ATLANTA — Eli Lilly’s investigational oral GLP-1 drug orforglipron produced significant weight loss, A1c reduction, and cardiovascular risk factor improvements in the company’s Phase 3 ATTAIN-2 trial of adults with both obesity and type 2 diabetes (T2D).

Orforglipron is a once-daily small molecule (nonpeptide) that, unlike the current oral semaglutide formulation for T2D (Rybelsus), can be taken any time of day without restrictions on food and water intake or need for refrigeration.

The ATTAIN-2 findings track with those seen in people with obesity without diabetes in ATTAIN-1, reported and published in September 2025. Top-line results from ATTAIN-2 were announced in August 2025.

The full ATTAIN-2 results were presented on November 5, 2025, at Obesity Week 2025 by three of the trial’s investigators.

“This is historical. I believe that this molecule is going to change the way we practice obesity medicine…ATTAIN 1 and ATTAIN 2 both make up the backbone of the clinical trial program for orforglipron. The results are completed, which means we’re on our way to having a molecule that’s going to change obesity medicine practice…and we can now move forward,” ATTAIN 1 investigator Sean Wharton, MD, PharmD, medical director of the Wharton Medical Clinic, Burlington, Ontario, Canada, told Medscape Medical News.

Orforglipron is the farthest in development of the nonpeptide “nutrient-stimulated hormone (NuSH)”-based molecules for obesity and T2D, but there are several competitors not far behind, including at least one other (HRS-7535) in phase 3.

Obesity expert Donna H. Ryan, MD, professor emerita at Pennington Biomedical Research Center, Baton Rouge, Louisiana, who presented commentary at the end of the session, told Medscape Medical News, “The hope is that these nonbiological small molecules are going to be much easier to make, and easier to ship, so I think there’s a lot of hope in the future.”

However, Ryan also cautioned, “They’re metabolized differently than the peptides, so we’ll be watching the post marketing surveillance of this one particularly carefully.”

ATTAIN 2: Weight Loss and Metabolic Improvements Seen

The 72-week multinational phase 3 ATTAIN-2 trial randomized 1613 participants with obesity or overweight (BMI ≥ 27.0) and T2D to either 6 mg, 12 mg, or 36 mg orforglipron or placebo. Overall, 89.5% completed the study, with similar rates across groups.

The primary endpoint of significantly greater body weight loss compared with placebo at week 72 was met in the efficacy estimand (assuming all take as prescribed), with significant reductions of 5.5%, 7.8%, and 10.5% of body weight with the three orforglipron doses, respectively, vs just 2.2% with placebo.

The proportions achieving weight loss of at least 5% ranged from 49.8% to 72.8% across orforglipron doses compared with 24.4% with placebo. And with the 36 mg dose, half achieved at least a 10% weight reduction.

The weight loss in the placebo group is noteworthy, Rothberg said. “That is excellent with getting no medication. What was happening with the placebo group? They should look at that.”

Mean reductions in waist circumference were 5.6 cm, 7.2 cm, and 9.2 cm, respectively, vs just 2.7 cm with placebo, also significant for all three doses.

Orforglipron also lowered A1c from an average baseline of 8.0%, by 1.29, 1.60, and 1.79 percentage points, respectively, vs 0.14 with placebo. The proportions achieving an A1c of < 7% were 70.0%, 78.0%, and 85.1%, vs 23% with placebo.

Significant improvements were also seen with orforglipron in fasting serum glucose, systolic blood pressure, non-high-density lipoprotein cholesterol, and triglycerides. The highest orforglipron dose reduced high-sensitivity C-reactive protein by 50.6%.

The proportions of participants with serious adverse events was 9.2% overall and didn’t differ across groups. Discontinuations due to adverse events occurred in 7.3%, 10.3%, and 10.9% across orforglipron doses vs 4.6% with placebo. Deaths occurred in four participants each in the placebo and orforglipron 12 mg groups, two in the 36 mg group, and none in the 6 mg group.

Rates of reported nausea were 20.1%, 31.1%, and 36.4%, respectively, for the three orforglipron doses vs 8.4% for placebo. Diarrhea was reported for 27.4%, 24.8%, and 21.3%, respectively, vs 15.0%. And for vomiting, the rates were 23.1%, 20.2%, and 12.8% vs 3.8%. Most of these occurred primarily during dose escalation and were mild-to-moderate. 

Amy E. Rothberg, MD, clinical professor of internal medicine and of nutritional sciences at the University of Michigan, Ann Arbor, Michigan, told Medscape Medical News,“I think it’s valuable to have another oral option, but I am concerned about the rates of nausea and vomiting. They are not trivial.”

Rothberg noted, “We don’t know the numbers who were taking antiemetics or anti-diarrheals.”

No hepatic safety signal was observed. Hypoglycemia rates were low and occurred primarily when used in combination with sulfonylureas.

Also asked to comment, Simeon Taylor, MD, PhD, professor of medicine and director of the T32 Institutional Research Training Program in Diabetes & Obesity at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News, “a number of companies tried unsuccessfully in the early 21st century to discover and develop orally bioavailable small molecule GLP1 receptor agonists [RA]. So the development of small molecule GLP1 R agonists is a truly remarkable scientific accomplishment.”

Taylor also noted, “Many patients will likely have a preference for an orally bioavailable drug rather than an injectable drug. Furthermore, it is likely that it may be more practical and feasible to manufacture large quantities of this small molecule to provide therapy for the large number of people who are obese or overweight with or without diabetes.”

In her commentary at the meeting session, Ryan called orforglipron “a valuable asset, the first nonpeptide small molecule GLP-1 RA with some very appealing characteristics for patients and prescribers.” She also said it’s a “scalable asset,” in that “the small molecule can be mass-manufactured and shipped. It is an opportunity to grow the base of patients and prescribers.”

Lilly announced previously that it will submit its review package for orforglipron to the FDA in late 2025.

Lilly is also seeking an indication for orforglipron in treating T2D based on its phase 3 ACHIEVE trial platform.

Wharton disclosed receiving honoraria, serving on advisory boards, and conducting research for Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Amgen, Bausch Health, Metsera, AbbVie, AstraZeneca, and Pfizer. Ryan had disclosures with many obesity product manufacturers, including Eli Lilly and Novo Nordisk, and reported holding stock options with Epitomee and Scientific Intake. Rothberg reported being an advisor for Boehringer Ingelheim and a speaker for Lilly.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.