Tirzepatide trims risk of major adverse cardiovascular events

Treatment with tirzepatide 15 mg/week results in a 33-percent reduction in the risk of major adverse cardiovascular events (MACE), results of a meta-analysis have shown. Moreover, its efficacy is consistent across individuals with or without obesity.

MACE included a composite of adjudicated acute coronary syndrome, cerebrovascular accident, heart failure hospitalization, and cardiovascular death.

Moreover, “[w]eight loss and reductions in waist circumference (WC), diastolic blood pressure (DBP), and fasting blood glucose (FBG) during tirzepatide therapy suggest potential long-term benefits for MACE, highlighting their role in personalized treatment recommendations,” said lead author Dr Arya Aminorroaya, Yale School of Medicine, New Haven, Connecticut, US.

Aminorroaya and his team performed an individualized participant data (IPD) meta-analysis to assess the cardiovascular efficacy of tirzepatide and identify predictors of treatment response. They pooled individual-level data from 11 phase III randomized controlled trials (RCTs) that compared tirzepatide with placebo, insulin, or GLP-1 RAs in participants with or without type 2 diabetes (T2D).

Cardiovascular efficacy

“IPD from phase III trials of tirzepatide offer a unique opportunity to evaluate its cardiovascular efficacy and identify response correlates,” Aminorroaya said. “These insights may guide the clinical use of the drug while we await results from cardiovascular outcome trials (CVOTs), particularly in examining its cardiovascular effectiveness.”

Participants in the intervention arm (n=3,360) received tirzepatide 15 mg/week, the maximum tolerated dose, and were compared with pooled comparators (n=4,028), in line with ongoing CVOTs. Their median age was 55 years, and 52 percent were women.

A mixed-effects Cox proportional hazards model was used to assess MACE, with the intervention as a fixed effect and the trial as a random effect.

Furthermore, the authors used inverse probability weighting (IPW) to account for the differences in study design across RCTs. They also identified predictors of treatment response by analysing the MACE risk in those with vs without improvements in cardiometabolic components.

MACE risk

Of the pooled participants, only 119 (1.6 percent) experienced MACE over a median follow-up of 56 weeks. The use of tirzepatide 15 mg/week led to a significant decrease in the risk of MACE (hazard ratio, 0.67, 95 percent confidence interval, 0.51‒0.87), with an IPW-weighted incidence of 1.1 percent and 1.7 percent in the tirzepatide and comparator arms, respectively. [AHA 2025, abstract 4361308]

The cardiovascular efficacy of tirzepatide also persisted across subgroups. MACE benefits were more noticeable among participants with vs without obesity (p<0.001).

Notably, the risk of MACE was 81-percent lower among participants in the tirzepatide arm who showed improvements in weight, WC, DBP, and FBG, among other cardiometabolic component, than those who did not show such improvements.

When compared with semaglutide, tirzepatide substantially reduced weight and blood pressure in real-world patients with obesity or overweight and without T2D. In this study, a total of 12,590 patients were included, of whom 10,525 received semaglutide and 2,065 tirzepatide.  [AHA 2025, abstract 4367801]