Predicted 10-year cardiovascular disease risk reduction with tirzepatide use over 3 years for primary prevention of cardiovascular disease in obesity

AIM: This post hoc analysis assessed the durability of tirzepatide for primary cardiovascular disease (CVD) prevention in obesity, based on predicted CVD risk, in the SURMOUNT-1 (SM-1) 3-year study. METHODS: SM-1 was a phase 3, double-blind, randomised trial where individuals with obesity/overweight and prediabetes received tirzepatide (5, 10, 15 mg) or placebo for 176 weeks. Predicted 10-year CVD risk was calculated using the Framingham Heart Study (FHS) equation. The use of the FHS equation to predict treatment effect (model-derived hazard ratio, HR) was examined for consistency with the observed cardiovascular events in the REWIND trial. RESULTS: In SM-1, 2,539 participants were randomised, 1,032 of those had prediabetes, 976 did not have pre-existing CVD, and 962 participants had baseline and at least one post-baseline predicted CVD risk score for this post hoc analysis. For these participants, receiving tirzepatide 15 mg was associated with a reduction in the predicted 10-year CVD risk at week 72 (absolute risk reduction, (ARR) -1.92%), while placebo was associated with increased risk (absolute risk increase, (ARI) 1.10%) (p < 0.001; HR = 0.73). At week 176, tirzepatide-treated participants had a predicted risk reduction (ARR -1.31%) while predicted risk in placebo increased (ARI 3.84%) from baseline (p < 0.001; HR = 0.62).To test the predictability of FHS risk equations for treatment effect, REWIND data suggested that the HR for dulaglutide vs placebo based on risk prediction is consistent with the HR based on observed cardiovascular events (HR 0.83 and 0.85, respectively). CONCLUSION: These findings suggest that tirzepatide was associated with a lower predicted 10-year CVD risk vs placebo with long-term (3 years) treatment in individuals with obesity/overweight and prediabetes. The risk equation's predictive performance for treatment effect was supported by observed CVD events in the REWIND trial. The potential benefit of tirzepatide for primary CVD prevention needs to be confirmed in event-based cardiovascular outcomes trials such as SURMOUNT-MMO.