GLP-1 receptor agonist weight-loss drugs such as semaglutide may protect the cardiovascular system independent of weight loss. Digest
Doctors have long wondered whether the heart benefits of the GLP-1 receptor agonist semaglutide (Ozempic®/Wegovy®) come only from helping people lose weight, or if the drug directly protects the cardiovascular system. An analysis of the SELECT trial explored this question in adults with cardiovascular disease and overweight or obesity, but without diabetes.
The study followed 17,604 participants aged 45 years or older across 41 countries for an average of more than three years. Each person was randomly assigned to once-weekly semaglutide (target dose 2.4 mg) or to placebo. Researchers recorded heart attacks, strokes, and cardiovascular deaths (collectively known as major adverse cardiovascular events, or MACE) and repeatedly measured body weight and waist circumference.
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Here is what they found:
- Semaglutide lowered the risk of MACE by about 20% versus placebo.
- Early weight loss at 20 weeks did not predict lower subsequent MACE among those taking semaglutide; people who lost at least 5% of their body weight had similar event rates to those who lost less.
- In contrast, reductions in waist circumference at 20 weeks were associated with fewer subsequent events in the semaglutide group, possibly highlighting the importance of visceral fat loss (fat surrounding abdominal organs) rather than overall weight loss, which can also include lean mass such as muscle.
- Statistical modeling estimated that about one‑third of the treatment effect on MACE was mediated or marked by waist‑circumference reduction, while the remaining two-thirds came from other factors.
The researchers suggest that semaglutide's heart protection likely extends beyond weight or fat loss. By activating the glucagon-like peptide-1 receptor, the drug may directly influence blood vessel function, atherosclerotic processes, inflammation, blood pressure, and lipid metabolism. The authors note that adipose tissue can begin to change biologically before its overall mass declines, which might also help explain the early cardiovascular benefits seen in the trial.
The results show that patients with cardiovascular disease may benefit from semaglutide regardless of how much weight they lose, challenging prescribing rules that rely on body mass index thresholds or weight-loss targets. Future studies are needed to identify which biological processes drive these improvements and to determine whether similar benefits apply to broader populations. In Aliquot #128, I discuss how the new weight loss drugs like Ozempic® and Mounjaro® work, their pros and cons, and lifestyle strategies to optimize their effects for long-term health.