In appropriately selected individuals at high CVD risk, GLP-1RA therapy may complement existing primary prevention strategies, supporting the rationale for future randomized studies.
Key Findings
Results
Emulated GLP-1RA therapy reduced projected 10-year CVD incidence by approximately 22% relatively and 2.99% absolutely in obese individuals at high cardiovascular risk without established CVD.
Primary analysis included 21,720 individuals with BMI ≥27 kg/m² and SCORE2-derived baseline risk ≥7.5%
Observed 10-year CVD incidence was 13.82% (95% CI: 11.94%-15.71%)
Absolute reduction was 2.99% (95% CI: 2.67%-3.31%) and relative reduction was 22%
Results
Absolute reductions in projected CVD incidence were larger in men than in women, though relative reductions were similar across sexes.
Absolute reduction in men was 3.14% (95% CI: 2.82%-3.47%)
Absolute reduction in women was 2.7% (95% CI: 2.23%-3.16%)
Relative reductions were similar: 21% in men vs 23% in women
Analyses used sex-stratified, placebo-adjusted changes in risk factors observed in the SELECT trial
Results
Modeled cardiovascular risk reductions were attenuated in nonobese individuals and those in lower SCORE2 risk groups.
Secondary analyses examined nonobese and lower SCORE2 groups
Risk reductions diminished further with lower compliance assumptions
Primary analyses required BMI ≥27 kg/m² and SCORE2-derived baseline risk ≥7.5% for maximum projected benefit
This suggests patient selection is critical for maximizing potential benefit of GLP-1RA therapy in primary prevention
Methods
The study used a risk model built from 610,789 CVD-free individuals to estimate 10-year incidence of CVD and death from any cause based on five prespecified risk factors.
Model was fitted using data from European and North American Global Cardiovascular Risk Consortium cohorts
Five prespecified risk factors included: BMI, glycosylated hemoglobin, systolic blood pressure, high-sensitivity C-reactive protein, and non-HDL cholesterol
The model was applied to 200,012 individuals from 2 contemporary health examination surveys
GLP-1RA therapy was emulated by applying sex-stratified, placebo-adjusted changes in the 5 risk factors observed in the SELECT trial
Background
The study emulated GLP-1RA use for primary prevention by applying risk factor changes from the SELECT trial to obese individuals without established CVD.
SELECT trial examined semaglutide and cardiovascular outcomes in obesity without diabetes
SELECT trial enrolled individuals with established CVD, whereas this study targeted CVD-free individuals at risk
The emulation approach modeled the downstream effects of GLP-1RA-induced changes in BMI, glycosylated hemoglobin, systolic blood pressure, high-sensitivity CRP, and non-HDL cholesterol
This design addresses the gap in evidence regarding GLP-1RA benefit in primary prevention settings
What This Means
This research suggests that a class of medications called GLP-1 receptor agonists (GLP-1RAs), which includes drugs like semaglutide (Ozempic/Wegovy), might reduce the risk of heart disease and stroke in people who are overweight or obese and at high cardiovascular risk, even if they haven't yet had a heart attack or stroke. Rather than conducting a new clinical trial, researchers used a modeling approach: they took real-world data from over 600,000 people to build a risk prediction model, then used the risk factor improvements seen in a major clinical trial (SELECT) to estimate what would happen if similar people received GLP-1RA therapy. They found that, in people with a BMI of 27 or higher and elevated cardiovascular risk scores, GLP-1RA therapy could reduce 10-year rates of cardiovascular events from about 13.8% to about 10.8% — a roughly 22% relative reduction.
The benefits were somewhat larger in men than in women in absolute terms, though both sexes showed similar relative reductions (around 21-23%). Importantly, the projected benefits were smaller in people who were not obese, those at lower baseline cardiovascular risk, and those assumed to have lower medication adherence. This highlights that patient selection matters greatly — not everyone would be expected to benefit equally from these medications for heart disease prevention.
This research suggests that GLP-1RA medications could potentially play a role in preventing a first heart attack or stroke in carefully selected high-risk individuals, not just in those who have already had cardiovascular disease. The authors call for future randomized clinical trials to confirm these modeled findings, as this study is a simulation rather than a direct test of the drugs in primary prevention populations.
B. Schrage, Maximilian Lackner, Aisouda Hoshiyar, James A. de Lemos, Gunnar Engström, Elisa Grossmann, et al.. (2026). Emulated Effects of Glucagon-Like Peptide 1 Receptor Agonist Therapy in the General Population.. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2026.01.055