Orforglipron Shows Positive Efficacy, Tolerability in Weight Management

In the phase 3, 72-week, randomized, double-blind, placebo-controlled ATTAIN-1 trial (NCT05869903), orforglipron, an investigational, once-daily, small-molecule, nonpeptide, oral glucagon-like-peptide-1 receptor agonist (GLP-1 RA), delivered clinically meaningful weight loss as an adjunct to a healthy diet and physical activity. The primary end point and all key secondary end points were met compared with placebo.^1,2

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Understanding Obesity and Orforglipron

Individuals with a body mass index (BMI) of 30 or higher are considered obese, which can increase the risk of many other diseases and health complications, including heart disease, diabetes, high blood pressure, high cholesterol, liver disease, and sleep apnea.³

"Obesity is one of the most pressing global health challenges of our time, driving global chronic disease burden and impacting more than 1 billion people worldwide," Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a news release.¹

As an oral GLP-1, orforglipron could aid in weight management and lead to a healthier lifestyle for individuals with overweight or obesity by reducing body weight. The GLP-1 works by stimulating insulin release from the pancreas and slowing gastric emptying, which can promote satiety, reduce food intake, and lead to weight loss.¹

ATTAIN-1 Study Results and Objectives

In the study, researchers aimed to compare the efficacy and safety of 6 mg, 12 mg, and 36 mg of orforglipron as a monotherapy with placebo in adults with obesity or overweight with at least 1 other comorbidity, including hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea, but who did not have diabetes.¹

The primary objective of the study was to demonstrate orforglipron’s superiority to placebo for weight loss in adults with obesity or those who are overweight with a related health condition. A total of 3127 individuals were included and randomly assigned in a 3:3:3:4 ratio to receive either 6 mg, 12 mg, or 36 mg of orforglipron or placebo. After the initial dosage, participants gradually increased their dosage over time to improve tolerability. The study measured weight reduction from the beginning of the trial over a 72-week period.¹

The results demonstrated that the study met its primary end point, achieving an average 27.3 lbs of weight loss on the highest dose of orforglipron at 72 weeks. Additionally, 59.6% of individuals taking the highest dose of orforglipron lost nearly 10% of their body weight, and 39.6% lost at least 15% of their body weight, meeting the secondary end point.¹

Further results found that orforglipron also reduced markers of cardiovascular risk, including non-HDL cholesterol, triglycerides, and systolic blood pressure across all 3 doses.¹

The most common adverse events were gastrointestinal and were mild to moderate, including nausea, constipation, diarrhea, vomiting, and dyspepsia. Across all 3 doses, orforglipron had higher rates of adverse event-related discontinuation compared to the placebo, with the highest rate of 10.3% seen in the 3 mg group. However, the overall discontinuation rates, which include all reasons for leaving the study, were lower for all orforglipron groups compared to the placebo group.¹

"With orforglipron, we're working to transform obesity care by introducing a potential once-daily oral therapy that could support early intervention and long-term disease management while offering a convenient alternative to injectable treatments. With these positive data in hand, we are now planning to submit orforglipron for regulatory review by year-end and are prepared for a global launch to address this urgent public health need,” Custer said in the news release.¹

REFERENCES

1. Lilly's oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. Eli Lilly and Company. News release. August 7, 2025. Accessed August 21, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273

2. 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?intr=Orforglipron&rank=6

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