Tirzepatide Proves Noninferiority with Dulaglutide for MACE in Lilly's Landmark Incretin Face-Off

In a landmark head-to-head cardiovascular outcomes trial involving more than 13,000 adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD), Eli Lilly’s tirzepatide (Mounjaro), a GIP/GLP-1 dual receptor agonist, reduced the risk of major adverse cardiovascular events (MACE-3), a composite of CV death, myocardial infarction, or stroke, by 8% relative to dulaglutide (hazard ratio 0.92; 95.3% CI, 0.83 to 1.01), meeting the trial’s primary objective of non-inferiority.

The drug also led to a 16% reduction in all-cause mortality (HR 0.84; 95% CI 0.75 to 0.94; P =.002), an outcome suggesting broader cardiometabolic protection, Lilly said in the July 31 news release.

The SURPASS-CVOT match up between the 2 incretin-based therapies spanned more than 4.5 years and was conducted in 30 countries, making it the longest and largest study of tirzepatide to date.

"Cardiovascular disease remains the leading cause of death among people living with type 2 diabetes," Kenneth Custer, PhD, president of Lilly Cardiometabolic Health, said in the press release. "The SURPASS-CVOT results show that tirzepatide preserved the cardioprotective benefit of [dulaglutide], a GLP-1 receptor agonist, while providing additional benefits, including greater kidney protection and a reduced overall risk of death.

“These findings strengthen the case for [tirzepatide] as a potential front-line treatment for people with type 2 diabetes and cardiovascular disease.”

Beyond cardiovascular endpoints, tirzepatide delivered more robust improvements in glycemic control, weight reduction, and renal function compared with dulaglutide. At 36 months, HbA1c declined by 1.73% with tirzepatide vs 0.90% with dulaglutide, a difference of –0.83% (95% CI –0.88 to –0.78; P <.001). Mean weight loss reached 11.43 kg (25.20 lbs, –12.06%) with tirzepatide versus 4.65 kg (10.25 lbs, –4.95%) with dulaglutide. In study participants with high or very-high risk for chronic kidney disease, tirzepatide slowed eGFR decline by an estimated 3.54 mL/min/1.73 m² compared to dulaglutide (P <.001).

Despite these gains, tolerability remains an important consideration. Gastrointestinal side effects were the most common adverse events in both treatment arms, consistent with the GLP-1 class. A greater proportion of patients discontinued tirzepatide due to side effects (13.3%) compared with dulaglutide (10.2%).

Lilly plans to submit these data to the FDA later this year, potentially setting the stage for an expanded approval of tirzepatide in 2026. Tirzepatide is also marketed in the US as Zepbound for management of overweight and obesity. Zepbound is also approved in the US to treat adults with moderate-to-severe obstructive sleep apnea.

The company is pursuing additional cardiovascular indications and plans to present detailed SURPASS-CVOT results at the European Association for the Study of Diabetes annual meeting in September. The findings will also be submitted for publication in a peer-reviewed journal.

Lilly's Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefit in patients with type 2 diabetes and heart disease. News release. Eli Lilly and Company. July 31, 2025. Accessed July 31, 2025. https://investor.lilly.com/node/52671/pdf