Clinical implications of pharmacogenomics of statin treatment

The Pharmacogenomics Journal (2006) 6, 360–374 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj CLINICAL IMPLICATION Clinical implications of pharmacogenomics of statin treatment This review will summarize studies examining genetic influences on statin efficacy and toxicity, and discuss the potential for this information to guide the optimal clinical use of these compounds. LM Mangravite1, CF Thorn2 and RM Krauss1 Genetic influences on statin efficacy 1 Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, CA, USA and 2Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA The Pharmacogenomics Journal (2006) 6, 360–374. doi:10.1038/sj.tpj.6500384; published online 21 March 2006 b-hydroxy-b-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors, or statins, inhibit endogenous cholesterol production by competitive inhibition of HMG-CoA reductase (HMGCR), the enzyme that catalyzes conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol synthesis. By reducing intracellular cholesterol production, statin treatment results in upregulation of low-density lipoprotein (LDL) receptors, leading to increased plasma clearance of LDL, primarily by the liver. In addition, statins can reduce hepatic secretion of the ApoB-containing lipoproteins, very low-density lipoprotein (VLDL) and LDL. As a result of these effects, statins can reduce plasma levels of atherogenic LDL by as much as 50%. Other effects of potential clinical significance include reductions in plasma triglycerides (TGs), increases in high-density lipoprotein (HDL) cholesterol (HDLC), an indicator of reduced cardiovascular disease (CVD) risk, and reductions in inflammatory markers, notably C-reactive protein (CRP), that have been implicated in the development of CVD. Statin therapy has been shown in numerous large clinical trials to reduce risk of cardiovascular events by 20– 30%, an effect strongly related to the magnitude of LDL cholesterol (LDLC) reduction.1,2 On the basis of these findings, statin treatment in conjunction with lifestyle changes is indicated as first-line therapy for prevention of CVD in individuals who are considered to be at risk.3 Adoption of current guidelines for plasma LDL reduction has led to the widespread and increasing use of statins, which are now the most prescribed class of drugs worldwide. Clinical response to statin-mediated reduction of lipid and lipoprotein parameters is highly variable.4 Although statin dosages are often adjusted once individual response to treatment is assessed, nearly a third of statin-treated patients do not meet their lipid-lowering goals.5 In addition, adverse drug reactions (ADR), although rare, can be severe. Variability in response to statin therapy results from environmental and non-genetic factors, such as age, gender, diet, smoking status, and physical activity. Just as interindividual variability in plasma lipid and lipoprotein levels is governed by hereditary factors, it stands to reason that statin-response of these same parameters is also related to genetic heterogeneity. In fact, a recent study indicates clear population differences in rosuvastatin sensitivity between subjects of Caucasian, Chinese, Malaysian, and Indian decent all residing in Singapore that could not be accounted for by non-genetic factors.6 Genes involved in pharmacokinetic response (Figure 1) Genetic variations affecting statin pharmacokinetics can alter duration and magnitude of drug exposure, and hence both efficacy and toxicity (Table 1). Efficacy of statin response, measured by either lipid-lowering response or reduction in mortality, is dependent on hepatic rather than systemic statin exposure as these compounds undergo extensive first-pass clearance and the liver is the major site of action.7 Although unlikely to affect statin efficacy, genetic variation causing alterations in systemic statin exposure may create susceptibility to adverse drug reactions. Genetic variations affecting hepatic exposure are more likely candidates for altering treatment efficacy. There are six statin compounds currently on the market for use as cholesterol-lowering therapies: simvastatin, pravastatin, atorvastatin, lovastatin, fluvastatin, and rosuvastatin. The pharmacokinetic profiles of these compounds vary based on hydrophobicity. The more hydrophilic compounds, pravastatin in particular, require active transport into the liver, are less metabolized by the cytochrome P450 (CYP) family, and exhibit more pronounced active renal excretion; whereas the less hydrophilic compounds are transported by passive diffusion and are better substrates for both CYP enzymes and transporters involved in biliary excretion.8–10 Given the differential involvement of pharmacokinetic genes in the metabolism of statin compounds, variation in these genes may aid in determining treatment choice. Clinical implications of statin pharmacogenomics LM Mangravite et al 361 Figure 1 Candidate Genes in Pharmacokinetic Handling of Statins. Statins are dosed orally and enter the systemic circulation through enterocytes by active and passive mechanisms. Major organs of metabolism and elimination include the liver and, to a lesser extent, the kidney. Active transport across cellular membranes is executed by members of the solute carrier (SLC) and ATP-binding cassette (ABC) super families. Metabolism is catalyzed by cytochrome P450 (CYP) and glycosyltransferase (UGT) enzymes. All of these genes vary in their affinity for different statins and statin metabolites. For drug-specific views, please visit the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), http:// www.pharmgkb.org/search/pathway/statin/statin.jsp. Figure is color-coded as follows: pink, drug or metabolite; blue, transporter protein; purple, metabolizing enzyme. Figure printed with permission from PharmGKB. Drug metabolizing enzymes affecting statin therapy Statins undergo metabolism largely via the CYP3A (lovastatin, atorvastatin, simvastatin) or CYP2C (fluvastatin) families of metabolizing enzymes.11 Metabolism of these compounds may also be mediated, in part, by CYP2D6 or several glycosyltransferases (UGT1A1, UGT1A3, UGT2B7).7,12 Pravastatin and rosuvastatin interact minimally with metabolizing enzymes, are largely excreted unchanged, and are less likely to be affected by genetic variation in metabolizing enzymes. Polymorphisms in genes encoding several of these enzymes have been examined for associations with variability in statin efficacy or systemic exposure. Within the CYP3A family, there are four independent reports of association with lipid lowering response.13–18 None of these observations have survived replication. Within the CYP2C family, the CYP2C9*3 haplotype has been associated with The Pharmacogenomics Journal Clinical implications of statin pharmacogenomics LM Mangravite et al 362 T (...truncated)