Semaglutide's heart benefit is not explained by weight loss alone, SELECT analysis suggests

Semaglutide, a GLP-1 receptor agonist used for diabetes and obesity, is known to lower the risk of serious cardiovascular events. A study published in the European Heart Journal on 23 September asked how much of that benefit comes from weight loss and improvements in other classic risk factors.

The data

The team, led by Professor Helen Colhoun of the University of Edinburgh, re-analysed SELECT — a randomised trial in which half of 17,604 people with overweight or obesity (and without diabetes) received semaglutide and half a placebo. Over two years the researchers tracked body weight, waist circumference, blood pressure and blood tests, including cholesterol and markers of diabetes, inflammation and kidney function, and related them to rates of heart attack, stroke and cardiovascular death.

The result

People on semaglutide lost weight, their waists shrank and their blood tests improved, and they had about 20% fewer major cardiovascular events. Yet whichever risk factors the researchers examined, separately or together, no more than half of that reduction could be explained by changes in them. Colhoun said the findings suggest semaglutide should be seen as a drug that reduces cardiovascular disease, “not just a weight loss drug”.

What else could be at work

The mechanism is not known. Suggested explanations include anti-inflammatory effects not fully captured by the measured markers, and direct effects on the heart muscle or the lining of blood vessels.

Limitations

The analysis depends on statistical estimates of risk, and data collection during the trial was affected by the COVID-19 pandemic. Some participants may also have lost weight for other reasons, such as frailty, which raises rather than lowers cardiovascular risk. An accompanying editorial by Professor Subodh Verma of the University of Toronto and colleagues called the conclusion “appropriately humble” and said the lack of a clear mechanism should not be a barrier to using these drugs to prevent vascular events.