Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial.
Orforglipron showed a statistically significant reduction in body weight in adults with type 2 diabetes compared to placebo, but the clinical relevance of this weight loss is uncertain.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This phase 3 trial evaluated orforglipron, an oral GLP-1 receptor agonist, in adults with type 2 diabetes and obesity. Participants received doses of 6 mg, 12 mg, or 36 mg, with results showing statistically significant weight reduction compared to placebo. The study included 1613 participants and lasted 72 weeks.
Abstract
<h4>Background</h4>Obesity is a chronic disease that significantly contributes to type 2 diabetes and its complications. We aimed to evaluate orforglipron, an oral small-molecule (non-peptide) GLP-1 receptor agonist, for obesity treatment in adults with type 2 diabetes.<h4>Methods</h4>This 72-week, phase 3, double-blind, placebo-controlled trial was conducted across 136 sites in ten countries. Participants with a BMI of 27 kg/m<sup>2</sup> or higher and glycated haemoglobin (HbA<sub>1c</sub>) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1:2) to once-daily orforglipron 6 mg, 12 mg, 36 mg, or placebo. The primary endpoint was the mean percent change in bodyweight from baseline to week 72. The treatment regimen estimand (using data from all randomly assigned participants, regardless of intercurrent events) was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT05872620) and is completed.<h4>Findings</h4>From June 5, 2023, to Feb 15, 2024, 2859 participants were screened, and 1613 (757 [46·9%] female) were randomly assigned, following a dose-escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification; 1444 (89·5%) completed the study. Baseline bodyweight was 101·4 kg (SD 22·5), BMI 35·6 kg/m<sup>2</sup> (SD 6·6), and HbA<sub>1c</sub> 8·05% (SD 0·75; 64·4 mmol/mol [SD 8·2]). For the treatment regimen estimand, the mean percent change in bodyweight from baseline to week 72 was -5·1% (95% CI -6·0 to -4·2) with 6 mg (estimated treatment difference [ETD] -2·7 [95% CI -3·7 to -1·6]; p<0·0001), -7·0% (-7·8 to -6·2) with 12 mg (ETD -4·5 [-5·5 to -3·6]; p<0·0001), and -9·6% (-10·5 to -8·7) with 36 mg orforglipron (ETD -7·1 [-8·2 to -6·1]; p<0·0001), versus -2·5% (-3·0 to -1·9) with placebo (all p<0·0001 compared with placebo). All prespecified weight and cardiometabolic measures including HbA<sub>1c</sub> statistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6·1-9·9%) versus placebo (4·1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation. Ten deaths were reported during the study: six with orforglipron and four with placebo. Investigators deemed all deaths unrelated to the study treatment, except for one case in the placebo group and one case in the 12 mg orforglipron group. For the case in the orforglipron group, no treatment-related association was reported.<h4>Interpretation</h4>In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.<h4>Funding</h4>Eli Lilly and Company.
Background
The study addresses the need for effective obesity treatments in individuals with type 2 diabetes, a condition that significantly contributes to various health complications. Prior research has established the role of GLP-1 receptor agonists in weight management, but the efficacy of oral formulations like orforglipron had not been fully evaluated. This trial aims to fill that gap and provide insights into the potential of orforglipron as a treatment option.
Methods
This was a phase 3, double-blind, placebo-controlled trial conducted across 136 sites in ten countries. A total of 1613 participants with a BMI of 27 kg/m² or higher and HbA1c levels of 7-10% were randomly assigned to receive either orforglipron (6 mg, 12 mg, or 36 mg) or placebo for 72 weeks. The primary outcome was the mean percent change in body weight from baseline to week 72.
Results
The primary endpoint showed that participants receiving 36 mg of orforglipron experienced a mean percent change in body weight of -9.6% (95% CI -10.5 to -8.7) at week 72, with a statistically significant treatment difference of -7.1 (95% CI -8.2 to -6.1) compared to placebo (mean change -2.5%, 95% CI -3.0 to -1.9, p<0.0001). Other weight and cardiometabolic measures, including HbA1c, also improved significantly with orforglipron.
Interpretation
The findings indicate that orforglipron provides a statistically significant reduction in body weight compared to placebo, which aligns with previous literature on GLP-1 receptor agonists. However, the clinical significance of the weight loss, particularly at lower doses, may be limited. Confounding factors include the study's industry funding, the relatively high dropout rate, and the short duration of follow-up, which may affect the generalizability of the results.
Key findings
- Mean percent change in bodyweight at week 72 was -5.1% with 6 mg (ETD -2.7, p<0.0001), -7.0% with 12 mg (ETD -4.5, p<0.0001), and -9.6% with 36 mg (ETD -7.1, p<0.0001) versus -2.5% with placebo.
- Baseline bodyweight was 101.4 kg (SD 22.5), BMI 35.6 kg/m² (SD 6.6), and HbA1c 8.05% (SD 0.75).
- Treatment discontinuations due to adverse events were 6.1-9.9% for orforglipron versus 4.1% for placebo.
- Ten deaths were reported: six with orforglipron and four with placebo, with investigators deeming all but two deaths unrelated to treatment.
Limitations
- Industry-funded by Eli Lilly and Company.
- High dropout rate with 1444 (89.5%) completing the study.
- Short follow-up of 72 weeks may not capture long-term effects.
- Adverse events were primarily gastrointestinal, raising safety concerns.
- Weight loss may not be clinically significant at lower doses.