What You Should Know:
– Eli Lilly and Company has announced positive topline results from its Phase 3 ATTAIN-2 trial, which evaluated orforglipron, an investigational oral GLP-1 receptor agonist, in adults with obesity or overweight and type 2 diabetes.
– All three doses of the drug met the primary and all key secondary endpoints, showing significant weight loss, meaningful A1C reductions, and improvements in cardiometabolic risk factors over 72 weeks.
Significant Weight Loss and A1C Reduction
The ATTAIN-2 trial was a 72-week, randomized, double-blind, placebo-controlled study that compared three doses of orforglipron (6 mg, 12 mg, and 36 mg) with a placebo. The trial’s primary objective was to show that orforglipron was superior to placebo in reducing mean body weight from baseline at 72 weeks.
For the primary endpoint, the highest dose of orforglipron (36 mg) led to an average weight loss of 10.5% (22.9 lbs). This was compared to a 2.2% (5.1 lbs) loss with the placebo. These results were achieved without food and water restrictions.
In a key secondary endpoint, orforglipron reduced A1C by 1.3% to 1.8% from a baseline of 8.1% across all doses. Furthermore, 75% of participants taking the highest dose of orforglipron achieved an A1C of ≤6.5%, which meets the American Diabetes Association’s definition of diabetes remission.
According to Dr. Louis J. Aronne, a world-renowned obesity specialist, the data suggests orforglipron has the potential to offer an efficacy, safety, and tolerability profile consistent with injectable GLP-1s, providing a new option for patients who prefer oral therapies.
Improved Cardiometabolic Health and Safety
The trial also showed clinically meaningful benefits across several cardiovascular risk factors, 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 50.6%.
The overall safety profile of orforglipron in the ATTAIN-2 trial 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. Treatment discontinuation rates were balanced across the groups.
With the completion of ATTAIN-2, Eli Lilly now has the full clinical data package needed to begin global regulatory submissions for orforglipron. Kenneth Custer, Ph.D., president of Lilly Cardiometabolic Health, stated that the company is “moving with urgency” toward these submissions to meet the needs of patients. He added that if approved, orforglipron could be a convenient, once-daily pill that could be scaled globally.
