Why some people don’t lose weight with Wegovy

Clinical trials have shown that people using weight-loss jabs, such as Wegovy and Mounjaro, lose anywhere between 16% and 21% of their body weight. But the drugs don’t work for everyone.

In those trials, a group of participants lost less than 5% of their body weight (weight loss of 5% or more is considered to be “clinically meaningful”). These so-called non-responders made up 10% to 15% of participants. Anecdotal evidence, provided by obesity experts to Associated Press, suggests that outside the highly controlled confines of clinical trials, as many as 20% of people don’t respond well to the drugs. Why might this be?

First, it’s important to recognise that the causes of obesity are multifaceted. Our understanding of the genetic basis for obesity has grown significantly over the past decade, revealing that for many people, genetic variations have a significant effect on their weight. For example, a 2021 study found that 0.3% of the UK population (equivalent to over 200,000 people) carry a genetic mutation in part of the brain circuitry that regulates appetite, leading to an average 17kg of additional weight by age 18.

This genetic variability in the underlying causes of obesity could be one explanation for why some people show a blunted response to these drugs.

It is also important to recognise how these new anti-obesity drugs work. Anyone who has tried to lose weight through diet and exercise will know that these attempts are typically met with increasing feelings of hunger and tiredness.

This is the body’s normal response to weight loss. It aims to protect what the brain considers its “normal” body weight, which for some may be in the obese range. The new weight-loss medications work by switching this physiological response off, making it easier to lose weight through changes to diet and exercise.

In clinical trials, participants are provided with exercise support and access to dietitians and psychologists. These experts provide participants with individualised support on the lifestyle changes necessary to maximise the benefits of these drugs.

This support is seldom available to people outside of clinical trials, and their absence may limit the effectiveness of the drugs if the necessary lifestyle modifications are not supported by these experts.

Several studies have sought to identify what factors may predict weight loss responses to weight-loss jabs. One common factor for clinically meaningful weight loss is a higher starting body weight.

A lot of hype

Since their introduction, the media hype around the new weight-loss jabs has sent demand soaring among those for whom the drugs were developed (people with obesity), and those who aren’t obese but are looking to shed a few kilograms.

In the UK, the National Institute for Health and Care Excellence (Nice) sets guidelines on what clinical parameters are needed for a drug to be prescribed. For Wegovy and Mounjaro, the person must be obese and have at least one obesity-related health problem – such as sleep apnoea or high blood pressure.

Because of the lack of alternative effective weight-loss drugs, and probably because of the media coverage that these drugs have received, there have been reports of off-licence prescribing of these drugs for people who don’t meet Nice’s criteria.

One likely consequence of this is that people who have lower body weights than the guidelines stipulate are being prescribed these drugs for weight loss, and as such are losing less weight than clinical trials demonstrated.

Despite the minority of people for whom these drugs don’t work, their introduction promises to provide significant health benefits to millions of people who have previously struggled to lose weight.

Simon Cork does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.