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.

PubMed16 Apr 2026Diabetes, obesity & metabolism● 7/10i

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.

Lu Y, Chen J, Guo Y, Ding H, Liu YL et al.

Semaglutide 7.2 mg achieved the highest cardiometabolic efficacy index (0.86), followed by orforglipron 36 mg (0.68) and semaglutide 2.4 mg (0.66), all producing placebo-adjusted weight reductions ≥10%. Network meta-analysis of 19 RCTs with 13,117 adults with overweight or obesity, evaluating composite outcomes across seven cardiometabolic parameters. This provides the first head-to-head comparison of oral orforglipron against both approved and investigational semaglutide doses across multiple cardiometabolic endpoints, with orforglipron showing competitive performance despite being the first small-molecule oral GLP-1.

Strategic Signal

The data validates orforglipron's positioning as a competitive oral alternative to injectable semaglutide, strengthening Eli Lilly's medical narrative for Foundayo against Novo's established Wegovy franchise. Payers will likely view the comparable cardiometabolic profiles as supporting equivalent formulary positioning, reducing Novo's pricing leverage for higher-dose semaglutide formulations. The composite endpoint approach mirrors value-based care trends, positioning both companies to pursue bundled reimbursement strategies with health systems seeking comprehensive metabolic outcomes rather than weight loss alone.

GLP-1Weight lossDrug comparisonsEli Lilly Novo Nordisk

Original 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.

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