A Comprehensive Systematic Review of the Role of Semaglutide Anti-Obesity Therapy in Multiple Metabolic Diseases: A Systematic Review of Randomized Controlled Trials and Primary Studies

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Introduction: Obesity constitutes the pathophysiological hub of interconnected metabolic diseases including type 2 diabetes mellitus (T2DM), atherosclerotic cardiovascular disease (ASCVD), heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), metabolic dysfunction-associated steatohepatitis (MASH) and peripheral artery disease (PAD). Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been evaluated across all these domains. This systematic review synthesised primary evidence on semaglutide across multiple metabolic diseases to determine consistency of benefit across organ systems. Methods: The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Eligible designs comprised randomized controlled trials and observational studies evaluating semaglutide in obesity or obesity-related metabolic disease. Systematic reviews were excluded from primary tabulation but retained as contextual comparators. Two reviewers independently screened, extracted data and appraised risk of bias using Cochrane RoB 2 and ROBINS-I; certainty was graded with GRADE. Synthesis was narrative and semi-quantitative by outcome domain. Results: Twenty-seven primary studies (24 RCTs, 3 observational cohorts) encompassing >180,000 participants across 15 outcome domains were included. Semaglutide 2.4 mg weekly produced mean weight reductions of -14.9% to -16.0% versus -2.4% to -5.7% with placebo (all P