SURPASS-CVOT presented in full at EASD 2025 in Vienna

Eli Lilly's SURPASS-CVOT trial was presented in full on Sept. 18 at the European Association for the Study of Diabetes annual meeting in Vienna, where Stephen J. Nicholls, MBBS, PhD, of Monash University walked through the component-level numbers behind the headline finding: tirzepatide (Mounjaro) was noninferior to dulaglutide (Trulicity) for major cardiovascular events, but it did not prove superior ^[1][2].

The trial randomly assigned 13,165 adults with type 2 diabetes and established atherosclerotic cardiovascular disease to a maximum tolerated dose of tirzepatide (5 mg, 10 mg or 15 mg once weekly) or dulaglutide 1.5 mg once weekly with sham dose escalation. Median follow-up was 4 years ^[1]. Enrollment ran at 640 sites in 30 countries between May 29, 2020 and June 27, 2022 ^[2]. At 36 months, 72.7% of the tirzepatide group was taking the 15 mg dose ^[2].

The numbers

The primary composite endpoint — cardiovascular death, heart attack or stroke — occurred in 801 tirzepatide patients (12.2%) and 862 dulaglutide patients (13.1%) ^[2]. That produced a hazard ratio of 0.92 (95.3% CI, 0.83-1.01). Noninferiority was met (P = .003); superiority was not (P = .086) ^[1].

Broken into components, Nicholls reported myocardial infarction in 4.7% of the tirzepatide group versus 5.4% on dulaglutide, stroke in 3.5% versus 3.8%, and cardiovascular death in 5.6% versus 6.2% ^[2]. The corresponding hazard ratios all trended in tirzepatide's favor without reaching statistical significance: MI 0.86 (95% CI, 0.74-1.00), stroke 0.91 (0.76-1.09), cardiovascular death 0.89 (0.77-1.02) ^[1].

The clearest separation was in deaths from any cause: 8.6% with tirzepatide versus 10.2% with dulaglutide ^[2], a hazard ratio of 0.84 (95% CI, 0.75-0.94) ^[1]. Tirzepatide also did better on HbA1c, body weight and change in estimated glomerular filtration rate ^[1].

Serious adverse events occurred in roughly 32% of both groups. Nausea was reported by 25.1% on tirzepatide and 22.4% on dulaglutide; diarrhea by 24.8% and 19.1% ^[1]. More tirzepatide patients stopped treatment because of an adverse event — 13.3% versus 10.2% ^[2].

Because there was no placebo arm, the researchers also ran a prespecified "putative placebo" analysis, matching SURPASS-CVOT patients to participants from REWIND, the placebo-controlled dulaglutide trial. That indirect model estimated a 28% lower risk of the primary outcome versus placebo (HR = 0.72; 95% CI, 0.55-0.94; P = .02) ^[1].

What critics said

Cardiologist Eldad Einav, MD, FACC, called the lack of superiority "disappointing," noting that dosing favored tirzepatide — titrated up to 15 mg, while dulaglutide stayed fixed at 1.5 mg — and that the trial ran against modern background therapy, with about 30% of patients on SGLT2 inhibitors at baseline ^[1][2].

He also flagged the comparator itself. In REWIND, dulaglutide's effect on major cardiovascular events was modest (HR = 0.88; 95% CI, 0.79-0.99) and came mostly from a primary prevention population, while SURPASS-CVOT enrolled only secondary prevention patients ^[1]. The mortality finding, he said, was a secondary outcome not adjusted for multiplicity and was not accompanied by a clear cut in cardiovascular death, so "non-CV drivers" or chance cannot be ruled out ^[1]. The noninferiority margin of 1.05 was drawn from a Bayesian meta-analysis of six GLP-1 outcomes trials and was designed so that tirzepatide would preserve at least 50% of dulaglutide's benefit ^[1][2].

Why it matters for patients

For people with type 2 diabetes and existing heart disease, the practical takeaway is that tirzepatide looks cardiovascularly safe and performed about as well as an established GLP-1 drug, with better glucose, weight and kidney measures ^[1]. What the trial did not do is show that tirzepatide beats that drug at preventing heart attacks and strokes.

That distinction matters for labeling. Einav noted that FDA typically grants a "reduces risk of CV death, MI or stroke" claim when a trial shows superiority against placebo, and that no diabetes drug has received a cardiovascular indication based on noninferiority to an active comparator ^[1]. Whether Lilly seeks or receives such a claim from SURPASS-CVOT is not yet known from these sources.

What happens next

Einav suggested tirzepatide would likely need superiority on a prespecified cardiovascular endpoint in further outcomes work, such as the ongoing SURMOUNT-MMO trial, plus supporting real-world data and meta-analyses ^[1]. Results timing for that trial is not stated in these sources.