Is semaglutide the long-awaited ‘wonder drug’ for weight loss?

Semaglutide – under the brand name Wegovy – was made available in 2023 as a weight loss drug in the UK. It has been deemed a ‘wonder drug’. But does it actually work? And are there downsides?

The evidence shows that semaglutide is certainly effective for losing weight. But there are – as you might expect – several downsides: Nearly half of the weight loss comes from muscle; there are various side effects, including nausea; and it has to be taken in perpetuity to keep the weight off.

The Institute for Health and Care Excellence (NICE) recommends semaglutide, for a maximum of two years, for obese patients with at least one obesity-related comorbidity who are within a specialist NHS weight management service. So, it’s available, but only to those for whom NICE believes it to be cost effective.

Back in March 2021, a study published in the New England Journal of Medicine (one of the top medical journals), showed how effective semaglutide is for weight loss. Nearly 2,000 overweight or obese patients were recruited for the 68-week trial. In addition to a receiving a ‘lifestyle intervention’ (diet and exercise advice) the patients received either semaglutide or a placebo.

In the semaglutide group, average weight loss was 15.3 kg (14.9% of body weight), compared to only 2.6 kg (2.4% of body weight) in the placebo group.

An impressive 86.4% of the semaglutide group achieved weight loss of at least 5% of body weight. And 32.0% achieved weight loss of at least 20% of body weight. This compared to 31.5% and 1.7% respectively in the placebo group.

So, as far as weight loss is concerned, semaglutide clearly works very well.

It works by suppressing appetite, and it does this by delaying gastric emptying and slowing intestinal motility, and by acting directly on one or more appetite regulating circuits in the brain. The result is reduced hunger, reduced food cravings, reduced calorie intake, and weight loss.

But is weight loss the right end point to focus on? Calorie restriction – if it can be maintained – will lead to weight loss (at least initially). But typically the lost weight includes both fat and muscle. Indeed, the weight loss in this semaglutide trial was around 60% fat and 40% muscle. That’s far from ideal from an overall health perspective. Excess fat is the problem, not muscle. And muscle mass and strength are required for metabolic health and physical function. So, a better end point would be fat loss plus muscle maintenance – in other words, improvement in body composition.

The best way to mitigate the muscle loss during semaglutide treatment (or any other weight loss intervention) would be to increase protein intake and do plenty of strength training, both of which enhance muscle protein synthesis.

In addition to the muscle loss, semaglutide can be difficult to tolerate for some people. The main adverse events in the trial were gastrointestinal disorders, including nausea, diarrhoea, vomiting, and constipation – which occurred in 74.2% of the semaglutide group and 47.9% in the placebo group.

Another problem is that semaglutide needs to be taken in perpetuity to keep the weight off. A year after the trial had ended, the researchers followed up with 327 of the patients. The semaglutide group had regained two-thirds of the weight lost during the trial.

Semaglutide is a GLP-1 agonist – an analogue of glucagon-like peptide 1, a hormone which is released by intestinal cells in response to food intake and is involved in the regulation of blood glucose and appetite. Semaglutide was originally developed as a type 2 diabetes drug, and is now also being repurposed as a weight loss drug. It’s certainly effective in both cases, but as always, there are downsides to consider.

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