Tirzepatide vs Dulaglutide: What the SURPASS-CVOT Trial Showed About Heart Attacks, Strokes and Deaths

SURPASS-CVOT tested whether tirzepatide protects the heart or simply lowers blood sugar and weight. Tirzepatide was compared with dulaglutide, a GLP-1 medicine already shown to lower cardiovascular events, and it proved at least as good, although it did not prove better on the main measure even as several secondary results leaned in its favor. This guide explains the design, the results on heart attacks, strokes and deaths, the kidney and heart failure analyses, and the resulting change to the Mounjaro label.

What was the SURPASS-CVOT trial?

SURPASS-CVOT was a double blind cardiovascular outcomes trial that tested tirzepatide against an active comparator in people with type 2 diabetes and atherosclerotic cardiovascular disease (Nicholls et al., New England Journal of Medicine, 2025). Participants were randomly assigned 1:1 to a weekly injection of tirzepatide up to 15 mg or dulaglutide 1.5 mg, and of the 13,299 people randomized, 134 were later excluded for not meeting entry criteria, which left 6586 in the tirzepatide group and 6579 in the dulaglutide group.

The participants carried high cardiovascular risk: the average participant was 64.1 years old, had lived with diabetes for 14.7 years, and had an HbA1c of 8.4% and a BMI of 32.6. According to the updated Mounjaro prescribing information, 65% had coronary artery disease, 47% had a prior heart attack and 86% were taking statins.

Tirzepatide was started at 2.5 mg and increased by 2.5 mg every 4 weeks to 15 mg or the highest dose each person tolerated. Median follow up was 210.1 weeks, roughly four years.

Why was tirzepatide compared with dulaglutide instead of a placebo?

Tirzepatide was compared with dulaglutide because withholding an established heart protective medicine from people with diabetes and heart disease raises ethical problems. Dulaglutide had already shown a cardiovascular benefit in the REWIND trial (Gerstein et al., Lancet, 2019), in which 9901 people were randomized to dulaglutide 1.5 mg or placebo and followed for a median of 5.4 years. The main cardiovascular outcome occurred in 12.0% of people on dulaglutide and 13.4% on placebo, a hazard ratio of 0.88.

That choice makes SURPASS-CVOT a harder test than a placebo trial, so matching dulaglutide is a meaningful result even when it reads as a tie. One limitation is that dulaglutide was held at 1.5 mg throughout, although higher doses exist for blood sugar control.

Did tirzepatide reduce heart attacks and strokes?

Tirzepatide lowered heart attacks, strokes and cardiovascular deaths to a degree similar to dulaglutide, with a small numerical edge that did not reach statistical significance. The primary endpoint, a composite of cardiovascular death, heart attack or stroke, occurred in 801 people (12.2%) on tirzepatide and 862 people (13.1%) on dulaglutide, for a hazard ratio of 0.92 with a 95.3% confidence interval of 0.83 to 1.01 (Nicholls et al., 2025).

The trial set a noninferiority margin of 1.05. Because the upper end of the confidence interval (1.01) sat below 1.05, tirzepatide was declared noninferior (P = 0.003), but superiority would have required that upper end to fall below 1.00, which it did not (P = 0.09 for superiority).

The FDA label breaks the composite into its parts below. These results were not controlled for multiple comparisons, so they show direction rather than proof.

What does noninferior actually mean?

Noninferior means the trial ruled out, with statistical confidence, that tirzepatide is meaningfully worse than dulaglutide at preventing heart attacks, strokes and cardiovascular deaths. The term does not mean tirzepatide is better or that the two drugs are identical, but it does show tirzepatide performs at least as well as a medicine with proven heart protection.

Did fewer people die on tirzepatide?

Fewer people died from any cause on tirzepatide in SURPASS-CVOT, but the finding comes with an important caveat. In the label's analysis, 567 people (8.5%) on tirzepatide died during follow up compared with 670 people (10.1%) on dulaglutide, a hazard ratio of 0.84 with a 95% confidence interval of 0.75 to 0.94. The label states that this result was not controlled for the familywise type I error rate, so it is treated as a supportive signal that deserves confirmation.

How would tirzepatide compare with no treatment at all?

No trial has compared tirzepatide with placebo for heart outcomes in this population, so any answer is an estimate. A prespecified exploratory analysis tried to fill that gap by combining SURPASS-CVOT with matched participants from REWIND (Sattar et al., Diabetes Care, 2026), multiplying the effect of tirzepatide versus dulaglutide by the effect of dulaglutide versus placebo. Using 2,055 REWIND participants who would have qualified for SURPASS-CVOT, the analysis estimated a hazard ratio of 0.72 for cardiovascular death, heart attack or stroke and 0.61 for all cause death. These indirect estimates rest on assumptions about how similar the two populations were and carry more uncertainty than a randomized comparison.

What did SURPASS-CVOT show about the kidneys?

Tirzepatide was associated with fewer major kidney events than dulaglutide in a prespecified exploratory analysis (Zoungas et al., Lancet Diabetes & Endocrinology, 2026). Over a median of 4.0 years, the composite occurred in 6.0% of people on tirzepatide and 7.6% on dulaglutide, a 23% lower risk (hazard ratio 0.77). Our guide to tirzepatide and kidney protection covers the background.

A separate post hoc analysis combined heart and kidney outcomes into a broader six part composite, which occurred in 23.7% of people on tirzepatide and 27.4% on dulaglutide, a hazard ratio of 0.84 (Nissen et al., JAMA Cardiology, 2026). Post hoc analyses generate hypotheses rather than confirm them.

Did tirzepatide help people with heart failure?

People with a history of heart failure appeared to do at least as well on tirzepatide as on dulaglutide, based on an exploratory subgroup analysis in which 20.3% of participants had prior heart failure (Nicholls et al., European Journal of Preventive Cardiology, 2026). In that group, the hazard ratio for death from any cause or a heart failure hospitalization or urgent visit was 0.83 (95% CI 0.70 to 0.99), compared with 0.88 (95% CI 0.78 to 1.00) in people without heart failure. The dedicated heart failure trial for tirzepatide is SUMMIT, which we cover in our article on tirzepatide and heart failure.

What side effects showed up in SURPASS-CVOT?

Gastrointestinal side effects were the main difference between the two medicines. The journal paper reported that overall adverse events appeared similar between groups while gastrointestinal events were more frequent with tirzepatide, and the JAMA Cardiology analysis found gastrointestinal adverse events in 42.5% of people on tirzepatide and 35.9% on dulaglutide.

Gastrointestinal effects are not the whole safety picture. According to the Mounjaro prescribing information, tirzepatide carries a boxed warning about thyroid C-cell tumors and is not used in people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2, and the label also warns about pancreatitis, gallbladder disease and low blood sugar when tirzepatide is combined with insulin or a sulfonylurea, so a clinician reviews these risks before prescribing.

What changed on the Mounjaro label after SURPASS-CVOT?

The FDA approved Mounjaro label now includes a second indication, which is to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal heart attack or nonfatal stroke) in adults with type 2 diabetes who are at high risk for these events (Mounjaro prescribing information). The original indication for blood sugar control alongside diet and exercise remains in place and covers adults and children 10 years and older with type 2 diabetes.

SURPASS-CVOT tested branded tirzepatide (Mounjaro) at doses up to 15 mg, so its results and the new cardiovascular indication apply to that product as it was studied. They do not apply to compounded tirzepatide, which has not been studied in cardiovascular outcome trials, and the FDA notes that compounded drugs are not FDA approved.

Does SURPASS-CVOT apply to people without diabetes?

SURPASS-CVOT does not directly answer this question, because every participant had type 2 diabetes and existing atherosclerotic disease. Tirzepatide improves several cardiovascular risk factors in people without diabetes, as described in tirzepatide and heart health, but whether that translates into fewer events requires separate outcome data.

What does SURPASS-CVOT mean for someone considering tirzepatide?

In adults with type 2 diabetes and heart or artery disease, SURPASS-CVOT found that branded tirzepatide was noninferior to dulaglutide for major cardiovascular events. Whether tirzepatide is appropriate depends on health history, other medications and goals, which a licensed clinician can review. Individual results vary.

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