ATTAIN-1: GLP-1RA pill confers weight-loss benefits in adults with obesity

In adults with obesity but without diabetes, treatment with the oral small-molecule, nonpeptide glucagon-like peptide-1 receptor agonist (GLP-1RA) orforglipron yields substantial reductions in body weight, as shown in the phase III ATTAIN-1 trial.

After 72 weeks, participants who received orforglipron vs placebo achieved a significant and clinically meaningful dose-dependent weight loss. Mean body weight decreased by 7.5 percent (95 percent confidence interval [CI], −8.2 to −6.8) with 6 mg of orforglipron, by 8.4 percent (95 percent CI, −9.1 to −7.7) with 12 mg, and by 11.2 percent (95 percent CI, −12.0 to −10.4) with 36 mg as opposed to only 2.1 percent (95 percent CI, −2.8 to −1.4) with placebo (p<0.001 for all). [N Engl J Med 2025;doi:10.1056/NEJMoa2511774]

Significantly more patients across all the orforglipron groups met the weight-reduction thresholds compared with those in the placebo group. Specifically, among those who received the highest dose of orforglipron, 71.8 percent lost ≥5 percent of their body weight, 54.6 percent lost ≥10 percent, 36 percent lost ≥15 percent, and 18.4 lost ≥20 percent, as compared with 26.8 percent, 12.9 percent, 5.9 percent, and 2.8 percent of placebo-treated patients, respectively (p<0.001 for all).

Additional benefits were observed with orforglipron, with significantly greater improvements in waist circumference, systolic blood pressure, triglyceride levels, and non-high‒density lipoprotein cholesterol levels relative to placebo.

“Results of exploratory analyses in the current trial suggested that patients who received orforglipron had a higher likelihood of having a normal BMI or a near-normal waist-to-height ratio than those who received placebo, particularly among patients who had class I obesity or a BMI of 27–30 kg/m² and associated complications at baseline,” the investigators noted.

Safety consistent with class

“Small molecules may bind to off-target receptors, which raises the potential for additional adverse effects. No such effects have been detected in the orforglipron development program to date, and the orforglipron safety profile has been consistent with peptide GLP-1RAs in phase III clinical trials,” the investigators said. [N Engl J Med 2021;384:989-1002; Lancet 2023;402:705-719]

Treatment-emergent adverse events (AEs) occurred in 83.4 percent in the orforglipron 6-mg group, 86.6 percent in the 12-mg group, 85.2 percent in the 36-mg group, and 80.5 percent in the placebo group during the 72-week trial period. The most common AEs with the GLP-1RA were gastrointestinal events—nausea, constipation, diarrhoea, vomiting, and dyspepsia—which were mostly mild to moderate.

AEs resulted in treatment discontinuation in 5.3 percent to 10.3 percent of the patients in the orforglipron groups and in 2.7 percent of those in the placebo group. Between 3.8 percent and 5.5 percent of orforglipron-treated patients and 4.9 percent of those who received placebo had serious AEs.  Three deaths were reported: one each in the orforglipron 6- and 12-mg groups and one in the placebo group.

Oral pill advantage

Incretin-based therapies, such as GLP-1RAs, have proven to be useful in the treatment of obesity, yielding mean weight reductions of between 15 percent and 20 percent. Beyond weight loss, these therapies also confer cardioprotective effects. [Nat Rev Drug Discov 2025;24:631-650; N Engl J Med 2022; 387:205-216; N Engl J Med 2023;389:2221-2232; N Engl J Med 2021;384:989-1002]

The main drawback is that most GLP-1RA medications must be administered as a subcutaneous injection, which can be a barrier that limits treatment initiation and adherence, according to the investigators. [Int J Obes (Lond) 2025;49:433-451; Obes Pillars 2025;15:100181]

“Oral small-molecule GLP-1 receptor agonists may mitigate the limitations of peptide GLP-1 therapies while retaining their biologic properties. These agents may be amenable to easier storage, distribution, and administration. In addition, many patients prefer oral to injectable medications,” they said.

The investigators emphasized that the convenience of oral GLP-1RA medications could increase access to the therapy and ultimately deliver broader health benefits, while allowing patients to select a formulation aligned with their needs.

ATTAIN-1

The study included 3,127 adults (mean age 45 years, 64.2 percent female, 56.5 percent White) with a BMI of ≥30 or 27–30 kg/m² and have at least one obesity-related complication, including hypertension, dyslipidaemia, cardiovascular disease, or obstructive sleep apnoea, and a history of at least one unsuccessful dietary effort to lose body weight. None of these patients had diabetes and a change in body weight (either gain or loss) of >5 kg within 90 days before screening. The mean BMI was 37 kg/m².

The patients were randomly assigned to receive once-daily orforglipron at 6 mg (n=723), 12 mg (n=725), or 36 mg (n=730), or placebo (n=949) as an adjunct to healthy diet and physical activity for 72 weeks. The primary endpoint was the percent change in body weight from baseline to week 72.

“In this study, a healthy, balanced diet, rather than a hypocaloric diet with a 500-kcal deficit, was implemented as part of the recommended lifestyle modifications in line with recent expert recommendations. It remains uncertain whether this regimen influenced the trial results,” the investigators said. [Obes Pillars 2025;15:100181]

They also acknowledged that ATTAIN-1 was limited by the lack of comparison with currently approved obesity-management medications, the use of cutoffs for BMI inclusion criteria that have been developed in White populations, and the exclusion of patients with lower BMI values who may also have adiposity-related risks.