Pharmacogenetic Approaches to Enhancing Efficacy and Safety of Statins as Illustrated by the Example of Atorvastatin

Statins are efficacious lipid-lowering drugs used for prevention of cardiovascular complications in patients with high blood cholesterol. The efficacy and safety of this group of drugs is largely determined by genetic factors. The aim of the study was to analyse the effect of gene polymorphisms on the efficacy and safety of atorvastatin in patients undergoing hospital treatment. Materials and methods. The authors carried out a retrospective study of the medical records of 76 hospital patients who were prescribed atorvastatin for confirmed hyperlipidemia. All the patient records contained the results of genotyping of single nucleotide polymorphisms that presumably affect the pharmacokinetics and pharmacodynamics of statins. Results. The analysis of literature data suggested that the pharmacological response and safety of statins could be affected by polymorphisms of the following genes: SLCO1B1, ABCB1, CYP2C9, and CYP2C19. The study showed that atorvastatin had high efficacy in the carriers of the 3435C allele of the ABCB1 gene and in the carriers of the CYP2C19*2 allele of the CYP2C19 gene. The patients carrying ABCB1 genotypes demonstrated a tendency to increasing levels of low-density lipoproteins and total cholesterol in the following order: 3435СС → 3435СТ → 3435ТТ. The only adverse reaction of atorvastatin in the patient groups was an increase in the activity of hepatic transaminases, however, no connection with the studied gene polymorphisms was observed. Conclusions. The study of the effect of gene polymorphisms on the efficacy and safety of statins will be continued to obtain statistically valid confirmation of the observed trends in a much larger group of patients.

pharmacogenetics, genotyping, genetic biomarkers, statins, atorvastatin, single nucleotide polymorphisms, P-glycoprotein, organic anion transporters, SLCO1B1, ABCB1, CYP2C9, CYP2C19

1. Chazov EI. Ho w to reduce mortality from cardiovascular diseases. Terapevticheskiy arkhiv = Therapeutic Archive. 2008;80(8):11–6 (In Russ.)

2. Oshchepkova EV, Efremova IuE, Karpov IuA. Myocardial infarction morbidity and mortality in the Russian Federation in 2000–2011. Terapevticheskiy arkhiv = Therapeutic Archive. 2013;85(4):4–10 (In Russ.)

3. Smirnova MD, Ageev FT. Statins — old myths and new facts. RMZh = RMJ. 2017;(20):1421–8 (In Russ.)

4. Sukhaterina NA. Dynamics of lipid spectrum and markers of infl ammation in the patients receiving atorvastatin in hypertensive patients combined with chronic obstructive pulmonary disease. Ateroskleroz i dislipidemii = Journal of Atheros clerosis and Dyslipidemias. 2016;(3):68– 74 (In Russ.)

5. Nedogoda SV. Rosuvastatin: evidence base and signifi cance for real clinical practice. RMZh = RMJ. 2015;(15):886 (In Russ.)

6. Kukharchuk VV, Semenova AE. Correction of hyperlipidemia: statin treatment at post-marketing the COMPLIANCE study. Ateroskleroz i dislipidemii = Journal of Atherosclerosis and Dyslipidemias. 2015;(1):5–11 (In Russ.)

7. Ezhov MV, Bliznyuk SA, Alekseeva IA, Vygodin VA. Prevalence of hypercholesterolemia and statins intake in the outpatient practice in the Russian Federation (ICEBERG study). Ateroskleroz i dislipidemii = Journal of Atherosclerosis and Dyslipid emias. 2017;(4):5–17 (In Russ.)

8. Barbarash OL, Kashtalap VV, Shibanova IA. A patient after an episode of acute coronary syndrome. Lipid control after the acute coronary syndrome. Ateroskleroz i dislipidemii = Journal of Atherosclerosis and Dyslipidemias. 2019;10(2):5–14 (In Russ.)

9. Drapkina OM. Statins in acute coronary syndrome. Kardiovaskulyarnaya terapiya i profi laktika = Cardiovascular Therapy and Prevention. 2009;8(5):69–73 (In Russ.)

10. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin–fi brate therapy: safety aspects. Diabetes Obes Metab. 2009;11(2):89–94. https://doi.org/10.1111/j.1463-1326.2008.00917.x

11. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, et al. Eff ect of statins on skeletal muscle function. Circulation. 2013;127(1):96–103. https://doi.org/10.1161/CIRCULATIONAHA.112.136101

12. Bays H, Cohen DE, Chalasani N, Harrison SA, The National Lipid Association’s Statin Safety Task Force. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S47–57. https://doi.org/10.1016/j.jacl.2014.02.011

13. Goroshko OA, Krasnykh LM, Kukes VG, Zozina VI. Evaluation of coenzyme Q10 redox status as a biomarker of oxidative stress. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2019;9(3):146–52 (In Russ.) https://doi.org/10.30895/1991-2919-2019-9-3-146-152

14. Hoenig MR, Walker PJ, Gurnsey C, Beadle K, Johnson L. The C3435T polymorphism in ABCB1 infl uences atorvastatin effi cacy and muscle symptoms in a high-risk vascular cohort. J Clin Lipidol. 2011;5(2):91–6. https://doi.org/10.1016/j.jacl.2011.01.001

15. Ramakumari N, Indumathi B, Katkam SK, Kutala VK. Impact of pharmacogenenetics on statin-induced myopathy in South-Indian sudjects. Indian Heart J. 2018;70(Suppl 3):S120–5. https://doi.org/10.1016/j.ihj.2018.07.009

16. Talameh JA, Kitzmiller JP. Pharmacogenetics of statin-induced myopathy: a focused review of the clinical translation of pharmacokinetic genetic variants. J Pharmacogenomics Pharmacoproteomics. 2014;5(2):128. https://doi.org/10.4172/2153-0645.1000128

17. Buzková H, Pechandová K, Danzig V, Vařeka T, Perlík F, Žák A, Slanař O. Lipid-lowering eff ect of fl uvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population. Med Sci Monit. 2012;18(8):CR512–7. https://doi.org/10.12659/msm.883272

18. Pitt B, Loscalzo J, Monyak J, Miller E, Raichlen J. Comparison of lipid-modifying effi cacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol. 2012;109(9):1239–46. https://doi.org/10.1016/j.amjcard.2011.12.015

19. SEARCH Collaborative Group, Link E, Parish S, Armit age J, Bowman L, Heath S, et al. SLCO1B1 variants and statininduced myopathy — a genomewide study. N Engl J Med. 2008;359(8):789–99. https://doi.org/10.1056/NEJMoa0801936