In eagerly awaited results from a new study, the pharmaceutical company Eli Lilly reports that a pill its scientists developed causes people who are overweight or obese, but not diabetic, to lose significant amounts of weight.
The drug, called orforglipron, differs from Lilly’s injectable drug, tirzepatide (which is approved as Mounjaro to treat diabetes and as Zepbound to treat obesity and some forms of obstructive sleep apnea). While tirzepatide targets two hormones, GLP-1 and GIP, orforglipron just targets GLP-1. Lilly and other companies that make similar medicines have been racing to create oral weight-loss drugs, since weekly injections are not always appealing to patients.
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The trial included more than 3,100 overweight or obese adults who had an obesity-related medical problem but not diabetes. Those taking the pill daily for almost a year and a half lost 12% of their body weight on average, or 27 pounds. People taking a placebo lost just over two pounds. The findings have not yet been published in a peer-reviewed journal but will be presented in September at the annual meeting of the European Association for the Study of Diabetes.
Based on the results, Lilly says it plans to file for approval of orforglipron from the U.S. Food and Drug Administration to treat obesity by the end of the year. If approved, Lilly says, it will be able to provide the pills by next year. The company is waiting for final results from a similar study of weight loss in people with diabetes; early results released in April indicate that the drug helped people with diabetes lower their blood sugar.
“The results we got were as good as we can possibly achieve with an oral small molecule GLP-1,” says Dr. Dan Skovronsky, Lilly’s chief scientific officer. “The safety, tolerability, and efficacy were all in line with what we achieved with the injectable drug, yet now delivered in an easy-to-use, once-a-day pill.”
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Among people in the study who took the drug, risk factors for heart disease such as LDL cholesterol, triglycerides, blood pressure, and a marker of inflammation also dropped, Skovronsky notes. That supports earlier data finding that GLP-1 drugs can lower the risk of heart disease as well.
As with the injectable form, people taking the pills had to gradually increase their dose before reaching the maximum dose, mainly to minimize the side effects of gastrointestinal distress. In the study, people started out at 6 mg, then increased to 12 mg four weeks later, then to the maintenance dose of 36 mg four weeks after that.
Orforglipron’s side effect profile was similar to that of the injectable drugs, which is reassuring, says Skovronsky. “There were two things I worried about,” he says. “One, when you take something orally, you are exposing the stomach and intestines to a higher concentration of the drug. If that’s where the side effects are caused, then [the oral] form could make them worse. But it wasn’t the case at all.”
It also wasn’t clear what would happen if people in the study missed doses, since it’s sometimes challenging to take a pill every day. Because the dose is carefully titrated up, Skovronsky said it wasn’t known if people who missed pills for a few days would lose the tolerance they had built up to the side effects and have to restart their dosing schedule. “What we found was that the side effects were similar to the injections, even though people missed the dose every once in a while,” he says.
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Novo Nordisk, a competitor that makes Ozempic for treating diabetes and Wegovy for weight management, also has an oral form of its active ingredient, semaglutide, that is already approved to treat diabetes. The company has applied for approval to treat obesity in people without diabetes and expects a decision by the end of the year.
If orforglipron is approved, it could increase access to GLP-1 medications in the U.S. and around the world. The oral drug is cheaper than the injectable, since it does not require a sterile injectable pen. Some people are also reluctant to inject themselves weekly, so taking the medication by mouth would be a welcome option.
As more doctors and patients figure out the best way to use GLP-1 drugs to manage weight, a pill could either kickstart weight loss or become part of a long-term maintenance program for people who have hit their weight-loss goal. “This can enable us to go earlier in the disease course, because people sometimes hold off on the injections until the disease—in this case, obesity—is more severe,” says Skovronsky. “We want to treat obesity at its earliest stages, and this provides a good opportunity to do that.” Skovronsky says Lilly is also studying weight-maintenance approaches with orforglipron.