Atorvastatin Pharmacogenetics: What is the Evidence for Genetic Association with Efficacy & Safety?

Abstract

Hyperlipidemia, characterized by elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and/or decreased high-density lipoprotein cholesterol (HDL-C), is a key contributor to the development of cardiovascular diseases (CVD), which remain the leading cause of morbidity and mortality worldwide. Statins, especially atorvastatin, are the mainstay pharmacological agents used to lower cholesterol levels and prevent atherosclerotic complications. Atorvastatin inhibits HMG-CoA reductase, reducing hepatic cholesterol synthesis and upregulating LDL receptor expression. However, the efficacy and safety of atorvastatin therapy are significantly influenced by genetic polymorphisms in drug-metabolizing enzymes, transporters, and lipid-regulating genes. This review comprehensively examines the pharmacogenetics of atorvastatin, focusing on genetic variants influencing drug absorption, distribution, metabolism, and pharmacodynamic response. Polymorphisms in hepatic uptake transporters (SLCO1B1), efflux transporters (ABCB1, ABCG2), drug-metabolizing enzymes (CYP3A4 and CYP3A5), and lipid-regulating genes (APOE, APOA5, APOB, LDLR) are critically evaluated across diverse populations. Among these, the SLCO1B1 c.521T>C (rs4149056) variant emerges as a key determinant of atorvastatin exposure and myopathy risk, though its clinical relevance varies by ethnicity. Pharmacogenetic studies show population-specific variations in atorvastatin outcomes, emphasizing the need for precision medicine in hyperlipidemia management.