EDITORIAL COMMENT
The Pharmacogenetics of Statin TherapyWhen the Body Aches, the Mind Will Follow*
Joseph S. Rossi, MD and
Howard L. McLeod, PharmD*
University of North Carolina Schools of Medicine and Pharmacy, Carolina Center for Cardiovascular Biology, and the Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina
* Reprint requests and correspondence: Dr. Howard L. McLeod, University of North Carolina, Chapel Hill, Campus Box 7361, Genetic Medicine Building, Room 1094, Chapel Hill, North Carolina 27599 (Email: hmcleod{at}unc.edu).
Key Words: hydroxymethylglutaryl-CoA reductase inhibitors • pharmacogenetics • single nucleotide polymorphisms • myopathy
Despite the increasing prevalence of cardiovascular risk factors such as obesity, diabetes, and hyperlipidemia in the U.S., there has been a surprising decrease in cardiovascular mortality among patients with various presentations of coronary artery disease (1). It is likely, if not certain, that a large reason for this decline is the increased use of HMG-CoA reductase inhibitors to lower serum cholesterol and promote stabilization of atherosclerotic plaque. Despite high levels of statin adherence in clinical trials, other studies have suggested poor adherence in high-risk patient populations, particularly the elderly (2,3). Although the safety data for this class of medications suggest a very low incidence of severe adverse reactions, such as rhabdomyolysis and myopathy, myalgias without serum creatine kinase (CK) elevation remain a common side effect and the most common reason for discontinuation of therapy. Although myalgia appears to be a class effect (it has been described with all available agents), there is a significant amount of variability within the class, which has lead to the investigation of genetic determinants of statin metabolism and toxicity.
The safety of statin therapy has been vigorously debated during the last decade, and the balance of clinical trial data has been reassuring. Cerivistatin was removed from the market after multiple cases of severe myopathy and rhabdomyolysis, and this led to focused scrutiny of all other available agents. Randomized trials involving tens of thousands of patients have been performed demonstrating the safety and efficacy of simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, and lovastatin. Although each agent has a unique pharmacology and drug interaction profile, when used as monotherapy for hyperlipidemia, there is a very low incidence of severe toxicity. In a meta-analysis of 65,000 patients treated with statin or placebo, there was no increased risk of rhabdomyolysis among patients treated with statins (4). An analysis of 11 managed care plans revealed only 24 cases of hospitalization for rhabdomyolysis over 252,000 patient-years (5). However, the use of high doses of statins in combination with other drugs that alter their metabolism can lead to increasing blood levels with consequent risk of liver or muscle toxicity. This has been demonstrated for virtually all available agents, but most commonly for agents metabolized by the CYP450 3A4 enzyme. Simvastatin in particular has been associated with an increased risk of rhabdomyolysis when taken in combination with multiple inhibitors of CYP3A4 (6).
In this issue of the Journal, Voora et al. (7) report the results of the STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study, and suggest that reduced-function single nucleotide polymorphisms (SNPs) of the SLCO1B1 gene may be responsible for myopathy and myalgia. SLCO1B1 encodes the enzyme OATP1B1, responsible for liver transportation of statins. This study was unique because in addition to confirming the previously suggested association between reduced function alleles for this gene and CK elevation, they also confirmed an association between the SLCO1B1*5 allele and myalgia symptoms without CK elevation. Elevated levels of simvastatin metabolites (but not pravastatin) were seen among patients with the targeted SNP. These exciting results demonstrate for the first time that there may be a strong genetic susceptibility to both myopathy and statin-induced myalgias in the absence of elevated serum CK, and that genetic testing may provide important prognostic information to guide individualized statin therapy.
The SLCO1B1 gene has previously been identified as a likely factor in the development of simvastatin-induced myopathy (8). In a genomewide study of approximately 300,000 markers among 85 subjects with confirmed myopathy from in the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) study, the odds ratio for myopathy was 16.9 for patients with homozygous reduced-function SNPs at this locus. The role of SLCO1B1 in the metabolism of other statins remains unclear. The STRENGTH study suggests that pravastatin metabolites are not significantly elevated in patients with the homozygous SLCO1B1 genotype. There was an increase in the risk of myalgia among SNP carriers taking atorvastatin; however, the difference was not statistically significant. No other agents were studied, and it is unknown whether the same findings could be replicated for rosuvastatin, lovasatin, and fluvastatin.
Despite these exciting findings and their clinical relevance, they likely do not tell the whole story. Each individual statin agent is dependent upon liver uptake for its biologic effect; however, the dependence on transporter proteins such as OATP1B1 vary according to agent. Lipophilic statins can enter the liver via passive diffusion, whereas hydrophilic statins require active transportation. Fluvastatin, for instance, has previously been shown to have pharmacokinetic properties that are independent of genetic variation at the SLCO1B1 locus (9). SLCO1B1 polymorphism has previously been shown to increase blood levels of simvastatin acid (10). The search is on for additional genetic variants that may alter statin metabolism and cause adverse events.
The analysis by Voora et al. (7) also confirms a previous association between female sex and adverse events among patients receiving statin therapy. Although the exact mechanism of this interaction is unknown, it is likely multifactorial. It is possible that female sex attenuates the activation of metabolizing enzymes. It is also likely that lower mean body weight and muscle mass affects the volume of distribution of some statin agents, making females more susceptible to elevated circulating drug levels. These findings suggest that lower doses of simvastatin should be considered in female patients, and that changing agents is a reasonable alternative in both males and females with likely statin-induced myalgias even in the absence of elevated serum CK.
Further studies will undoubtedly identify other genetic factors associated with adverse reactions to statin agents. For now, the risk of severe reactions is fortunately rare and not likely to be improved by routine genetic testing. One of the important issues that require additional investigation is the role of SLCO1B1 in patients taking statin agents other than simvastatin. The OATP1B1 enzyme is responsible for the transport of multiple statins, but it remains unclear whether the genetic variants will have a similar effect on the incidence of myalgias and myopathy. Voora et al. (7) found a nonsignificant increase in myopathy among carriers of the SLCO1B1 alleles among patients taking atorvastatin, but found no increase in myopathy among patients taking pravastatin. Previous research indicates that the enzyme encoded by SLCO1B1 affects simvastatin and pravastatin metabolism, but not fluvastatin (9,10). The data by Voora et al. (7) suggest that simvastatin acid may be a more clinically important substrate for this transporter enzyme.
Genetic testing may someday become an important adjunct to risk stratification among patients with cardiovascular disease. The prediction of adverse events based on genetic variation is a focus of intense investigation for statins, ADP receptor antagonists, and warfarin. It seems reasonable, for now, to choose a statin based on known drug interactions, particularly CYP450 interactions, and goal low-density lipoprotein level. High doses should be reserved for patients at intermediate to high risk of recurrent vascular events, and particular care should be taken to screen for muscle symptoms among patients requiring high-dose therapy. If a patient develops myalgias or CK elevation while taking simvastatin, a SNP at the SLCO1B1 locus should be suspected, and changing agents may provide relief of symptoms. Further studies should examine the role of the OATP1B1 enzyme in the transport and metabolism of rosuvastatin and atorvastatin, 2 of the most commonly prescribed agents currently available. The elimination of myalgias has the potential to dramatically improve statin adherence and, therefore, clinical outcomes, and the vigilance of investigators in the field supports our current level of optimism that genetic testing will one day become an important clinical tool.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2009;119:e21-e181.[Free Full Text]2. Tikkanen MJ, Holme I, Carter NB, et al. Comparison of efficacy and safety of atorvastatin (80mg) to simvastatin (20 to 40 mg) in patients aged <65 versus > or =65 years with coronary heart disease (from the Incremental DEcrease through Aggressive Lipid Lowering (IDEAL) study Am J Cardiol 2009;103:577-582.[CrossRef][Web of Science][Medline] 3. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes JAMA 2002;288:462-467.[Abstract/Free Full Text] 4. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients J Am Coll Cardiol 2008;52:1769-1781.[Abstract/Free Full Text] 5. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs JAMA 2004;292:2585-2590.[Abstract/Free Full Text] 6. Christopher R, Allen DB, Parivash N, et al. Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors Pharmacoepidemiology and Drug Safety 2009;18:301-309.[CrossRef][Web of Science][Medline] 7. Voora D, Shah SH, Spasojevic I, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects J Am Coll Cardiol 2009;54:1609-1616.[Abstract/Free Full Text] 8. The SCG. SLCO1B1 variants and statin-induced myopathy—a genomewide wtudy N Engl J Med 2008;359:789-799.[CrossRef][Medline] 9. Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin Clin Pharmacol Ther 2006;80:356-366.[CrossRef][Web of Science][Medline] 10. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid Pharmacogen Genomics 2006;16:873-879.[CrossRef]
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