Orforglipron, a once-daily oral GLP-1, met all primary and key secondary endpoints in ATTAIN-2, a phase 3, 72-week randomized, placebo-controlled trial, prompting Eli Lilly and Company to prepare global regulatory submissions for obesity.

ATTAIN-2 compared the efficacy and safety of orforglipron 6 mg, 12 mg, and 36 mg as monotherapy vs placebo in more than 1600 adults with obesity or overweight and type 2 diabetes in 11 countries.

In an announcement, Lilly said all three doses of the drug delivered significant weight loss, A1c reductions, and improvements in cardiometabolic risk factors at 72 weeks, providing the full clinical data package required to initiate global regulatory submissions for orforglipron.

Global submissions for the treatment of overweight and obesity are planned by the end of 2025, with diabetes submissions to follow in 2026, a Lilly spokesperson told Medscape Medical News. “Lilly anticipates that orforglipron could receive approval for its first indication as early as next year.”

Key Results in ATTAIN-2

Overall, clinically meaningful benefits of orforglipron emerged from ATTAIN-2, including:

• Participants taking the highest dose (36 mg) lost an average of 22.9 lb (10.5%) at 72 weeks using the efficacy estimand.
• Orforglipron lowered A1c by 1.3%–1.8% from a baseline of 8.1% across doses.
• 75% of participants taking the highest dose (36 mg) achieved an A1c ≤ 6.5%.
• Orforglipron showed benefits across cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure, and triglycerides. In a prespecified exploratory analysis, the highest dose reduced high-sensitivity C-reactive protein levels, a marker of inflammation, by 50.6%.

Each dose of orforglipron led to statistically significant improvements across the primary and key secondary endpoints, including:

• Percentage weight reduction: -5.1% at 6 mg; -7.0% at 12 mg; -9.6% at 36 mg; and -2.5% with placebo.
• Percentage of participants achieving body weight reductions of ≥ 10%: 22.6% (6 mg); 31.2% (12 mg); 45.6% (36 mg); and 9% (placebo).
• Percentage of participants achieving body weight reductions of ≥ 15%: 6.8% (6 mg); 14.4% (12 mg); 26% (36 mg); and 3% (placebo)
• A1c reduction: -1.2% (6 mg); -1.5% (12 mg); -1.7% (36 mg); and -0.5% (placebo)
• Percentage of participants achieving A1c < 7%: 64.6% (6 mg); 75.9% (12 mg); 75.5% (36 mg); and 30.5% (placebo)
• Percentage of participants achieving A1c ≤ 6.5%: 52.5% (6 mg); 57.6% (12 mg); 66.6% (36 mg); and 15.4% (placebo)

Overall, the safety profile of orforglipron was consistent with the GLP-1 receptor agonist class. The most commonly reported adverse events were gastrointestinal-related (eg, nausea, vomiting, diarrhea, dyspepsia) and generally mild to moderate in severity.

Treatment discontinuation rates were balanced across treatment groups, with 19.1% (6 mg), 22.3% (12 mg), and 20.5% (36 mg) for orforglipron vs 20% with placebo. No hepatic safety signal was observed.

"With these positive data in hand, we are moving with urgency toward global regulatory submissions,” said Kenneth Custer, PhD, Lilly executive vice president and president of Lilly Cardiometabolic Health.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.