Orforglipron Shows Significant Weight Loss in New Phase 3 Study

Orforglipron, an investigational oral glucagon-like peptide-1 (GLP-1) receptor agonist from Eli Lilly, demonstrated significant weight loss, meaningful hemoglobin A_1c reductions, and improvements in cardiometabolic risk factors at 72 weeks, according to results from the phase 3 ATTAIN-2 (NCT05872620) trial.¹

Orforglipron shows results in weight loss and diabetes management, offering a new oral treatment option for patients. | Image Credit: New Africa - stock.adobe.com

"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, MD, FACP, DABOM, founder and Chair Emeritus of the American Board of Obesity Medicine, said in a news release.¹ "Orforglipron could help health care providers expand treatment options for patients who prefer oral therapies without compromising clinical results."

Investigators of the study determined the safety and efficacy of the oral treatment compared with the placebo for adults with obesity or overweight and type 2 diabetes. The trial lasted approximately 77 weeks and included up to 22 clinic visits, according to the clinical trial information. Patients included in the study had a body mass index of 27 kg/m² or greater, at least 1 self-reported unsuccessful dietary effort to lose body weight, and a diagnosis of type 2 diabetes with a hemoglobin A_1c from 7% to 101% and were on stable treatment for at least 90 days prior to screening.²

In the study, patients received 1 of 3 doses of orforglipron (6 mg, 12 mg, and 36 mg) or the placebo. The primary end point included mean percent change from baseline in body weight at week 72. And secondary outcomes included mean change from baseline in waist circumference, hemoglobin A_1c fasting glucose, systolic blood pressure, fasting triglycerides, fasting nonhigh-density lipoprotein cholesterol, fasting insulin, diastolic blood pressure, and short form 26 version 2 health survey acute form domain scores from baseline to week 72.²

Investigators found that the primary end point was -5.5% for orforglipron 6 mg, -7.8% for 12 mg, and -10.5 for 36 mg compared with -2.2% for the placebo. For body weight reductions of 10% or more, 23.9%, 35.5%, and 50.1% of patients, respectively, compared with 7% taking the placebo. For reductions of 15% or more in body weight, 7.3%, 17.7%, and 28.4%, respectively, achieved this outcome compared with the placebo.¹

Furthermore, for hemoglobin A_1c, patients receiving 6 mg, 12 mg, and 36 mg achieved reductions from an average of 8.1% by -1.3%, -1.6%, and -1.8%, respectively, compared with -0.1% with the placebo. Approximately 70%, 78%, and 85.1% of patients, respectively, achieved a hemoglobin A_1c less than 7% compared with 23% on the placebo, and 56.2%, 67.5%, and 75%, respectively, achieved a 6.5% or lower hemoglobin A_1c compared with 10.6% receiving the placebo.¹

As for safety, the drug was generally consistent with other drugs in the GLP-1 class, and most adverse events were gastrointestinal in nature, including nausea, vomiting, diarrhea, constipation, and dyspepsia.¹

The company previously announced positive results from the ATTAIN-1 (NCT05869903) trial, showing that the therapy was efficacious and safe for weight loss for adults with overweight or obesity. In this study, they found that 59.6% of people lost at least 10% of their body weight and 39.6% lost at least 15%.³

READ MORE: Obesity Management Resource Center

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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. News release. Eli Lilly. August 26, 2025. Accessed September 3, 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). ClinicalTrials.gov identification: NCT05872620. Updated April 17, 2025. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT05872620

3. Meara K. Oral GLP-1 orforglipron shows meaningful weight loss in phase 3 trial. Drug Topics. August 7, 2025. Accessed September 3, 2025. https://www.drugtopics.com/view/oral-glp-1-orforglipron-shows-meaningful-weight-loss-in-phase-3-trial