Jared Holz thought about taking one of the new GLP-1 drugs for weight loss for months before he actually filled the prescription. And even when he got the drug, he waited a month before using it.
Part of his hesitation: He dislikes needles, and all the drugs in this class that have been approved for weight loss come as shots that users give themselves once a week.
“This has been really challenging,” Holz, 44, said about a week into treatment.
But the need for needles may soon change. At least a dozen similar experimental weight-loss drugs designed to be taken as pills are working their way through clinical trials, with the most advanced now in the third and final stage of testing.
They’re likely to “drastically change the landscape for weight management in several ways,” said Dr. Jody Dushay, an assistant professor of medicine at Harvard Medical School and an attending physician in endocrinology at Beth Israel Deaconess Medical Center, who prescribes weight-loss medications.
It’s a field that’s already undergoing a revolution, with millions of people across the US now using semaglutide and tirzepatide, sold as Wegovy and Zepbound for weight loss (and for diabetes as the better-known Ozempic and Mounjaro).
Dushay cited hopes that pill versions of GLP-1 drugs could ease shortages, come at lower cost and enhance convenience. But she and other doctors also warn about the potential for misuse, a problem that could become more pervasive with daily pills instead of weekly injections; they could make it easier to take more than recommended or to share medication inappropriately.
There’s “a lot to be learned about the oral versions,” Dushay said.
Semaglutide in a pill
The most advanced of these pills include a form of semaglutide, the active ingredient in Ozempic and Wegovy, being developed by Novo Nordisk. The Danish drugmaker reported last year that a late-stage study in people who don’t have diabetes showed that the daily pill led to an average weight loss of 15% over 68 weeks, a similar result as seen in trials of Wegovy.
But Novo Nordisk declined to say whether it’s filed for approval of the drug from the US Food and Drug Administration, and sales of an oral form of semaglutide for type 2 diabetes, approved as Rybelsus, have been dwarfed by those of injectable Ozempic.
Although it’s a pill, Rybelsus also comes with some challenges: It must be taken daily on an empty stomach, with no eating, drinking or taking other medications for at least 30 minutes, and doctors report that it may not be as effective as injections yet still comes with side effects.
And the dose of oral semaglutide for obesity is much higher, which comes with the potential for side effects to be even more pronounced, said Dr. Jorge Moreno, an obesity specialist and assistant professor of medicine at the Yale School of Medicine. The dose for weight loss is 25 to 50 milligrams a day, compared with 14 milligrams for Rybelsus and a maximum of 2.4 milligrams a week for injections of Wegovy.
“I have seen more significant [gastrointestinal] side effects with oral semaglutide than with injectable,” Moreno said, noting that he wonders “what differences in side effects may occur when using such high doses of semaglutide compared with [the] injectable dose.”
In the trial, Novo Nordisk said, the “vast majority” of side effects of oral semaglutide were “mild to moderate and diminished over time.” All GLP-1 medications are associated with side effects including nausea, vomiting and abdominal pain, although not all patients experience them.
The oral GLP-1 race
Right on the heels of oral semaglutide is a group of drugs led by Eli Lilly’s orforglipron, an oral medication that also targets GLP-1, which is a hormone implicated in insulin regulation, appetite and digestion.
Lilly, which also makes Zepbound and Mounjaro, reported last year that a midstage trial found that people taking orforglipron for 36 weeks lost an average of 15% of their body weight – about the same amount as oral semaglutide in less time. Results from a later-stage study are expected in the first half of next year, according to Evan Seigerman, a research analyst with financial firm BMO Capital Markets.
Drugmakers including Pfizer and Roche, as well as smaller companies like Structure Therapeutics, Terns Pharmaceuticals and Viking Therapeutics, also have oral weight-loss drugs in earlier stages of development, BMO research shows.
And Novo Nordisk isn’t stopping with semaglutide; it has multiple programs in the early stages of development to bring next-generation weight-loss pills to market.
Earlier this month, data presented at the European Association for the Study of Diabetes conference showed that study participants who got a higher dose of the experimental drug amycretin lost an average of 13% of their body weight in 12 weeks. The drug targets both GLP-1 and another hormone, amylin.
Novo Nordisk also agreed to spend up to $1.1 billion last year to acquire Inversago Pharma, gaining an experimental oral drug called monlunabant that’s designed to block a cannabinoid receptor important in regulating appetite. Results from a midstage study on that drug are expected this year, according to BMO’s research.
‘Maintenance dosing’
Not all of these experimental drugs will necessarily make it to market, but one of the primary roles they may play if they do is as “long-term maintenance dosing” for people who’ve lost a sufficient amount of weight on injectable medications, Dushay said.
The medicines could provide “an excellent off-ramp to weekly injections,” Dushay said. “They may not be as effective for maximum weight loss as initial therapy but could be excellent for weight-loss maintenance, which is a different and arguably much more important destination for lasting health benefits.”
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Holz, who closely follows the weight-loss drug race in his role as a health-care strategist for an investment firm, said he hopes to switch to an oral option from the injectable drug he’s taking weekly now, if one becomes available, to maintain his weight loss.
In three months, Holz said, he’s shed just over 10% of his body weight, and he is enthusiastic about GLP-1 drugs not just for weight loss but for their protective effects on the heart and other potential health benefits.
The weekly injection he’d been concerned about turned out to be nearly painless, he said – something the drug’s makers have worked to achieve with autoinjector pens – and, he reflected, he wishes he’d started sooner.