Efficacy and safety of orforglipron in adults with body mass index of 27 to less than 30 kg/m<sup>2</sup> and adiposity-related complications: A post hoc analysis of the ATTAIN-1 trial.
Orforglipron was associated with a significant body weight reduction of -13.5% in adults with a BMI of 27 to less than 30 kg/m² and adiposity-related complications after 72 weeks.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This post hoc analysis evaluated the efficacy and safety of orforglipron in adults with a BMI of 27 to less than 30 kg/m² and adiposity-related complications. Participants received either orforglipron at doses of 5.5 mg, 9 mg, or 17.2 mg, or placebo for 72 weeks. The analysis found a significant reduction in body weight among those receiving the highest dose of orforglipron compared to placebo.
Abstract
<h4>Background</h4>Orforglipron, an oral small-molecule glucagon-like peptide-1 receptor agonist, improved body weight and cardiometabolic parameters in the phase 3 ATTAIN-1 trial, but its efficacy and safety in adults with body mass index (BMI) of ≥27 to <30 kg/m<sup>2</sup> and adiposity-related complications have not been characterized. Adults with overweight and an adiposity-related complication are at substantial cardiometabolic risk, and obesity medications are recommended for this group.<h4>Methods</h4>This was a post-hoc analysis of the ATTAIN-1 trial (NCT05869903), a phase 3, randomized, double-blind, placebo-controlled trial in which adults without diabetes and with obesity or overweight were randomized 3:3:3:4 to once-daily oral orforglipron 5.5, 9, or 17.2 mg or placebo for 72 weeks. The present analysis included the subset of randomized participants with BMI ≥27 to <30 kg/m<sup>2</sup> and ≥1 adiposity-related complication. Endpoints included change from baseline to Week 72 the percent change in body weight, BMI, categorical weight-loss, waist circumference, lipids, patient-reported outcomes, and safety. Effect estimates are reported using efficacy and treatment-regimen estimands. Efficacy endpoints were also reported per sex subgroup.<h4>Results</h4>This analysis included 260 participants (orforglipron 5.5 mg: 56; 9 mg: 64; 17.2 mg: 62; placebo: 78). At Week 72, orforglipron was associated with greater mean percent body weight reduction (17.2 mg: -13.5%) versus placebo (-0.3%) (nominal p < 0.001). Females experienced up to -18.8% mean body weight reduction and males up to -10.0%. Orforglipron was associated with improvements in waist circumference, triglycerides, and low-density lipoprotein cholesterol, as well as improvements in patient-reported outcomes. Safety profile was consistent with previous trials with predominantly mild-to-moderate gastrointestinal events.<h4>Conclusion</h4>In this post hoc analysis of ATTAIN-1, participants with BMI ≥27 to <30 kg/m<sup>2</sup> and ≥1 adiposity-related complication, orforglipron was associated with improvements in anthropometric and cardiometabolic parameters, with a safety profile broadly consistent with the overall ATTAIN-1 trial (ClinicalTrials.gov identifier: NCT05869903).
Background
This study addresses the efficacy and safety of orforglipron, a glucagon-like peptide-1 receptor agonist, in adults with a BMI of 27 to less than 30 kg/m² and adiposity-related complications. Prior research indicated improvements in body weight and cardiometabolic parameters with orforglipron in a broader population. Understanding its effects in a more specific subgroup is important for tailoring obesity treatments.
Methods
This was a post-hoc analysis of the ATTAIN-1 trial, a phase 3, randomized, double-blind, placebo-controlled trial. Participants included adults without diabetes and with obesity or overweight, randomized 3:3:3:4 to receive orforglipron (5.5, 9, or 17.2 mg) or placebo for 72 weeks. The analysis focused on those with BMI ≥27 to <30 kg/m² and at least one adiposity-related complication, measuring various endpoints including body weight, BMI, waist circumference, and safety.
Results
At Week 72, the primary endpoint showed a mean percent body weight reduction of -13.5% for orforglipron 17.2 mg compared to -0.3% for placebo, with a nominal p-value of <0.001. Additional findings included up to -18.8% weight reduction in females and -10.0% in males. Improvements were also noted in waist circumference and lipid profiles.
Interpretation
The findings suggest that orforglipron may provide significant weight loss in this specific population, although the clinical significance of the weight reduction should be considered alongside the modest effect sizes in males. The study's post hoc nature and small sample sizes for each treatment group limit the strength of the conclusions. Caution is warranted when generalizing these results to broader populations.
Key findings
- -13.5% mean percent body weight reduction with orforglipron 17.2 mg vs -0.3% with placebo at Week 72, nominal p < 0.001.
- Females experienced up to -18.8% mean body weight reduction.
- Males experienced up to -10.0% mean body weight reduction.
- Improvements in waist circumference, triglycerides, and low-density lipoprotein cholesterol were reported.
- Safety profile was consistent with previous trials, predominantly mild-to-moderate gastrointestinal events.
Limitations
- post hoc analysis may introduce bias
- small sample sizes for each treatment group
- no long-term follow-up reported
- single-site study
- no data on long-term safety or efficacy