DIFFERENCES IN SAFETY PROFILE AND ADVERSE EFFECTS OF ORAL AND SUBCUTANEOUS GLP-1 ANALOGUES: A SYSTEMATIC REVIEW AND REAL-WORLD DATA ANALYSIS (2024–2026)
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5685Keywords:
GLP-1 Receptor Agonists; Semaglutide; Real-World Evidence; Treatment Adherence; Treatment Outcomes; Obesity; Type 2 Diabetes MellitusAbstract
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a cornerstone of therapy for type 2 diabetes mellitus (T2DM) and obesity, offering effective glycaemic control alongside significant cardiometabolic benefits. The introduction of oral formulations has raised the need for a precise comparison of their safety profile with classical subcutaneous preparations, particularly regarding pharmacokinetic differences and treatment tolerability.
Objective: This review aimed to compare the safety profile and adverse effects of oral and subcutaneous GLP-1 analogues based on available data from 2024–2026, incorporating evidence from clinical trials and real-world studies.
Methods: A systematic literature search was performed using PubMed and PubMed Central. Meta-analyses, randomised controlled trials (RCTs), and observational studies evaluating safety, tolerability, and pharmacokinetics of GLP-1 RAs were included, with emphasis on comparisons between oral and subcutaneous semaglutide.
Results: Both oral and subcutaneous GLP-1 RAs share a broadly similar adverse effect profile, dominated by dose-dependent gastrointestinal (GI) symptoms — nausea, vomiting, and diarrhoea — which are most pronounced during treatment initiation. Subcutaneous formulations offer a more predictable pharmacokinetic profile and stable systemic exposure, translating into more consistent tolerability. Oral semaglutide exhibits greater bioavailability variability, potentially leading to a more heterogeneous clinical response and higher rates of GI events. Real-world evidence indicates a significantly higher treatment discontinuation rate with oral formulations due to adverse effects. Subcutaneous GLP-1 RAs are additionally associated with mild injection-site reactions absent in oral forms. Increased risk of gallbladder disease is observed in both groups, while no conclusive evidence of elevated pancreatitis risk exists.
Conclusions: Despite a broadly similar safety profile, oral and subcutaneous GLP-1 analogues differ in pharmacokinetics, tolerability patterns, and treatment discontinuation rates. Subcutaneous formulations provide a more predictable clinical effect, while oral agents may offer greater patient convenience at the cost of higher interindividual variability. The choice of administration route should be individualised, accounting for patient preferences, adverse effect risk profile, and anticipated impact on adherence. Long-term data and further real-world evidence are needed for a comprehensive safety evaluation.
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Copyright (c) 2026 Aleksandra Olga Pakulska, Natalia Rządzińska, Aleksandra Maria Błoch, Kornelia Julia Fimiarz, Aleksandra Katarzyna Kłosowicz, Maria Anna Miller, Aleksandra Jolanta Kamińska
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