Does weight come back after stopping GLP-1 weight loss drugs?

Meta-analysis: Patients who stop taking obesity drugs gain weight back but maintain some of their weight loss after one year.

A meta-analysis found that patients who stop taking anti-obesity drugs rapidly regain weight, but, importantly, they retain some of their initial weight loss a year after stopping treatment. This highlights the challenges and potential of long-term obesity treatment.

In a recent review study published in the journal BMC Medicine, researchers systematically analyzed randomized controlled trials (RCTs) to assess the impact of stopping anti-obesity medications (AOMs) on long-term weight change.

The study found that significant weight gain began eight weeks after stopping the drugs and continued through week 20, particularly in people who had previously taken glucagon-like peptide-1 (GLP-1) receptor agonists or who had achieved the greatest weight loss during treatment or who continued to follow the lifestyle intervention. However, in several subanalyses, such differences (e.g. between people with greater or lesser initial weight loss) did not reach statistical significance by week 12.

Concerns about stopping medication

More than 2.2 billion adults worldwide were obese in 2020, and the number could reach 3.3 billion by 2035. The condition is associated with serious health risks, including cancer, cardiovascular disease, and type 2 diabetes.

Treatment typically involves lifestyle changes, medications, and bariatric surgery. Among these approaches, anti-obesity drugs have been shown to be highly effective in promoting weight loss and improving related health outcomes.

However, it is concerning that after stopping drugs such as semaglutide and orlistat, patients often regain weight and metabolic parameters such as blood sugar and blood pressure worsen. Lipid profiles and insulin levels have also been reported to return after weight gain.

However, most studies have previously focused on surgical or behavioral approaches to obesity treatment, leaving a gap in understanding the consequences of discontinuing pharmacological treatment.

About the study

The aim of this meta-analysis is to fill this gap by systematically assessing the long-term effects of AOMs withdrawal, particularly the trajectory of weight changes in the following weeks and months.

The analysis included data from 11 randomized controlled trials involving 2,466 participants (1,573 in the treatment group and 893 in the control group) that recorded weight data both during and after treatment.

The review included a variety of drugs: six studies of GLP-1 agonists, one study of a dual GLP-1/GIP agonist, one study of orlistat, two studies of the phentermine-topiramate combination, and one of naltrexone-bupropion.

Eight studies used placebo and three used active drugs as controls. All studies were assessed as having a low risk of bias.

Pattern of weight gain after drug withdrawal

Weight gain began approximately eight weeks after drug cessation and continued until week 20, after which it leveled off. No significant differences were observed after four weeks, but beginning at week eight, patients previously treated with AOMs gained more weight than controls.

Average weight gain values:

• 1.5 kg at 8 weeks,
• 1.76 kg on the 12th,
• 2.5 kg on the 20th,
• 2.3 kg on the 26th,
• 2.47 kg at 52 weeks.

However, after 52 weeks, patients taking the drugs maintained a net weight loss from baseline, indicating long-term benefit even after the drugs were stopped.

Weight gain was observed across the different baseline weight subgroups, but there was no statistically significant difference. Interestingly, significant weight gain as measured by body mass index (BMI) was only observed in participants with a BMI below 35, which was unexpected.

BMI increased similarly to weight starting at week 10. The increase in BMI was 0.70 and 0.82 kg/m² at weeks 26 and 52, respectively.

Meta-regression analysis showed that baseline BMI, general health status, gender, and age had no significant effect on weight gain. There was also no effect of control type, treatment duration, follow-up time, or rate of weight loss on subsequent weight gain.

Other factors

Significant weight gain was reported in both placebo-controlled and active-controlled studies, with no significant difference between the two.

Both patients with isolated obesity and patients with obesity and type 2 diabetes showed comparable weight gain after discontinuation of therapy.

Participants taking GLP-1 therapy showed significant weight gain, while no statistically significant gain was observed in studies with other drugs. However, the difference between the GLP-1 and non-GLP-1 groups was not statistically significant.

Interestingly, even in studies where behavioral interventions (physical activity, diet) were continued after drug withdrawal, participants still gained an average of 1.83 kg. In contrast, no such gain was observed in studies without continued behavioral support, but this is based on a limited number of data and should be viewed with caution. The authors point out that these data contradict previous findings on the benefits of continuing behavioral strategies.

Participants who lost more weight during treatment were also more likely to regain weight after stopping treatment. However, after 12 weeks, there was little difference between those with more and less initial weight loss. Rapid and slow weight losers also gained weight about the same.

Some studies have reported side effects, but there was not enough data to establish a link between them and subsequent weight gain.

Conclusions

A meta-analysis found that stopping anti-obesity drugs often results in significant weight gain, beginning at about eight weeks and stabilizing by six months. This pattern is similar to relapse after bariatric surgery or behavioral therapy.

Weight gain occurred across groups, regardless of baseline weight, BMI, and health status, and was greater in those who lost more weight. However, many differences between subgroups were not statistically significant, and the number of studies was limited.

GLP-1 treatments showed the most pronounced rebound, likely due to the cessation of the drug's metabolic and appetite-suppressing effects. Psychological and hormonal factors may influence behavior and physiology, but these are not well understood. Behavioral interventions did not prevent weight gain, which is inconsistent with previous data—possible reasons for this may be the small number of studies and differences in methodologies.

The main limitations are the small number of studies, heterogeneity of design, and insufficient focus on post-treatment outcomes. Also, most of the data only concerned weight and BMI. Longer-term studies are needed to better understand the mechanism of weight gain and improve obesity treatment strategies.