Oral GLP-1 Drug Yields 12% Weight Loss in Nondiabetic Patients With Obesity

Once-daily orforglipron, an oral glucagon-like peptide-1 (GLP-1) receptor agonist, met its primary endpoint of greater weight loss compared to placebo in nondiabetic adults with obesity, or overweight plus a weight-related medical problem, the manufacturer Eli Lilly and Company announced today.

The data come from the ATTAIN-1 trial, in which those on the highest dose of orforglipron lost an average of 27 lb, or about 12% of their body weight, over 72 weeks. In April, the company reported top-line results from another trial, ACHIEVE-1, which is testing orforglipron in diabetic patients with obesity. Those patients lost, on average, about 8% of their body weight within 40 weeks on the highest dose.

ATTAIN-1, a phase III trial, enrolled 3,127 participants from 10 countries who had a body mass index (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 weight. All were randomized to placebo or orforglipron 1 mg once daily, which was increased in a stepwise approach at 4-week intervals to achieve a maintenance dose of 6 mg, 12 mg, or 36 mg.

For the primary endpoint of mean percent change in body weight at 72 weeks, from a baseline average of 103.2 kg (227.5 lb), the mean weight loss was 7.8% in the 6-mg group, 9.3% in the 12-mg group, and 12.4% in the 36-mg group. Over the same time period, the placebo group had a mean loss in body weight of 0.9% (1 kg, or 2.2 lb).

Secondary endpoints looked at the percentage of patients in each arm who lost higher amounts of their starting weight.

Proportion of Patients at Different Levels of Weight Loss From Baseline

The most commonly reported adverse events were nausea, constipation, diarrhea, vomiting, and dyspepsia. Adverse events led to treatment discontinuation in 5.1%, 7.7%, and 10.3% of patients on orforglipron doses of 6 mg, 12 mg, and 36 mg, respectively.

In the press release, Lilly said the ATTAIN-1 results will be presented next month at the European Association for the Study of Diabetes (EASD) Annual Meeting 2025 and will also be published.