Indianapolis-based Eli Lilly’s orforglipron helped people maintain weight loss after switching from injectable incretins to oral GLP-1 therapy in first-of-its-kind Phase 3 trial. Photo from Eli Lilly and Company.

News Release

INDIANAPOLIS — Eli Lilly and Co. announced Thursday, Dec. 18 that its experimental daily GLP-1 pill, orforglipron, successfully helped patients maintain significant weight loss after they stopped using popular injectable treatments like Wegovy and Zepbound.

The Phase 3 ATTAIN-MAINTAIN trial is the first of its kind to demonstrate that a “small molecule” oral drug can prevent the weight regain that often occurs when patients cease injectable incretin therapies. Lilly confirmed it has submitted the drug to the U.S. Food and Drug Administration for approval.

In the 52-week study, participants who switched from Wegovy to orforglipron maintained almost all of their progress, seeing an average weight change of less than one kilogram. Those who switched to the pill from Zepbound saw a modest average increase of 5 kilograms but fared significantly better than those on a placebo, who experienced rapid weight regain.

“Obesity is a chronic, progressive disease, and sustaining weight loss remains a significant challenge,” said Kenneth Custer, Lilly’s executive vice president of cardiometabolic health in a press release. He noted that the pill offers a “convenient alternative” for long-term weight management without the need for weekly needles.

Orforglipron works as a GLP-1 receptor agonist, similar to the active ingredients in current injectables, but its chemical structure allows it to be absorbed effectively through the digestive tract. Current blockbuster treatments are peptides, meaning short chains of amino acids. Because they are large, fragile molecules, the human stomach would digest them like the protein in steak or eggs before they could enter the bloodstream. This is why they must be injected into the fatty tissue to bypass the digestive system.

Orforglipron is a small molecule drug. Unlike peptides, these are chemically synthesized to be much smaller and more stable. They are designed to survive the harsh, acidic environment of the stomach and pass through the intestinal wall into the blood.

The study reported that side effects were primarily gastrointestinal, such as nausea and constipation, and were generally mild to moderate. No new safety concerns or liver issues were identified.

If approved, orforglipron would represent a major shift in the obesity market, providing a shelf-stable, easy-to-take option for millions of individuals transitioning out of the intensive weight-loss phase of their treatment.