Tirzepatide is a medication that addresses type 2 diabetes and is also used for weight management. As type 2 diabetes often occurs with cardiovascular risk factors, evaluating the cardiovascular safety of new medications is important. This ensures new treatments do not increase heart-related problems, and ideally, they might even offer some cardiovascular benefit.
Understanding Cardiovascular Outcomes Trials
Cardiovascular Outcomes Trials (CVOTs) are clinical studies assessing the impact of new medications on heart and blood vessel health. These trials are required for new diabetes and weight loss drugs to confirm they do not worsen cardiovascular risk and, ideally, demonstrate a positive effect. This requirement arose from past concerns about certain glucose-lowering drugs negatively affecting cardiovascular mortality.
A common endpoint in CVOTs is Major Adverse Cardiovascular Events (MACE), which combines several serious heart-related events. The classical 3-point MACE includes cardiovascular death, non-fatal myocardial infarction (heart attack), and non-fatal stroke. Other MACE definitions may include hospitalization for heart failure or urgent revascularization procedures. These composite endpoints increase statistical power and reduce trial duration and cost.
CVOTs aim to demonstrate either non-inferiority or superiority. Non-inferiority means a new treatment is no worse than an existing standard treatment or placebo, within a predefined margin. If non-inferiority is established, trials may then assess for superiority, where the new treatment provides a greater benefit.
The SURPASS-CVOT Trial Design
The SURPASS-CVOT trial is a randomized, double-blind, active-controlled study evaluating the cardiovascular safety and efficacy of tirzepatide. Its main goal is to demonstrate tirzepatide is not inferior to dulaglutide, another diabetes medication, regarding cardiovascular outcomes, and to investigate potential superior benefits.
The trial enrolled 13,299 participants from 640 sites across 30 countries, all with type 2 diabetes and established atherosclerotic cardiovascular disease or high cardiovascular risk. Participants were aged 40 or older, with a BMI of 25 kg/m² or higher, and an HbA1c between 7.0% and 10.5%. The mean age was 64.1 years, with an average diabetes duration of 14.7 years and a mean BMI of 32.6 kg/m².
Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (at doses up to 15 mg) or dulaglutide 1.5 mg. The primary endpoint is the time to the first occurrence of a MACE (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Key secondary endpoints include all-cause mortality and the time to occurrence of each MACE component. The trial is event-driven, continuing until 1,615 adjudicated MACE events occur.
Key Findings of the SURPASS-CVOT Trial
The SURPASS-CVOT trial aimed to provide definitive evidence regarding the cardiovascular safety and efficacy of tirzepatide. Preliminary data from an observational study emulating SURPASS-CVOT indicated tirzepatide was associated with a 37% reduction in MACE compared to dulaglutide over approximately six months, suggesting tirzepatide may be superior in preventing MACE events.
The trial’s primary analysis sought to establish non-inferiority of tirzepatide versus dulaglutide for the time to first MACE, by demonstrating an upper confidence limit less than 1.05. If non-inferiority is confirmed, the trial will then assess for superiority to determine if tirzepatide offers a greater cardiovascular benefit. The full, official results from the SURPASS-CVOT trial will provide comprehensive data on these endpoints.
Beyond MACE, tirzepatide has shown other cardiovascular benefits in related trials. In the SUMMIT trial, for patients with heart failure with preserved ejection fraction (HFpEF) and obesity, tirzepatide led to a 38% lower rate of cardiovascular death or worsening heart failure compared to placebo over one year. This reduction was observed in patients with and without chronic kidney disease. Tirzepatide has also been observed to improve kidney function, reduce blood pressure, and decrease signs of inflammation, which can contribute to its cardiovascular effects.
Impact on Patient Care
The SURPASS-CVOT trial findings are expected to influence treatment for type 2 diabetes, particularly for individuals with existing cardiovascular disease or high risk. Demonstrating cardiovascular safety and potential benefits positions tirzepatide as a comprehensive treatment option, moving beyond just blood sugar control. This supports an integrated approach to managing diabetes, where reducing cardiovascular risk is a primary consideration alongside glycemic management.
The trial’s results support the use of incretin-based therapies, like tirzepatide, for their broader cardiometabolic effects. For patients, this could mean a single medication addresses both their diabetes and protects their heart health. Healthcare providers may consider tirzepatide for patients who require both glycemic control and cardiovascular risk reduction. The overall risk-benefit profile of tirzepatide is favorable, given its established efficacy in blood glucose and weight reduction, coupled with the emerging cardiovascular outcomes data.