Anti-obesity medication semaglutide may help to prevent heart attacks and other major cardiac events regardless of how much weight people lose while taking the drug, according to a new study led by a UCL researcher.
The finding, the researchers say, suggests there are multiple ways the drug benefits the heart, rather than its protective effect on cardiovascular health being due solely to weight loss.
The study, published in the Lancet journal and funded by Novo Nordisk, looked at data from 17,604 people aged 45 and over who were overweight and had cardiovascular disease, who were randomly assigned either weekly injections of semaglutide or placebo.
Previous analysis* of this data by the same international team found that semaglutide reduced heart attacks, strokes and other major cardiac events by 20% in this group.
In the new study, the team found that this reduction in major adverse events was similar regardless of participants' weight at the start of the trial. That is, people only marginally classed as overweight, with a body mass index (BMI) of 27 (the average BMI for adults in the UK), saw similar benefits as those with obesity who had the highest BMIs.
The benefits were also largely independent of how much weight people lost in the first four and a half months of taking the drug. However, the researchers found a link between shrinking waistlines (the reduction in waist circumference) and heart benefits, with this accounting for a third of the drug's protective effect on the heart after two years.
Lead author Professor John Deanfield (UCL Institute of Cardiovascular Science) said: "Abdominal fat is more dangerous for our cardiovascular health than overall weight and therefore it is not surprising to see a link between reduction in waist size and cardiovascular benefit. However, this still leaves two thirds of the heart benefits of semaglutide unexplained.
"These findings reframe what we think this medication is doing. It is labelled as a weight loss jab but its benefits for the heart are not directly related to the amount of weight lost. In fact it is a drug that directly affects heart disease and other diseases of ageing.
"This work has implications for how semaglutide is used in clinical practice. You don't have to lose a lot of weight and you don't need a high BMI to gain cardiovascular benefit. If your aim is to reduce cardiovascular disease, restricting its use to a limited time only and for those with the highest BMIs doesn't make sense.
"At the same time, the benefits need to be weighed against potential side effects. Investigations of side effects become especially important given the broad range of people this medicine and others like it could help."
While the findings focus on semaglutide, they are likely to apply to other 'weight loss' drugs that target the same hormone (glucagon-like peptide-1, or GLP-1).
The mechanisms by which GLP-1s may help cardiovascular health, the researchers said, include supporting the health of the lining of blood vessels, reduced inflammation, improved blood pressure control and lower lipid levels (levels of cholesterols and other fats in the bloodstream).
The study looked at data from the landmark SELECT trial – the largest and longest clinical trial of the effects of semaglutide on weight in over 17,000 adults who did not have diabetes but who were overweight or had obesity. The international team that runs the trial includes Professor Deanfield.
Semaglutide, a GLP-1 receptor agonist, simulates the functions of the body's natural incretin hormones, which help to lower blood sugar levels after a meal. It was initially prescribed for adults with type 2 diabetes.
Semaglutide is the active ingredient in Wegovy and Ozempic. Last year, thanks to evidence from the SELECT trial, the UK medicines regulator approved Wegovy as a treatment for those with cardiovascular disease, meaning it can be prescribed privately.
On the NHS, Wegovy is prescribed for weight loss at specialist weight management clinics. Another GLP-1 agonist, Mounjaro, is prescribed by GPs in England for those with a BMI of 40 or over (or 37.5 if from a minority ethnic background) and four out of five conditions (type 2 diabetes, high blood pressure, heart and vascular disease, high cholesterol and obstructive sleep apnoea).
In their section on limitations, the authors of the new study noted that a majority of study participants were male and a high proportion were white. In future, they said, GLP-1 receptor agonist trials should examine responses by ethnicity and sex.
The preliminary analysis of SELECT data which formed the basis of this study was presented by Professor Deanfield and co-authors at the European Congress on Obesity (ECO) last year.
* https://www.nejm.org/doi/full/10.1056/NEJMoa2307563
