The gap no trial has filled
For years, GLP-1 receptor agonists—such as semaglutide and liraglutide—have been prescribed for weight loss and, more recently, to reduce cardiovascular risks in patients with existing heart disease. The SELECT study demonstrated their effectiveness in secondary prevention, showing fewer heart attacks and strokes among those with established conditions. However, the question of primary prevention—whether these drugs could prevent the first cardiovascular event in high-risk but otherwise healthy individuals—has not been tested in clinical trials. This leaves a notable uncertainty in medical guidance.
Researchers from the German Center for Cardiovascular Research (DZHK) addressed this uncertainty by using modeling techniques. Instead of conducting a large-scale, long-term clinical trial, the team analyzed data from over 610,000 individuals without known heart disease, focusing on modifiable risk factors such as obesity, high blood pressure, and elevated blood sugar. Using this data, they developed a model to predict how these factors contribute to heart attacks, strokes, and deaths, then simulated the potential effects of GLP-1 therapy.
What the model shows—and what it doesn’t
The simulation focused on individuals with a body mass index (BMI) of 27 or higher and an elevated SCORE2 risk score but no history of heart disease. In this group, the estimated 10-year risk of a cardiovascular event was 13.82%. When accounting for the modeled effects of a GLP-1 drug—including reductions in weight, blood pressure, blood sugar, and inflammation—this risk decreased to 10.83%. This represents an absolute risk reduction of nearly 3 percentage points, or a relative reduction of 22%.
These findings are not clinical evidence but projections based on observed changes from prior studies, applied to population data. The researchers described the work as an estimate of what might occur if these drugs were used in a setting where they are not currently prescribed. The model does not capture all variables, such as variations in patient response or broader health system considerations. While the results suggest potential benefits, they remain theoretical rather than proven.
The distinction between modeling and clinical trials is important. In a clinical trial, researchers measure actual outcomes in real patients over time. Here, the DZHK team used data to simulate those outcomes, providing insights where direct evidence is lacking. Such approaches have been used in public health decision-making, though they require careful interpretation. The results indicate possible benefits but do not replace the need for further study.
The stakes for patients and doctors
The model’s projections suggest that if these benefits were confirmed in real-world settings, the impact on cardiovascular disease prevention could be meaningful. Cardiovascular disease remains a leading cause of death worldwide, and primary prevention has traditionally relied on lifestyle changes and medications like statins. GLP-1 drugs, already approved for weight loss and secondary prevention, could expand into this area—but only if clinical trials support the model’s predictions.
The DZHK study does not alter existing guidelines. However, it raises questions about whether these medications could be considered for high-risk patients before a first heart attack or stroke. The answer depends on future research, including controlled trials that measure actual outcomes rather than projections. Until then, the findings represent a hypothesis with enough potential to justify further investigation.
For patients, the study does not provide definitive answers. It does not prove that GLP-1 drugs prevent first-time heart events, nor does it outline specific recommendations for use. Instead, it highlights an important unknown in cardiovascular care: Could these medications, which have already transformed obesity and diabetes treatment, also help prevent heart disease before it develops?
What to watch
The next step is clear: clinical trials are needed to validate the model’s projections. Researchers will need to design studies that enroll high-risk, heart-healthy individuals and track outcomes over time. The results could influence guidelines, prescribing practices, and the role of weight-loss drugs in public health strategies.
In the meantime, the study underscores the boundaries of current evidence. The SELECT trial demonstrated that GLP-1 drugs reduce risks for those with existing heart disease. The DZHK model suggests they might offer similar benefits for those at risk but still healthy. The difference between these two scenarios—a gap between potential and proof—will shape the future of this research.
