Lilly’s Oral GLP-1 Meets Endpoints in Phase 3 Trial

Patients in a phase 3 clinical trial taking Lilly’s orforglipron, an investigational oral GLP-1 receptor agonist, lost an average of 10.5%, or 22.9 pounds, with an A1C that was reduced by 1.8%, the company announced today.

Louis J. Aronne, M.D.

“Based on my experience leading clinical trials in obesity and diabetes, these data show the potential for orforglipron to offer an efficacy, safety, and tolerability profile consistent with the injectable GLP-1 class,” Louis J. Aronne, M.D., FACP, DABOM, founder and Chair Emeritus of the American Board of Obesity Medicine, said in a news release. “Orforglipron could help health care providers expand treatment options for patients who prefer oral therapies without compromising clinical results.”

In the ATTAIN-2 trial, orforglipron met the primary endpoint of weight reduction and all key secondary endpoints, with a safety profile consistent with injectable GLP-1 medicines. Patients taking orforglipron 36 mg, the highest dose, lost an average of 22.9 lbs (10.5%) at 72 weeks.

In a key secondary endpoint, orforglipron lowered A1C by 1.3% to 1.8% from a baseline of 8.1% across doses. In another key secondary endpoint, 75% of participants taking orforglipron 36 mg achieved an A1C ≤6.5%. The American Diabetes Association recommends a goal of less than 7% for A1C, the estimated average glucose.

Additionally, orforglipron showed clinically meaningful benefits across key cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure and triglycerides. In a pre-specified exploratory analysis, the highest dose of orforglipron reduced high-sensitivity C-reactive protein (hsCRP) levels, a marker of inflammation, by 50.6%.

The overall safety profile of orforglipron in ATTAIN-2 was consistent with the established GLP-1 receptor agonist class. The most commonly reported adverse events were gastrointestinal-related and generally mild-to-moderate in severity. The most common adverse events for participants treated with orforglipron were nausea, vomiting, diarrhea, constipation, and dyspepsia. Treatment discontinuation rates due to adverse events were 6.1% for the 6 mg dose, 10.6% for the 12 mg dose and 10.6% for the 36 mg dose.

Lilly officials said the completion of this trial completes the clinical package for regulatory submissions. Lilly will submit orforglipron to global regulatory authorities for the treatment of obesity or for weight loss by the end of 2025, with diabetes submissions to follow in 2026.

The results of ATTAIN-2 results will be presented at a future medical meeting and published in a peer-reviewed journal, according to Lilly officials. The ATTAIN phase 3 global clinical development program for orforglipron has enrolled more than 4,500 people with obesity or for weight loss across two global registration trials.

Oral Wegovy awaiting approval

If approved, orforglipron could be the second oral GLP-1 drug available to treat obesity. In December 2025, the FDA is expected to make a decision on Novo Nordisk’s once-daily, 25 mg oral formulation of Wegovy (semaglutide) for adults living with obesity and to reduce the risk of major adverse cardiovascular events (MACE) in adults who are overweight or have obesity and an established cardiovascular disease.

Novo Nordisk already markets an oral semaglutide product. Rybelsus is approved to treat type 2 diabetes. It is available in both 7 mg and 14 mg and has a list price of $997.58 per package. People with commercial insurance may pay as little as $10 for a one-, two-, or three-month prescription.

In March 2025, Novo Nordisk reported the results of the SOUL trial, which assessed Rybelsus 14 mg to lower cardiovascular risk in adults with type 2 diabetes. This trial found that Rybelsus reduced the risk of major adverse cardiovascular events (MACE) by 14% compared with placebo in adults with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). These data were presented at the American College of Cardiology’s Annual Scientific Session and Expo.

Novo Nordisk has submitted a supplemental application to the FDA for Rybelsus 14 mg for this indication. A regulatory decision is anticipated in 2025.