A recently published clinical trial of the anti-obesity drug, semaglutide, has produced a degree of weight loss which has led some to dub the medication a “game changer” in the treatment of obesity.
The trial looked at 1,961 adults who were overweight or obese. Approximately 75% of participants were female. Participants were given a weekly injection of semaglutide, a drug normally used to control blood sugar in the treatment of diabetes. Participants were also advised on how to manage their weight through dieting and exercise.
After 68 weeks of treatment, participants lost an average of 15.3kg (around 15% of their body weight) with semaglutide compared to just 2.6kg in those who received the placebo injection, alongside diet and exercise advice. This is the largest effect ever observed with an anti-obesity medication. The weekly dose was administered via subcutaneous injection – which is unusual, as most anti-obesity drugs are given as a tablet taken by mouth.
But while the degree of weight loss is certainly promising, there’s still much researchers don’t know about semaglutide – including whether the drug was effective on its own, or whether it was the combination of the drug, how it was administered, and whether it would produce the same magnitude of weight loss without the lifestyle changes.
Semaglutide is a molecule that works by controlling appetite. This has been shown in numerous studies, including research conducted in 2017 by the University of Leeds which found that, in people with obesity, a once-weekly injection of semaglutide (the same dose as used in this recent study) was able to reduce daily calorie intake by 24% and reduce some meal sizes by more than 30%. Despite consuming less food, people experienced no increase in hunger and reported feeling fuller. This study also showed that semaglutide decreased cravings for (and consumption of) high-fat foods, and made people feel more control over their appetite.
Semaglutide controls appetite by acting on the brain’s GLP1 receptors. GLP1 is a hormone which influences appetite and is released from cells in the gastrointestinal tract where it stimulates the release of insulin and slows emptying of the stomach. Research shows that GLP1 receptors are located widely throughout the brain, including in regions involved in aspects of appetite such as hunger and enjoyment of food.
Interestingly, recent research in rodents has shown semaglutide acts on brain areas responsible for both satiety and pleasure. However, the actions of semaglutide on brain processes are complex and remain to be fully worked out.
Although semaglutide appears to be effective in controlling appetite over a long period, there are three factors which might have influenced how effective it was: the semaglutide molecule itself, the route of administration (injection) and having participants change their diet and exercise habits.
There’s no doubt that the semaglutide molecule is potent in and of itself. But delivering it by injection could have affected how effective it was. The authors believe the weekly injection may make it easier for patients to stick to treatment than if they had to take it as a tablet, because they saw it as a “medical” procedure. It may also make patients more likely to conform with the dietary and exercise advice as well because an injection is perceived as a more serious medical intervention than taking a pill. This could remind people of the seriousness of obesity and motivate them to stick to dietary and exercise advice.
It’s uncertain whether semaglutide would be as effective for weight loss if it was given orally as a daily tablet, as opposed to an injection. In a 12-week study on people with diabetes, research showed a daily oral dose of semaglutide is clearly effective in controlling appetite – resulting in a loss of body fat. This indicates that oral dosing could be effective for weight loss but should be tested in a long-term trial in people with obesity.**
Patients in the trial were also instructed to diet and exercise to ensure they burned at least 500 calories more than they consumed. This lifestyle modification was enforced through monthly individual counselling sessions. The authors of the study state the drug should be delivered alongside a lifestyle modification programme – so it’s uncertain if the drug would have been as effective without making lifestyle changes.
This isn’t to say the study’s results aren’t promising. Semaglutide controls appetite by inhibiting the drive to eat and increasing feelings of fullness. All of this may be particularly effective at reducing body weight, especially in a society which promotes unhealthy lifestyles and overeating – and where unhealthy high-calorie foods are everywhere.
This suppression of appetite is also long-lasting. In the clinical trial, body weight continued to decline for more than a year – body weight was at its lowest around week 60. Semaglutide’s continued action on the brain’s GLP1 receptors effectively inhibited the drive to eat at a level far beyond what’s been seen in the past. Of course, if a person stops taking the drug, appetite will return to normal. And if no lifestyle changes are made, this could result in weight regain.
It’s also worth pointing out that although participants lost around 15% of their body weight on average and one-third lost 20% of their bodyweight, half lost less than 15%. This means that semaglutide can’t guarantee a specific amount of weight loss, which will vary from person to person. Another limitation of the study was that 75% of the participants were female. Future research will need to investigate if gender affects semaglutide’s efficacy.
Nevertheless, when semaglutide is approved for use in the UK, it could very well be a promising new treatment for managing obesity – when combined with healthy lifestyle changes.
John Blundell has in the past received research funding from Roche, Servier, Sanofi, Lilly, Merck,Nestle, Danone Glaxo, Abbott and Novo Nordisk. JB has served on Obesity Advisory Committees or been a consultant for Servier, Sanofi, Merck, Nestle. Danone, Abbott, and Novo Nordisk. JB is currently a scientific governor of the British Nutrition Foundation and a member of the Scientific Advisory Board of Zoe Global.