Tirzepatide and Dulaglutide Cardiorenal Outcomes in SURPASS-CVOT

Key Takeaways

• Tirzepatide was associated with fewer first 6-component cardiorenal events than dulaglutide, with a hazard ratio of 0.84.
• Individual component results and narrower sensitivity composites remained directionally favorable, and the alternative 6-component version using cardiovascular death also remained favorable.
• Gastrointestinal adverse events and treatment-emergent discontinuations were more common with tirzepatide, while other adverse events were broadly similar.

A SURPASS-CVOT post hoc analysis found first 6-component cardiorenal events in 23.7% of patients with type 2 diabetes and established cardiovascular disease treated with tirzepatide up to 15 mg weekly and 27.4% treated with dulaglutide 1.5 mg weekly (HR 0.84, 95% CI 0.79-0.90; P<.001). The comparison came from a head-to-head randomized trial in patients with preexisting cardiovascular disease. The broader endpoint extended beyond traditional cardiovascular events to include heart failure and kidney outcomes.

The parent completed randomized clinical trial used a parallel design and double blinding, enrolling 13,165 patients at 640 centers across North and South America, Europe, Asia, and Oceania. Participants had a mean age of 64 years, 71.0% were male, mean HbA1c was 8.4%, and median treatment duration was 46.9 months. The comparison was tirzepatide up to 15 mg weekly versus fixed-dose dulaglutide 1.5 mg weekly. The 6-component endpoint included all-cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, and a composite kidney outcome. The kidney composite covered persistent macroalbuminuria, persistent doubling of serum creatinine with eGFR below 45 mL/min/1.73 m2, continuous kidney replacement therapy, or death due to kidney disease.

All components of the 6-component endpoint contributed to the overall association. All-cause mortality occurred in 8.6% versus 10.2% (HR 0.84, 95% CI 0.75-0.94), while coronary revascularization occurred in 8.0% versus 9.4% (HR 0.84, 95% CI 0.75-0.95). The composite kidney endpoint occurred in 4.9% versus 6.1% (HR 0.79, 95% CI 0.68-0.91), and myocardial infarction occurred in 4.7% versus 5.4% (HR 0.86, 95% CI 0.74-1.00). Stroke occurred in 3.5% versus 3.8% (HR 0.91, 95% CI 0.76-1.09), and heart failure hospitalization occurred in 3.0% versus 3.1% (HR 0.96, 95% CI 0.79-1.17). The overall pattern reflected contributions across the full composite rather than a single isolated driver.

Time-to-event analyses used a Cox proportional hazards model stratified by baseline SGLT-2 inhibitor use. Sensitivity results remained aligned, with the 5-component endpoint at 20.2% versus 23.0% (HR 0.86, 95% CI 0.80-0.93). The 4-component endpoint was 19.1% versus 21.8% (HR 0.86, 95% CI 0.80-0.93), and the alternative 6-component version was 20.6% versus 23.7% (HR 0.85, 95% CI 0.79-0.92). No interaction was found by sex, age, region, race, ethnicity, HbA1c, diabetes duration, prior myocardial infarction, heart failure history, impaired kidney function, or baseline SGLT-2 inhibitor use. Only a marginal BMI interaction was reported, keeping these subgroup and sensitivity findings within an exploratory post hoc frame.

Gastrointestinal adverse events were more common with tirzepatide than dulaglutide, occurring in 42.5% versus 35.9%. Treatment-emergent discontinuations were also higher with tirzepatide, at 20.4% versus 15.6% among those with a cardiorenal endpoint and 11.0% versus 8.1% among those without one. Acute kidney injury as a serious adverse event was reported in both groups, while other adverse events were broadly similar. This was a post hoc analysis of a trial whose primary comparison was narrower, and no power calculations addressed the expanded endpoint. Subgroup and sensitivity analyses were not multiplicity adjusted, and applicability beyond this high cardiovascular-risk population remains uncertain.