Weight-suppressant drugs have helped millions to lose weight. But once they're stopped, people tend to regain most of what they shed. What does this mean for their long-term health?
As director of the Washington Centre for Weight Management and Research, Domenica Rubino has become frustrated with growing perceptions over the last three years that weight loss drugs such as Novo Nordisk's Ozempic and Wegovy, and Eli Lilly's Mounjaro, are permanent cures for obesity.
"Obesity is not like an infection where you take antibiotics and you're done," says Rubino, sighing. "It's not any different than hypertension or diabetes or the many other chronic illnesses that we deal with, where you have to use chronic medication."
For over the past three years, the arrival of a new class of drugs known as GLP-1 agonists, so-called for their ability to mimic the action of the natural GLP-1 gut hormone that promotes satiety, has transformed the weight-loss field.
Initially, the US Food and Drug Administration approved Wegovy, the brand name for a GLP-1-based medicine called semaglutide, for chronic weight management in June 2021. The insatiable demand saw Mounjaro or tirzepatide arrive at the end of 2023 and now a newer, reportedly more effective drug called retatrutide is in the pipeline.
There is no question that GLP-1 drugs are effective at helping people lose weight. A landmark clinical trial of semaglutide, published in 2021, found that participants experienced an average of 15% weight loss over the course of 68 weeks while those on placebo lost 2%. Some of those taking the drug, however, shed as much as 20% of their starting weight. The purported health benefits now appear to be even more far-reaching, with the latest data from a trial called Select, published in 2023, showing that semaglutide can slash the risk of heart attacks and strokes by a fifth in patients with an existing history of cardiovascular disease.
But given their high prices – a month's supply of Wegovy costs $1,350 (£1,062) – and onerous side effects which can include nausea, stomach pain and heartburn, the question has always been, what happens when people stop taking them?
Various studies have attempted to examine this particular question, and all seem to point to the same answer – the pounds swiftly pile back on. In one trial, around 800 people received weekly semaglutide injections accompanied by dietary adjustments, a prescribed exercise regime and psychological counselling, all of which helped them to lose nearly 11% of their starting weight over four months. But when a third of the participants were subsequently switched to a placebo injection for another year, they regained 7% of the lost weight.
The same trend was seen after the 2021 trial, known as Step 1. After 68 weeks of semaglutide injections, the average patient lost more than 15% of their body weight, but within 12 months of treatment ending, patients regained two thirds of their prior weight loss on average. This was associated with a similar level of reversion to the patients' original baselines in some markers of their cardiometabolic health – a category which includes conditions such as diabetes and heart attacks.
Both Rubino and other experts around the world have seen similar patterns when administering GLP-1 drugs in their clinics. "There will be a small proportion of people, 10% maximum, that are able to maintain [all] the weight they've lost," says Alex Miras, a clinical professor of medicine at Ulster University.
The trajectory of weight regain is typically faster than the time it takes people to lose the weight in the first place, according to Miras. "People put most of it back on in the first three to six months," he says.
Miras and others are keen to emphasise that this could have been expected. For all chronic illnesses, from rheumatoid arthritis to asthma to high blood pressure, patients usually relapse as soon as their treatment stops. But understanding why this happens with semaglutide, tirzepatide and other GLP-1 drugs could be crucial to understanding their longer-term health consequences and how best to prescribe them in future.
The regain problem
The main theory for why the majority of patients regain weight so rapidly when they stop taking medication is because the regions of the brain relating to appetite are still dysregulated, priming the person to overconsume. GLP-1 drugs only mask this dysregulation, and when their effect is removed, their food cravings soon return.
"People don't always appreciate this," says Rubino. "I try to explain that these are chronic medications, but I think everybody secretly feels, 'Yeah, but you know what, I'm different, and once I hit my weight goal, I'll be ok.' But the reality is, the brain is quite powerful."
But this may not be the only explanation. Martin Whyte, an associate professor of metabolic medicine at the University of Surrey, explains one possible theory as to why people tend to regain weight after they stop these medications. The doses of GLP-1 provided by semaglutide and tirzepatide are far greater than the body would naturally expect to receive, he says, which may suppress the body's ability to secrete GLP-1 on its own. As a result, people's hunger may return even more voraciously when they cease their doses, he explains.
"What may be happening, and we don't know for sure, is that when you stop them, your body's left in a GLP-1 deficit which has a major impact on the satiety signal going to the brain," says Whyte.
The potential physiological consequences of this weight regain is currently one of the biggest health concerns for practitioners in the field. In one trial, those switched to placebo injections not only began to reaccumulate body fat, but their waist circumference
also began to revert back to its original size. Excess fat in this area is linked to numerous problems ranging from heart disease to insulin resistance and fatty liver disease.
Miras says that many people who regain weight after medication or dieting experience a change in their body composition which could potentially be even worse for their long-term health than if they had simply maintained their existing weight.
"Weight regain is usually accompanied by accumulation of fat and less muscle," says Miras. "So you end up going back to a higher fat mass and a lower muscle mass. That's not good from a metabolic perspective because having more muscle is good for reducing risk of diabetes and heart disease," he says.
However, there is not yet any direct evidence that someone's body composition would be worse after stopping weight-loss drugs than before they started.
Understanding obesity
But while these are the general trends, responses to GLP-1 drugs can vary considerably on an individual level. To begin with, not everyone benefits from the medications. The groundbreaking 2021 clinical trial of semaglutide still found that almost 14% of participants failed to even lose 5% of their body weight, even after taking the drug for more than one year.
While trials suggest the weight loss achieved while taking semaglutide can be maintained while still taking the drugs, we also know that some people start to regain some weight, even before they stop. Miras points to data from people taking an earlier GLP-1 formulation known as Saxenda or liraglutide. "At one year, weight loss is about 8%, but by three years, it's gone down to 6%," he says. "So that seems to happen, and we see it with bariatric [obesity-management] surgery too."
Rubino says that some people can regain weight after quitting semaglutide, but still retain some of the metabolic health benefits achieved while taking the drug, such as improved blood sugar control. Often that improved blood sugar control will persist for a while (up to three years according to one study), and there could be many reasons for that, says Rubino.
"That person may be able to be more active after losing the weight, perhaps they're sleeping better and having fewer sleep apnea events (which have been linked as a risk factor for type two diabetes). All of these factors can dynamically affect someone's metabolic complications," she says.
Some of this variation could also be because there are different subtypes of obesity. Until relatively recently, scientists viewed obesity as a single disease, but now experts around the world have begun to realise that it is far more complex.
And there may also be other lasting beneficial effects. One study of women with polycystic ovary syndrome (PCOS) and obesity treated them with semaglutide injections for 16 weeks, in addition to the diabetes drug Metformin. Over the course of treatment, the study participants lost weight, their cardiometabolic parameters improved and their free testosterone levels – which tend to be elevated in women with PCOS – decreased. Two years after they stopped taking semaglutide, their weight and free testosterone levels remained significantly lower. However, the participants' cardiometabolic markers had returned to the levels they were at when the study began.
However, the popularity of GLP-1 drugs has presented a unique opportunity. According to data released by Novo Nordisk earlier this year, 25,000 Americans are signing up for Wegovy each week. With such a large sample size, scientists may be able to learn more about the different types of obesity, through the prism of how people respond to the medicines – both while taking them, and after their treatment ends.
Novo Nordisk, the manufacturer of Ozempic and Wegovy, provided the following statement to the BBC.
"There is no evidence to indicate that patients will completely regain all the weight after stopping the medication. Novo Nordisk reported the results from the STEP 1 extension trial on the impact of treatment withdrawal, which found that one year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss. These findings also confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health."
A new European consortium known as Sophia (Stratification of Obese Phenotypes to Optimize Future Obesity Therapy), led by scientists at University College Dublin, is now attempting to investigate this in more detail. "We want to try and get different predictors – whether it's blood tests or psychological tests – which can help us understand how a patient is likely to fare with each of these drugs," says Miras. "At the moment, I give them a drug for three months and if they lose weight, it means I was lucky. We're completely shooting in the dark."
Miras predicts a future where such information will be used to identify the most suitable weight loss drug for a particular patient, the likelihood that they will become resistant to it over time, and different combinations of drugs which could be used to keep their weight under control.
One thing seems certain though, many people with obesity will ultimately have to remain on medication permanently to avoid relapses, says Whyte. According to Rubino, clinical trials are now being planned to assess whether higher doses of GLP-1 drugs can be used in the acute phase to help patients lose weight, followed by lower "maintenance" doses, which come with fewer side effects and can be prescribed on a long-term basis.
While concerns have been raised at the sheer cost of medicating obesity to the healthcare system – the National Health Service (NHS) in the UK currently only covers Wegovy for a two-year period – the coming wave of lower-cost generic alternatives could make this more viable.
Novo Nordisk's patent for Saxenda expires later this year, and rivals Teva, Pfizer and Mylan are all expected to launch generic versions of liraglutide later in 2024. Generic alternatives to Ozempic are expected to become available within the next decade.
"While liraglutide isn't nearly as efficacious as semaglutide, the costs will likely come down as patents expire," says Whyte. "So people might soon start thinking about that as a longer term option, and as the overall costs of GLP-1 drugs come down, they will become easier to prescribe as chronic medications," he says.
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