SURPASS-CVOT: Tirzepatide Bests Dulaglutide for Cardiovascular Protection

Eli Lilly and Company has announced topline results from the phase 3 SURPASS-CVOT trial, a head-to-head cardiovascular outcomes trial comparing 2 incretin therapies, namely tirzepatide (Mounjaro) and dulaglutide (Trulicity), in > 13,000 adults with type 2 diabetes and established atherosclerotic cardiovascular disease across 30 countries.1

According to a July 31, 2025, press release, in SURPASS-CVOT, tirzepatide achieved the primary objective by demonstrating a non-inferior rate of major adverse cardiovascular events (MACE-3), including cardiovascular death, heart attack or stroke, versus dulaglutide. Additionally, while not controlled for multiplicity-adjusted type-1 error, tirzepatide showed improvements on key measures of A1C, weight, renal function and all-cause mortality.1

"Cardiovascular disease remains the leading cause of death among people living with type 2 diabetes," Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health, said in a statement.1 "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."

A once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist, tirzepatide activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide decreases calorie intake, and the effects are likely mediated by affecting appetite.1

Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are ongoing, and it is currently approved by the US Food and Drug Administration as Mounjaro for adults with type 2 diabetes to improve glycemic control, and as Zepbound for adults with obesity, or some adults who are overweight and also have ≥ 1 weight-related medical problem, to lose weight and keep it off. Additionally, Zepbound is FDA-approved to treat adults with moderate-to-severe obstructive sleep apnea and obesity.1,2,3

With > 13,000 participants enrolled across 30 countries and a duration > 4.5 years, SURPASS-CVOT is the largest and longest study of tirzepatide to date. In the trial, participants were randomized in a 1:1 ratio across 640 sites in 30 countries to receive the maximum tolerated dose (MTD) of tirzepatide (5 mg, 10 mg or 15 mg) or dulaglutide (1.5 mg) administered subcutaneously once weekly. The primary objective of the trial was to demonstrate that tirzepatide provided a non-inferior reduction in the risk of MACE-3 compared to dulaglutide.1

Results showed the risk of cardiovascular death, heart attack, or stroke was 8% lower for tirzepatide versus dulaglutide (hazard ratio [HR], 0.92; 95.3% CI, 0.83 to 1.01), meeting the prespecified criteria for non-inferiority (upper limit of 95.3% CI of the hazard ratio < 1.05). Of note, tirzepatide showed consistent results across all 3 components of the MACE-3 composite endpoint, and the rate of all-cause mortality was 16% lower for tirzepatide versus dulaglutide (HR, 0.84; 95.0% CI, 0.75 to 0.94).1

A pre-specified indirect comparison analysis of matched patient-level data from the REWIND and SURPASS-CVOT studies found that tirzepatide reduced the risk of MACE-3 by 28% (HR, 0.72; 95.0% CI, 0.55 to 0.94) and all-cause mortality by 39% (HR, 0.61; 95.0% CI: 0.45 to 0.82) compared to a putative placebo. In another key pre-specified analysis of participants with high or very-high risk of CKD, tirzepatide slowed eGFR decline by 3.54 mL/min/1.73 m2 at 36 months versus dulaglutide (95.0% CI, 2.57 to 4.50).1

In the trial, treatment with tirzepatide also led to greater improvements in A1C, weight and cardiovascular biomarkers, including lipids and systolic blood pressure, compared to dulaglutide. The safety and tolerability of tirzepatide and dulaglutide were generally consistent with their established profiles, with the most commonly reported adverse events in SURPASS-CVOT for both treatments being gastrointestinal-related, generally mild-to-moderate in severity, and mostly resolved after dose escalation was complete. During the trial, 13.3% of participants taking tirzepatide discontinued treatment due to adverse events, compared to 10.2% of participants taking dulaglutide.1

According to Eli Lilly and Company, detailed results for SURPASS-CVOT will be presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2025 in September 2025 and published in a peer-reviewed journal. Additionally, the Company described plans to submit these data to global regulatory authorities by the end of 2025.1

References

1. Eli Lilly and Company. 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. July 31, 2025. Accessed July 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated

2. Iapoce C. FDA Approves Tirzepatide for Obstructive Sleep Apnea in Obesity. HCPLive. December 20, 2024. Accessed July 31, 2025. https://www.hcplive.com/view/fda-approves-tirzepatide-for-obstructive-sleep-apnea-in-obesity

3. Campbell P. FDA Approves Tirzepatide (Zepbound) for Chronic Weight Management. HCPLive. November 8, 2023. Accessed July 31, 2025. https://www.hcplive.com/view/fda-approves-tirzepatide-zepbound-chronic-weight-management