Metabolic and Glycemic Effects of Orforglipron, a GLP-1 Receptor Agonist, in Adults With or Without Diabetes: A Network Meta-Analysis of Randomised Clinical Trials.

BACKGROUND AND AIM: Orforglipron (OFG), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1 RAs), showed potential benefits for type 2 diabetes mellitus (T2DM) and obesity. Its dose-response effects on body weight-related parameters and glycemic outcomes remain incompletely analysed. This network meta-analysis aims to address this gap across multiple doses of OFG (3, 12, 24, 36 and 45 mg) in adults with or without T2DM at 12, 26 and 36 weeks. METHODS: PRISMA guidelines were followed in our study. Embase, PubMed, Web of Science and Scopus were searched for randomised controlled trials. Random-effects models expressed OFG effects as odds ratios (OR), mean difference (MD) and standardised mean difference (SMD) with 95% confidence intervals (95% CI). RStudio software (version 4.5.1) was used for analysis. RESULTS: Six RCTs comprising 4878 participants were included. OFG demonstrated reductions in body weight, BMI and waist circumference across all follow-ups. OFG 45 mg dose produced the greatest effects in body weight (SMD: -1.71 kg at 12 weeks, MD: -8.81 kg at 26 weeks and MD: -12.13 kg at 36 weeks vs. placebo). Categorical weight-loss analyses showed that individuals receiving 24-45 mg increased the odds to achieve ≥ 5%, ≥ 10% and ≥ 15% weight loss at 26 weeks. Glycemic outcomes improved across all doses, with the greatest HbA1c reduction at 45 mg (-1.65%; 95% CI -1.98 to -1.32) and greatest fasting glucose improvement at 36 mg dose. Treatment-emergent adverse events increased with dose. CONCLUSION: OFG demonstrated improvements in weight-related outcomes and glycemic outcomes. Adverse events increased with dose, consistent with expected class tolerability.