**6. Testing for statin intolerance in clinic–current status and treatment recommendations**

The spectrum of evidence supporting the association between the lead SNP rs4149056 and statin, namely simvastatin-induced myopathy prompted application of the *SLCO1B1* genotyping for clinical usage. This translation to diagnostics aims mainly at reducing risk of simvastatin induced muscle toxicity and at increased adherence to therapy [43, 51, 52]. Another possible outcome of genotyping is the option to use alternate agents of the statin class.

In clinical practice, the adverse effect of *SLCO1B1* polymorphism depends on the genotype (being highest in homozygotes), statin dose and statin type. This has been reflected in the guidance for prescribers provided primarily by the Clinical Pharmacogenetics Implementation Consortium (CPIC); the working group produces guidelines for simvastatin use in individual carriers risk allele in SLCO1B1 gene [43]; the guidelines have been recently updated [53]. In patients with one or two copies of *SLCO1B1* rs4149056 C allele, simvastatin should be avoided or reduced dosage should be considered, pravastatin or rosuvastatin are preferred alternatives according to the CPIC guidelines, however other clinical and patients specific factors should be taken into account [43, 53].

Apart from this general, non-compulsory guidance, there have been more systematic efforts to apply *SLCO1B1* genotyping into practice. This direction is represented e.g. by pre-emptive programs performed from the initiative by U.S. Pharmacogenetics Research Network at eight sites [54]. Similarly, aiming of introducing genotype-guided prescribing, pre-emptive genotyping has

#### KEY MESSAGE

were obtained in animal model, again for simvastatin however not for pravastatin or atorvastatin [49]. **Table 2** lists main studies investigating effect of simvastatin on statin intolerance/

**Table 2.** Basic studies that have reported a strong association between the rs4149056 single nucleotide polymorphism

**Study Simvastatin dose Outcome Reference** SEARCH 80 mg OR 4.5 per C allele [21]

Heart protection study 40 mg OR 2.6 per C allele [21] Brunham 10-80 mg OR 2.3 per C allele [45]

OR 16.9 for CC homozygotes

It is crucial that in agreement with the rules for performing association studies [50] the data obtained in the SEARCH study has been independently replicated within the Heart Protection Study, in 10,000 patients who received 40 mg Simvastatin [21]. The meaningful data obtained in this way provided starting point for reflection of the observations from genetic and pharmacokinetic studies into clinical practice, including formulation of treatment recommenda-

**6. Testing for statin intolerance in clinic–current status and treatment** 

The spectrum of evidence supporting the association between the lead SNP rs4149056 and statin, namely simvastatin-induced myopathy prompted application of the *SLCO1B1* genotyping for clinical usage. This translation to diagnostics aims mainly at reducing risk of simvastatin induced muscle toxicity and at increased adherence to therapy [43, 51, 52]. Another possible outcome of genotyping is the option to use alternate agents of the statin class.

In clinical practice, the adverse effect of *SLCO1B1* polymorphism depends on the genotype (being highest in homozygotes), statin dose and statin type. This has been reflected in the guidance for prescribers provided primarily by the Clinical Pharmacogenetics Implementation Consortium (CPIC); the working group produces guidelines for simvastatin use in individual carriers risk allele in SLCO1B1 gene [43]; the guidelines have been recently updated [53]. In patients with one or two copies of *SLCO1B1* rs4149056 C allele, simvastatin should be avoided or reduced dosage should be considered, pravastatin or rosuvastatin are preferred alternatives according to the CPIC guidelines, however other clinical and patients specific factors should be taken into account [43, 53].

Apart from this general, non-compulsory guidance, there have been more systematic efforts to apply *SLCO1B1* genotyping into practice. This direction is represented e.g. by pre-emptive programs performed from the initiative by U.S. Pharmacogenetics Research Network at eight sites [54]. Similarly, aiming of introducing genotype-guided prescribing, pre-emptive genotyping has

tions which will be subject of the next section of our chapter.

myopathy in humans.

and simvastatin induced myopathy.

132 Genetic Diversity and Disease Susceptibility

Note: OR, odds ratio.

**recommendations**


also been investigated in Europe by the EU Horizon 2020-funded Ubiquitous Pharmacogenomics (U-PGx) Consortium (http://upgx.eu) in seven European countries [55]. Last but not least, recommendations were formulated also on a national level - in France: the French National Network of Pharmacogenetics (RNPGx) [56] is in favour of rs4149056 testing before starting therapy or early after treatment onset in patients with one or more risk factors. If the genotype is not known early, the RNPGx considers that a polymorphism test is potentially useful also in the event of already occurring muscle toxicity in patients treated with statins, in order to rule out or confirm a genetic cause. From the above examples it is clear that pharmacogenetic genotyping for prediction/confirmation of statin intolerance undergoes ongoing development and progress; further updates of the recommendations are expected. It should be noted that there have been opinions as well that the current status of knowledge has not been yet sufficient to allow clinical application of genotyping for risk of statin intolerance [52]. There have been several arguments, however especially those economical ("the tests are too costly") are not substantiated; some "con" opinions have been also "traditionalistic", from conservative point of view on doubting any new test or medical management measure including pharmacogenetics. However, this reluctant or at least "sceptical" attitude about pharmacogenetic contribution to routine statin usage, well known also from other applications of pharmacogenetics, has been gradually changing–it only takes time, systematic information on the evidence and particularly education to overcome it [57].
