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Lilly's Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial
 

(ABU DHABI) - Eli Lilly and Company (NYSE: LLY) announces topline results from SURPASS-CVOT, a first-of-its-kind head-to-head Phase 3 cardiovascular outcomes trial comparing two incretin therapies in adults with type 2 diabetes and established atherosclerotic cardiovascular disease. Mounjaro (tirzepatide), a GIP/GLP-1 dual receptor agonist, was compared to Trulicity (dulaglutide), a GLP-1 receptor agonist that showed a definitive cardiovascular benefit in the REWIND study. In SURPASS-CVOT, Mounjaro achieved the primary objective by demonstrating a non-inferior rate of major adverse cardiovascular events (MACE-3), including cardiovascular death, heart attack, or stroke, vs. Trulicity. In addition, while not controlled for multiplicity-adjusted type-1 error, Mounjaro showed improvements on key measures of A1C, weight, renal function, and all-cause mortality. The trial, which enrolled more than 13,000 participants across 30 countries and lasted more than four and a half years, is the largest and longest study of tirzepatide to date.

"Cardiovascular disease remains the leading cause of death among people living with type 2 diabetes," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "The SURPASS-CVOT results show that Mounjaro preserved the cardioprotective benefit of Trulicity, 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 Mounjaro as a potential front-line treatment for people with type 2 diabetes and cardiovascular disease."

In the trial, the risk of cardiovascular death, heart attack, or stroke was 8% lower for Mounjaro vs. Trulicity (hazard ratio: 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). Mounjaro showed consistent results across all three components of the MACE-3 composite endpoint. The rate of all-cause mortality was 16% lower for Mounjaro vs. Trulicity (hazard ratio: 0.84; 95.0% CI: 0.75 to 0.94).

A pre-specified indirect comparison analysis of matched patient-level data from the REWIND and SURPASS-CVOT studies found that Mounjaro reduced the risk of MACE-3 by 28% (hazard ratio: 0.72; 95.0% CI: 0.55 to 0.94) and all-cause mortality by 39% (hazard ratio: 0.61; 95.0% CI: 0.45 to 0.82) compared to a putative placebo.3,4 In another key pre-specified analysis of participants with high or very-high risk of chronic kidney disease, Mounjaro slowed eGFR decline by 3.54 mL/min/1.73 m2 at 36 months vs. Trulicity (95.0% CI: 2.57 to 4.50).

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

Detailed results for SURPASS-CVOT will be presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2025 in September and published in a peer-reviewed journal. Lilly plans to submit these data to global regulatory authorities by the end of this year.

About SURPASS-CVOT

SURPASS-CVOT (Cardiovascular Outcomes Trial; NCT04255433) was an event-driven, randomized, double-blind, parallel group Phase 3 trial evaluating the efficacy and safety of Mounjaro (tirzepatide) compared with Trulicity (dulaglutide) in adults with type 2 diabetes and established atherosclerotic cardiovascular disease, which lasted approximately five years (with a median follow-up of four years). In the trial, 13,299 participants were randomized 1:1 across 640 sites in 30 countries to receive the maximum tolerated dose (MTD) of Mounjaro (5 mg, 10 mg, or 15 mg) or Trulicity (1.5 mg), both administered subcutaneously once weekly. The primary objective of the trial was to demonstrate that Mounjaro provided a non-inferior reduction in the risk of major adverse cardiovascular events (MACE-3)—a composite of cardiovascular death, heart attack, or stroke—compared to Trulicity. SURPASS-CVOT utilized MTD of 5 mg, 10 mg, or 15 mg once weekly. The starting dose of 2.5 mg Mounjaro was increased by 2.5 mg every four weeks until MTD was achieved. Participants who tolerated 15 mg continued on 15 mg as their MTD. Participants who tolerated 10 mg but did not tolerate 15 mg continued on 10 mg as their MTD, and participants who tolerated 5 mg but did not tolerate 10 mg continued on 5 mg as their MTD.

About REWIND (2019)

REWIND (NCT01394952) was a multicenter, randomized, double-blind, placebo-controlled trial, published in 2019, designed to assess the effect of Trulicity (1.5 mg) compared to placebo in adults with type 2 diabetes with and without established cardiovascular disease. The primary cardiovascular outcome was the first occurrence of MACE-3. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. In the trial, 9,901 participants from 24 countries had a mean duration of diabetes of 10.5 years and a median baseline A1C of 7.2%.
                              



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