Lilly’s Mounjaro (tirzepatide) demonstrated cardiovascular protection in a head-to-head trial
Mounjaro met the primary objective of non-inferiority vs. Trulicity with an 8 per cent lower rate of MACE-3 events, while delivering greater reductions in A1C and weight
Eli Lilly and Company announced 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.
In the trial, the risk of cardiovascular death, heart attack, or stroke was 8 per cent lower for Mounjaro vs. Trulicity (hazard ratio: 0.92; 95.3 per cent CI: 0.83 to 1.01), meeting the prespecified criteria for non-inferiority (upper limit of 95.3 per cent CI of the hazard ratio < 1.05).1,2 Mounjaro showed consistent results across all three components of the MACE-3 composite endpoint. The rate of all-cause mortality was 16 per cent lower for Mounjaro vs. Trulicity (hazard ratio: 0.84; 95.0 per cent CI: 0.75 to 0.94).1,3
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 per cent (hazard ratio: 0.72; 95.0 per cent CI: 0.55 to 0.94) and all-cause mortality by 39 per cent (hazard ratio: 0.61; 95.0 per cent 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 per cent CI: 2.57 to 4.50).3,5,6
Primary and Select Secondary Endpoints:
| Mounjaro (tirzepatide) | Trulicity (dulaglutide) | |
| Primary Endpoint | ||
| Time-to-first
occurrence of MACE-3 (i) |
Hazard Ratio = 0.92
95.3 per centii CI: 0.83 to 1.01 (iii ) p = 0.086 |
|
| Secondary Endpoints | ||
| Time to all-cause death (i) | Hazard Ratio = 0.84
95.0 per cent CI: 0.75 to 0.94 p = 0.002iv |
|
| Change in eGFR in chronic kidney
disease population from mean baseline of 53.4 mL/min/1.73 m2 at 36 months (v) |
-4.97 mL/min/1.73 m2 | -8.51 mL/min/1.73 m2 |
| Estimated treatment difference:
3.54 mL/min/1.73 m2(95.0 per cent CI: 2.57 to 4.50) p = 0.001iv |
||
| A1C reduction from mean baseline of 8.39 per cent at 36
months (v,vi) |
1.73 per cent | 0.90 per cent |
| Estimated treatment difference:
-0.83 per cent (95.0 per cent CI: -0.88 to -0.78) p < 0.001iv |
||
| -12.06 per cent (-11.43 kg / -25.20 lbs) | -4.95 per cent (-4.65 kg / -10.25 lbs) | |
2
| Change from mean baseline of 92.6 kg (204.15 lbs) in body weight at 36
monthsv,vi |
Estimated treatment difference:
-7.1 per cent (95.0 per cent CI: -7.4 to -6.8) p < 0.001iv |
i. Time-to-first event analysis using Cox proportional hazard model.
ii. 95.3 per cent CI reported due to type 1 error rate adjusted for efficacy interim analysis.
iii. Boundary for non-inferiority statistical significance < 1.05.
iv. Not controlled for multiplicity-adjusted type 1 error rate.
v. Baseline values represent the overall mean combining the Mounjaro and Trulicity groups. viAnalysis of change from baseline to 36 months using ANCOVA model with multiple imputation of missing data.
In the trial, Mounjaro also led to greater improvements in A1C, weight and cardiovascular biomarkers, including lipids and systolic blood pressure, compared to Trulicity.3 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 per cent of participants taking Mounjaro discontinued treatment due to adverse events, compared to 10.2 per cent of participants taking Trulicity.7
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.
Endnotes and References
- Time-to-first event analysis using Cox proportional hazard model.
- 95.3 per cent CI reported due to type 1 error rate adjusted for efficacy interim analysis.
- Not controlled for multiplicity-adjusted type 1 error rate.
- Hazard ratio (HR) estimates related to indirect comparison used Cox proportional hazard model adjusted with stabilized inverse-probability weight based on probability of a patient belonging to SURPASS-CVOT given baseline covariates.
- Analysis of change from baseline to 36 months using ANCOVA model with multiple imputation of missing data.
- Subgroup defined as patients with high or very-high risk chronic kidney disease, per KDIGO 2025 guidelines. Kidney function was assessed by change in eGFR using the CKD EPI Creatinine-Cystatin 2021 equation over 36 months. 7. Percentage calculated based on modified intent-to-treat population.