A meta-analysis confirms weight regain after discontinuing anti-obesity drugs

This paper is a comprehensive analysis of the available data on weight regain after cessation of weight loss treatments (note that I am lead author for the STEP 1 extension trial with semaglutide and am also an author for some of the other trials that have addressed this question).  I note that quite a lot of the data concerns older medicines that are no longer available, however agree that the data seems to be valid across medication classes and for the newer medicines that are now most commonly used:

1.  The results are not surprising.  Obesity is a chronic disease that usually relapses when treatment is stopped.  We do not expect interventions for other chronic diseases (e.g. diabetes, high blood pressure or high cholesterol) to continue working when treatment is stopped and there is no scientific reason to expect obesity to be different.
2. We do know from studies in diabetes and from the SELECT trial of semaglutide in people without diabetes that people at high risk of cardiovascular disease are less likely to have an adverse cardiovascular event such as a heart attack or stroke if they take GLP1 based drugs long term (these studies are usually of 3-5 years duration).
3. Hence, we should consider these as long-term treatments, not as a quick fix.
4. I note weight regain tended to be slower after intensive lifestyle interventions.  I would be cautious about interpretation of this as the populations included in these trials are likely to be different from those included in trials of medication, and I would always advocate lifestyle support to be used alongside weight loss medications to optimise outcomes anyway.

This systematic review and meta-analysis brings together 37 studies with 9,341 participants and shows a consistent pattern: after stopping weight management medication, weight is regained and improvements in cardiometabolic risk markers tend to diminish over time.  The authors estimate an average weight regain of around 0.4 kg per month after treatment cessation, with weight projected to return to baseline at approximately 1.7 years.  In the included trials, weight regain following medication cessation was greater than that observed after behavioural weight management programmes, even when accounting for the amount of weight lost during treatment.  The authors also modelled changes in markers such as HbA1c, blood pressure and lipids, projecting a return towards baseline within around 1.4 years after stopping.

 The press release broadly reflects the study’s findings, but it is important to distinguish between observed data and modelled projections.  The analysis includes a mix of study designs, and many studies were not at low risk of bias.  For newer incretin-based medicines such as semaglutide and tirzepatide, the evidence base remains relatively small and follow-up after stopping treatment is limited to around 12 months.  As a result, longer-term statements, including full weight regain within two years, rely on extrapolation beyond the available data.  Comparisons with behavioural programmes are indirect and should therefore be interpreted as suggestive rather than definitive.

 In real-world terms, the findings reinforce that obesity management typically requires long-term planning.  If people stop medication, many are likely to need ongoing nutritional and behavioural support, and health services should anticipate that cardiometabolic benefits may lessen as weight is regained.  The study does not show that behavioural support reliably prevents regain after stopping medication, highlighting the need for further research into effective, scalable strategies for long-term weight maintenance alongside pharmacotherapy.

This is a timely and important paper that focuses not on weight loss but on the far greater issue of maintaining any lost weight.  Weight recidivism is a common issue seen across all weight loss interventions, and some weight regain in those coming off GLP-1 drugs would be arguably inevitable.  Yet, what this paper importantly suggests is that weight regain is amplified when you cease taking these drugs.  There are plausible explanations for why.  The first relates to how these drugs work.  Artificially providing GLP-1 levels several times higher than normal over a long period may cause you to produce less of your own natural GLP-1, and may also make you less sensitive to its effects.  No problem when taking the drugs, but as soon as you withdraw this GLP-1 “fix”, appetite is no longer kept in check, and overeating is far more likely.  Like any addict, going cold turkey is a real challenge.  This is further exacerbated if the individual in question has relied solely on GLP-1 to do the heavy lifting during weight loss, i.e. artificially suppressing their appetite without them establishing any dietary or behavioural changes that would help them in the long run.

These authors acknowledge that this review is limited by the length of time people have been followed up and by potential bias in these studies.  Nevertheless, the authors project, based on the observed studies, that all weight would be regained within 2 years.  Yet more worryingly, we know from other weight-loss studies that some people don’t just regain the lost weight but overshoot their original weight.  This is particularly concerning given that many people who pay privately for these drugs may not be that overweight to start with.

 So, the key message this paper supports is that weight-loss drugs (GLP-1 agonists) have arguably made weight loss very easy, but maintaining the weight loss is now a bigger challenge than ever.  Especially given the massive wave of people who will likely be coming off these drugs in the coming months and years.  This emphasises the even greater need for sound diet, behaviour, and lifestyle strategies at both the individual and public health levels.

This is an excellent analysis given the data limitations, but the findings are not unexpected and align with what we already know: weight-loss drugs work well when taken consistently, and weight regain typically occurs after stopping them.  It’s also unsurprising that weight loss with medication is somewhat faster than with lifestyle changes, as participants in lifestyle trials tend to be more motivated and have greater self-efficacy compared to those in drug trials.

Importantly, continued use of these medicines over 3–4 years enables people to maintain significantly lower weight than they would otherwise – a benefit not typically seen with lifestyle-induced weight loss, where many regain weight over time.

This paper cannot yet tell us whether short-term use offers lasting benefits for organs, but it’s plausible that being lighter for even 2–3 years due to short term use of the medicines could help slow damage to joints or hearts and kidneys.  Larger and longer outcome trials will be needed to answer that question.

Finally, while the editorialist argues that ‘healthy dietary and lifestyle practices should remain the foundation for obesity treatment,’ this overlooks the reality of our highly obesogenic environments.  In such settings, medicines are essential for many people living with very high BMIs to manage their weight effectively.