Introduction

Studies have demonstrated that the dual glucagon-like peptide 1  (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide in non-inferior to a GLP-1 agonist, dulaglutide, in terms of reduced risk of the composite outcome of cardiovascular (CV) death, myocardial infarction (MI), or stroke in patients with type-2 diabetes mellitus (T2DM) and cardiovascualr disease (CVD). Neverthelss, a comparison of these two medications for a comprehensive range of major adverse CV and renal outcomes has not been reported yet.

Aim

To compare the effects of tirzepatide and dulaglutide in terms of reduced incidece of a borad range of cardiorenal outcomes (including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and serious adverse renal outcomes) in patients with T2DM and CVD.

Patient Profile

• Adult patients (age ≥40 years) with T2DM and established atherosclerotic vascular disease (ASCVD; including coronary, cerebral or peripheral vascular disease). The glycosylated hemoglobin (HbA1c) levels for the study participants ranged from 7.0% to 10.5%.

Methods

Study Design

• A post hoc analysis of the SUPRPASS CVOT trial.
• SURPASS CVOT was an active comparator, parallel-design double-blind trial that enrolled patients with diabetes and preexisting CVD across 640 centers in North and South America, Europe, Asia, and

Treatment Strategy

• The study participants were randomized 1:1 to receive subcutaneous tirzepatide up to 15 mg (n = 6586) or a fixed dose of dulaglutide, 5 mg (n = 6579), administered weekly.
• Tirzepatide was initiated at a dose of 2.5 mg weekly and was escalated every 4 weeks to a maximm dose of 15 mg weekly or to the highest maintenance dose tolerated by the patient.

Outcomes

Primary Efficacy Outcome

• The first occurrence of a 6-component composite of cardiorenal adverse outcomes, including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure (HHF), and a composite of adverse renal outcomes [defined as persistent macroalbuminuria or persistent doubling of serum creatinine level with estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m², need for continuous kidney replacement therapy, or death due to kidney disease).

Secondary Efficacy Outcomes

• Incidence of all-cause mortality, coronary revascularization, HHF, and adverse renal outcomes.

Safety Outcomes

• Incidence of treatment emergent adverse events (TEAEs).

Results

• A total of 13 ,165 patients were enrolled (mean age: 64 years; 71% were males and 29% were females). The mean HbA1c for the study populaiton was 4%.
• After a median treatment duration of 9 months, the primary cardiorenal outcome occurred in 23.7% of the tirzepatide-treated patients and 27.4% dulaglutide-treated patients [hazard ratio [HR], 0.84; 95% CI, 0.79-0.90; P < 0.001) (Fig. 1).

Fig. 1: Incidence of primary composite outcome in the study groups

• The event rates for each of the individual component of the composite outcome were as mentioned in Table 1.
• Sensitivity analyses revealed similar hazard ratios for a narrower 5-component outcome (without the renal composite outcome) and the 4-component composite (without either renal outcomes or heart failure (Table 1).

Table 1:Time-to-event efficacy outcomes in the study groups

 NA: Not applicable

• The incidence of gastrointestinal adverse events was more frequent with tirzepatide than dulaglutide treatment (5% vs. 35.9%). The incidence of other adverse events was similar in both the study groups.

Conclusion

• As per the findings of the post hoc analysis, the dual GLP-1 and GIP agonist tirzepatide was associated with lower incidence of a broad 6-component cardiorenal outcome in patients with T2DM and established CVD.

JAMA Cardiol. March 28, 2026 (Published online); doi:10.1001/jamacardio.2026.0767.