Skip to main content
SpringerLink
Log in

Towards a More Personalized Treatment of Dyslipidemias to Prevent Cardiovascular Disease

  • Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Today, statins are the first choice to lower LDL cholesterol and concomitantly the risk of atherosclerotic cardiovascular disease. There is a significant minority of statin-treated patients who are more susceptible to occasionally serious side effects that may increase morbidity and lead to compliance problems or the discontinuation of therapy. This review addresses the question of whether genetics can provide meaningful insights into the risk of statin side effects or therapy success.

Recent Findings

The use of genome-wide association studies has significantly reduced the number of predictive genetic markers for statin effects, and the isolated effect of the surviving markers is low; more promising are approaches to stratify patients with genetic risk scores.

Summary

Patients reveal a pronounced individual response to the administration of statins. The idea of being able to adequately describe this variability with single genetic markers has failed, genetic risk scores will be the method of choice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACC:

American College of Cardiology

AHA:

American Heart Association

ALA:

Alanine

APOB:

Apolipoprotein B

APOE:

Apolipoprotein E

ASCOT:

Anglo-Scandinavian Cardiac Outcomes Trial

ASCVD:

Atherosclerotic cardiovascular disease

ASP:

Aspartate

CAD:

Coronary artery disease

CARDIA:

Coronary Artery Risk Development in Young Adults

CARE:

Cholesterol and Recurrent Events

CHD:

Coronary heart disease

CYP:

Cytochrom P

COQ2:

Coenzyme Q2, polyprenyltransferase

CPRD-STAGE:

Clinical Practice Research Datalink-STATin-Induced Muscle Toxicity: Exploration Using the UK GEmeal Practice Research Database

EAS:

European Atherosclerotic Society

ESC:

European Society of Cardiology

FOURIER:

Further Cardio­vascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk

GATM:

Glycine Amidinotransferase

GIST consortium:

Genomic Investigation of Statin Therapy consortium

GLUT4:

Glucose transporter 4

GLY:

Glycine

GoDARTS:

Genetics of Diabetes and Audit Research Tayside Study

GRS:

Genetic risk score

HMGCR:

3-hydroxy-methylglutaryl-CoA reductase

IMPROVE-IT:

Improved Reduction of Outcomes: Vytorin Efficacy International Trial

JUPITER:

Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin

LDL-C:

Low-density lipoprotein cholesterol

LDLR:

Low-density lipoprotein receptor

LESS-DM:

Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome

LILRB5:

Leukocyte immunoglobulin-like receptor subfamily-B 5

Lp(a):

Lipoprotein (a)

NNT:

Number needed to treat

NOD:

New onset of diabetes

NPC1L1:

Niemann-Pick C1-Like 1

PREDICTION-ADR:

Personalization of tREatment In Cardiovascular disease adverse drug reaction

PROVE IT-TIMI 22:

Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22

PCSK9:

Proprotein convertase subtilisin/kexin Type 9

RCT:

Randomized controlled trials

SAMS:

Statin-associated muscle syndromes

SIM:

Statin-induced myopathy

SLCO1B1:

Solute carrier organic anion transporter family member 1B1

SORT1:

Sortilin

SNP:

Single nucleotide polymorphism

Val:

Valine

WHO:

World Health Organization

WOSCOPS:

West of Scotland Coronary Prevention Study

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fredrickson DS, Lees RSA. System for phenotyping Hyperlipoproteinemia. Circulation. 1965;31:321–7.

    Article  PubMed  CAS  Google Scholar 

  2. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation. 1994;89(3):1333–445.

    Article  Google Scholar 

  3. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129(25 Suppl 2):S1–45. https://doi.org/10.1161/01.cir.0000437738.63853.7a.

    Article  PubMed  Google Scholar 

  4. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81. https://doi.org/10.1093/eurheartj/ehw106.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocr Pract. 2017;23(Suppl 2):1–87. https://doi.org/10.4158/EP171764.APPGL.

    Article  PubMed  Google Scholar 

  6. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489.

    Article  PubMed  CAS  Google Scholar 

  7. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.

    Article  PubMed  CAS  Google Scholar 

  8. Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J. 2016;37(11):908–16. https://doi.org/10.1093/eurheartj/ehv641.

    Article  PubMed  Google Scholar 

  9. De Vera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78(4):684–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. • Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018; https://doi.org/10.1007/s40256-017-0259-7. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.

  11. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289(13):1681–90. https://doi.org/10.1001/jama.289.13.1681.

    Article  PubMed  CAS  Google Scholar 

  12. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2(5):205–7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. •• Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis JB, et al. Recommendations for management of cccclinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2016;134(21):e468–e95. https://doi.org/10.1161/CIR.0000000000000456. This statement of the AHA reviews the basics of drug-drug interactions, the pharmacological differences in the various statins and the significance of statins DDIs with select medications used in patients with CVD.

    Article  PubMed  Google Scholar 

  14. Deljehier T, Pariente A, Miremont-Salame G, Haramburu F, Nguyen L, Rubin S, et al. Rhabdomyolysis after co-administration of a statin and fusidic acid: an analysis of the literature and of the WHO database of adverse drug reactions. Br J Clin Pharmacol. 2018;84:1057–63. https://doi.org/10.1111/bcp.13515.

    Article  PubMed  CAS  Google Scholar 

  15. Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmacogenomics Pers Med. 2016;9:97–106. https://doi.org/10.2147/PGPM.S86013.

    Article  CAS  Google Scholar 

  16. Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014;96(4):423–8. https://doi.org/10.1038/clpt.2014.125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Siddiqui MK, Maroteau C, Veluchamy A, Tornio A, Tavendale R, Carr F, et al. A common missense variant of LILRB5 is associated with statin intolerance and myalgia. Eur Heart J. 2017;38(48):3569–75. https://doi.org/10.1093/eurheartj/ehx467.

    Article  Google Scholar 

  18. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207. https://doi.org/10.1056/NEJMoa0807646.

    Article  PubMed  CAS  Google Scholar 

  19. Kohli P, Knowles JW, Sarraju A, Waters DD, Reaven G. Metabolic markers to predict incident diabetes mellitus in statin-treated patients (from the treating to new targets and the stroke prevention by aggressive reduction in cholesterol levels trials). Am J Cardiol. 2016;118(9):1275–81. https://doi.org/10.1016/j.amjcard.2016.07.054.

    Article  PubMed  CAS  Google Scholar 

  20. Casula M, Mozzanica F, Scotti L, Tragni E, Pirillo A, Corrao G, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Nutr Metab Cardiovasc Dis. 2017;27(5):396–406. https://doi.org/10.1016/j.numecd.2017.03.001.

    Article  PubMed  CAS  Google Scholar 

  21. Vallejo-Vaz AJ, Kondapally Seshasai SR, Kurogi K, Michishita I, Nozue T, Sugiyama S, et al. Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis. 2015;241(2):409–18. https://doi.org/10.1016/j.atherosclerosis.2015.06.001.

    Article  PubMed  CAS  Google Scholar 

  22. Park JB, Jung JH, Yoon YE, Kim HL, Lee SP, Kim HK, et al. Long-term effects of high-doSe pitavaStatin on diabetogenicity in comparison with atorvastatin in patients with metabolic syndrome (LESS-DM): study protocol for a randomized controlled trial. Trials. 2017;18(1):501. https://doi.org/10.1186/s13063-017-2229-4.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS. Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metab Clin Exp. 2014;63(6):735–45. https://doi.org/10.1016/j.metabol.2014.02.014.

    Article  PubMed  CAS  Google Scholar 

  24. • Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, et al. HMG-coenzyme a reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385(9965):351–61. https://doi.org/10.1016/S0140-6736(14)61183-1. The first publication from a series of articles that has attempted a genetic approach to explain the development of diabetes among patients treated with statins.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375(22):2144–53. https://doi.org/10.1056/NEJMoa1604304.

    Article  PubMed  CAS  Google Scholar 

  26. Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5(2):97–105. https://doi.org/10.1016/S2213-8587(16)30396-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50. https://doi.org/10.1016/S2213-8587(17)30313-3.

    Article  PubMed  CAS  Google Scholar 

  28. Leiter LA, Muller-Wieland D, Baccara-Dinet MT, Letierce A, Samuel R, Cariou B. Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials. Diabet Med. 2018;35(1):121–30. https://doi.org/10.1111/dme.13450.

    Article  PubMed  CAS  Google Scholar 

  29. Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA. 2016;316(13):1383–91. https://doi.org/10.1001/jama.2016.14568.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313(10):1029–36. https://doi.org/10.1001/jama.2015.1206.

    Article  PubMed  CAS  Google Scholar 

  31. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565–71. https://doi.org/10.1016/S0140-6736(12)61190-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. • Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet. 2017;49(12):1758–66. https://doi.org/10.1038/ng.3977. First exome-wide association study of plasma lipids adding several new loci associated with lipid levels.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. • Leusink M, Onland-Moret NC, de Bakker PI, de Boer A, Maitland-van der Zee AH. Seventeen years of statin pharmacogenetics: a systematic review. Pharmacogenomics. 2016;17(2):163–80. https://doi.org/10.2217/pgs.15.158. A very comprehensive review, in which the studies are not only collected, but also critically evaluated in terms of their quality.

    Article  PubMed  CAS  Google Scholar 

  34. Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012;5(2):257–64. https://doi.org/10.1161/CIRCGENETICS.111.961144.

    Article  PubMed  CAS  Google Scholar 

  35. Hopewell JC, Parish S, Offer A, Link E, Clarke R, Lathrop M, et al. Impact of common genetic variation on response to simvastatin therapy among 18705 participants in the heart protection study. Eur Heart J. 2013;34(13):982–92. https://doi.org/10.1093/eurheartj/ehs344.

    Article  PubMed  CAS  Google Scholar 

  36. •• Postmus I, Trompet S, Deshmukh HA, Barnes MR, Li X, Warren HR, et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun. 2014;5:5068. https://doi.org/10.1038/ncomms6068. So far the biggest meta-analysis for GWAS studies exploring the LDL-C lowering effect of statins.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Marcovina SM, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71(2):177–92. https://doi.org/10.1016/j.jacc.2017.11.014.

    Article  PubMed  CAS  Google Scholar 

  38. •• Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet. 2015;385(9984):2264–71. https://doi.org/10.1016/S0140-6736(14)61730-X. The first application of a genetic risk score to stratify patients on statins for their cardiovascular risk in primary as well as secondary prevention.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. • Natarajan P, Young R, Stitziel NO, Padmanabhan S, Baber U, Mehran R, et al. Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation. 2017;135(22):2091–101. https://doi.org/10.1161/CIRCULATIONAHA.116.024436. In addition to the validity of a genetic risk score in statin treated patients, the authors have investigated the association with subclinical atherosclerosis by looking for coronary artery calcification and carotid artery plaque burden.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve. 2006;34(2):153–62. https://doi.org/10.1002/mus.20567.

    Article  PubMed  CAS  Google Scholar 

  41. •• Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375(24):2349–58. https://doi.org/10.1056/NEJMoa1605086. A very important study showing that healthy lifestyle can modify the impact of genetic risk on cardiovascular disease.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Clinical Chemistry and Laboratory Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, D-79106, Freiburg, Germany

    Michael M. Hoffmann

  2. Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Michael M. Hoffmann

Authors
  1. Michael M. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael M. Hoffmann.

Ethics declarations

Conflict of Interest

Dr. Hoffmann reports personal fees from Sanofi and Akcea, and non-financial support from Diasys.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hoffmann, M.M. Towards a More Personalized Treatment of Dyslipidemias to Prevent Cardiovascular Disease. Curr Cardiol Rep 20, 56 (2018). https://doi.org/10.1007/s11886-018-0996-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-018-0996-5

Keywords

Search

Navigation