A major BMJ review finds that the benefits of popular weight loss medications fade fast after treatment ends, raising questions about short-term use and long-term obesity care strategies.
Study: Weight regain after cessation of medication for weight management: systematic review and meta-analysis. Image credit: Corona Borealis Studio/Shutterstock.com
In a recent systematic review published in BMJ, researchers conducted an extensive meta-analysis to investigate and quantify the trajectory of weight regain following the cessation of weight management medications (WMMs). The review collated and analysed data from more than 9,000 participants across 37 studies (63 intervention arms).
Weight loss benefits fade rapidly after drug cessation
Review findings revealed that while modern drugs like semaglutide and tirzepatide drive significant weight loss, discontinuation leads to a rapid "rebound" effect. On average, patients were projected to return to their starting weight within approximately 1.7 years, with cardiometabolic markers (blood pressure and blood sugar) projected to return to pre-intervention levels within about 1.4 years, with some markers reverting even sooner. However, the authors emphasise that individual trajectories varied substantially between participants.
Crucially, the study found that weight rebounds significantly faster after stopping medication (pharmacological interventions) than it does after stopping behavioral diet and exercise programs in an indirect comparison between evidence bases.
From lifestyle programmes to powerful incretin-based therapies
The scientific community increasingly recognises obesity, the unwanted and suboptimal accumulation of fat (body mass index (BMI ≥ 30 kgm-2)), as a chronic, relapsing condition rather than a simple failure of willpower. Decades of research have established behavioral weight management programs (BWMPs) as the cornerstone of weight management. These programs focus on diet restriction and increased physical activity.
More recent evidence suggests that while safe, BWMPs often yield modest results that are difficult to sustain over time. The relatively novel discovery and introduction of glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (Wegovy, Ozempic), and dual agonists like tirzepatide (Zepbound, Mounjaro), have significantly shifted today's landscape of WMMs. These incretin mimetics have demonstrated the ability to help patients lose 15% to 20% of their body weight, and clinical trials have shown associated improvements in cardiometabolic risk factors.
Unfortunately, a growing body of evidence highlights adherence as a significant challenge to achieving and maintaining sustainable weight loss. Real-world data suggest that approximately 50% of patients discontinue these medications within 12 months, often due to high costs, supply shortages, or gastrointestinal side effects.
Previously, the precise rate of physiological rebound following intervention discontinuation was not fully quantified, leaving patients and doctors uncertain about the long-term prognosis of short-term drug use.
Large meta-analysis quantifies post-treatment weight regain
The present review aims to address this uncertainty and inform future weight loss policy by leveraging a meta-analytical approach to elucidate the trajectory of weight regain following the cessation of WMMs.
The study aggregated data from 37 published scientific studies, comprising 63 intervention arms and a total of 9,341 adult participants with overweight or obesity. The included studies were predominantly randomized controlled trials, with some non-randomised and observational cohorts, in which participants were followed for at least 4 weeks after discontinuing their medication.
The study data included a broad range of pharmacological interventions, including older drugs like orlistat and sibutramine, as well as the newer, more potent incretin mimetics (semaglutide and tirzepatide). Mixed-effects and time-to-event statistical models were utilized to analyze participant data and project individual trajectories for body weight and specific biomarkers over time.
Notably, the review compared the present meta-analysis results (pharmaceutical) with data from a previous review of behavioral weight management programs, using a harmonised and indirect comparison, thereby allowing for the evaluation of whether the specific weight loss intervention method influences the speed of regain.
Weight returns quickly, especially after newer incretin drugs
Review findings revealed that across all medication types, the average rate of weight regain was 0.4 kg per month. However, when specifically examining the newer, highly effective incretin mimetics (semaglutide and tirzepatide), the regain was observed to be twice as fast, averaging 0.8 kg per month.
Statistical projection models predicted that patients stopping any weight management medication would return to their baseline body weight within 1.7 years. However, these outcomes were exacerbated for those stopping the newer, more potent drugs; the return to baseline was projected to occur even sooner (approximately 1.5 years). These estimates extend beyond the observed follow-up duration in many studies, particularly for newer incretin mimetics, and should therefore be interpreted with caution.
The most concerning review outcomes were those of cardiometabolic health. The analysis of established cardiac and metabolic biomarkers (systolic blood pressure, HbA1c (average blood sugar), and cholesterol) revealed that, while these markers improved significantly during treatment, they deteriorated rapidly upon cessation. Specifically, the analysis predicted that all beneficial changes in blood pressure, glucose, and lipids would disappear within approximately 1.4 years of stopping the medication, with some markers returning to baseline within around one year.
Finally, comparisons between the present review outcomes (pharmacological) and previous behavioral weight management program data revealed that weight regain was significantly faster after stopping medication than after stopping behavioral interventions (by approximately 0.3 kg per month), regardless of the initial weight loss.
A need for long-term obesity management
The present review establishes, for the first time, that weight management medications are unlikely to produce sustained weight loss without continued use or alternative long-term management strategies. The findings suggest that the physiological mechanisms suppressed by these drugs, such as appetite and gastric motility, may resume once treatment is discontinued, potentially leading to faster regain than that seen after dietary restriction alone, though responses differ between individuals.
Consequently, the review emphasizes that without a long-term plan or a transition to alternative management strategies, the health benefits of short-term WMM use are fleeting and likely to be reversed upon discontinuation.
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