Discontinuation of anti-obesity drugs linked to higher weight regain than lifestyle programs

A research review cautions that consumers who stop weight loss medication quickly regain the lost pounds, at a rate of 0.4 kg per month. The authors note that weight and risk markers for diabetes and heart disease are predicted to return to pre-treatment levels in under two years after discontinuing the drugs.

Importantly, the authors project that people regain their weight four times faster after stopping weight loss drugs than after cessation of behavioral weight management programs. 

“This evidence cautions against short-term use of weight management medications, emphasizes the need for further research into cost-effective strategies for long-term weight control, and reinforces the importance of primary prevention,” note the researchers.

However, experts not involved in the review comment that the findings are not “unexpected.” They say that it is well-known that medications like GLP-1 receptor agonists work well when taken consistently, but often result in weight regain after consumers stop using them.

As such, they underscore the need for clinical and behavioral support — in addition to medications — to sustain weight loss. Moreover, they emphasize that obesity is a chronic disease and thus requires long-term treatment.

The research team from the University of Oxford, UK, reviewed 37 studies that included a total of 9,341 participants, covering weight loss medications, non-drug interventions, and placebos. On average, weight loss treatments lasted 39 weeks with an average follow-up of 32 weeks.

Weight regain after medications

The paper, published in The BMJ, projects that participants treated with weight loss drugs return to their pre-treatment weight 1.7 years after stopping treatment, while projecting cardiometabolic risk markers return to pre-treatment levels within 1.4 years.

Independent of initial weight loss, the authors note that on average, individuals who stopped medications experienced higher monthly weight regains than people who participated in weight management programs.

Experts note that medications like GLP-1s work well when taken consistently, but often result in weight regain after consumers stop using them.An expert not involved in the study, Dr. Adam Collins, associate professor of Nutrition at the University of Surrey, UK, notes that some weight regain in people coming off GLP-1 drugs “would be arguably inevitable.” However, he says that the paper’s projections, which suggest that weight regain is amplified when people cease taking these drugs, is an important distinction. Collins offers several explanations.

“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.”

Collins adds that this is further exacerbated when users artificially suppress their appetite without establishing any dietary or behavioral changes that would help them in the long run.

Meanwhile, John Wilding, professor of Medicine in the Department of Cardiovascular and Metabolic Medicine at the University of Liverpool, UK, counters: “I would be cautious about the interpretation of this, as the populations included in these trials are likely to be different from those included in trials of medication.”

Wilding was the lead author of a 2022 paper that found one year after the withdrawal of semaglutide medication, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables.

Side effects

The external experts note that cessation of GLP-1 and other weight loss drugs is common for several reasons, such as access or costs, a lack of effects early in the treatment, or side effects.

According to external researchers, clinical and behavioral support in addition to weight loss drugs are crucial to sustain weight loss.In earlier research, ADM identified side effects such as digestive discomfort, dehydration, or feeling weak. Along with other companies in the nutrition industry, the supplier highlighted the opportunity to develop complementary products that support users in reducing such side effects or maintaining weight loss after stopping the medication.

Jason Halford, professor of Biological Psychology and Health Behaviours at the University of Leeds, UK, notes that GLP-1 drugs also take a while to titrate up to the full dose due to these side effects and that discontinuation is expected.

“Discontinuation will see appetite rebound — increased hunger, reduced satiety, greater cravings, and decreased ability to resist those. Longer use with support in behavioral change would likely produce better post-dosing outcomes; however, coming off medication requires both clinical and behavioral support to sustain this.”

“This is why these drugs need to be used as an adjunct to other evidence-based components of obesity management programs.”

Lifestyle and nutrition support

Tricia Tan, professor of Metabolic Medicine, Diabetes, and Endocrinology, at Imperial College London, UK, says the review highlights the importance of starting weight loss drugs properly. Tan was not involved in the review.

Research increasingly indicates that structured exercise is key to preventing weight regain after ceasing medications.She notes that obesity and associated metabolic conditions are chronic relapsing conditions and require continuous and long-term treatment. “Just like when we start blood pressure drugs: patients are aware that this is lifelong, although doses can be adjusted over time depending on the concurrent patient status.”

Tan points to increasing evidence that structured exercise is key to preventing weight regain after ceasing medications. However, she argues that the study does not discuss this as a strategy to reduce the problem, which she notes is at odds with the conclusion that weight gain after non-drug interventions is slower than after stopping weight loss medications.

“Obesity management, as a whole, must be managed as a national long-term strategy for the benefit of the nation,” she argues. “This should integrate not only GLP-1 drugs but the associated lifestyle therapies and the option of weight loss surgery (which remains our best long-term weight loss treatment).”

Meanwhile, experts at the University of California, Davis, US, previously told Nutrition Insight that emerging science and drug product developments are poised to transform the GLP-1 landscape in the US. 

They noted that new products are underway that can be used for indications beyond weight loss and diabetes, combine hormones with fewer side effects, and are available in more convenient delivery formats. For example, Novo Nordisk just launched its Wegovy GLP-1 medication in pill format for the first time.