Original Abstract

IMPORTANCE: The dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was noninferior to a GLP-1 agonist, dulaglutide, for effects on the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke. However, comparison for a comprehensive range of major adverse cardiovascular and kidney outcomes has not been reported. OBJECTIVE: To perform a post hoc analysis for an expanded range of adverse outcomes in a completed randomized clinical trial comparing the effects of tirzepatide and dulaglutide in patients with type 2 diabetes and cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: This parallel-design double-blind trial enrolled patients with diabetes and preexisting cardiovascular disease (from May 29, 2020, to June 27, 2022) at 640 centers in North and South America, Europe, Asia, and Oceania. Data were analyzed from July 2025 to February 2026. INTERVENTIONS: Participants were randomized to receive subcutaneous tirzepatide up to 15 mg (n = 6586) or a fixed dose of dulaglutide, 1.5 mg (n = 6579), administered weekly. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was time from randomization to first occurrence of a 6-component composite of cardiorenal adverse outcomes, including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes. RESULTS: Among the 13 165 patients enrolled, the mean (SD) age was 64 (8.8) years; 9348 patients (71.0%) were male and 3817 were female (29.0%). The mean (SD) hemoglobin A1c was 8.4% (0.93). After a median (IQR) treatment duration of 46.9 (34.6-50.6) months, the primary cardiorenal end point occurred in 1559 tirzepatide-treated patients (23.7%) and 1803 dulaglutide-treated patients (27.4%; hazard ratio [HR], 0.84; 95% CI, 0.79-0.90; P < .001). Sensitivity analyses showed similar hazard ratios for a narrower 5-component end point (without the kidney composite outcomes: HR, 0.86; 95% CI, 0.80-0.93) and the 4-component composite (without either kidney or heart failure end points: HR, 0.86; 95% CI, 0.80-0.93). Gastrointestinal adverse events were more common with tirzepatide (2827 patients [42.5%]) than dulaglutide (2387 patients [35.9%]) treatment. Other adverse events were similar. CONCLUSIONS: In this post hoc analysis, the dual GLP-1 and GIP agonist tirzepatide, compared with the GLP-1 agonist dulaglutide, was associated with a lower incidence of a broad 6-component composite cardiovascular and kidney end point in patients with diabetes and established cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255433.