Orforglipron's Success in Phase 3 Trial Triggers Regulatory Submissions for Obesity Treatment

In the phase 3, 72-week, randomized, double-blind, placebo-controlled ATTAIN-2 (NCT05872620) trial, orforglipron, an investigational, once-daily, small molecule, nonpeptide, oral glucagon-like peptide-1 receptor agonist (GLP-1 RA), met the primary and all key secondary end points, demonstrating significant weight loss, meaningful A1C reductions, and improvements in cardiometabolic risk factors. With the completion of the ATTAIN-2 clinical trial, Lilly noted that it now has all the data it needs to start the global regulatory submission process.^1,2

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

Orforglipron’s Role in Obesity Management

As an oral GLP-1, orforglipron works by stimulating insulin release from the pancreas and slowing gastric emptying, which promotes satiety, reduces food intake, and leads to weight loss. The GLP-1 could aid weight management and promote a healthier lifestyle for individuals with obesity, identified as a body mass index (BMI) of 30 or higher. Treatment to lower an individual’s BMI can also reduce the risk of other related conditions, including heart disease, diabetes, high blood pressure, high cholesterol, liver disease, and sleep apnea.³

Orforglipron as a monotherapy has previously demonstrated superiority to placebo for weight loss in adults with obesity or those who are overweight with a related health condition in the phase 3 ATTAIN-1 study (NCT05869903). The study also met its secondary end point, as individuals treated with 36 mg of orforglipron lost a significant amount of their body weight.^4,5

ATTAIN-2 Study Results

Researchers compared the efficacy and safety of 6 mg, 12 mg, and 36 mg of orforglipron as a monotherapy with placebo in over 1600 adults with obesity or overweight with type 2 diabetes (T2D). The participants were randomly assigned in a 1:1:1:2 ratio to receive either 1 of the 3 orforglipron doses or a placebo. The researcher aimed to show that orforglipron is more effective than a placebo for adults with a BMI of 27.0 kg/m² or higher who also have T2D. All participants taking orforglipron began with a 1 mg dose, which was gradually increased every 4 weeks until they reached their assigned maintenance dose. Individuals could only decrease their dose if they experienced gastrointestinal adverse events that could not otherwise be resolved.¹

The results demonstrated that orforglipron was more effective than a placebo at reducing body weight. Individuals on the highest dose of orforglipron lost an average of nearly 23 lbs after 72 weeks. Further results found that orforglipron also lowered A1C levels by 1.3% to 1.8%. Additionally, 75% of individuals on the highest dose of orforglipron achieved an A1C level of 6.5% or lower, which is the American Diabetes Association’s target for managing diabetes. The drug also showed benefits for cardiovascular health by improving factors like non-HDL cholesterol, blood pressure, and triglycerides.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 the news release. "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."¹

REFERENCES

1. Lilly's oral GLP-1, orforglipron, is successful in third Phase 3 trial, triggering global regulatory submissions this year for the treatment of obesity. Eli Lilly and Company. August 26, 2025. Accessed August 27, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-successful-third-phase-3-trial

2. A Study of Orforglipron in Adult Participants With Obesity or Overweight and Type 2 Diabetes (ATTAIN-2). Updated April 17, 2025. Accessed August 27, 2025. https://clinicaltrials.gov/study/NCT05872620

3. Mayo Clinic. Obesity. July 22, 2023. Accessed August 21, 2025. https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-causes/syc-20375742

4. Ferruggia K. Orforglipron Shows Positive Efficacy, Tolerability in Weight Management. Pharmacy Times. August 21, 2025. Accessed August 27, 2025. https://www.pharmacytimes.com/view/orforglipron-shows-positive-efficacy-and-tolerability-in-weight-management

5. A study of orforglipron (LY3502970) in adult participants with obesity or overweight with weight-related comorbidities (ATTAIN-1). Updated August 12, 2025. Accessed August 21, 2025. https://clinicaltrials.gov/study/NCT05869903