Tirzepatide matches dulaglutide on heart risk in SURPASS-CVOT but shows no significant edge
In adults with type 2 diabetes and established heart disease, tirzepatide matched dulaglutide for cardiovascular deaths, heart attacks and strokes, but did not beat it by a statistically significant margin.
Tirzepatide was noninferior to dulaglutide for preventing cardiovascular events in adults with type 2 diabetes and atherosclerotic cardiovascular disease, but it did not show a statistically significant advantage, according to results of the SURPASS-CVOT trial published in the New England Journal of Medicine [1].
The trial randomly assigned 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease to weekly subcutaneous injections of either tirzepatide at doses up to 15 mg or dulaglutide 1.5 mg, a drug that has been shown to reduce the incidence of cardiovascular events [1]. The study was double-blind and used dulaglutide as an active comparator rather than a placebo [1]. After randomization, 134 patients were excluded because they did not meet inclusion criteria, leaving 6,586 people in the tirzepatide group and 6,579 in the dulaglutide group in the main analysis [1].
The primary endpoint was a composite of death from cardiovascular causes, myocardial infarction (heart attack), or stroke. A primary endpoint event occurred in 801 patients (12.2%) taking tirzepatide and 862 patients (13.1%) taking dulaglutide [1]. The hazard ratio was 0.92, with a 95.3% confidence interval of 0.83 to 1.01 [1].
Noninferiority was defined in advance as an upper limit of the confidence interval below 1.05. The result was 1.01, and the P value for noninferiority was 0.003 [1]. Superiority would have required an upper limit below 1.00; that threshold was not met, and the P value for superiority was 0.09 [1]. In plain terms, the two drugs produced similar rates of cardiovascular events in this group, and the small numerical difference favoring tirzepatide could have been due to chance.
Patients in the trial had a mean age of 64.1 years, 29.0% were women, the mean body-mass index was 32.6, the mean glycated hemoglobin level was 8.4%, and the mean duration of diabetes was 14.7 years [1]. The incidence of adverse events appeared similar between the groups, although more gastrointestinal adverse events were observed in the tirzepatide group [1]. The trial was funded by Eli Lilly [1].
Why it matters for patients
Dulaglutide already had evidence that it reduces cardiovascular events, and SURPASS-CVOT compared tirzepatide against that drug rather than against a placebo or no incretin therapy [1]. The results therefore show that tirzepatide is at least as good as dulaglutide on this combined heart and stroke outcome. They do not show that tirzepatide reduces cardiovascular events compared with no GLP-1 or dual-incretin treatment; whether tirzepatide lowers cardiovascular risk relative to placebo was not tested here and has not been established by this trial [1].
The findings apply to a specific high-risk group: adults with type 2 diabetes plus atherosclerotic cardiovascular disease, averaging 64 years old and living with diabetes for about 15 years [1]. People who take these medications mainly for weight loss, or who do not have diagnosed heart or blood vessel disease, were not the population studied, so the results may not carry over to them [1].
Tirzepatide is the molecule in the brands Mounjaro and Zepbound. Gastrointestinal side effects were more frequent with tirzepatide than with dulaglutide in this trial, a difference patients and clinicians may weigh alongside the cardiovascular results [1].
What happens next
The trial is complete and its results are published; it is registered as NCT04255433 [1]. The New England Journal of Medicine has also published several letters responding to the trial along with a reply from the authors [1]. No further analyses, regulatory decisions, or label changes tied to SURPASS-CVOT have been reported [1]. Whether the numerical difference between the two drugs grows or shrinks with longer follow-up has not been disclosed [1].
Sources
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