Orforglipron Delivers Weight Loss, A1C Reductions in Phase 3 ATTAIN-2 Trial

Eli Lilly and Company has announced positive topline results from the phase 3 ATTAIN-2 trial evaluating orforglipron, an investigational oral GLP-1 receptor agonist, in adults with obesity or overweight and type 2 diabetes.1

According to an August 26, 2025, press release from the Company, all 3 doses of orforglipron met the trial’s primary and all key secondary endpoints, delivering significant weight loss, meaningful A1C reductions, and improvements in cardiometabolic risk factors at 72 weeks. With the completion of ATTAIN-2, Lilly now has the full clinical data package required to initiate global regulatory submissions for orforglipron.1

"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 Aronne, MD, an obesity specialist, founder and Chair Emeritus of the American Board of Obesity Medicine, and former president of The Obesity Society, Fellow of the American College of Physicians, said in a statement.1 "Orforglipron could help health care providers expand treatment options for patients who prefer oral therapies without compromising clinical results."

An investigational, once-daily small molecule (non-peptide) oral GLP-1 receptor agonist, orforglipron can be taken any time of the day without restrictions on food and water intake. It was discovered by Chugai Pharmaceutical Co and licensed by Lilly in 2018, with the latter currently running phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with ≥ 1 weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea and hypertension in adults with obesity.1

The ATTAIN phase 3 global clinical development program for orforglipron has enrolled > 4500 people with obesity or overweight across 2 global registration trials. Lilly announced findings from ATTAIN-1 on August 7, 2025, showing that at 72 weeks, all 3 doses of orforglipron met the primary endpoint and all key secondary endpoints compared to placebo, delivering clinically meaningful weight loss as an adjunct to a healthy diet and physical activity. For the trial’s primary endpoint, orforglipron 36 mg, taken once per day without food and water restrictions, reduced weight by an average of 12.4% (27.3 lbs) compared to 0.9% (2.2 lbs) with placebo using the efficacy estimand.2

ATTAIN-2 is a phase 3, 72-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron 6 mg, 12 mg and 36 mg as monotherapy with placebo in adults with obesity or overweight and type 2 diabetes. The trial randomly assigned > 1600 participants across the US, Argentina, Australia, Brazil, China, Czechia, Germany, Greece, India, South Korea and Puerto Rico in a 1:1:1:2 ratio to receive either 6 mg, 12 mg or 36 mg orforglipron or placebo.1

The primary objective of the study was to demonstrate orforglipron (6 mg, 12 mg, 36 mg)’s superiority to placebo in mean body weight change from baseline at 72 weeks in people with a BMI ≥27.0 kg/m² and type 2 diabetes who are on stable treatment with either diet/exercise alone or ≤ 3 oral antihyperglycemic medications. All participants receiving orforglipron started the study at a dose of 1 mg once-daily and then increased the dose in a step-wise approach at 4-week intervals to their final randomized maintenance dose. Dose reduction was only allowed for GI tolerability if other mitigations failed.1

In ATTAIN-2, orforglipron met the primary endpoint of superior body weight reduction compared to placebo, with participants taking the highest dose of orforglipron losing an average of 22.9 lbs (10.5%) at 72 weeks compared to 2.2% (5.1 lbs) with placebo using the efficacy estimand. 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 the highest dose of orforglipron achieved an A1C ≤6.5%, which is at or below the American Diabetes Association's definition of diabetes.1

Additionally, investigators noted 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 levels by 50.6%.1

Investigators noted 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, with no hepatic safety signal observed.1

"The ATTAIN-2 results reinforce the potential for orforglipron, as a once-daily oral, to deliver meaningful weight loss and A1C reduction, consistent with similar landmark trials for injectable GLP-1s," Kenneth Custer, PhD, Lilly executive vice president and president of Lilly Cardiometabolic Health, said in a statement.1 "With these positive data in hand, we are moving with urgency toward global regulatory submissions to potentially meet the needs of patients who are waiting. If approved, we are ready to offer a convenient, once-daily pill that can be scaled globally — removing barriers and redefining how obesity is treated around the world."

References

1. Lilly. Lilly's oral GLP-1, orforglipron, is successful in third Phase 3 trial, triggering global regulatory submissions this year for the treatment of obesity. August 26, 2025. Accessed August 26, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-successful-third-phase-3-trial

2. Brooks A. ATTAIN-1: Orforglipron Achieves Up to 12% Weight Loss in Phase 3 Obesity Trial. HCPLive. August 7, 2025. Accessed August 26, 2025. https://www.hcplive.com/view/attain-1-orforglipron-achieves-up-to-12-weight-loss-in-phase-3-obesity-trial