Weight management remains a core component of care in adults with type 2 diabetes mellitus (T2DM) and obesity or overweight. In The Lancet, a 72-week, phase 3, double-blind, placebo-controlled trial assessed once-daily oral orforglipron in adults with body mass index (BMI) of 27 kg/m² or higher and glycated haemoglobin (HbA1c) 7-10% (53-86 mmol/mol).
The trial screened 2,859 individuals and randomly assigned 1,613 participants (46.9% female) to orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630) following dose escalation, with all groups receiving lifestyle modification. Overall, 1,444 participants (89.5%) completed the study. Mean baseline bodyweight was 101.4 kg (SD 22.5), mean BMI was 35.6 kg/m² (SD 6.6), and mean HbA1c was 8.05% (SD 0.75; 64.4 mmol/mol [SD 8.2]). Using the treatment regimen estimand, mean percent bodyweight change from baseline to week 72 was −5.1% (95% CI −6.0 to −4.2) with 6 mg, −7.0% (−7.8 to −6.2) with 12 mg, and −9.6% (−10.5 to −8.7) with 36 mg, compared with −2.5% (−3.0 to −1.9) with placebo. Estimated treatment differences were −2.7, −4.5, and −7.1 percentage points, respectively (all p<0.0001). All prespecified weight and cardiometabolic measures, including HbA1c, showed statistically significant improvement with orforglipron.
Discontinuation due to adverse events occurred in 6.1% to 9.9% of participants receiving orforglipron compared with 4.1% in the placebo group. The most frequently reported adverse events were mild to moderate gastrointestinal events, which predominantly occurred during dose escalation. Ten deaths were reported during the trial, including six in the orforglipron groups and four in the placebo group. Investigators considered all deaths unrelated to study treatment except one case in the placebo group and one case in the 12 mg orforglipron group; no treatment-related association was reported for the orforglipron case.
Once-daily oral orforglipron demonstrated statistically superior, dose-dependent bodyweight reduction compared with placebo in adults with obesity or overweight and type 2 diabetes.
