Statin therapy: does sex matter?

Abstract

Objective: Statins are a class of drugs that competitively bind to the active site of HMG-CoA reductase enzyme, thereby inhibiting the initial steps in cholesterol synthesis. Originally approved for use in lowering serum cholesterol, a risk factor for developing atherosclerosis and coronary heart disease, statins have subsequently been noted to have myriad extrahepatic effects, including potential effects on cognition, diabetes, breast cancer, bone, and muscle. This narrative review assesses the current state of the science regarding the risks and benefits of statin therapy in women to identify areas where additional research is needed.

Methods: Basic and clinical studies were identified by searching PubMed with particular attention to inclusion of female animals, women, randomized controlled trials, and sex-specific analyses.

Results: Statin therapy is generally recommended to reduce the risk of cardiovascular disease. None of the current clinical guidelines, however, offer sex-specific recommendations for women due to lack of understanding of sex differences and underlying mechanisms of disease processes. In addition, conclusions regarding efficacy of treatments do not consider lipid solubility for the drug, dosing, duration of treatment, interactions with estrogen, or comorbidities. Pleiotropic effects of statins are often derived from secondary analysis of studies with cardiovascular events as primary outcomes.

Conclusions: Many of the trials that have established the efficacy and safety of statins were conducted predominantly or entirely in men, with results extrapolated to women. Additional research is needed to guide clinical recommendations specific to women. : Video Summary:http://links.lww.com/MENO/A462.

Figure 1.. Mechanism of Action of Statins and Potential Interactions with Estrogen.

Orally administered statins (open circles) enter intestinal cells passively or through active transport. Simvastatin, atorvastatin, and lovastatin may undergo oxidative metabolism by CYP3A4/5 enzymes (triangles) within the intestinal cell. Next, statins are transported through the bloodstream into hepatocytes. OATP1B1 is one of several transporters responsible for hepatic uptake of statins. In the liver, statins competitively bind to the active site of HMG-CoA reductase, inhibiting the conversion of HMG-CoA to mevalonic acid (depicted by blunt-ended arrow), which is an early step in the cholesterol synthesis pathway (shown in center of hepatocyte). Simvastatin, lovastatin, and atorvastatin are metabolized by CYP3A4/5, while fluvastatin is metabolized primarily by CYP2C9 (metabolites depicted by triangles). Pravastatin, pitavastatin, and rosuvastatin undergo limited cytochrome P450-mediated metabolism. In addition, statins may also undergo glucuronidation or sulfation mediated by polymorphic glucuronosyltransferase and sulfotransferase enzymes (metabolites shown as squares). Finally, statins may be transported out of the hepatocyte and into bile for elimination or into the bloodstream for renal elimination. Estrogens (filled circles) may be administered orally or transdermally, or may be endogenously produced. Orally administered estrogens must pass through the intestinal cells where CYP3A4/5-mediated metabolism may occur (metabolites shown as inverted triangles). Transdermally administered estrogens and endogenous estrogens enter the hepatocytes from the blood where they may be metabolized by CYP3A4/5 and/or undergo sulfate and glucuronide conjugation (diamonds), similar to statins. Sulfate- and glucuronide-conjugated estrogens may use the same transporters as statins, including OATP1B1.