Systemic pathways linking subcutaneous therapies to gastrointestinal adverse effects: A Narrative review of mechanisms and mitigation strategies

Abstract: To systematically evaluate the spectrum, mechanisms, and prevention strategies of gastrointestinal (GI) adverse effects associated with subcutaneously administered drug therapies across multiple therapeutic classes. A comprehensive literature search was conducted in PubMed, EMBASE, and the Cochrane Library for studies published from January 2000 to June 2025. Eligible publications included randomized trials, observational studies, systematic reviews, meta-analyses, and regulatory label data reporting GI adverse effects of subcutaneous therapies. Drug classes analyzed included metabolic and endocrine agents, hematopoietic and bone-active drugs, cytokine modulators, biologic immunotherapies, vaccines, and selected miscellaneous agents. Data were extracted on incidence, clinical manifestations, mechanistic pathways, and mitigation strategies. Subcutaneously administered drugs were consistently associated with a wide range of GI adverse effects, including nausea, vomiting, diarrhea, abdominal pain, dyspepsia, and mucosal inflammation. Prominent contributors included glucagon-like peptide-1 receptor agonists, insulin analogs, growth factors, cytokine modulators, and biologic therapies. Mechanistic pathways identified included delayed gastric emptying, vagal and enteric nervous system activation, cytokine-mediated epithelial dysfunction, immune activation, and alterations of the gut microbiome. Interindividual variability in metabolic, immunologic, and neurohumoral responses influenced susceptibility. Despite bypassing the GI tract, subcutaneous therapies can induce clinically relevant GI toxicity through systemic neurohormonal, immune, and microbial pathways. Recognition of these mechanisms supports the use of dose titration, administration timing, dietary modification, and prophylactic pharmacotherapy to improve tolerability and treatment adherence.