Efficacy and safety of orforglipron 12 mg versus orforglipron 36 mg maintenance dose among patients with obesity with or without diabetes: a systematic review and comprehensive meta-analysis.

Obesity is projected to affect about one billion adults by 2030 and is associated with cardiometabolic morbidity. Orforglipron is an oral, non-peptide glucagon-like peptide-1 receptor agonist developed to provide weight and metabolic benefits. Prior meta-analyses have supported its efficacy and safety but were limited by shorter follow-up and a predominance of non-diabetic populations. This meta-analysis aims to provide the most comprehensive head-to-head comparison between the two most commonly studied maintenance doses (12 mg vs. 36 mg), assessing weight, glycemic, cardiometabolic, and safety outcomes. We searched PubMed, Web of Science, Cochrane, and Scopus until March 1, 2026, for randomized controlled trials (RCTs) comparing orforglipron 12 mg and 36 mg in obese adults. Outcomes of interest included percentage and absolute body weight change, BMI, HbA1c, waist circumference, lipid parameters, blood pressure, and adverse events. Results were pooled using a fixed-effects model, and prespecified subgroup analyses examined differences by diabetes status and treatment duration. Six RCTs (3459 participants) were included. Compared with the 12 mg dose, the 36 mg dose was associated with greater reductions in percentage body weight change (p < 0.00001), absolute body weight change (p < 0.00001), body mass index (p < 0.00001), HbA1c (p < 0.00001), waist circumference (P < 0.00001), percent change in triglycerides (P = 0.002), and systolic blood pressure (P = 0.002). Adverse events were comparable between doses. No significant differences were observed in gastrointestinal events or pancreatic functions. A small difference in pulse rate was noted but was not considered clinically significant. In obese adults, orforglipron 36 mg improved weight and metabolic outcomes compared with 12 mg. No statistically significant differences between doses were detected for the prespecified safety outcomes, although small increases in ALT and AST were observed with the 36 mg dose and the trials included were not powered to detect rare or long-term adverse events. These findings support consideration of the higher maintenance dose when clinically appropriate. Longer-term studies are needed to confirm the benefit and cardiovascular outcomes. Not applicable.