Semaglutide May Cut Cardiovascular Risk Before Weight Loss

Medscape

14-05-2025

MÁLAGA, Spain — Semaglutide (Wegovy) is associated with a 41% reduction in the risk for major adverse cardiovascular events (MACEs) within 6 months of initiation — well before patients achieve substantial weight loss or reach the full 2.4 mg weekly dose — according to new data from the SELECT trial.
'The cumulative incidence of MACEs during the first 6 months showed a hazard ratio of 0.59,' said Donna Ryan, MD, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana.
Ryan, a member of the SELECT steering committee, presented the data alongside Jorge Plutzky, MD, director of Preventive Cardiology at Brigham and Women's Hospital and professor of medicine at Harvard Medical School, Boston. The findings were presented at the European Congress on Obesity (ECO) 2025.
Early Benefits
The early cardiovascular (CV) benefit emerged before participants reached the target dose of semaglutide or experienced meaningful weight reduction.
The hazard ratio (HR) of MACEs for patients receiving semaglutide was 0.63 (95% CI, 0.41-0.95) during the first 3 months.
'The HRs for MACEs were below 1 before the weight loss started and before participants reached the top dose,' Ryan said. 'Almost immediately, the risk is less on semaglutide than on placebo.'
The first statistically significant reduction in MACEs occurred by day 20 after randomization, with sustained significance evident by day 86.
In the first 6 months, 67 MACEs occurred in the semaglutide arm vs 113 in the placebo arm (HR, 0.59; 95% CI, 0.44-0.80). The researchers observed a 53% reduction in CV deaths (14 deaths with semaglutide vs 30 deaths with placebo) and a 43% reduction in nonfatal myocardial infarction. The reduction in nonfatal stroke was not statistically significant (HR, 0.87; 95% CI, 0.47-1.58).
Design and Execution
These new findings add to results from the main SELECT trial, which previously was reported by Medscape Medical News . That trial found a 20% reduction in MACEs over nearly 40 months in patients with overweight or obesity and established CV disease (CVD; HR, 0.80; 95% CI, 0.72-0.90; P < .001).
'The design and precision of execution give us confidence in the results,' Ryan said.
SELECT enrolled 17,604 participants aged 45 years or older with overweight or obesity (body mass index ≥ 27) and established CVD, which was defined as prior myocardial infarction, stroke, or symptomatic peripheral artery disease. Eligible participants did not have type 2 diabetes, although two-thirds of participants had prediabetes. Participants were randomly assigned to once-weekly subcutaneous semaglutide or placebo (titrated to 2.4 mg by week 16) alongside standard-of-care treatments including statins, antihypertensives, and antiplatelet therapy.
'This was not a weight loss study,' Ryan emphasized. 'We thought that the drug itself might have properties beneficial to cardiovascular outcomes apart from weight loss.'
CV Benefits First
In the first 12 months, semaglutide was associated with a 9% reduction in body weight. However, this degree of weight loss was not yet apparent when the early CV benefit emerged.
At week 4, change in body weight was −1.1% for patients on semaglutide compared with placebos (95% CI, −1.2 to −1.1). By week 12, the difference was −3.6% (95% CI, −3.7 to −3.5).
To explore whether weight loss explained the early benefit, investigators compared daily hazard ratios for MACEs with average weight change over time. The dissociation between the curves suggested that the early CV benefit may occur independently of weight loss.
Potential Mechanisms
Asked to comment by Medscape Medical News , Jason Halford, PhD, head of the School of Psychology at the University of Leeds, Leeds, England, and past president of the European Association for the Study of Obesity, London, England, said that the results were surprising.
'This [study] suggests that [the benefits are] not mediated by weight loss and that there must be some other mechanism underpinning it,' Halford said. 'Possibly a reduction in inflammation, because obesity is an inflammatory disease, and it's a component of many other diseases.'
These findings may inform early treatment decisions in patients with obesity and CVD, even before significant weight loss has been achieved. Halford suggested that the findings could have implications for CV medicine. 'Of course, they are managing CVD with other therapies, and it would be interesting to compare not one antiobesity drug with another but to see how this impacts existing treatments for CVD. It might be preferable to use one drug to treat two things, for example.'
Halford also noted that as new antiobesity drugs and combinations of mechanisms emerge, comparisons should extend beyond weight loss to include CV outcomes. 'These early data shift the narrative. We knew the long-term benefits, but the short-term effect is unexpected.'