mortality.

What is a non-inferiority trial? It is a study designed to show that a new treatment is not meaningfully worse than an established one, rather than proving it is better. Because dulaglutide already reduces cardiovascular risk, matching it implies benefit — without denying any participant effective treatment.

Sources

1. Nicholls, S.J., Pavo, I., Bhatt, D.L., et al. “Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes.” New England Journal of Medicine, 2025;393:2409–2420. ClinicalTrials.gov NCT04255433.
2. American College of Cardiology — “SURPASS-CVOT: Is Tirzepatide Superior to Dulaglutide?” Journal scan, January 2026.
3. Eli Lilly and Company — SURPASS-CVOT topline results, July 31, 2025.
4. tctmd (Cardiovascular Research Foundation) — “SURPASS-CVOT Published,” December 19, 2025.
5. HCPLive — “SURPASS-CVOT: Tirzepatide Bests Dulaglutide for Cardiovascular Protection,” 2025.