Research Highlights

Individualizing Statin Therapy: Beyond Cytochrome P450

Statin therapy is a relatively safe and effective way to lower cholesterol levels, and with that, reduce morbidity and mortality [1]. However, response to statin therapy varies. Some patients have a lipid-lowering effect that is inadequate, and others develop adverse drug reactions, such as myopathy and rhabdomyolysis [2]. Many factors are involved in the variation in drug response. Better knowledge regarding these factors will result in the identification of patients with an inadequate response or patients who will develop adverse drug reactions prior to start of therapy. Individualization of statin therapy with alternative doses or alternative drugs will result in the improvement of the effectiveness and safety of statin therapy.

Factors that are involved in variation of statin response are the effects of genetic variation and the effects of co-prescribed drugs. Two regularly used statins, simvastatin and atorvastatin, are metabolized by the CYP3A4 enzyme to hydroxymetabolites [3,4]. The area under curve (AUC) of simvastatin increases five- to 20-fold if itraconazol, a potent CYP3A4 inhibitor, is co-prescribed, and the AUC of atorvastatin increases two- to four-fold [5]. The risk of myopathy with these statins is markedly increased if combined with drugs inhibiting CYP3A4 enzymes [5,6]. Although less well elucidated, genetic variation in the CYP3A4 gene also affects the metabolism of simvastatin and atorvastatin [7].

Of course, many more transporters and enzymes than just CYP3A4 are involved in the pharmacokinetics of statins. Knowledge on the role of transporters and enzymes is slowly being added to. Recently, in a genome-wide association (GWA) study, a strong association between a polymorphism in the SLCO1B1 gene (SLCO1B1*5) and severe statin-induced myopathy was identified [8]. The SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1), expressed at the basolateral membrane of hepatocytes. Genetic variation in the SLCO1B1 gene impairs the uptake of substrates. The risk of myopathy was 17-times higher in homozygous carriers of the risk allele verses homozygous carriers of the nonrisk allele.

Statins can exist in acid form and in lactone form. Atorvastatin lactone is a pharmacologically inactive metabolite of atorvastatin, while simvastatin and pravastatin are given as lactones and metabolized to the pharmacologically active simvastatin acid and pravastatin acid, respectively. One of the complicating factors in studying the adverse drug reactions during statin therapy is that the cyclic lactones may be more myotoxic than the acid form of the statin [9,10]. The role of the acid and lactone form is analyzed separately in some studies.

SLCO1B1*5 Polymorphism and Mild Side Effects During Statin Therapy

Evaluation of: Voora D, Shah SH, Spasojevic I et al.: The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J. Am. Coll. Cardiol. 54(17), 1609–1616 (2009).

In the abovementioned GWA study by Link et al., only severe cases of myopathy with increased creatine kinase (CK) levels were included [8]. They found an association between the SLCO1B1*5 polymorphism and severe myopathy. In clinical practice, statin-induced side effects are often not caused by increased CK levels, and cases of severe myopathy during statin therapy are rare. The incidence of mild side effects during statin therapy is estimated to be approximately 5–10% and results in many discontinuations.

In the study by Voora et al., the association between the SLCO1B1*5 polymorphism and statin-induced myopathy was further elucidated [11]. Study participants were randomly assigned to simvastatin, atorvastatin or pravastatin therapy, with an 8-week low-dose treatment followed by an 8-week high-dose treatment. The composite end point was discontinuation in case of any side effects, myalgia or muscle cramps, or elevated CK levels. In this study, associations between genetic variation in the CYP2D6, CYP2C8, CYP2C9, CYP3A4 and SLCO1B1 genes and the occurrence of the composite end point was assessed. In a subgroup of patients, simvastatin acid, lactone, pravastatin acid and lactone concentrations were measured.

A total of 22% of the participants had at least one end point. Carriers of the SLCO1B1*5 allele had a higher risk for adverse events (noncarriers: 19%; carriers of one allele: 27%; and carriers of two alleles: 50%). The effect was owing to the simvastatin and atorvastatin users; in the pravastatin users, no association was found between the number of SLCO1B1*5 variant alleles and adverse events. If the analyses were limited to those participants with adverse events but no elevated CK level, associations remained.

There was no difference between carriers and noncarriers of the SLCO1B1*5 polymorphism in terms of low-density lipoprotein cholesterol reduction. There was a positive association between the SLCO1B1*5 risk allele and simvastatin acid concentration during the high-dose period. No association was found for pravastatin.

From the GWA analyses, it was already known that SLCO1B1*5 is associated with elevated CK level adverse events. This study adds to the fact that the association is also present for non-CK elevated adverse events. This effect was not found for pravastatin. Both simvastatin and pravasatin are substrates for OATP1B1 encoded by the SLCO1B1 gene, making the differences hard to explain. The SLCO1B1*5 polymorphism was associated with higher simvastatin acid levels, suggesting that simvastatin acid may mediate the side effects observed. The higher levels of simvastatin acid are contrary to the studies that indicate that the lactone form is more myotoxic than the acid form [9,10].

SLCO1B1*5 Polymorphism and the Interaction Between Rifampicin and Atorvastatin

Evaluation of: He YJ, Zhang W, Chen Y et al.: Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin. Chim. Acta 405(1–2), 49–52 (2009).

Pravastatin and simvastatin acid concentrations are affected by SLCO1B1 polymorphisms. Rifampicin alters the pharmacokinetics of atorvastatin on the level of CYP enzymes and on the level of hepatic transporters. Rifampicin inhibits the activity of OATP1B1 in humans, encoded by the SLCO1B1 gene. In the study by He et al., the impact of the SLCO1B1*5 polymorphism on the interaction between atorvastation and rifampicin was analyzed [12].

A total of 16 subjects were given, in random sequence, a single dose of atorvastatin plus rifampicin and a single dose of atorvastatin plus placebo with a 2-week wash-out period. This was followed by a single dose of rifampicin. Venous blood samples were collected and analyzed and the AUC from 0 to 48 h calculated. The change in atorvastatin pharmacokinetics with and without co-administration of rifampicin was analyzed.

Co-administration of rifampicin with simvastatin resulted in higher AUC_0–48 for simvastatin. This increase was larger with the number of SLCO1B1*5 wild-type alleles. The increase in AUC_0–48 value was nearly tripled in participants homozygous for the wild-type SLCO1B1*5 genotype compared with participants homozygous for the SLCO1B1*5 variant allele. Also, the percentage decrease in half-life and clearance divided by the bioavailability were influenced.

No differences in the pharmacokinetics of rifampicin were found between SLCO1B1*5 genotypes, and therefore, the differences in atorvastatin AUCs cannot be explained by the effect on the pharmacokinetics of rifampicin.

Apparently, the SLCO1B1 genotype has an important role in the interaction between rifampicin and atorvastatin. Rifampicin‘s interaction with atorvastatin mimics the effect of the SLCO1B1 genotype, and rifampicin may increase the risk of myopathy.

Statin Myotoxicity, UGT and the Acid and Lactone Form

Evaluation of: Riedmaier S, Klein K, Hofmann U et al.: UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin. Pharmacol. Ther. 87(1), 65–73 (2009).

It is suggested that the lactone form of statins are more myotoxic than the acid form. Atorvastatin-treated patients experiencing atorvastatin-related myopathy demonstrated two- to three-fold higher plasma concentrations of atorvastatin lactone and certain metabolites, including CYP3A-formed hydroxylated metabolites, but no change in the level of atorvastatin itself [9]. In a cellular myotoxicity model, lactones have been demonstrated to be more cytotoxic than the corresponding acids [10]. However, this association is not well established.

Atorvastatin was given as atorvastatin acid. Atorvastatin lactonization may occur both nonenzymatically at low intestinal pH and enzymatically through an unstable acyl glucuronide or a coenzyme A intermediate. Glucuronidation of atorvastatin is catalyzed by the UDP-glucuronyltransferases (UGTs) UGT1A1 and UGT1A3. In the study by Riedmaier et al., the role of interindividual UGT variation and polymorphism in the formation of statin lactones has been studied both in vitro and in vivo[13].

In vitro, atorvastatin lactonization was correlated with the amount of UGT1A3 protein and mRNA, and not with the amount of UGT1A1 protein and mRNA. This indicates that UGT1A3 is the major isoenzyme catalyzing atorvastatin lactonization in human liver microsomes. The authors tested whether UGT1A1*28 has an association with atorvastatin lactonization, and, surprisingly they found a strong association. This unexpected finding could be explained by linkage disequilibrium between UGT1A1*28 and genetic variation in UGT1A3. UGT1A3*2 was significantly associated with the amount of UGT1A3 mRNA, protein and atorvastatin lactonization.

A total of 56 volunteers, who had received single-dose atorvastatin in previous studies, were genotyped for UGT1A3. Significant associations were found between UGT1A3*2 and atorvastatin lactone/acid AUC_0–∞, between UGT1A3*2 and 2-hydroxyatorvastatin lactone/acid AUC_0–∞ and between UGT1A3*2 and 2-hydroxyatorvastatin lactone AUC_0–∞. No associations were found with atorvastatin lactone AUC_0–∞ or atorvastatin acid AUC_0–∞.

The data of this study suggest that genetic variation in UGT1A3 is a candidate gene that influences atorvastatin toxicity, since UGT1A3 is associated with atorvastatin lactonization and atorvastatin lactone is associated with toxicity. The association between genetic variation in UGT1A3 and atorvastatin lactonization was found both in human liver microsomes and in atorvastatin-treated volunteers.

From these three studies, it can be concluded that both SLCO1B1 and UGT1A3 may play an important role in the response to statin therapy. However, their exact roles still need to be clarified before they can be used in clinical practice. The results on the role of the acid and lactone forms are interesting although, at this time, contradictory. Overall, response to statin therapy is an interesting topic for further research.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.