Tirzepatide was associated with fewer six-component cardiorenal events vs dulaglutide among patients with type 2 diabetes and established cardiovascular disease in a post hoc analysis of the SURPASS-CVOT randomized clinical trial.

In the SURPASS-CVOT trial, researchers evaluated a broader composite outcome beyond traditional major adverse cardiovascular events. The analysis included 13,165 patients enrolled across 640 global centers between May 2020 and June 2022. Patients were aged 40 years or older with type 2 diabetes and established atherosclerotic cardiovascular disease and were randomly assigned to receive weekly subcutaneous tirzepatide (up to 15 mg; n = 6,586) or dulaglutide (1.5 mg; n = 6,579).

The primary outcome for this analysis was time to first occurrence of a six-component composite of cardiorenal events, including all-cause mortality, myocardial infarction (MI), stroke, coronary revascularization, hospitalization or urgent visit for heart failure, and adverse kidney outcomes. Following a median treatment duration of 47 months, events occurred in 24% of patients receiving tirzepatide compared with 27% receiving dulaglutide.

Component Outcomes and Effect Size

Event rates for individual components were generally numerically lower with tirzepatide:

• All-cause mortality: 9% vs 10%

• MI: 5% vs 5%

• Stroke: 4% vs 4%

• Coronary revascularization: 8% vs 9%

• Kidney composite outcome: 5% vs 6%

• Heart failure hospitalization or urgent visit: 3% vs 3%

The absolute risk reduction for the composite outcome was 4%, corresponding to a number needed to treat of 27 to prevent one event.

Sensitivity analyses showed consistent findings across alternative composite definitions:

• Five-component outcome (excluding kidney events): 20% vs 23%

• Four-component outcome (excluding kidney and heart failure events): 19% vs 22%

Subgroups and Baseline Risk

Subgroup analyses showed a marginal interaction by body mass index category, while no interaction was observed for age, sex, race, ethnicity, hemoglobin A1c level, duration of diabetes, history of MI, history of heart failure, impaired kidney function, or baseline sodium-glucose cotransporter 2 inhibitor use.

Patients who experienced cardiorenal events were older, more often male, had lower estimated glomerular filtration rates, and more frequently had prior myocardial infarction, stroke, revascularization, heart failure, or peripheral arterial disease. Tobacco use and higher urinary albumin-to-creatinine ratios, including microalbuminuria and macroalbuminuria, were also associated with higher event rates.

Safety and Adverse Events

Gastrointestinal adverse events occurred in 43% of patients receiving tirzepatide and 36% receiving dulaglutide. Treatment-emergent adverse events leading to drug discontinuation were more frequent with tirzepatide. These events were associated with a higher occurrence of cardiorenal end points within the analysis, although causality cannot be established. Other adverse events were similar between groups.

Methodological Considerations

Time-to-event data were analyzed using Cox proportional hazards models stratified by sodium-glucose cotransporter 2 inhibitor use. This was a post hoc analysis, and no power calculations were performed for the expanded composite outcome.

The trial included only patients with high cardiovascular risk, and outcomes in lower-risk populations were not studied. The broader composite end point resulted in approximately double the number of events compared with the original trial design, yielding greater statistical power than intended.

Context and Interpretation

The original trial showed that tirzepatide was noninferior to dulaglutide for the three-component composite of cardiovascular death, myocardial infarction, or stroke. This post hoc analysis evaluated an expanded six-component composite of cardiovascular and kidney outcomes.

As Steven E. Nissen, MD, of the Cleveland Clinic Coordinating Center for Clinical Research and Cleveland Clinic in Ohio, and colleagues wrote, the findings “provide a comprehensive comparison of the dual [glucagon-like peptide]-1/[glucose-dependent insulinotropic polypeptide] incretin tirzepatide with the [glucagon-like peptide]-1 agonist dulaglutide on major cardiorenal adverse outcomes.”

Disclosures

The study was funded by Eli Lilly and Company, the manufacturer of tirzepatide. Several researchers reported relationships with pharmaceutical companies, including Eli Lilly.

Source: JAMA Cardiology