Following discontinuation of weight management medications such as semaglutide, liraglutide, and tirzepatide, weight regain occurred rapidly in patients, at a rate projected to return them to their baseline weight within less than two years, according to a systematic review and meta-analysis published in The BMJ.
The analysis comes as glucagon-like peptide-1 (GLP-1) receptor agonist use expands rapidly in the UK and US, raising practical questions about whether these drugs should be viewed as short-term interventions or chronic therapies. In an accompanying opinion piece to the study, Sam West, Dimitrios A. Koutoukidis, and Susan A. Jebb wrote that obesity is a chronic, relapsing condition and so contemporary treatment strategies must reflect this reality.
In The BMJ systematic review, the researchers analyzed 37 weight loss studies, including 9,341 adults with overweight or obesity who had used weight management medications for at least eight weeks, and were followed for at least four weeks after stopping treatment.
Across all weight management medications (WMMs), participants lost an average of 8.3 kg during active treatment. However, shortly after WMM discontinuation, weight was regained at a mean rate of 0.4 kg per month, with modeling suggesting that baseline weight would be regained within 1.7 years. In randomized clinical trials, weight differences between medication and control groups disappeared after about 1.4 years.
The rebound was more pronounced for newer incretin mimetics. Among patients treated with semaglutide or tirzepatide, weight regain was estimated at 0.8 kg per month, with projected return to baseline weight by 1.5 years. The researchers noted that although these drugs produce greater initial weight loss, their benefits appear to diminish quickly once therapy is stopped, “implying that the benefits on cardiovascular health will probably also attenuate more rapidly.”
Cardiometabolic markers generally improved during treatment, but were projected to return to baseline within a similar timeframe. Improvements in HbA1c, fasting glucose, blood pressure, cholesterol, and triglycerides also diminished steadily after medication cessation.
The accompanying opinion piece emphasized that continued treatment may be the most straightforward solution to the issue, paralleling long-term management of other known cardiometabolic risk factors, like hypertension and dyslipidemia. The commentators noted that longer-term trials of semaglutide have demonstrated weight maintenance when treatment continues. However, they cautioned that continued treatment “is not a silver bullet” and real-world discontinuation rates appear high, with emerging evidence suggesting around half of patients stop GLP-1 receptor agonists within a year due to side effects, cost, or else dissatisfaction when their weight loss plateaus.
The systematic review also compared weight regain following medication cessation with regain following behavioral weight management programs, with modeling suggesting that weight would return to baseline nearly four years after behavioral programs compared with less than two years after medications.
The opinion piece also raised implications for cost-effectiveness of GLP-1 receptor agonists, particularly for publicly funded systems like the National Health Service (NHS). The commentators note that the National Institute for Health and Care Excellence (NICE) model assumes semaglutide to be cost-effective if weight is regained over three years. However, based on this updated study data indicating that weight returns to baseline within 1.5 years, semaglutide could exceed the standard NICE willingness-to-pay threshold.
Both the study authors and the commentators emphasize that there are no quick fixes for obesity. The systemic review researchers conclude that weight management medications may require long-term use to sustain benefit, while the commentators argue that these drugs should be deployed as part of a broader obesity treatment portfolio that includes adjunct behavioral support and equitable access.
The systematic review reported no conflicts of interest. In the opinion piece, the commentators reported support from the National Institute for Health and Care Research and disclosed involvement in publicly funded trials, including some in which weight loss interventions were donated by commercial entities. Full disclosures are available in The BMJ.
Source: The British Medical Journal