Obesity rates have been increasing in the US for decades, but in 2023 they fell – at least in part because of the burgeoning popularity of the “miracle drug” semaglutide. Approved for treating obesity only in 2021, it is in short supply and is very expensive, but it has already had an extraordinary impact (“How semaglutide and similar drugs work”, below).
Yet this could just be start. With many companies racing to market rival versions of semaglutide in cheaper and easier-to-take forms, as well as mounting evidence that that GLP-1 drugs can target a host of health conditions, the treatments could have an impact that goes way beyond reversing the worldwide trend of rising obesity and possibly even putting a dent in alcohol sales. So what lies ahead for these drugs – and what are the stumbling blocks?
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This article is part of a special series investigating the GLP-1 agonist boom. Read more here.
A growing number of studies show that semaglutide seems to have many beneficial effects in addition to weight loss. For instance, in a -year trial involving nearly 18,000 people, 6.5 per cent of those on semaglutide had a heart attack or stroke compared with 8 per cent of those receiving a placebo.
The treatment may even reduce many kinds of craving, not just those for food (see What do GLP-1 drugs really tell us about the brain’s reward system?). “There are anecdotal reports of people reducing their alcohol intake substantially on semaglutide,” says at the University of Edinburgh, UK. “I think that this is one of the exciting potential future directions.” While these effects need to be confirmed by large trials, one big investor recently sold off shares in drinks companies amid concern that as more people take GLP-1 drugs.
Given the broad health benefits, it could be that some people would be better off taking these drugs for the rest of their lives (see “Ozempic endgame”). But there is still much to be discovered about the mechanisms through which GLP-1 medications work, such as the extent to which their impact is due to the health benefits of reducing obesity. A recent study in pigs, for instance, confirmed that some of the drugs’ heart benefits don’t depend on weight loss. This makes sense given that GLP-1 receptors are found throughout the body, including in the heart. However, it is a confusing picture, especially with regard to the medications’ effects on the brain, and one that we are only just beginning to untangle.
It also isn’t clear whether people who aren’t overweight could benefit, as few trials have included this demographic. “We would need new trials to prove that GLP-1 medicines reduce heart disease in people without type 2 diabetes or obesity,” says at the Lunenfeld-Tanenbaum Research Institute in Toronto.
There is no evidence that GLP-1 drugs can cause weight loss to an unhealthy extent, but they usually aren’t prescribed for people who aren’t overweight. While the approval of semaglutide for treating type 2 diabetes didn’t specify that people have to be overweight to get a prescription – unlike those being treated for heart disease – in practice, this is the case, says at Imperial College London. “I’m not aware of any reputable clinician who would initiate Ozempic in someone with diabetes with a BMI of less than 25,” she says.
If weight loss does turn out to be undesirable or excessive in some cases, it may be possible to develop GLP-1 drugs that don’t cause it. In fact, a GLP-1 treatment called albiglutide was found to with only minor weight loss in trials, says Tan. However, this drug is no longer manufactured as it wasn’t profitable.
Pharmaceutical companies
For now, the cost of GLP-1 drugs and the need to inject them remain a major practical barrier to their wider use, she says. But as patents start to expire in some countries and the competition among pharmaceutical companies heats up, prices should come down. are now in development, according to healthcare data firm Ozmosi, including the “triple G” drug retatrutide, which binds to the receptor for glucagon – triggering the release of fat stores – as well as to receptors for the satiety hormones GLP-1 and GIP. Retatrutide appears to be for weight loss.
Because semaglutide, tirzepatide and retatrutide are all proteins and thus larger than most drugs, they cannot normally enter the body via the digestive tract, hence the need for injections. Manufacturing proteins is more difficult than making small-molecule drugs, and the need to package them in an injectable form has also contributed to shortages.
There is a drug called Rybelsus that consists of semaglutide plus a substance called salcaprozate, which enables some semaglutide to get through the gut, but it has to be taken half an hour before eating or drinking. Rybelsus is only approved for treating diabetes so far.
But a number of pharmaceutical firms are developing small-molecule GLP-1 drugs that can be taken like standard pills and whose manufacture should be easier to scale up. “These have the potential to be much cheaper,” says at the University of Liverpool in the UK. A small-molecule drug called and could be approved next year. There are also protein-based drugs in development that would require only monthly injections.
Side effects
Other obstacles to the wider use of GLP-1 drugs will be harder to get around. Nearly half of people taking GLP-1 drugs have gastrointestinal side effects, including nausea, diarrhoea, vomiting and constipation. These usually diminish within days, but can persist for much longer in a few people. More than 1 in 20 users .
The nausea is thought to be caused by GLP-1 drugs directly affecting a part of the brain called the area postrema in the medulla oblongata, says at the University of Aberdeen, UK, who is trying to find ways to prevent this side effect. But it could also, for example, be a result of the drug causing the stomach to empty more slowly – like much about GLP-1 drugs, we just don’t know yet.
Other unwanted side effects can include bone loss and muscle atrophy, To address this, some companies are combining GLP-1 drugs with ones , with some promising results.
The upshot of all these developments is that semaglutide and related drugs hold the promise of improving the health of billions of people. But this doesn’t mean we can forget about the issues that have led to obesity becoming so common in the first place, such as the heavy advertising of calorie-dense foods with poor nutritional value, says Colhoun. “We need to redouble efforts at population and societal levels to reduce the social determinants of obesity,” she says. “It is vital that anti-obesity medicines are not seen as a panacea.”
How they work
Drugs such as semaglutide (sold as Wegovy for weight loss and Ozempic for diabetes), liraglutide (sold as Saxenda and Victoza) and exenatide (sold as Byetta) mimic the actions of glucagon-like peptide-1 (GLP-1). This hormone promotes the feeling of fullness, or satiety, after eating and stimulates insulin production, lowering blood sugar levels.
Overall, this means that these drugs – technically known as GLP-1 receptor agonists – reduce hunger levels, leading to reduced energy intake from food and significant weight loss for most people when used long term. Recently, a drug called tirzepatide (sold as Mounjaro and Zepbound) has also come on the market, which mimics GLP-1 plus another satiety hormone, GIP.
Ozempic endgame
Unfortunately, "Ozempic rebound" is real. Most people regain much of the weight they have lost when they stop taking GLP-1 drugs and their full appetite returns. For instance, a 2022 trial with nearly 2000 people found that a year after they stopped taking semaglutide, the participants had .
"We know that, for all medicines tested so far for obesity, weight regain is very common when treatment is stopped," says John Wilding at the University of Liverpool, UK. However, with continued use of GLP-1 drugs, weight loss is maintained. In the , people took either semaglutide or a placebo for four years. Those on the drug lost weight for the first nine months, on average, and after that their weight remained stable while they kept taking it.
Given the drugs' other benefits, many people may be better off staying on GLP-1 medications indefinitely, says Wilding. "If you want long-term benefits, then long-term treatment is necessary." Statins are used in this way, based on trials that also ran for four or five years. But regaining weight after stopping GLP-1 drugs isn't inevitable if people change their lifestyles, says Helen Colhoun at the University of Edinburgh, UK. "Unfortunately, many people are using this class of drugs to reduce their weight without any clear dietary plan or advice."
