Quitting GLP-1 drugs triggers rapid regain, but 25% of weight loss may last

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A year after stopping taking weight-loss drugs such as Ozempic and Wegovy, people regain—on average—60% of their lost weight. But beyond this, their regained weight plateaus, with individuals managing to keep off 25% of the weight lost to treatment, say researchers at the University of Cambridge. The work appears in eClinicalMedicine.

It isn’t clear, however, whether the weight regain constitutes both fat and muscle, or mainly fat. Previous studies have suggested that lean body mass—including muscle—can constitute up to 40% of total weight lost during treatment.

More than a billion people worldwide are living with obesity, which increases the risk of diseases such as 2 diabetes, cardiovascular disease and cancer. Weight loss can help mitigate these complications, but losing weight through diet and exercise alone can prove challenging.

Powerful new drugs reshape treatment

In the past few years, a new generation of weight-loss drugs has emerged that target a protein known as the glucagon-like peptide 1 receptor (GLP-1R). These drugs help control blood sugar and reduce appetite, and clinical trials have shown they can lead to weight loss of 15 to 20%.

Approximately half of all patients who begin taking these drugs discontinue their use within the first year, however, and three-quarters have stopped after two years. This is likely to be due to their potential side effects and to limited access under insurance coverage policies and national prescribing guidelines.

Team tracks what happens next

A team of students at Trinity College, University of Cambridge, has investigated the impact of stopping the medication, modeling the trajectory of weight regain over 12 months and beyond. Their findings are published today in eClinicalMedicine.

The team first carried out a systematic review of existing scientific and medical literature, identifying and summarizing all the relevant evidence. They followed this with a meta-analysis, which pools the results of multiple studies to estimate an overall effect. This approach allowed them to draw more robust conclusions from studies which, on their own, may provide insufficient evidence and sometimes disagree with each other.

In total, the team examined 48 relevant studies, comprising 36 randomized controlled trials (RCTs) and 12 non-randomized studies.

As most of these studies only followed patients for a few weeks after stopping the drugs, the team selected the six RCTs (comprising more than 3,200 individuals in total) that followed patients for up to 52 weeks after discontinuation of the weight loss drugs. They used these to model the trajectory of weight regain, including to extrapolate beyond 52 weeks.

Trajectory of projected weight regain following cessation of GLP-1RA weight loss drugs. Credit: Steven Luo, University of Cambridge

Model suggests partial weight loss persists

The model estimated that when individuals stopped taking the medication, they underwent rapid initial weight regain, which slowed progressively. By 52 weeks, individuals had regained 60% of their original weight loss.

At 60 weeks, weight regain begins to plateau and is projected to taper off at 75% of the original weight loss. This means that 25% of the initial weight loss may be sustained in the long term. For an individual who had lost a fifth of their weight while on the drugs, this would correspond to a sustained weight reduction of around 5%.

Weight regain trajectories appeared broadly similar for the different types of weight loss drugs targeting GLP-1R.

Doctors urge lifestyle support on stopping

Brajan Budini, a medical student at the School of Clinical Medicine and Trinity College, University of Cambridge, said, “Drugs such as Ozempic and Wegovy act like brakes on our appetite, making us feel full sooner, which means we eat less and therefore lose weight. When people stop taking them, they are essentially taking their foot off the brake, and this can lead to rapid weight regain.”

The researchers say there are several reasons why people may not return to their original weight even a year after stopping the medications. One reason is that by reducing appetite, these drugs may help individuals develop healthier eating habits, such as reduced portion sizes or more nutritionally-balanced meals, and these habits may persist even after treatment is discontinued. The drugs may also affect the body long-term, altering hormone levels and “resetting” the brain’s appetite control mechanisms.

Steven Luo, also a medical student at the School of Clinical Medicine and Trinity College, said, “When stopping weight loss drugs, doctors and patients should be aware of the potential for weight regain and consider ways to mitigate this risk.

“It’s important that people are given advice on improving their diet and exercise, rather than relying solely on the drugs, as this may help them maintain good habits when they stop taking them.”

Open questions on muscle and limitations

There are significant concerns about the long-term consequences of GLP-1R drugs on body composition, with studies indicating that 40 to 60% of the weight lost during treatment is muscle. It was not clear whether individuals regain both fat and muscle.

Budini added, “Our projections show that even though people regain most of the weight they have lost, they still maintain some of the weight loss, but what we currently don’t know is if the same proportion of lean mass is recovered. If the regained weight is disproportionately fat, individuals may ultimately be worse off than before in their fat-to-lean mass ratio, which may have adverse consequences for their health.”

The researchers say there are several limitations to their study. Most importantly, the trial data used to fit their model only extended to 52 weeks after cessation. They also restricted their analysis to studies reporting at least 3 kg of on-treatment average weight loss.