Abstract and Introduction
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, more commonly referred to as statins, comprise a family of lipid-lowering drugs that are prescribed on a global scale on account of their proven safety and efficacy in reducing mortality from cardiovascular disease. Beyond their potent pharmacologic inhibition of cholesterol biosynthesis, statins appear to have pleiotropic effects, including modulation of cell growth, apoptosis, and inflammation. Through modulation of these pathways, statins have the potential to influence a wide range of disease processes, including cancer. Much attention has focused on the association between statins and colorectal cancer, raising the prospect that these well-tolerated compounds could form the basis of future chemopreventive strategies. Herein, we review the epidemiologic, clinical, and preclinical data relevant to statins and colorectal neoplasia, and discuss the current status and future potential of statins as chemopreventive agents.
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, more commonly referred to as statins, were first identified in the 1970s by Japanese biochemist, Akira Endo, and colleauges, and received market approval for the treatment of hypercholesterolemia in the late 1980s. As a result of their proven efficacy in the primary and secondary prevention of cardiovascular mortality and stroke, statins have become one of the most widely prescribed medications in the world. Approximately 11% of the US population use statins, with prevalence increasing to 44% in those older than 65 years of age. Statins competitively inhibit HMG-CoA reductase, which catalyzes the rate-limiting step in the mevalonate pathway. By preventing the conversion of HMG-CoA to mevalonate, statins potently reduce endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein (LDL) cholesterol. Independent of their lipid-lowering properties, statins appear to possess a variety of pleiotropic effects, including inhibition of cell proliferation, enhanced apoptosis, and modulation of inflammation, endothelial function, and angiogenesis.[6,7] Indeed, some of these additional actions are thought to contribute to their proven cardioprotective benefit.[6,8,9] Through these diverse mechanisms, statins have been hypothesized to influence a wide range of additional disease processes, including cancer.
A significant body of evidence suggests that statins might have a role in cancer chemoprevention.[10,11] However, the association between statins and cancer risk has a rather checkered history. After the market approval of statins, concerns were raised regarding the long-term safety of pharmacologic cholesterol lowering in human beings, based largely on observational data suggesting that noncardiovascular mortality, including cancer, may be increased by low serum cholesterol levels.[12,13] In retrospect, this association was probably largely explained by uncontrolled confounding and reverse causality, with low cholesterol levels being a consequence of occult malignancy.[14,15] Anxieties regarding long-term statin use were compounded further by preapproval studies that suggested statins were carcinogenic in rodents. Data from an early cardiovascular randomized controlled trial (RCT) of pravastatin, showing an increased incidence of breast cancer in the treatment arm, and findings of a later case-control study suggesting an increased risk of breast and prostate cancer among statin users, did little to allay fears over statin safety.
A number of subsequent RCTs have, reassuringly, suggested a neutral effect of statin use on overall cancer risk.[19,20,21,22] Furthermore, some, but not all, observational studies have raised the possibility of inverse associations between statins and overall cancer risk,[23,24,25] and risks of specific cancers, including colorectal cancer.[26,27,28,29] In this article, we review the experimental, epidemiologic, and clinical data relevant to statins and colorectal neoplasia, and discuss the current status and future potential of statins as chemopreventive agents.
Clin Gastroenterol Hepatol. 2013;11(2):109-118. © 2013 AGA Institute