Cardiometabolic Profiles of Oral and Subcutaneous Glucagon‐Like Peptide‐1 Receptor Mono‐Agonists in Adults With Overweight or Obesity: A Systematic Review and Network Meta‐Analysis

ABSTRACT Aims To characterize the cardiometabolic profiles of oral and subcutaneous glucagon‐like peptide‐1 (GLP‐1) receptor mono‐agonists in adults with overweight or obesity, with or without type 2 diabetes (T2D), using network meta‐analysis (NMA). Materials and Methods PubMed, Embase and CENTRAL were searched (January 2014–November 2025) for randomized controlled trials (RCTs) evaluating GLP‐1 receptor mono‐agonists (semaglutide, liraglutide and orforglipron) in adults with overweight or obesity. The primary outcome was the cardiometabolic efficacy index (CEI), a ranking‐based composite (0 to 1) summarizing performance across seven cardiometabolic endpoints: total body weight loss percentage, triglycerides, HDL cholesterol‐C, LDL‐C, waist circumference, HbA1c and systolic blood pressure. Secondary outcomes included treatment effects for each individual CEI component. Results Nineteen RCTs ( N = 13 117) were analysed. Semaglutide 7.2 mg achieved the highest CEI (0.86), followed by orforglipron 36 mg (bioequivalent to Foundayo 17.2 mg tablet) (0.68) and semaglutide 2.4 mg (0.66), all exhibiting placebo‐adjusted weight reductions ≥ 10%. CEI rankings were generally consistent across T2D and non‐T2D subgroups. Among oral formulations in non‐T2D adults, OFG 36 mg showed a CEI comparable to oral semaglutide 25 mg (0.67 vs 0.63). Conclusions Higher‐dose GLP‐1 receptor mono‐agonists, particularly semaglutide 7.2 mg and orforglipron 36 mg (Foundayo 17.2 mg tablet), demonstrated the most consistent multidimensional cardiometabolic improvements, although domain‐specific differences were observed across agents.