Efficacy and safety of orforglipron in type 2 diabetes mellitus and obesity: a GRADE-assessed meta-analysis and trial sequential analysis with subgroup evaluations by diabetic status, obesity status, and dose regimens.

BACKGROUND: Orforglipron, an oral non-peptide GLP-1 receptor agonist, is being evaluated for type 2 diabetes mellitus (T2DM) and obesity. A quantitative synthesis of efficacy and safety across doses and phenotypes is needed. OBJECTIVE: To assess the efficacy and safety of orforglipron versus placebo in adults with T2DM and/or obesity, including prespecified subgroup analyses by dose and metabolic phenotype, along with certainty evaluation using GRADE and trial sequential analysis (TSA). METHODS: Following PRISMA 2020, randomized controlled trials comparing orforglipron with placebo were combined using random-effects meta-analysis to determine mean differences (MD) or risk ratios (RR) with 95% confidence intervals. Heterogeneity (I²), influence (leave-one-out analysis), dose groups (3, 6, 24, 36 mg), and phenotype subgroups (obese/non-diabetic vs. non-obese/diabetic) were analyzed; TSA evaluated the required information size and monitoring boundaries. RESULTS: Five trials (n = 2,672; orforglipron 1,413; placebo 1,259) were included. Orforglipron reduced HbA1c (primary MD − 1.07%, 95% CI − 2.00 to − 0.13; I²=100%; sensitivity MD − 1.45%, 95% CI − 1.49 to − 1.41; I²=0%), body weight (primary MD − 5.25 kg, 95% CI − 6.72 to − 3.77; I²=96%; sensitivity MD − 4.21 kg, 95% CI − 4.40 to − 4.02; I²=0%), BMI (MD − 1.99 kg/m², 95% CI − 2.97 to − 1.01; I²=97%), and systolic blood pressure (primary MD − 3.90 mmHg, 95% CI − 6.44 to − 1.35; I²=91%; sensitivity MD − 2.56 mmHg, 95% CI − 4.64 to − 0.48; I²=22%). Fasting plasma glucose decreased significantly overall (MD − 25.77 mg/dL, 95% CI − 58.70 to − 7.18; very high heterogeneity; dose-response evident). Diastolic blood pressure was neutral (primary MD − 0.32 mmHg, 95% CI − 2.36 to 1.71; sensitivity MD + 0.68 mmHg, 95% CI − 0.02 to 1.39). Heart rate increased (primary MD + 6.38 bpm, 95% CI + 2.99 to + 9.77; high heterogeneity). Hypoglycemia (RR 1.05, 95% CI 0.23 to 4.86) and serious adverse events (RR 1.10, 95% CI 0.75 to 1.62) did not differ from placebo. TSA supported strong evidence for weight, BMI, and SBP; additional data is needed for DBP, heart rate, hypoglycemia, and SAEs. CONCLUSIONS: Reported as primary pooled effects, orforglipron improves HbA1c, weight, BMI, SBP, and fasting plasma glucose, with a class-consistent increase in heart rate and no excess in hypoglycaemia or serious adverse events versus placebo. Sensitivity analyses generally reduced heterogeneity without reversing conclusions. TSA indicates conclusions for weight, BMI, and SBP are robust; longer-term comparative trials should refine DBP and safety signals.