Rationale for the use of metformin and exercise to counteract statin-associated side effects

Introduction: Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. They are usually well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). Methods: A PubMed search was carried out using the following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. Results: Mitochondrial damage and muscle atrophy are likely the central mechanisms producing SAMS, whereas decreased glucose transport, fatty acid oxidation and insulin secretion are likely involved in the development of NOD. Metformin and exercise training share many pathways that could potentially contrast SAMS and NOD. Clinical evidence also supports the combination of statins with metformin and exercise. Conclusion: This combination appears attractive both from a clinical and an economical viewpoint, since all three therapies are highly cost-effective and their combination could result in diabetes and cardiovascular disease prevention.