Metformin: Beyond Glycemic Control - A Comprehensive Review Of Its Adverse Effects And Emerging Therapeutic Potential

Abstract

Metformin, traditionally prescribed as a first-line therapy for type 2 diabetes mellitus, has garnered widespread attention for its therapeutic potential beyond glycemic control. Recent reviews have deepened our understanding of its pleiotropic mechanisms, including modulation of AMP-activated protein kinase (AMPK), suppression of mitochondrial complex I, and inhibition of the mTOR pathway. Contemporary pharmacokinetic insights reveal population-specific considerations in dosing, absorption, and elimination. Updated safety profiles emphasize gastrointestinal tolerability, rare risks such as lactic acidosis, and nutrient deficiencies, especially in long-term therapy. Expanding clinical evidence, supported by recent trials and meta-analyses, supports the repurposing of metformin in oncology, cardiovascular protection, neurodegeneration, polycystic ovary syndrome (PCOS), aging, and weight management.

Key reviews, including those by Foretz et al. (2023) and Silverii et al. (2024), highlight both the molecular complexity and translational applications of metformin. Advances in nano-formulations and biomarker-guided approaches are opening new avenues for targeted delivery and patient-specific therapy. Nevertheless, variability in individual responses, gaps in long-term safety data, and a need for robust randomized controlled trials remain pressing challenges. As recent studies, such as Zhou & Xue (2025) and Petrie (2024) suggest, the future of metformin lies in precision medicine, where its multifaceted pharmacology may be leveraged for broader chronic disease management.