VIENNA — Tirzepatide (Mounjaro) is cardioprotective in people with type 2 diabetes (T2D) and established atherosclerotic cardiovascular (CV) disease, but not more so than dulaglutide (Trulicity), results from the SURPASS-CVOT trial suggest. 

The full study results were presented at the European Association for the Study of Diabetes 2025 Annual Meeting, following the release of top line data earlier this year. 

Eli Lilly’s phase 3 randomized clinical trial is the first-ever CV outcomes trial for a T2D drug to use an active comparator rather than a placebo. “I think it’s a big deal to do an active comparator trial. It’s not been done before,” said lead investigator Stephen Nicholls, MD, PhD, director of the Victorian Heart Institute and professor of cardiology, Monash University, Melbourne, Australia, during a press briefing at the meeting. 

“I think what it demonstrates is that tirzepatide is a good cardioprotective agent,” he added. 

Asked whether he thought patients taking dulaglutide should be switched to tirzepatide based on these data, Nicholls said “I think that we're really entering this new era of personalized medicine, and I think we need to think about the individual patient in front of us. Certainly, for individuals who have a higher risk for renal consequences, I would be inclined to move to tirzepatide.” 

Other Benefits Besides Cardioprotection

In SURPASS-CVOT, 13,165 adults with T2D and established atherosclerotic CV disease and A1c 7%-10.5% were randomized 1:1 to either the maximum tolerated dose of tirzepatide (2.5 mg titrated up to 5 mg, 10 mg, or 15 mg) or dulaglutide 1.5 mg (with sham titration), both injected once weekly. Participants were continued on other non-GLP-1 receptor agonist (RA) medications. The trial took place at 640 sites in 30 countries, with a median follow-up of 4 years. About 99% of both groups completed the study. 

The primary composite CV endpoint of CV death, myocardial infarction, or stroke was 8% lower for tirzepatide vs dulaglutide, an insignificant difference (hazard ratio [HR], 0.92), meeting the prespecified criteria for noninferiority (P = .003) but not superiority (P = .086). However, the tirzepatide group experienced significantly lower rates of all-cause death (8.6% vs 10.2%; HR, 0.84).

Tirzepatide was also associated with greater reductions in both A1c (-1.7 vs -0.9 percentage points) and body weight (-12.1% vs -5.0%) and in triglycerides and blood pressure compared with dulaglutide, but not LDL cholesterol.

Individual components of the combined primary endpoint also didn’t differ significantly, and there were no differences in the primary or secondary outcomes by subgroups, including by age, BMI, A1c, diabetes duration, CV event history, baseline estimated glomerular filtration rate (eGFR) category, or baseline SGLT2 inhibitor use. 

For the primary kidney endpoint of time to first occurrence of persistent macroalbuminuria, persistent 50% or greater reduction in eGFR, end-stage kidney disease, or death from kidney disease, results were significantly better with tirzepatide in the overall study population (HR, 0.81) and among the 2923 participants with chronic kidney disease (CKD) at baseline (HR, 0.78). The differences were significant for all individual components except death from kidney disease. 

Change in eGFR from baseline didn’t differ significantly in the overall group but was significantly less with tirzepatide in the high-risk CKD group (-4.97 vs -8.51 mL/min/1.73m²). 

The treatment-associated adverse events that were significantly greater with tirzepatide were nausea (25.1% vs 22.4%), diarrhea (24.8% vs 19.1%), decreased appetite (17.1% vs 9.7%), constipation (12.7% vs 11.6%), vomiting (11.6% vs 9.7%), and dyspepsia (9.9% vs 8.2%). No other studied adverse events differed significantly, including hypoglycemia. 

Compared to a Putative Placebo 

While SURPASS-CVOT didn’t have a placebo group, the investigators compared the tirzepatide primary endpoint to those seen in the placebo participants from the REWIND study who would have qualified for SURPASS-CVOT based on established CV risk. 

REWIND, led by study commentator Hertzel C. Gerstein, MD, MSc, professor and chair in diabetes research and care at McMaster University and Hamilton Health Sciences, Ontario, Canada, was the 2019 trial that established CV benefit for dulaglutide in comparison with placebo, in people with T2D with or without established CV disease. 

In the current analysis, tirzepatide performed significantly better than placebo for the combination of CV death, myocardial infarction, or stroke (HR, 0.72; P = .02), all-cause death (HR, 0.61; P = .001), and CV death or heart failure events (HR, 0.70; P = .03). 

Gerstein generally praised the SURPASS-CVOT study design but also pointed out that the dulaglutide dose used, 1.5 mg/week, was lower than the approved doses of 3 mg and 4.5 mg and wasn’t titrated up as was the tirzepatide dose, which could have affected the outcome. 

“In people with T2D and prior CV disease, tirzepatide up to 15 mg per week is cardioprotective and probably more cardioprotective than the GLP-1RAs at the doses tested,” Gerstein said. 

But, he added, tirzepatide also “probably has more adverse effects than the GLP-1RAs at the doses tested,” and it “does not appear to be qualitatively different than the GLP-1RA drugs. It has effects consistent with a high-dose GLP-1RA.” 

Regarding switching, Gerstein told Medscape Medical News, “I think it would depend. If somebody's doing reasonably well with dulaglutide and you think you're getting good effect, I don't think that I would switch them.” However, “you’re going to get a bigger effect with tirzepatide depending on what you’re trying to accomplish.

“You have a big choice here. Tirzepatide is more potent, but it has more side effects, so you have to weigh that balance. Side effects vary from patient to patient,” he added. 

Gerstein also referred to a meta-analysis of all GLP-1RAs, including dulaglutide, that showed similar results to SURPASS-CVOT. 

“We now have lower and higher potency ways to target the key incretin pathways, that improve clinical measures and prevent or delay serious health outcomes,” he concluded. 

Independent diabetes industry consultant Charles Alexander, MD, scientific and medical advisor for the diaTribe Foundation, San Francisco, noted to Medscape Medical News, “The results as well as other data show the dissociation between glucose improvement, weight loss, and CV disease benefits. We really don’t understand what is driving CV disease benefits. It’s not simply A1c and weight.”

SURPASS-CVOT was funded by Eli Lilly. Nicholls serves as a consultant for, and/or receives research support from, Abcentra, Akcea Therapeutics, Amarin, Amgen, Anthera Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cerenis Therapeutics, CSL Behring, CSL Seqirus, Cyclarity, Daiichi Sankyo, Eli Lilly & Co., Esperion, InfraReDx, LipoScience, Merck, NewAmsterdam Pharma, Novartis, Omthera Pharmaceuticals, Resverlogix, Roche, Sanofi-Regeneron, Scribe Therapeutics, Silence Therapeutics, Takeda, The Medicine Company, and Vaxxinity. Gerstein Has received grants/research support, speakers honoraria, and/or consulting fees from Sanofi, Eli Lilly, Novo Nordisk, Boehringer-Ingelheim, AstraZeneca, Jiangsu-Hansen, Abbott, Bayer, and Zealand. Alexander has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social