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In the 1980s, researchers identified a hormone in the human gut called GLP-1 that triggers the release of insulin, which controls blood sugar levels. The discovery would eventually launch a new class of diabetes drugs known as GLP-1 receptor agonists, the first of which was approved in 2005.
The drugs not only kept blood sugar in check. Curiously, they also seemed to suppress appetite, and some people taking them lost a modest amount of weight. The revelation led the US Food and Drug Administration to approve the first GLP-1 drug for weight loss in 2014. Called liraglutide and sold under the brand name Saxenda, the weekly injectable led to a nearly 3 percent reduction in body weight on average in trial participants who took it.
By then, Novo Nordisk, the maker of Saxenda, was already working on a better GLP-1. This new drug, semaglutide, was first approved for diabetes in 2017 under the brand name Ozempic and then in 2021 for weight loss as Wegovy. In trials of the drug, participants who received Wegovy lost around 15 percent of their initial body weight—a total game changer.
Hot on the heels of semaglutide is Eli Lilly’s tirzepatide, approved as Mounjaro in 2022 for diabetes and as Zepbound in 2023 for weight management. In studies of Zepbound, patients taking the highest dose lost around 21 percent of their body weight. In a head-to-head comparison of semaglutide and tirzepatide published earlier this month, tirzepatide was found more likely to lead to significant weight loss.
These drugs are now wildly popular, in shortage as a result, and hugely profitable for the companies making them. Their success has sparked a frenzy among pharmaceutical companies looking for the next blockbuster weight-loss drug. Researchers are now racing to develop new anti-obesity medications that are more effective, more convenient, or produce fewer side effects than the ones currently on the market. The existing drugs can cause nausea, headaches, and other unpleasant side effects that lead some people to stop taking them.
They have other downsides too. In the United States, they can cost more than $1,000 a month and aren’t always covered by insurance. They have to be injected under the skin once a week. And while most people who stay on them see positive results, others don’t lose much weight at all. Not to mention ongoing shortages of GLP-1s are making it hard for patients to start and continue taking them as prescribed.
Having more drugs on the market would mean more choices for patients—and more profits for the companies selling them. “It’s an extraordinarily exciting and busy time in the field of obesity,” says Darren McGuire, a cardiologist and professor of internal medicine at University of Texas Southwestern Medical Center.
Semaglutide and tirzepatide work by activating GLP-1 receptors in the pancreas to stimulate the production of insulin, which helps to control blood sugar levels in people with type 2 diabetes. These drugs also slow down the emptying of the stomach and interact with GLP-1 receptors in the brain to tamp down hunger. As a result, people tend to eat less and have fewer food cravings while taking them.
It’s possible that tirzepatide is slightly more effective because it’s a dual receptor agonist. In addition to GLP-1, it also activates receptors of GIP, another hormone involved in regulating blood sugar and appetite. But McGuire says GIP isn’t well understood, and it’s not clear whether the addition of GIP is driving the increased weight loss or if tirzepatide is just better at activating GLP-1. “We just don’t have a way to unravel that biology right now,” he says.
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That hasn’t stopped pharma companies from pursuing GIP as a target. Viking Pharmaceuticals is also developing a drug that activates both the GLP-1 and GIP receptors. The San Diego company is testing both an injectable and pill form. In a trial of the injectable version, participants lost nearly 15 percent of their weight over 13 weeks. And data released in March from an early-stage trial showed that people who took Viking’s daily pill version lost around 5 percent of their weight on average in just a month.
Novo Nordisk, Eli Lilly, and Pfizer are all working on their own GLP-1 pills. Some patients may prefer taking a daily pill over a weekly injection. Pills are also easier to manufacture than the injector pens used to administer Wegovy and Zepbound. The pens also have to be refrigerated.
“All of that makes these drugs more expensive,” says Laura Davisson, director of the weight management program at the West Virginia University Health System. “If we could get oral versions on the market, maybe the prices would come down.”
Amgen, meanwhile, thinks a less frequently taken medication could be convenient for some patients. The company is working on an injectable drug called MariTide that would be given just once a month. The drug also targets GLP-1 and GIP, but instead of stimulating GIP receptors, MariTide blocks them. It’s not entirely clear why both stimulating and blocking these receptors seems to promote weight loss.
Amgen’s approach is based on research showing that mice that lack GIP, as well as people with mutations in this receptor, have lower body weight. In results published in February, people taking MariTide in an early-stage trial lost up to more than 14 percent of their body weight in 12 weeks.
Eli Lilly is hoping to make an even more potent drug than Zepbound by adding a third mechanism involved in weight loss. It’s working on an investigational drug dubbed retatrutide that targets the receptors for GLP-1, GIP, and glucagon, the latter of which can help break down fat stores. In trial data published last year, retatrutide helped people lose more than 17 percent of their body weight, or 41 pounds, after 24 weeks. At 48 weeks, participants had lost an average of 24 percent of their body weight, or about 58 pounds—more than any other drug on the market.
“We have not seen results like this before in a trial of less than one-year duration with an anti-obesity medication,” said Ania Jastreboff, an endocrinologist and weight specialist at the Yale School of Medicine during a press conference last year at the American Diabetes Association annual meeting.
Davisson was also wowed by the results. “The data is absolutely amazing,” she says, adding to the evidence that targeting additional receptors thought to be involved in the brain’s appetite centers may boost drug effects.
Other companies are pursuing drugs with different targets that could be used on their own or in combination with GLP-1 drugs. One of those, Denmark-based firm Zealand Pharma, is developing an injectable drug called petrelintide that mimics a hormone called amylin that’s produced in the pancreas and secreted alongside insulin after a meal. Amylin seems to reduce the amount of food people eat by signaling a sense of fullness to the brain.
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In June, Zealand released positive data from an early trial showing that a high dose of the drug helped people lose nearly 9 percent of their body weight on average at 16 weeks. David Kendall, chief medical officer at Zealand Pharma, thinks alternatives to GLP-1s are needed because some people don’t respond well to them, losing only relatively little weight.
Patients on GLP-1 drugs can also hit a plateau, where weight loss slows or stops. Kendall says in those situations, it would be helpful to have alternative medications for people to try. “We think it’s good to have options,” he says.
He thinks Zealand’s drug may also come with fewer side effects than current GLP-1 drugs. Only one participant out of 48 dropped out of the trial due to nausea and vomiting. No other participants reported vomiting. But the drug will need to be tested in much bigger trials to assess its effects in larger groups of people.
“Novo and Lilly broke the dam,” Kendall says. “Previously, weight-loss therapies weren’t very effective. Now that we’ve shown that hormone-based therapies can be so effective, I think it’s changed the world’s perspective that it’s not a losing battle to treat obesity.”
Daniel Drucker, professor of medicine at the University of Toronto, who codiscovered GLP-1 in the 1980s, says more drugs are needed because there’s no telling how long the current shortage of Wegovy and Zepbound will last. Novo Nordisk and Eli Lilly are both building new manufacturing plants, but it could take years before those facilities are up and running. “Even then, it’s unlikely that those companies could supply even a fraction of the global demand,” he says. “Having new entrants in the field can only increase the supply of these medicines.”
And beyond GLP-1, Drucker says there are likely new mechanisms involved in hunger and appetite that scientists have yet to uncover yet. “With this flurry of activity, we’re probably going to see some very exciting new medicines that could be even better than the ones we have now.”
