Statin Intolerance and Adverse Effects in Lipid-Lowering Therapy – Pathomechanisms, Management Strategies, and Alternative Treatment Approaches

Abstract

Statins are essential in preventing cardiovascular diseases by lowering LDL cholesterol levels. Landmark trials like 4S and HPS demonstrated significant reductions in cardiovascular events and mortality with statin use. Statins inhibit hepatic cholesterol synthesis and upregulate LDL receptors, improving endothelial function and exerting anti-inflammatory effects. However, adverse effects can lead to discontinuation. Musculoskeletal symptoms, including myalgia and rhabdomyolysis, affect 5-20% of patients, often linked to mitochondrial dysfunction and coenzyme Q10 depletion. Hepatotoxicity, although less frequent, presents as elevated transaminases, particularly with lipophilic statins. Statins may also increase new-onset diabetes risk by 9-12%, potentially due to impaired insulin signaling and mitochondrial dysfunction. Cognitive effects remain controversial, with some reports of memory impairment, especially with lipophilic statins. Managing statin intolerance involves dose reduction, switching to hydrophilic statins, or coenzyme Q10 supplementation. Alternative therapies for statin-intolerant patients include ezetimibe, PCSK9 inhibitors, and bempedoic acid. Lifestyle interventions like a Mediterranean diet and regular exercise further support cardiovascular health while minimizing adverse effects.