Lilly’s oral GLP-1 orforglipron shows meaningful weight loss and cardiometabolic improvements

Results from the Phase 3 ATTAIN-1 trial, evaluating the safety and efficacy of orforglipron, an investigational oral glucagon-like peptide-1 (GLP-1) receptor agonist, in adults with obesity, or overweight with a weight-related medical problem and without diabetes, revealed that at 72 weeks, all three doses (6mg, 12mg and 36mg) of orforglipron met the primary endpoint of superior body weight reduction compared to placebo.

In addition, all three doses delivered clinically meaningful results compared to placebo across the key secondary endpoints of body weight reduction (≥10%, ≥15% and ≥20%), and waist circumference reduction. Results from the trial were presented at the European Association for the Study of Diabetes Annual Meeting 2025 and simultaneously published in The New England Journal of Medicine.

"Obesity is a complex, global health challenge and patients need treatment options that are both effective and easy to integrate into everyday life," said Dr Sean Wharton, director at Wharton Medical Clinic and lead investigator. "In this Phase 3 study, orforglipron demonstrated strong efficacy results and safety consistent with the GLP-1 class, reinforcing its potential as a first-line treatment in primary care. Additionally, orforglipron could help reduce known markers of cardiovascular risk associated with obesity and support meaningful improvements in public health."

Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.

ATTAIN-1 is a Phase 3, 72-week, randomised, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron 6mg, 12mg and 36mg as a monotherapy to placebo in adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease, who did not have diabetes.

The trial is the first Phase 3 study of this patient population in which treatment was evaluated as an adjunct to exercise and a balanced, healthy diet rather than a reduced-calorie diet. The trial randomised 3,127 participants across the US, Brazil, China, India, Japan, South Korea, Puerto Rico, Slovakia, Spain and Taiwan in 3:3:3:4 ratio to receive either 6mg, 12mg or 36mg orforglipron or placebo.

The primary objective of the study was to demonstrate that orforglipron (6mg, 12mg, 36mg) is superior 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 at least one weight-related comorbidity and a history of at least one self-reported unsuccessful dietary effort to lose body weight. All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1mg once-daily and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 6mg (via steps at 1mg and 3mg), 12mg (via steps at 1mg, 3mg and 6mg) or 36mg (via steps at 1mg, 3mg, 6mg, 12mg and 24mg). Dose reduction was only allowed for GI tolerability if other mitigations failed.

In the ATTAIN-1 trial, orforglipron met the primary endpoint of superior body weight reduction compared to placebo, with participants taking the highest dose losing an average of 27.3 lbs (12.4%) at 72 weeks using the efficacy estimand. In key secondary endpoints, 59.6% of participants taking the highest dose of orforglipron lost at least 10% of their body weight, while 39.6% lost at least 15% of their body weight. Among the 1,127 participants who had prediabetes at the start of the study, up to 91% of those taking orforglipron achieved near-normal blood sugar levels compared to 42% of those taking placebo at 72 weeks.

Additionally, orforglipron showed clinically meaningful improvements across key cardiovascular risk factors often associated with obesity, 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 (hsCRP) levels, a marker of inflammation, by 47.7%.

"People living with obesity have broad and varied needs - whether it's improving weight, A1C, lipids, blood pressure, or other health markers that primary care physicians routinely address with their patients," said Dr Kenneth Custer, executive vice president and president of Lilly Cardiometabolic Health. "We're encouraged to see orforglipron improve many of these areas in ATTAIN-1. As a convenient, once-daily pill that can be scaled globally, orforglipron could be ideally suited for early adoption in primary care - where proactive intervention has the potential to lead to meaningful, long-term health improvements."

The safety profile of orforglipron in ATTAIN-1 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. The most common adverse events for participants treated with orforglipron (6mg, 12mg and 36mg, respectively) were nausea (28.9%, 35.9% and 33.7%) vs. 10.4% with placebo, constipation (21.7%, 29.8% and 25.4%) vs. 9.3% with placebo, diarrhea (21.0%, 22.8% and 23.1%) vs. 9.6% with placebo, and vomiting (13.0%, 21.4% and 24.0%) vs. 3.5% with placebo. Treatment discontinuation rates due to adverse events were 5.3% (6mg), 7.9% (12mg) and 10.3% (36mg) for orforglipron vs. 2.7% with placebo. No hepatic safety signal was observed.

Lilly is advancing orforglipron toward global regulatory submissions for the treatment of obesity, with regulatory action expected to occur as early as next year. Submission for the treatment of type 2 diabetes is anticipated in 2026.

Orforglipron was discovered by Chugai Pharmaceutical Co and licensed by Lilly in 2018. Lilly is running Phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnoea and hypertension in adults with obesity.

Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment', published in The New England Journal of Medicine. To access this paper, please click here (log-ion maybe required)