Highlights
In a post hoc analysis of the completed SURPASS-CVOT randomized clinical trial, tirzepatide was associated with a significantly lower risk of a broad 6-component cardiorenal composite than dulaglutide.
The benefit was consistent across narrower sensitivity analyses that excluded kidney and/or heart failure components, supporting robustness of the overall signal.
Gastrointestinal adverse events were more frequent with tirzepatide, while other adverse events were similar between groups.
Because this was a post hoc comparison of expanded outcomes, the findings are important but should be interpreted as hypothesis-generating rather than definitive for all cardiorenal endpoints.
Study Background
Patients with type 2 diabetes and established cardiovascular disease remain at high risk for recurrent myocardial infarction, stroke, heart failure, progressive kidney disease, and premature death despite contemporary therapy. Over the past decade, GLP-1 receptor agonists have become central to cardiometabolic risk reduction because several agents reduce major adverse cardiovascular events and may also slow kidney disease progression. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, has shown substantial effects on glycemic control and body weight, and it has already demonstrated cardiovascular noninferiority compared with dulaglutide in SURPASS-CVOT.
The clinical question addressed here is broader: beyond the traditional three-point cardiovascular composite, does tirzepatide offer additional protection across a wider range of clinically meaningful cardiorenal outcomes compared with an established GLP-1 receptor agonist? This matters because diabetes-related morbidity is often driven not by a single event, but by a cluster of vascular, renal, and heart failure complications that accumulate over time.
Study Design
This was a post hoc analysis of the parallel-design, double-blind SURPASS-CVOT randomized clinical trial. The parent trial enrolled patients with type 2 diabetes and preexisting cardiovascular disease at 640 centers across North and South America, Europe, Asia, and Oceania between May 29, 2020, and June 27, 2022. Data were analyzed from July 2025 to February 2026.
A total of 13,165 participants were randomized to receive once-weekly subcutaneous tirzepatide, titrated up to 15 mg (n = 6586), or fixed-dose dulaglutide, 1.5 mg (n = 6579). The mean age was 64 years, 71.0% were male, and baseline hemoglobin A1c averaged 8.4%, indicating a population with substantial residual glycemic burden despite high cardiovascular risk.
The primary efficacy measure for this post hoc analysis was time to first occurrence of a 6-component composite endpoint: all-cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes. Sensitivity analyses examined a narrower 5-component composite excluding kidney outcomes and a 4-component composite excluding both kidney and heart failure outcomes.
Key Findings
Over a median treatment duration of 46.9 months, the primary 6-component cardiorenal endpoint occurred in 1559 patients assigned to tirzepatide (23.7%) and 1803 assigned to dulaglutide (27.4%). This translated into a hazard ratio of 0.84 (95% CI, 0.79-0.90; P < .001), indicating a 16% relative risk reduction with tirzepatide compared with dulaglutide for the composite outcome.
Put differently, the event curves separated in favor of tirzepatide over nearly 4 years of follow-up, suggesting that the dual GIP/GLP-1 agonist may confer incremental benefit beyond the established GLP-1 receptor agonist comparator. While the composite endpoint included outcomes of different clinical weight, the consistency of the signal is notable because it spans both cardiovascular and kidney-related events.
In sensitivity analyses, tirzepatide remained favorable when kidney outcomes were removed from the composite. The 5-component endpoint yielded a hazard ratio of 0.86 (95% CI, 0.80-0.93). Likewise, the 4-component composite, excluding both kidney and heart failure endpoints, also showed a hazard ratio of 0.86 (95% CI, 0.80-0.93). These closely aligned estimates strengthen confidence that the observed effect was not solely driven by one domain, such as kidney events or heart failure hospitalization, although the analysis cannot identify which specific component contributed most to the overall advantage without more granular event-level reporting.
Safety findings were broadly consistent with what is expected from incretin-based therapies. Gastrointestinal adverse events were more common with tirzepatide, occurring in 2827 patients (42.5%), compared with 2387 patients (35.9%) receiving dulaglutide. Other adverse events were similar between groups, suggesting no major new safety signal in this analysis. For clinicians, this reinforces a familiar trade-off: greater cardiometabolic efficacy may come with higher rates of nausea, vomiting, diarrhea, or treatment discontinuation related to tolerability, particularly during dose escalation.
Clinical Interpretation
These findings are clinically meaningful because they compare tirzepatide not with placebo, but with dulaglutide, a GLP-1 receptor agonist with proven cardiovascular benefit. Demonstrating superiority over an active comparator is a higher bar than showing benefit versus usual care. The result suggests that dual agonism at GIP and GLP-1 receptors may offer incremental protection across a broader cardiorenal spectrum in patients with diabetes and established atherosclerotic cardiovascular disease.
Several mechanisms could plausibly contribute to this effect. Tirzepatide produces larger reductions in hemoglobin A1c and body weight than many comparators, and these changes may improve blood pressure, inflammatory burden, insulin resistance, and renal hemodynamics. It may also influence lipid metabolism and visceral adiposity. However, this post hoc analysis does not prove mechanism, and the extent to which the observed benefit is mediated by glycemic control, weight loss, or direct receptor effects remains uncertain.
From a practical standpoint, the study may influence how clinicians frame therapy selection for patients with type 2 diabetes who already have cardiovascular disease and are at risk for kidney decline. If a patient can tolerate tirzepatide and has no contraindications, these data support consideration of tirzepatide as a potentially stronger option than dulaglutide for broad cardiorenal risk reduction. That said, treatment choice should still reflect individual tolerability, access, cost, injection preferences, renal function, and the need for individualized glycemic targets.
Expert Commentary
There are several strengths to this analysis. The trial was large, international, double-blind, and event-driven, and the follow-up was long enough to capture clinically relevant outcomes. The active-comparator design enhances clinical relevance because it reflects real therapeutic decision-making rather than placebo-controlled efficacy alone.
Nevertheless, the most important limitation is that this was a post hoc analysis. The expanded 6-component endpoint was not the original primary endpoint of the parent cardiovascular outcomes trial, so the findings should be considered exploratory relative to a prespecified hypothesis. Composite endpoints also require careful interpretation because components vary in severity and frequency; a reduction in the composite does not necessarily mean that each constituent outcome improved to the same degree. Without detailed component-level results, it is difficult to know whether the signal was driven mainly by myocardial infarction, heart failure hospitalization, kidney outcomes, or other elements.
Generalizability is good for patients resembling the trial population: adults with type 2 diabetes, established cardiovascular disease, and relatively poor glycemic control. It may be less certain for patients without known cardiovascular disease, those with advanced kidney failure, or those who cannot tolerate high-dose incretin therapy. The higher rate of gastrointestinal adverse events also remains clinically relevant, especially in older adults or patients who struggle with dehydration, frailty, or medication adherence.
Current diabetes and cardiovascular guidelines increasingly emphasize use of agents with proven cardiorenal benefit in patients with type 2 diabetes and high cardiovascular risk. These data add to the growing evidence base supporting tirzepatide as a potent cardiometabolic therapy, but they do not replace the need for individualized care or longer-term postmarketing and comparative effectiveness data.
Conclusion
In this post hoc analysis of SURPASS-CVOT, tirzepatide was associated with fewer broad cardiorenal events than dulaglutide in patients with type 2 diabetes and established cardiovascular disease. The benefit was consistent across sensitivity analyses, while gastrointestinal adverse events were more common with tirzepatide and other safety outcomes were similar.
The study strengthens the case for tirzepatide as a high-efficacy option in cardio-metabolic risk reduction, but the post hoc nature of the analysis means the results should be interpreted cautiously. Future work should clarify which specific cardiorenal outcomes are most improved, how benefits vary across patient subgroups, and whether these findings translate into everyday practice across broader populations.
Funding and Clinical Trial Registration
ClinicalTrials.gov Identifier: NCT04255433.
Published in JAMA Cardiology, 2026;11(6):544-552. PMID: 41903177.
References
1. Nissen SE, Wolski K, D’Alessio D, et al. Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial. JAMA Cardiol. 2026;11(6):544-552. PMID: 41903177.
2. SURPASS-CVOT Investigators. Tirzepatide versus dulaglutide in patients with type 2 diabetes and cardiovascular disease. ClinicalTrials.gov NCT04255433.
3. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes—2025. Diabetes Care. 2025.
4. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023.