Four key questions on the new wave of anti-obesity drugs
It’s rare to find a product so successful that its makers stop advertising it. But that’s what happened to the weight-loss drug Wegovy in May. In the United States, where prescription drugs can be advertised, developer Novo Nordisk pulled its television adverts because it couldn’t keep up with demand.
The injectable medication, called semaglutide, works by imitating a hormone that curbs appetite and was approved as an obesity treatment by the US Food and Drug Administration (FDA) in 2021. In a study, participants who took semaglutide for over a year lost more than twice as much body weight on average — almost 16% — as did people taking an older weight-loss drug that mimics the same hormone1.
Semaglutide’s approval for treatment of weight loss came four years after the drug was approved for type 2 diabetes under the trade name Ozempic, also made by Novo Nordisk, based in Bagsværd, Denmark. Demand for Ozempic has skyrocketed as physicians prescribe it for weight loss outside its approved use.
Now, even more-potent medications for obesity are on the way. The drug tirzepatide, which is FDA-approved for type 2 diabetes under the name Mounjaro and made by Eli Lilly in Indianapolis, Indiana, imitates two hunger-related hormones. And the company’s drug retatrutide, which mimics three hormones, showed promising results for weight loss in its mid-stage clinical trial, announced at a conference in June.
Neither of these newcomers has been approved for obesity. But treating the condition is more urgent than ever. Obesity rates have tripled in the past 50 years, and carrying significant extra weight often brings a heightened risk of other health complications, including type 2 diabetes, heart disease and some cancers. It can also impede quality of life in other ways, such as limiting a person’s range of movement or resulting in feelings of shame because of weight stigma.
With this wave of drugs comes a fresh set of questions for researchers. “We are currently in such a dynamic phase of these transformative developments,” says physician-scientist Matthias Tschöp, chief executive of Helmholtz Munich, a research centre in Germany. “We’re still overwhelmed with curiosity.”
How do the drugs work?
These drugs seem to reduce people’s appetites, but exactly how they do so is still being worked out. Semaglutide, the first of this wave to be approved, mimics a hormone called glucagon-like peptide 1, or GLP-1. The hormone is produced in the gut in response to food and instructs the pancreas to make insulin. GLP-1 hormone mimics were first developed to treat type 2 diabetes, in which the body makes too little insulin and blood sugar levels become raised.
But researchers running those clinical trials noticed a surprising side effect: participants’ appetites diminished. Although the initial GLP-1 mimics were designed to work in the gut, the hormone’s receptors also exist in brain regions associated with appetite regulation and reward. Activating the body’s receptors using GLP-1 copycats — which remain intact in the body longer than the natural hormone does — induces feelings of fullness, slows the emptying of the stomach and reduces the feelings of reward associated with eating. That might help to explain anecdotal reports of lowered cravings for alcohol, smoking and gambling while taking semaglutide. Scientists have been investigating GLP-1 mimics as potential addiction treatments for at least a decade, and a handful of clinical trials are now under way.
For more than ten years, researchers have also been developing drugs that mimic both GLP-1 and another hormone, glucose-dependent insulinotropic polypeptide (GIP), to see whether activating both receptors leads to more weight loss. One such drug is Eli Lilly’s Mounjaro, which, in a late-stage clinical trial investigating it as an obesity treatment, led to a 21% average loss in body weight in people who took the highest dose for almost 1.5 years2.
Scientists had long thought that the GIP receptor should be shut off to induce weight loss, but “it’s emerging now that GIP may be just as important, if not more important, than GLP,” Tschöp says. A short-term study presented at the American Diabetes Association meeting in San Diego, California, in June found that solely activating GIP receptors decreases weight in humans (see go.nature.com/3rnbgsp).
Drugs that activate the brain’s GIP receptors seem to have another upside for obesity treatment. Beyond their action on weight, they seem to suppress some gastrointestinal effects of GLP-1 mimics, including nausea and vomiting3.
Still, some drugs in development do the opposite, and inhibit the GIP receptor. One candidate, developed by biopharmaceutical company Amgen in Thousand Oaks, California, turns off GIP receptors while turning on GLP-1 receptors. The highest dose in an early-stage clinical trial led to a loss of about 15% of body weight after three months (see go.nature.com/44tj4mw).
Tschöp says that because the Amgen drug contains an antibody — a larger molecule than the other hormone mimics — it probably isn’t reaching the brain. Instead, it might just stay in the gut, where inactivation of GIP receptors leads to modest weight loss.
Although the drug’s ability to penetrate the brain has not been studied formally, it can access a region that is unshielded by the blood–brain barrier and deals with food intake, says Elissa Snook, a media spokesperson at Amgen. Furthermore, Snook notes, signals transmitted through the peripheral nervous system probably help to curb appetite, so direct access to the brain might not be necessary.
Scientists are also exploring yet another gut hormone: glucagon. In contrast to agents that act on GLP-1 and GIP receptors, activating the glucagon receptor raises blood sugar by signalling the liver to produce glucose. Because of this, researchers, again, had thought that these receptors should be inactivated to promote health. That conclusion overshadowed glucagon’s energy- and fat-burning potential, says biologist Timo Müller, acting director of the Institute for Diabetes and Obesity at Helmholtz Munich.
As well as producing glucose, activating the liver’s glucagon receptors kicks off a process that breaks down fat in the organ. It also boosts energy expenditure, possibly by stimulating the sympathetic nervous system, which drives the fight-or-flight response.
But “everything that activates the sympathetic nervous system is also prone to increase heart rate and blood pressure,” says Müller, who collaborates with Novo Nordisk. That effect was reflected in the retatrutide trial, in which many participants experienced an increased heart rate that peaked around the six-month mark then declined over time4. This hints that drugs such as retatrutide — ‘triple agonists’ that turn on receptors for glucagon, GIP and GLP-1 — should be reserved for people in good health, Müller says.
In that mid-stage clinical trial, participants lost, on average, 24% of their body weight when taking the highest dose for almost a year4.
Imitating each hormone individually can lead to weight loss, Tschöp says. But together, they work synergistically to keep each other in check. GIP activation suppresses GLP-1 activation’s side effects, and both of these hormone copycats stimulate insulin, preventing glucagon from raising blood glucose too high.
Now, several companies are developing single drugs that imitate more than one hormone. At least ten compounds are being tested in clinical trials and could soon hit the market.
Who will lose weight?
Although the drugs offer impressive weight-loss benefits in clinical trials, they’re not effective for everyone. “There is a small population of patients that lose very little body weight when you give them GLP-1,” Müller says. “Why this is the case is not entirely clear.”
Obesity has a plethora of contributing factors, many of which could affect someone’s response to treatment. Genetics usually plays a part, leading some people to prefer certain foods, causing an imbalance of satiety signals or manifesting in other ways. But lack of sleep, chronic stress, poor nutrition and a sedentary lifestyle also contribute to metabolism rate and weight.
Environmental factors paired with a genetic predisposition to weight gain create “a perfect storm”, says Susan Yanovski, co-director of the Office of Obesity Research at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.
Now, researchers are beginning to work out who might lose weight with the aid of hormone mimics. One study categorized people with obesity on the basis of factors such as metabolic speed and how much they need to eat before feeling full. Researchers found that, in participants with obesity who felt hungry soon after eating, an older GLP-1 mimic called liraglutide led to twice as much weight loss after a year than it did in people with obesity from a general population5.
Another approach could involve genetics. Two studies6,7 in people with type 2 diabetes found that some gene mutations affecting GLP-1 receptor activation alter how much people’s insulin and blood-glucose levels shifted in response to the drugs. However, those mutations don’t seem to be linked to weight change while taking GLP-1 mimics.
“There still may be multiple rare variants that underlie lack of response to the weight-reduction effects of these drugs,” says Ewan Pearson, a clinical researcher at the University of Dundee, UK, who authored one of the studies. He is working with Eli Lilly to identify clinical predictors of who will respond well to tirzepatide, the drug mimicking both GLP-1 and GIP. Other companies are likely to be conducting similar studies on their own obesity drugs, he adds.
But even without looking at genetics, Pearson says, there might be simple yet robust ways to forecast how well someone will respond.
People with type 2 diabetes, for instance, tend to lose less weight than do people without the disease when taking GLP-1 mimics. Although a few hypotheses exist as to why, the reason still eludes researchers. “If I could figure that out, I’d probably have some really nice prize,” says Jamy Ard, a clinical researcher at Wake Forest University School of Medicine in Winston-Salem, North Carolina. Ard consults for and receives research funding from several companies that have obesity-related drug programmes.
Someone’s sex and starting weight could affect their response, too. In the retatrutide trial, female participants lost, on average, a higher proportion of their body weight than did male participants at all tested drug doses4. And animal studies8 show that the greater a mouse’s starting weight, the greater the amount of weight loss with triple-acting drugs such as retatrutide, Müller says. “The triple agonist is more something for the extreme population.”
Are there long-term risks?
The short-term side effects of this drug class are clear: nausea, vomiting, diarrhoea and other digestion-related issues. The problems cause some people to stop taking the medications. One study found that GLP-1 mimics raise the risk of intestinal blockages requiring hospitalization9. A small number of people given the drugs have reported thoughts of suicide.
The drugs could lead to the loss of more than just fat. In a subset of trial participants taking semaglutide and whose body composition was assessed, lean body mass — including muscle and bone — accounted for almost 40% of the weight they lost10. Still, they ended up with a healthier proportion of lean to total body mass, and losing weight typically involves losing lean body mass, whatever the method.
For those who begin treatment involving hormone mimics — and can weather any short-term side effects — these drugs are likely to become a lifelong commitment to keep weight off. “Bodies like to gain weight; they don’t like to lose it,” says Arya Sharma, an obesity specialist formerly at the University of Alberta in Edmonton, Canada, now based in Berlin, who consults part-time for some companies that have an interest in obesity. When someone starts losing weight, he says, the body responds by slowing the metabolism and increasing food cravings. But “that system does not care about whether you have diabetes or sleep apnoea or fatty liver disease”, Sharma says.
Anti-obesity medications help to reduce this response, tweaking a user’s biology so that they feel satisfied on fewer calories. But for most people, removing this external aid will simply result in regained weight. So researchers think that most patients who start taking the drugs will stay on some form of them for life.
Such long-term use could bring about negative effects. Risks “may be rare, so you only see them when [the drugs] start being used by millions of people”, Yanovski says. “Or they may require a long time, like several years, to actually become evident.”
But many researchers are fairly certain the drugs will be safe in the long term. The first drug to activate the GLP-1 receptor, exenatide, was approved for treatment of type 2 diabetes by the FDA in 2005.
“We’ve had a long history now, I would say from a medical standpoint, of seeing chronic therapy with these medications,” Ard says. Clinicians and researchers will continue monitoring patients, but he is confident that there have been no signs of increased risk for adverse events. Other researchers who spoke to Nature agree.
To minimize possible negative effects, Tschöp envisions that people might first lose weight with one drug that activates multiple receptor types, then switch to a milder one.
Yet one group might give some researchers and clinicians greater cause for concern: teens. Some weight-loss medications, including Wegovy, are approved for use in adolescents. Those years are a crucial time for growth and development. There’s a good argument for reducing weight early in life, because children and adolescents with obesity tend to remain in that weight class throughout adulthood. But clinicians must ensure the drugs aren’t stopping young people from consuming all the nutrients and protein they need for normal growth, says Katherine Morrison, a paediatric endocrinologist at McMaster University in Hamilton, Canada, who is on the advisory board for Novo Nordisk and Rhythm Pharmaceuticals in Boston, Massachusetts, which works on treatments for rare genetic forms of obesity.
Although less research exists on how the drugs affect adolescents, Morrison says that for most teens with obesity, the benefits might trump the risks. “If we can actually improve their quality of life and improve their physical health, that’s also the upside,” she says. “We can’t forget that in our worry.”
Are these medications changing how we think about obesity?
The latest wave of drugs has researchers and clinicians abuzz with excitement. “I’m just delighted for patients,” Tschöp says. “There’s light at the end of the tunnel now.”
And scientists hope that insight into the biological basis and chronic nature of obesity will persuade insurers to pay for the drugs.
Müller says these medications demonstrate that obesity is not due to “a lack of willpower”. Exercising more and eating less usually aren’t enough, he adds. Because the brain instructs us when and how much to eat, that’s where the biological imbalance — and therefore treatment potential — lies.
But not everyone shares that enthusiasm. “There are people who are really worried about the uptake and the excitement around these medications,” says Sarah Nutter, a psychologist and weight-stigma researcher at the University of Victoria in Canada. Some people fear that the existence of these drugs could exacerbate eating disorders and weight stigma, Nutter says.
These drugs enter a world with ever-present diet culture and societal pressure to be slim. “What we need to do,” Nutter says, “is develop a better understanding of health as being independent of weight.”
One study found that almost 30% of participants who were considered obese had good cardiometabolic health11, defined by factors including blood pressure and cholesterol levels. Health exists at every size, says Geoff Ball, a clinical researcher specializing in paediatric obesity at the University of Alberta, who has served on a national advisory board on the subject for Novo Nordisk. “There’s no right weight for people.”
Nature 620, 28-30 (2023)
doi: https://doi.org/10.1038/d41586-023-02445-4
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