Tirzepatide has demonstrated significant cardiovascular benefits in patients with type 2 diabetes, showing noninferiority to dulaglutide for major adverse cardiovascular events while providing superior mortality outcomes in the landmark SURPASS-CVOT trial. The GIP/GLP-1 dual agonist also showed enhanced cardiovascular protection compared to other GLP-1 receptor agonists in patients with concurrent obstructive sleep apnea.
SURPASS-CVOT Trial Results Show Noninferiority with Mortality Benefit
The phase 3 randomized double-blind SURPASS-CVOT trial enrolled 13,299 participants with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD). Participants were randomly assigned to receive maximum tolerated doses of tirzepatide (5 mg, 10 mg, or 15 mg once weekly) or dulaglutide (1.5 mg once weekly).
Over a median follow-up of 4 years, tirzepatide demonstrated noninferiority to dulaglutide for the primary endpoint of three-point major adverse cardiovascular events (MACE), which included cardiovascular death, myocardial infarction, and stroke (HR = 0.92; 95.3% CI, 0.83-1.01; P = .083). The trial met its prespecified noninferiority criteria with an upper limit of 95.3% confidence interval below 1.05.
Most notably, tirzepatide was associated with a 16% lower risk for all-cause mortality compared to dulaglutide (HR = 0.84; 95% CI, 0.75-0.94; P = .002). The drug also provided superior kidney protection, with a smaller decrease in estimated glomerular filtration rate among adults at high or very high risk for chronic kidney disease (estimated treatment difference, 3.54 mL/min/1.73 m²; 95% CI, 2.57-4.5; P < .001).
Enhanced Glycemic and Weight Control
Patients receiving tirzepatide achieved greater improvements in glycemic control and weight management compared to the dulaglutide group. HbA1c reductions were significantly greater with tirzepatide (estimated treatment difference, −0.83 percentage points; 95% CI, −0.88 to −0.78; P < .001), as were body weight reductions (estimated treatment difference, −7.1 percentage points; 95% CI, −7.4 to −6.8; P < .001).
"CVD remains the leading cause of death among people living with type 2 diabetes," said Kenneth Custer, PhD, executive vice president and president of 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."
Real-World Evidence in OSA Patients
A separate retrospective cohort analysis published in Annals of the American Thoracic Society examined cardiovascular outcomes in patients with both obstructive sleep apnea (OSA) and type 2 diabetes. The study compared tirzepatide with liraglutide and semaglutide over 18 months using propensity score matching.
In the comparison with liraglutide (7,836 patients in each group), tirzepatide significantly reduced the risk for composite MACE by 42% (HR = 0.58; 95% CI, 0.51-0.66). The composite MACE incidence rate was substantially lower with tirzepatide (28.9 vs. 54.6). Individual cardiovascular events showed significant risk reductions for acute coronary syndrome (HR = 0.48; 95% CI, 0.33-0.72), cerebrovascular accident (HR = 0.56; 95% CI, 0.44-0.71), and heart failure (HR = 0.48; 95% CI, 0.4-0.58).
When compared to semaglutide (7,394 patients in each group), tirzepatide demonstrated a 14% reduction in composite MACE risk (HR = 0.86; 95% CI, 0.74-0.99), with a lower incidence rate (27.6 vs. 36). The primary individual benefit was seen in cerebrovascular accident risk reduction (HR = 0.74; 95% CI, 0.55-0.97).
Clinical Expert Perspectives
Howard Weintraub, MD, clinical director of the center for the prevention of cardiovascular disease at NYU Langone Heart, acknowledged mixed feelings about the SURPASS-CVOT results. "I think the data on tirzepatide is good, but it is a little disappointing that they didn't meet significance [for CV risk]," Weintraub said. "But the mortality data I think is something you can't overlook."
Richard E. Pratley, MD, medical director of AdventHealth Diabetes Institute, expressed that the results aligned with expectations. "I expected that there would be a CV benefit from tirzepatide and this study would demonstrate noninferiority to dulaglutide, which does have CV benefit," Pratley noted. He added that the cardiovascular benefit would likely be sufficient to support FDA approval for a new indication.
Safety Profile and Regulatory Timeline
Safety and tolerability profiles for both tirzepatide and dulaglutide remained consistent with previously established data, with gastrointestinal-related events being the most common adverse effects. Most gastrointestinal events were mild to moderate and resolved after dose escalation completion. Discontinuation rates due to adverse events were 13.3% for tirzepatide and 10.2% for dulaglutide.
Eli Lilly plans to submit the SURPASS-CVOT data to global regulatory agencies by the end of 2025. Full trial results will be presented at the European Association for the Study of Diabetes annual meeting in September and published in a peer-reviewed journal.
