BACKGROUND: 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.
METHODS: 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/mor higher and glycated haemoglobin (HbA) 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. 2 1c
FINDINGS: 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(SD 6·6), and HbA8·05% (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 HbAstatistically 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. 2 1c1c
INTERPRETATION: 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.
FUNDING: Eli Lilly and Company.
