Understanding the molecular mechanisms of statin pleiotropic effects

• Published in: Archives of toxicology Vol. 97; no. 6; pp. 1529 - 1545
• Main Authors: German, Charles A., Liao, James K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2023; Springer Nature B.V
• Subjects: Arteriosclerosis; Atherosclerosis; biochemical pathways; Biomedical and Life Sciences; biomedical research; Biomedicine; blood serum; Cardiovascular diseases; Cardiovascular system; Cholesterol; Cholesterol, LDL; Cognitive ability; cognitive disorders; Density; diabetes; Diabetes mellitus; Drug therapy; Environmental Health; Hemorrhage; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hypolipidemic Agents - therapeutic use; inflammation; Kexin; lipoprotein receptors; Literature reviews; Low density lipoprotein; low density lipoprotein cholesterol; Molecular modelling; Occupational Medicine/Industrial Medicine; Oxidative stress; oxidoreductases; Pharmacology/Toxicology; Pleiotropy; Proprotein convertases; reaction kinetics; Receptor density; Reductases; Review; Review Article; Risk Factors; Side effects; Statins; Stroke; Subtilisin; Thromboembolism; Thrombosis; Cardiovascular disease; Statin; LDL; Cholesterol; Atherosclerosis
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-023-03492-6

Statins represent the cornerstone of pharmacotherapy for the prevention of atherosclerotic cardiovascular disease. These medications not only reduce low-density lipoprotein cholesterol (LDL-C) via inhibition of 3-hydroxy-3-methylglutarate attached to CoA reductase, the key rate-limiting step in the cholesterol biosynthetic pathway, but also upregulate expression of the low-density lipoprotein receptor, improving serum clearance. Given LDL-C is a causal risk factor for the development of atherosclerosis, these complementary mechanisms largely explain why statin therapy leads to reductions in major adverse cardiovascular events. However, decades of basic and clinical research have suggested that statins may exert other effects independent of LDL-C lowering, termed pleiotropic effects, which have become a topic of debate among the scientific community. While some literature suggests statins may improve plaque stability, reduce inflammation and thrombosis, decrease oxidative stress, and improve endothelial function and vascular tone, other studies have suggested potential harmful pleiotropic effects related to increased risk of muscle-related side effects, diabetes, hemorrhagic stroke, and cognitive decline. Furthermore, the introduction of newer, non-statin LDL-C lowering therapies, including ezetimibe, proprotein convertase subtilisin/Kexin Type 9, and bempedoic acid, have challenged the statin pleiotropy theory. This review aims to provide a historical background on the development of statins, explore the mechanistic underpinnings of statin pleiotropy, review the available literature, and provide up to date examples that suggest statins may exert effects outside of LDL-C lowering and the cardiovascular system.