ATTAIN-1: Orforglipron Achieves Up to 12% Weight Loss in Phase 3 Obesity Trial

Eli Lilly and Company has announced positive topline results from the phase 3 ATTAIN-1 trial evaluating orforglipron, an investigational oral glucagon-like peptide-1 (GLP-1) receptor agonist, in 3127 adults with obesity, or overweight with a weight-related medical problem and without diabetes.1

According to an August 7, 2025, press release from the Company, 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.1

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

An investigational, once-daily small molecule oral GLP-1 receptor agonist, orforglipron can be taken any time of the day without restrictions on food and water intake. It is in phase 3 studies for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with ≥ 1 weight-related medical problem and is additionally being studied as a potential treatment for obstructive sleep apnea (OSA) and hypertension in adults with obesity.1,2

The ATTAIN phase 3 global clinical development program for orforglipron has enrolled > 4500 people with obesity or overweight across 2 global registration trials. ATTAIN-1 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 to placebo in adults with obesity, or overweight with ≥ 1 of the following comorbidities: hypertension, dyslipidemia, OSA, or cardiovascular disease, who did not have diabetes.1

The trial randomly assigned 3127 participants across the US, Brazil, China, India, Japan, South Korea, Puerto Rico, Slovakia, Spain and Taiwan in a 3:3:3:4 ratio to receive either 6 mg, 12 mg or 36 mg orforglipron or placebo. The primary objective was to demonstrate orforglipron’s superiority to placebo in body weight reduction from baseline after 72 weeks in people with a BMI ≥30.0 kg/m² or a BMI ≥27.0 kg/m² with ≥ 1 weight-related comorbidity and a history of ≥ 1 self-reported unsuccessful dietary effort to lose body weight.1

All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at 4-week intervals to their final randomized maintenance dose of 6 mg (via steps at 1 mg and 3 mg), 12 mg (via steps at 1 mg, 3 mg and 6 mg) or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg). Dose reduction was only allowed for GI tolerability if other mitigations failed.1

As described in the release from Lilly, in ATTAIN-1, orforglipron met the primary endpoint for superior body weight reduction compared to placebo. Participants taking the highest dose of orforglipron lost an average of 27.3 lbs (12.4%) at 72 weeks using the efficacy estimand. In a key secondary endpoint, 59.6% of participants taking the highest dose of orforglipron lost ≥ 10% of their body weight, while 39.6% lost ≥ 15% of their body weight.1

In addition to achieving significant weight loss, orforglipron was also associated with reductions in known markers of cardiovascular risk, including non-HDL cholesterol, triglycerides and systolic blood pressure in pooled analyses across all doses. In a pre-specified exploratory analysis, the highest dose of orforglipron reduced high-sensitivity C-reactive protein levels by 47.7%.1

For the treatment-regimen estimand, investigators noted each dose of orforglipron led to statistically significant improvements across the primary and all key secondary endpoints.1

The overall safety profile of orforglipron observed in ATTAIN-1 was consistent with the established GLP-1 receptor agonist class, with the most commonly reported adverse events being gastrointestinal-related and generally mild-to-moderate in severity. The overall treatment discontinuation rates were 21.9% (6 mg), 22.5% (12 mg) and 24.4% (36 mg) for orforglipron versus 29.9% with placebo.1

As described in the release, Lilly plans to present the detailed ATTAIN-1 results at the European Association for the Study of Diabetes Annual Meeting 2025 and publish them in a peer-reviewed journal. More results from the ATTAIN phase 3 clinical trial program are expected to be shared later this year, along with findings from the ACHIEVE phase 3 clinical trial program evaluating orforglipron for adults with type 2 diabetes.1

References

1. Lilly. 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. August 7, 2025. Accessed August 7, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273

2. Campbell P. ACHIEVE-1: Oral GLP-1 Agonist Orforglipron Shows Strong HbA1c, Weight Reductions. HCPLive. June 21, 2025. Accessed August 8, 2025. https://www.hcplive.com/view/achieve-1-oral-glp-1-agonist-orforglipron-shows-strong-hba1c-weight-reductions