Efficacy and safety of orforglipron in obesity with type 2 diabetes mellitus: a GRADE-assessed meta-analysis of randomized controlled trials

BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) frequently coexist and markedly increase cardiometabolic risk. Orforglipron is a novel oral glucagon-like peptide-1 receptor agonist developed to improve adherence compared with injectable therapies. We performed a systematic review and meta-analysis to evaluate its efficacy and safety. METHODS: PubMed, Scopus, Cochrane CENTRAL, and Web of Science were searched through January 2026 for randomized controlled trials (RCTs) comparing orforglipron with placebo in adults with obesity and T2DM. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Three RCTs, including 2,505 participants, were analyzed. Dose-subgroup analyses demonstrated a consistent dose-response pattern across all efficacy outcomes. For body weight, reductions versus placebo ranged from MD - 2.43% at 3 mg to MD - 7.80% at 24 mg. BMI reductions ranged from MD - 0.88 kg/m² at 3 mg to MD - 2.70 kg/m² at 45 mg. Waist circumference reductions were significant at doses ≥ 6 mg, reaching MD - 5.90 cm at 24 mg. HbA1c reductions ranged from MD - 0.80% at 3 mg to MD - 1.67% at 45 mg, and fasting serum glucose reductions ranged from MD - 20.62 mg/dL at 3 mg to MD - 44.80 mg/dL at 45 mg. Treatment discontinuation due to adverse events was higher with orforglipron across doses, while serious adverse events were not significantly different from placebo at any dose. CONCLUSIONS: Orforglipron may improve weight and glycemic outcomes in obese patients with T2DM; however, these findings are based on only three randomized controlled trials, and several key efficacy outcomes were rated as low certainty, so the results should be interpreted cautiously pending larger confirmatory studies.