Type 2 diabetes mellitus (T2DM) and obesity represent major global health challenges. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as effective treatments for both conditions, providing significant glycemic control and weight-reduction benefits. Orforglipron is an investigational, oral, non-peptide GLP-1RA that does not require complex absorption enhancers or dosing restrictions. Preclinical and early clinical studies have demonstrated promising results in glycemic control and weight reduction. This systematic review and network meta-analysis aims to evaluate the efficacy and safety of various orforglipron doses in improving glycemic control and reducing body weight. We conducted a search across five databases. A frequentist network meta-analysis with random-effects models was performed using MetaInsight (version 3.14) to analyze randomized controlled trials(RCTs) comparing orforglipron with placebo in patients with obesity or diabetes. Efficacy outcomes (HbA1c, body weight, BMI, lipid profile, blood pressure) were reported as mean differences, and safety outcomes (adverse events) as risk ratios, with 95% CIs. Five RCTs involving multiple orforglipron doses (3-45 mg) demonstrated that higher doses, particularly 45 mg, significantly reduced BMI (MD = -3.52 kg/m²), body weight (MD = -9.34%), waist circumference (MD = -7.19 cm), HbA1c (MD = -1.33%), triglycerides (MD = -15.31% for 36 mg), and blood pressure compared to placebo. All doses showed higher rates of total adverse events and treatment discontinuation than placebo, while serious adverse events and specific gastrointestinal symptoms (nausea, vomiting, dyspepsia) were lower than placebo. Orforglipron is particularly suitable for patients preferring oral therapy over injectable GLP-1 receptor agonists. Orforglipron demonstrated significant dose-dependent improvements in patients with obesity (with or without comorbidities) and T2DM, with higher doses (36-45 mg) showing greater efficacy for weight loss and glycemic control, though at the cost of increased treatment discontinuation. Mid-range doses (24-36 mg) may be better suited for patients prioritizing lipid management and blood pressure control while seeking improved tolerability with a lower discontinuation risk.
