Weight-loss medications have attracted considerable attention in recent years. It is well established that GLP-1 receptor agonists reduce the risk of further cardiovascular events in individuals with overweight or obesity and established cardiovascular disease. However, it has remained unclear whether these agents could also help prevent myocardial infarction or stroke in people without existing cardiovascular disease but with an elevated cardiovascular risk profile.
A research team from the DZHK has now investigated this question using a modelling approach—not through a clinical trial, but by analysing large population-based datasets.
A Modelling Approach Rather Than a Clinical Trial
Cardiovascular disease remains the leading cause of death worldwide. Modifiable risk factors such as overweight, hypertension, elevated blood glucose levels, dyslipidaemia and inflammatory processes play a central role in prevention.
For their analysis, the researchers evaluated data from more than 610,000 individuals without known cardiovascular disease. Based on these data, they developed a model describing the relationship between these risk factors and the occurrence of myocardial infarction, stroke or death.
They then simulated the effects of GLP-1 therapy. Placebo-adjusted changes observed in the SELECT trial—including changes in body weight, blood pressure, blood glucose, blood lipids and inflammatory biomarkers—were mathematically applied to more than 200,000 participants from contemporary health studies. This allowed the researchers to estimate how cardiovascular risk might change under treatment.
The findings therefore do not represent directly measured treatment effects, but rather modelled projections based on specific assumptions.
“This subanalysis of the Global Cardiovascular Risk Consortium is primarily a thought experiment that estimates the potential effects of a therapy in a setting where it has not yet been used. At the same time, it demonstrates what can be achieved with population-level data when research begins with a clear clinical question and a strong underlying concept,” said Professor Christina Magnussen of the University Medical Center Hamburg-Eppendorf, the study’s senior author.
Greatest Benefit for Individuals at High Risk
The analysis focused on individuals with an elevated baseline risk, particularly those with a body mass index (BMI) of at least 27 kg/m² and an increased SCORE2 risk, but without established cardiovascular disease. In this group, the estimated 10-year incidence of cardiovascular disease was 13.82%. Under the modelled effects of GLP-1 therapy, this was reduced to 10.83%, corresponding to an absolute risk reduction of almost 3 percentage points and a relative risk reduction of 22%.
Mortality was also reduced in the modelled projections. The estimated effects were smaller among individuals at lower risk or without overweight, and they were attenuated when lower treatment adherence was assumed.
The authors emphasise that no direct clinical benefit can be inferred from the modelling exercise. Nevertheless, the findings may help guide the design of future randomised controlled trials and support the identification of patient populations most likely to benefit from such interventions.
Publication:
Schrage B, Lackner MK, Hoshiyar A, et al. Emulated Effects of Glucagon-Like Peptide 1 Receptor Agonist Therapy in the General Population. J Am Coll Cardiol. Published online February 28, 2026. doi:10.1016/j.jacc.2026.01.055
