Key Points
- In a post hoc analysis of the SURPASS-CVOT trial, tirzepatide was associated with a significant reduction in cardiorenal end points, including all-cause mortality, MI, stroke, coronary revascularization, heart failure hospitalization, and adverse renal outcomes; compared with dulaglutide.
- All-cause mortality was independently and significantly reduced with tirzepatide, as were coronary revascularization and the composite renal end.
- Sensitivity analyses for narrower 5-component and 4-component composites yielded consistent results, confirming that the benefit of tirzepatide over dulaglutide.
Tirzepatide targets both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, producing greater weight loss and more favorable glycemic and cardiometabolic biomarker effects compared to GLP-1 inhibitors. SURPASS-CVOT (NCT04255433) was the first active-controlled incretin cardiovascular outcome trial, designed in collaboration with regulatory authorities to compare tirzepatide with dulaglutide which has an established cardiovascular outcome benefit from the REWIND trial; using the same narrow 3-component MACE end point. The primary results, published in the New England Journal of Medicine in late 2025, showed noninferiority but not superiority for tirzepatide on that end point. The current post hoc analysis, presented as featured clinical research at ACC.26 and simultaneously published in JAMA Cardiology, examined whether the dual agonist confers broader benefits across the full spectrum of cardiorenal morbidity and mortality.
The analysis included all 13,165 patients enrolled at 640 centers across North and South America, Europe, Asia, and Oceania between May 2020 and June 2022. Patients had established type 2 diabetes and atherosclerotic cardiovascular disease, with a mean age of 64 years, mean HbA1c of 8.4%, and a high baseline cardiovascular risk burden; 47% had a prior MI, 19% prior stroke, and 25% peripheral arterial disease. Participants were randomized 1:1 to subcutaneous tirzepatide up to 15 mg weekly (n=6,586) or fixed dose dulaglutide 1.5 mg weekly (n=6,579). The primary efficacy measure was time to first occurrence of a 6-component cardiorenal composite: all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite adverse renal outcome. Renal events were defined as persistent macroalbuminuria, persistent doubling of serum creatinine with eGFR <45 mL/min/1.73m², need for kidney replacement therapy, or death from kidney disease.
After a median follow-up of 46.9 months, the primary 6-component end point occurred in 23.7% of tirzepatide group versus 27.4% of dulaglutide group (HR 0.84; 95% CI, 0.79–0.90; p<0.001). Each individual component contributed to the overall benefit. Notably, all-cause mortality was significantly lower with tirzepatide (8.6% vs. 10.2%; HR 0.84; 95% CI, 0.75–0.94). The composite renal end point also favored tirzepatide (4.9% vs. 6.1%; HR 0.79; 95% CI, 0.68–0.91). Heart failure hospitalization was numerically lower but did not reach significance (3.0% vs. 3.1%; HR 0.96; 95% CI, 0.79–1.17). The benefit was consistent across prespecified subgroups including sex, age, BMI, region, and baseline HbA1c, with no significant interactions detected. Gastrointestinal adverse events were more frequent with tirzepatide (42.5% vs. 35.9%) and were the principal cause of higher drug discontinuation rates in that group (13.2% vs. 10.1%). All other adverse events were similar between treatment arms.
According to lead investigator Steven E. Nissen, MD, of the Cleveland Clinic, the clinical relevance of this analysis lies in its comprehensiveness: “I proposed that we analyze the totality of benefits of these drugs, comparing the dual agonist, tirzepatide, to the mono-agonist, dulaglutide. The result was very striking.” He was direct about the context of the analysis: “Although it is a post-hoc analysis and therefore should be considered hypothesis generating, the results are pretty striking. And I do think they inform clinical practice, even though they will not inform regulatory policy.”
The investigators acknowledged that the analysis was not prespecified as a primary end point, knowledge of the primary trial outcome could have influenced end point selection, and the expanded composite nearly doubled the event count, substantially increasing statistical power beyond the original trial design. Generalizability is also limited to patients with established high cardiovascular risk.
These findings provide the first active-comparator evidence that tirzepatide confers broader cardiorenal protection than GLP-1 monotherapy relevant to patients with diabetes and established cardiovascular disease. It does that while positioning comprehensive end points, including all-cause mortality and renal outcomes, as essential benchmarks for future incretin-based outcome trials.