A new daily pill may help solve one of the biggest challenges faced by people taking GLP-1 drugs: how to keep the weight off once they stop injections.
In a late-stage clinical trial, people who switched from weekly injectable drugs — Wegovy for type 2 diabetes or Zepbound for obesity — to an experimental GLP-1 pill called orforglipron kept off nearly all the weight they’d lost over the course of a year.
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By contrast, people who switched to a placebo pill regained about 20 pounds (lb) after six months.
Most research shows that the majority of people regain a significant amount of the lost weight once they stop taking a weekly GLP-1 injection.
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The findings on orforglipron come from ATTAIN-MAINTAIN, a first-of-its-kind phase 3 trial conducted by the GLP-1 drugmaker Eli Lilly, which manufactures Zepbound and is developing the new oral medication.
“Orforglipron has the potential to redefine the maintenance phase of obesity care,” says Fatima Cody Stanford, MD, MPH, an obesity medicine physician-scientist and an associate professor of medicine and pediatrics at Harvard Medical School in Boston, who was not involved in the trial.
Obesity is a chronic disease that benefits from ongoing treatment, she adds.
People Who Switched to Orforglipron Kept the Weight Off
The trial included nearly 400 adults who were overweight or had obesity and who had already completed another large trial, SURMOUNT-5. In that earlier study, participants took either Wegovy or Zepbound for 72 weeks and lost substantial amounts of weight.
Those on Wegovy lost an average of 41 lb, and those on Zepbound dropped an average of 55 lb before reaching a plateau.
Those participants were then re-randomized to take either orforglipron or a placebo pill for another 52 weeks, while continuing diet and physical activity counseling. The treatment goal for this phase was weight maintenance, not weight loss.
After one year:
- People who switched from Wegovy to orforglipron maintained almost all their weight loss, with an average regain of about 2 lb.
- People who switched from Zepbound to orforglipron kept off most of the lost weight, with an average regain of about 11 lb.
Pills May Increase the Number of People Willing to Try a GLP-1
From a patient perspective, the option to take a pill reduces barriers related to injections, stigma, storage, travel, and daily logistics, says Dr. Stanford. “Knowing there may be an oral option for maintenance could make some patients more willing to [start] injectable GLP‑1 therapy, particularly those who are hesitant about long‑term injections,” she says.
GLP-1 pills activate the same hormone receptors responsible for regulating appetite as the injectable GLP-1s, but don’t work in exactly the same way, says Stanford. There are differences in how quickly the medicine is absorbed, how long it stays active, and how it’s cleared from the body.
Those differences can affect the dose an individual needs, side effects, and the ease with sticking to the medication long term.
When Will Orforglipron Be Available?
Eli Lilly has submitted orforglipron to the U.S. Food and Drug Administration (FDA) for approval as a treatment for obesity and overweight. The drug has received a Commissioner’s National Priority Voucher, which can speed up the FDA review process.
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“Lilly anticipates that orforglipron could receive approval for its first indication as early as next year,” said a company spokesperson. According to reports, if the FDA accepts the new proposed timeline, approval could happen as soon as March 28.
Another GLP-1 Pill May Be Available Even Sooner
Orforglipron isn’t the only daily obesity pill poised for FDA approval. Wegovy’s maker, Novo Nordisk, has created a semaglutide pill (nicknamed the Wegovy pill) that is expected to reach the market first, potentially by the end of this year or early next year.
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Orforglipron may be more convenient than the semaglutide pill because there are no food or other restrictions around its use. In contrast, people must take the semaglutide pill on an empty stomach, with no food or drink for a period of time afterward.
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Side effects for both pills are similar to the shots, and mainly include nausea and diarrhea.
GLP-1 Pills Have the Potential to Lower Costs
Evidence suggests that between 50 and 75 percent of people on a GLP-1 injectable drug stop taking it within a year, partly because they dislike injections or struggle with weekly dosing.
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Transitioning to a daily pill may help people stay on a GLP-1 treatment longer — and therefore have a better chance of keeping the weight off. That’s one of the most persistent unmet needs in obesity treatment today, says Stanford.
The pills also have the potential to lower costs, which would allow for more equitable access, says Stanford. Pills may be less expensive to manufacture, easier to distribute, and simpler to store and prescribe, which could broaden access across healthcare systems and people, she says.
Lilly recently made a deal with the U.S. government on pricing of orforglipron, once it’s approved. A Lilly spokesperson said that the lowest dose will cost $149 per month, with additional doses up to $399 when purchased through LillyDirect’s self-pay pharmacy channel.
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