GLP-1 pills are coming and could revolutionize weight loss treatment

CNN
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Jared Holz thought about taking one of the new GLP-1 weight-loss drugs for months before he actually filled the prescription. And even when he got the drug, he waited a month before taking it.

One reason for his hesitation: He doesn't like needles, and all drugs in this class that are approved for weight loss are administered as injections that the user has to administer to himself once a week.

“It was really a challenge,” said 44-year-old Holz about a week after starting treatment.

But the need for the shots may soon change. At least a dozen similar experimental weight-loss drugs, designed to be taken in pill form, are currently undergoing clinical trials. The most advanced drugs are currently in the third and final phase of testing.

They are likely to “dramatically change the landscape of weight control in several ways,” says Dr. Jody Dushay, an assistant professor of medicine at Harvard Medical School and chief endocrinologist at Beth Israel Deaconess Medical Center who prescribes weight-loss drugs.

A revolution is already taking place in this field: millions of people in the United States are currently using semaglutide and tirzepatide, sold under the names Wegovy and Zepbound, for weight loss (and for diabetes under the better-known names Ozempic and Mounjaro).

Dushay expressed hope that tablet versions of GLP-1 drugs could ease shortages and be less expensive and more convenient. But she and other doctors also warn about the potential for abuse, a problem that could be even more prevalent with daily pills instead of weekly injections; it could be easier to take more than recommended or split medications improperly.

“There is still a lot to learn from the oral versions,” Dushay said.

Among the most advanced of these pills is a form of semaglutide, the active ingredient in Ozempic and Wegovy, being developed by Novo Nordisk. The Danish pharmaceutical company reported last year that an advanced-stage study in people without diabetes showed that taking the pill daily for 68 weeks led to an average weight loss of 15 percent, a similar result to studies of Wegovy.

However, Novo Nordisk declined to comment on whether an application for approval for the drug had been submitted to the US Food and Drug Administration (FDA). In addition, sales of the oral form of semaglutide for the treatment of type 2 diabetes, which is approved under the name Rybelsus, are far outstripped by those of the injectable Ozempic.

Although Rybelsus is a tablet, it also comes with some challenges: it must be taken daily on an empty stomach, without eating, drinking or taking other medications for at least 30 minutes. Additionally, doctors report that it may not be as effective as injections and still has side effects.

And the dose of oral semaglutide for obesity is much higher, causing side effects to be even more pronounced, said Dr. Jorge Moreno, an obesity specialist and assistant professor of medicine at 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 Wegovy injections.

“I have more important [gastrointestinal] side effects with oral semaglutide than with injectable,” said Moreno, noting that he wonders “what differences in side effects may occur when such high doses of semaglutide compared to [the] injectable dose.”

According to Novo Nordisk, the side effects of oral semaglutide in the study were “mostly” mild to moderate and decreased over time. All GLP-1 drugs are associated with side effects such as nausea, vomiting and abdominal pain, although these do not occur in all patients.

Immediately following oral semaglutide is a group of drugs led by Eli Lilly's orforglipron, an oral drug that also targets GLP-1, a hormone involved in insulin regulation, appetite and digestion.

Lilly, maker of Zepbound and Mounjaro, reported last year that a mid-stage trial found that people who took orforglipron for 36 weeks lost an average of 15 percent of their body weight – about the same as when taking oral semaglutide in a shorter time. Results from a later-stage trial are expected in the first half of next year, according to Evan Seigerman, a research analyst at financial firm BMO Capital Markets.

Pharmaceutical companies such as Pfizer and Roche, as well as smaller companies such as Structure Therapeutics, Terns Pharmaceuticals and Viking Therapeutics, also have oral weight-loss drugs in earlier stages of development, according to BMO surveys.

And Novo Nordisk is not content with semaglutide; the company has several programs in early development to bring the next generation of 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 received a higher dose of the experimental drug amycretin lost an average of 13 percent of their body weight over 12 weeks. The drug targets both GLP-1 and another hormone, amylin.

Novo Nordisk also agreed last year to spend up to $1.1 billion to acquire Inversago Pharma, an experimental oral drug called monlunabant that is designed to block a cannabinoid receptor important for appetite regulation. Results from an interim study on the drug are expected later this year, according to BMO research.

“Maintenance dosage”

Not all of these experimental drugs will necessarily make it to market, but if they do, they could serve primarily as “long-term maintenance doses” for people who have lost enough weight with injectable drugs, Dushay says.

The drugs could offer “an excellent escape from weekly injections,” Dushay said. “They may not be as effective for maximal weight loss as initial therapy, but they could be excellent for maintaining weight loss, which is a different and arguably much more important target for lasting health benefits.”

Holz, who closely follows the race for the best weight-loss drugs in his role as a health strategist for an investment firm, said he hopes to switch from the injectable drug he currently takes weekly to an oral alternative when one becomes available to maintain his weight.

In three months, Holz said, he lost just over 10% of his body weight and he is excited about the GLP-1 drugs not only for their weight loss benefits but also for their protective effects on the heart and other potential health benefits.

The weekly injection that had worried him was nearly painless, he said — something the drug's makers tried to achieve with auto-injection pens — and he wished he had started earlier, he reflected.