Advanced metformin delivery systems and combination strategies for optimized glycemic control: a comprehensive review

Diabetes mellitus continues to place a significant global health burden, prompting sustained interest in developing safer and more effective therapeutic options. Metformin remains the cornerstone treatment for type 2 diabetes due to its strong glycemic efficacy, favourable safety profile, and affordability; however, its short half-life, poor intestinal absorption, and gastrointestinal intolerance restrict its full therapeutic potential. This review consolidates current evidence from PubMed, Scopus, and Google Scholar to explore the pharmacology of metformin, its limitations, and the evolution of advanced drug-delivery technologies designed to enhance its performance. Contemporary approaches including sustained-release matrices, gastro-retentive systems, nanoparticles, liposomes, microspheres, mucoadhesive films, and fast-dissolving formulations demonstrate meaningful improvements in bioavailability, controlled release, onset of action, and patient adherence. In addition, combination therapies involving DPP-4 inhibitors, SGLT2 inhibitors, sulfonylureas, or GLP-1 analogues provide synergistic glycemic control and reduce the overall therapeutic burden. Evidence further suggests that metformin-loaded nanocarriers may extend its utility beyond diabetes, offering potential benefits in oncology, infectious diseases, and inflammatory disorders. Collectively, these advancements reaffirm metformin’s relevance in modern therapy and highlight the growing role of formulation science in optimizing clinical outcomes. Continued innovation in targeted delivery, nanotechnology, and personalized approaches may further strengthen metformin’s future applications and improve long-term management of diabetes.