There are TikTok hashtags with millions of followers, endless column inches over celebrities’ waistlines and streams of media coverage when trial results come out. It is rare that a new medicine gets so much attention. Then again, it is even rarer that a licensed drug causes safe and rapid weight loss with minimal effort.
A year ago, most people hadn’t heard of semaglutide, a drug developed to treat type 2 diabetes around a decade ago under the brand name Ozempic. Then, in 2021, it was approved in the US as a weight-loss aid under the name Wegovy. The medicine can cause people to lose a whopping 15 per cent of their body weight.
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The impact of this new class of medicines could be unprecedented – potentially bringing to an end the world’s growing obesity epidemic. “I don’t think it’s fully sunk in yet,” says at Duke University in North Carolina, who investigates how these drugs affect the body.
For one thing, Wegovy was just the start. The next generation of these drugs is in development and will be cheaper, easier to use and, crucially, even more potent. What’s more, emerging evidence suggests Wegovy and its ilk work better when given at a younger age, so doctors are exploring their use in teenagers and young children. This raises the prospect of switching from obesity treatment to prevention. “We have watched the obesity landscape change dramatically over the last 40 years,” says Campbell. “Now, maybe we’re at a turning point where that goes backwards.”
Why obesity is on the rise
The rise in obesity has been happening since about the 1970s in the US, with other nations soon following suit. Today, more than two-thirds of adults in the US and the UK have obesity or are overweight. The same pattern is being seen in any low and middle-income countries where people are shifting to Western lifestyles, and the number of people who are overweight is rising nearly everywhere.
The precise reason for this trend is still debated, but most agree it is probably something to do with changes to diet. Our early ancestors had to spend a large part of their waking life scrabbling to get enough to eat, coping with swings from famine to feast by hanging on to every calorie they could. As a result, our bodies are designed to store fat for a rainy day. Today, for most of the world, those rainy days seldom come and instead we live with an abundance of high-fat, high-sugar, highly processed foods. “In the US, roughly two-thirds of the population has some intrinsic susceptibility to become [overweight] if they’re in an environment that predisposes to that,” says Michael Schwartz at the University of Washington in Seattle, who researches the causes of obesity. “And our environment does predispose to that, based on the type of foods that are available, the cost of the food and the amount of physical activity [people do].”
Doctors may not agree on the causes of obesity, but they do agree on its alarming consequences. Being overweight predisposes people to a multitude of other health problems, ranging from heart attacks to worn-out hips and knees, fatty livers and asthma. It also makes the body less sensitive to the hormone insulin, which regulates blood sugar, often leading to type 2 diabetes, where blood sugar gets too high.
Numerous initiatives have been trialled in order to slow the obesity juggernaut, with tactics including taxes on unhealthy food and drinks, changes to food labels, junk food advertising bans and teaching schoolchildren about healthy eating. Nothing has worked.
This shouldn’t be surprising, considering that weight control is so hard at an individual level. Most people who lose weight eventually regain it and often end up heavier than when they started. By some estimates, only a (see “Keeping it off”).
Until recently, there was little doctors could do to help unless someone was willing to have weight-loss surgery, such as a gastric bypass. This operation can be very effective, with people typically losing around 30 to 40 per cent of their weight within about two years. But it is a major procedure, with the associated risks, and to avoid malnutrition afterwards, people have to take several vitamin or mineral tablets daily for the rest of their lives. The operation is taken up by of those eligible in most countries.
A medicine that could do the same as surgery would be a different ball game. Semaglutide drugs, which are given through injections, exploit the fact that the body releases a slew of hormones in response to eating, including one called GLP-1. Its effects include triggering the release of insulin, which is helpful for treating diabetes, but also slowing food passage through the gut – which leads to feeling full – and acting on the brain to suppress appetite.
The drugs mimic this hormone, and when trialled as a treatment for blood sugar control in people with diabetes, they led to lower appetite and weight loss. Unsurprisingly, the pharmaceutical industry leapt to investigate their use explicitly for weight loss in people without diabetes. In fact, these medicines generally cause more weight loss when used in this group – perhaps because people with diabetes are less sensitive to insulin’s effects.
The first GLP-1 mimics were less appealing as they had to be injected once or twice daily. But Wegovy only needs to be administered once a week. The impressive happens within about a year, and then plateaus and is maintained at that level if people keep taking the drug. By comparison, most weight-loss interventions – such as diet and lifestyle counselling – would be considered successful if someone lost around 5 per cent of their body weight.
The injections are no magic wand and people still need to try to eat healthily and in moderation, says at the University of Glasgow, UK, who has prescribed them for many of his patients. But when people do so, their efforts are no longer sabotaged by constant hunger pangs. “They take away the drive to eat,” says Lean. “They are very, very effective.”
Wegovy doesn’t suit everyone. Nausea and diarrhoea are the most common side effects, but are usually transient and can be alleviated by starting with a smaller dose and raising it slowly, says Lean. There is variability in how people respond and, for unknown reasons, some people barely lose any weight, but they are in the minority – about 1 in 10 people, according to .
Another caveat is that if people stop the injections, slowly but surely the weight returns. According to one trial, . Essentially, that means taking Wegovy is a lifetime commitment.
What kind of impact would a 15 per cent weight loss have? If a person is very heavy, it won’t be enough to make them slim, but if someone begins treatment while hovering just on the threshold of obesity – with a body mass index (BMI) of 30 – it would lower their BMI to 25.5, within a hair’s breadth of the healthy weight category, defined as a BMI of 25.
Even more powerful weight-loss drugs
This means that to truly reverse the growing obesity trend, we need more. And that is where the new generation of drugs comes in. GLP-1 is just one of several hormones released after eating. Others include GIP and PYY, made by the gut, and glucagon and amylin, produced by the pancreas. At least some of these seem to have similar effects to GLP-1 in terms of quelling appetite and slowing digestion. Multiple drugs now in development target the natural receptors of two or three of these hormones in concert, with these medicines known as dual and triple agonists, respectively.
The closest to the clinic is one called tirzepatide (branded Mounjaro), which mimics both GLP-1 and GIP and is already used as a treatment for diabetes. When given to people without diabetes, it leads to , according to a large trial that was reported last year.
Then there is CagriSema, a mix of semaglutide and an amylin mimic. In one early-stage trial, it caused weight loss of 16 per cent after eight months – but this was carried out in people with diabetes, suggesting there would be .
Another contender is a triple agonist called retatrutide, which stimulates receptors for GLP-1, GIP and glucagon. Nicknamed “Triple G”, this has led to an average in people with obesity after 48 weeks, with the trend over time suggesting there would be further weight loss if the trial had continued for longer. Manufacturer Eli Lilly has predicted that the percentage weight loss will be in the high 20s and it has been touted as the most effective weight-loss drug to date. “When you combine these agonists, you start to get into additive effects,” says at the University of Minnesota in Minneapolis. “We might get near to 30 per cent.”
If the predictions are right and a drug becomes available that can result in weight loss of 30 per cent, the impact would be profound. That would lower someone with a BMI of 35, well into the obese category, down to 24.5, classed as being in the healthy weight category. “We start getting into the range of [weight-loss] surgery,” says Kelly. “It’s transformative.”
At the moment, price is the main barrier to these hormone mimics. Injections of Wegovy can cost several hundred dollars a month in the US, depending on insurance coverage. In other countries, the price can be lower thanks to partial state reimbursement of drug costs, but it can still be over ÂŁ100 a month to the user and most countries are saying that only the people who are heaviest should be eligible for such financial help. In almost every country, whether healthcare comes through private insurance or state-backed schemes, policy-makers are fearful of the potentially large sums involved in medically treating such a common condition.
The funding question is mired in long-standing societal judgements about fatness and the use of weight-loss drugs, in a way that doesn’t happen for people who need other lifelong medication, says at Leeds Beckett University in the UK, who runs an obesity clinic. “There’s an attitude of: it’s their own fault, they need to sort themselves out, they’re just lazy and greedy.”
However, in the longer term, the cost-benefit balance is likely to tilt more in favour of the drugs. The price of new medicines tends to fall over time, especially as competitors arrive and then, as patents expire, cheaper generic versions come to market.
Another game changer would be hormone mimics that could be taken orally, currently in trials. These would be easier to administer and could be cheaper than injectable versions. While a low-dose tablet form of semaglutide has been available since 2020, it was announced in May that a more potent, higher-dose version injections, although its price hasn’t yet been set.
Healthcare funders will look more favourably on these medicines if firms can produce evidence that they will save money overall by alleviating conditions such as heart disease and joint damage. One large study from 2016 found the in people with diabetes after two years of semaglutide injections and other trials looking at different health outcomes are ongoing.
So far, the focus has been on treating people who are already obese. But the success of Wegovy has prompted the question of whether we could prevent people from becoming so heavy in the first place.
Should we prescribe them to children?
Last year, a trial showed that Wegovy is at least as effective in teenagers as in adults, and perhaps more so. Weight loss in drug trials in teens is judged slightly differently than in adults, because their weight should nudge up over time as they grow taller. One measure is the difference between the percentage of body weight lost in the treatment group and those who got the placebo jabs. In what was in 12 to 18-year-olds, this figure was 17 per cent, while in a similar trial in adults the equivalent figure was 12 per cent.
There is good reason to consider earlier treatment, says Kelly. It seems to be harder for people to lose weight than it is for them to avoid gaining it in the first place. It may therefore be better for teenagers who are overweight to begin taking weight-loss drugs earlier in life than to wait until they are obese as adults. “If you allow the pounds to go on, it’s harder to draw back,” says Kelly. In other words, avoiding severe obesity is better than trying to reverse it.
Why stop at 12-year olds? Pharmaceutical firm Novo Nordisk is about to start a further trial in children with obesity as young as 6. “Obesity does start very early,” says at Paracelsus Medical University in Salzburg, Austria, who is involved in this trial. “There’s data showing that 80 per cent of those living with obesity during adolescence had already been living with obesity when they were preschoolers. It tracks from childhood to adolescence to adulthood.”
In May, Novo Nordisk opened a research department specifically focused on obesity prevention rather than treatment. The firm declined to answer questions from żěè¶ĚĘÓƵ about whether this involves GLP-1 mimics or other drugs, but has stated that the aim is to interrupt biological processes that promote weight gain before people get to the point of being obese.
What might such processes be? There is growing evidence that people with obesity have long-term changes to appetite-regulation networks in the brain that mean it takes more food to make them feel satisfied. After a meal, for example, they have involving the signalling chemical dopamine. In theory, this could have been the cause of obesity rather than the consequence, but the fact that this difference at least partly disappears two years after people lost a lot of weight with gastric bypass suggests it is more likely to be a consequence, says at Amsterdam University Medical Centers in the Netherlands, who was involved in this research. And it could help explain why it is so hard for most people to lose weight and keep it off.
If obesity does change the brain, offering people medication before they get very heavy could let them maintain a healthier weight on a lower dose. “You might want to prevent people from gaining more weight and getting in more trouble,” says Serlie. She stresses, however, that the science isn’t yet settled on how permanent the brain changes are, nor do we know how well the hormone mimics work in the long term: “Are they going to be effective after five years? Ten years? We don’t know.”
There could be other downsides to the widespread use of weight-loss drugs from an early age, says Gately – for example, it could disincentivise young people from adopting healthy habits around diet and exercise.
Despite such concerns, if the cost does fall, it is possible that wide use of these medications will change the curve of the obesity epidemic. There are already signs that policy-makers are waking up to their potential impact, even in England’s cost-conscious National Health Service (NHS). The initial decision on Wegovy in England was to restrict its NHS use to people attending hospital weight-loss clinics. But, in June, a large pilot scheme was announced to broaden access by letting family doctors prescribe it. A UK government statement said this would lead to “wider economic benefits”.
Arguments against
But there is already pushback. Anorexia charities have flagged that the . And campaigners say that governments should be getting tougher on the food industry to tackle the root causes of obesity, rather than using prescription medicines as a quick fix. “As a doctor, I would always try and avoid drugs if I possibly could,” says at Newcastle University, UK, who has led research if they manage to lose enough weight through dieting.
However, Campbell sees the benefits of being more proactive. He makes the analogy with modern dentistry aiming to keep people’s teeth in good shape through preventive measures such as regular descaling and putting fluoride in the water. “I don’t know if obesity will become the same, where you can treat it in a prophylactic way, rather than a reactive way,” he says. “But it is exciting to envision a world where there is effective management of obesity, simply because these drugs are so efficacious. At the moment, we are just starting to scratch the surface.”
You should always consult your doctor before taking or changing medications.
New obesity drugs – what’s the evidence?
Explore the topic with physiologist Simon Cork on 15 July
Keeping it off
Most people who lose weight by going on a diet eventually put it all back on. "It's a biologically defended level and if you try to change it by restricting calories, it tends to be resistant to change," says at the University of Washington in Seattle.
One reason is that dieting causes people's metabolism to slow, and this can . Researchers have also measured differences in the levels of hunger hormones including leptin and ghrelin.
The brain changes too, notably the hypothalamus, which is important in controlling appetite. Animal research shows that brain cells in that area called AgRP neurons – which normally drive appetite when blood sugar gets low – .
Drugs like Wegovy dampen activity in these neurons, which helps explain why people avoid the normal hunger response to weight loss if they are taking these medicines, says Schwartz. "But if you stop taking the drug, all of a sudden, the brain is saying: wait a minute, my weight is way below where it's supposed to be."
Clare Wilson is a senior medical reporter for żěè¶ĚĘÓƵ
