Prevention 2014: Statin Pharmacogenetics

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Deepak Voora, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • ABCB1 is a protein that resides in the apical membrane of the enterocyte and hepatocyte and is primarily responsible for the efflux of molecules out of the cell and into the intestinal lumen and biliary tree, respectively. Therefore, the action of this transporter serves to reduce the oral bioavailability of many dugs.
  • Overall effects are mild
  • Major allele/haplotype associated with attenuated response
  • Prevention 2014: Statin Pharmacogenetics

    1. 1. Deepak voora, md Statin pharmacogenetics
    2. 2. Rationale for statin pgx • Statins are increasingly used/recommended for prevention of CVD • Concern from patients/providers of the risk/benefit ratio • Low risk patients (e.g. low 10yr risk) for CVD • High risk for adverse events (e.g. pre-diabetes) • Can we use genetics to identify those with an optimal risk/benefit ratio for statins? • Patients with unusual responses (therapeutic and adverse)
    3. 3. 3 The “responses" to statins • Common responses to statin medications 1. LDLc reduction 2. Prevention of cardiovascular disease 3. Myopathy 4. Adherence to statin therapy • Each is a “response” to statin medications amenable to genetic analysis • Other responses that are less studied and will not be covered but likely involve unrelated pathways • CRP lowering • Risk of diabetes • Cognitive dysfunction
    4. 4. 1. LDLc reduction • Large interindividual variability in LDLc reduction • Few clinical predictors 4 Simon et al, Am J Cardiol 2006;97:843–850
    5. 5. Statin PK genes •Little convincing evidence for genetic variation in drug metabolizing enzymes and LDLc reduction •Two genes with most consistent data •ABCB1 •ABCG2
    6. 6. ABCB1 – LDLc reduction 6 Thompson et al, The Pharmacogenomics Journal (2005) 5, 352–358. Association of T-T-T haplotype with attenuated LDLc lowering with pravastatin validation • 1,507 pravastatin treated patients • 10.5% lesser LDLc reduction Mega et al, Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1310.
    7. 7. ABCG2 – LDL Reduction • JUPITER trial substury • ~5-6% difference in LDLc with each allele Chasman et al, Circ Cardiovasc Genet. 2012 Apr 1;5(2):257-64
    8. 8. Statin PD • HMGCR
    9. 9. HMGCR 9 Krauss et al, Circulation. 2008;117:1537-1544 Chasman et al, JAMA. 2004;291:2821-2827.
    10. 10. LDLc genes • APOE
    11. 11. APOE – GWAS and others • The most replicated genetic variant for LDLc response 11 Thompson et al, Circulation: Cardiovascular Genetics. 2009;2:173-181 Table 1. Relationship between APOE genotypes and commonly observed haplotypes rs429358 allele C T rs7412 allele C ε4 (20-30%) ε3 (90-95%) T Rare ε2 (15-20%) Numbers in parentheses represent prevalence in Caucasian populations.
    12. 12. LDLc summary • 4 genes – all related to known statin/lipid biology • ABCB1* • ABCG2 • APOE* • HMGCR • Clinical implications • In combination associated with minor (<10 mg/dl) differences in LDLc lowering • Unlikely to reach clinical application especially as we move away from “treat to target” * = Clinically available genetic test 12
    13. 13. 2. Protection from CV events • Statins are well known to have beneficial effects outside of LDLc lowering • Pleotropic statin effects • Genetic predictors for this benefit? • KIF6 locus • Trp719Arg (rs20455) variant associated with increased risk of 1st and recurrent MI 13
    14. 14. KIF6 and statin treatment 14 Iakoubova et al, JACC 51 (4): 449- 455 Iakoubova et al JACC. 51(4): 435-43
    15. 15. KIF6 – follow up studies • JUPITER substudy • Similar benefit of rosuvastatin in KIF6 carriers/noncarri ers
    16. 16. Prevention of cv events - Summary • 1 gene may modify effects of statins • KIF6* • Despite initial reports, JUPITER and subsequent studies failed to replicate findings • Discrepancy remains unexplained • Unlikely to be useful in guiding statin therapy * = Commercially available genetic test
    17. 17. 3. Statin myopathy • Statins are well tolerated however • Myalgia is a common side effect: • Without CK (common) • With CK elevation • Asymptomatic CK elevations • Rhabdomyolysis (rare) • Discrepancy in incidence from clinical trials • No reliable clinical predictors • Unrelated to statin potency or LDLc lowering 17
    18. 18. SLCO1B1 – GWAS of CK > 10x ULN 80mg simvatstatin myopathy • For each copy of variant allele: 4.5 increased odds of myopathy 18 SLCO1B1*5 variant (Val174Ala, rs4149056) Link et al, N Engl J Med. 2008 Aug 21;359(8):789-99
    19. 19. SLCO1B1*5 Variant CK (-) myopathy Trend p-value = 0.01 19% 27% 50% Number of SLCO1B1*5 Alleles Voora et al, JACC. 2009 Oct 20;54(17):1609-16
    20. 20. Statin specific effects by SLCO1B1*5 genotype P = 0.01 P = 0.3 P = 0.97 Voora et al, JACC. 2009 Oct 20;54(17):1609-16
    21. 21. Risk of muscular complaints by treatment groups and SLCO1B1 genotypes in JUPITER Fewer events associated with “C” allele More events associated with “C” allele More events P-interaction† 0.57 P-interaction 0.30 P-interaction 0.36 P-interaction 0.22 (Allelic risk model)* (Genotype risk model)** (Allelic risk model)* (Genotype risk model)** Fewer events associated with “C” allele More events associated with “C” allele Slide created by Paul Ridker, MDDanik et al, JACC, 59 (13_Suppl_S) E1621
    22. 22. Statin myopathy summary • 1 gene associated with risk of myopathy • SLCO1B1* • *5 variant associated with musculoskeletal side effects on simvastatin s: • Odds Ratio for CK negative myopathy = 1.8 • Odds Ratio for CK negative myopathy = 4.7 • Clinical implications • Low dose simvastatin, rosuvastatin, or pravastatin may be alternatives for carriers to avoid myopathy * = Clinically available test
    23. 23. 4. Statin adherence • Statin nonadherence 20-25% in CAD patients 23 Ho et al, American Heart Journal 155 (4),772-779 Voora et al, JACC. 2009 Oct 20;54(17):1609-16
    24. 24. Statin adherence • Primarily simvastatin treated patients • Intolerance, included statin discontinuation Donnely et al, Clinical Pharmacology & Therapeutics (2011) 89 2, 210–216
    25. 25. Can genetics be used to improve responses to statin therapy? • Adherence response: • AKROBATS study • Delivered KIF6 genetic test results to statin treated patients • Tested the hypothesis that patient knowledge of better response to statins would be associated with improved adherence • Addresses patient concerns that statins will not benefit them • Knowledge of genetic information associated with higher statin adherence and persistence Charland et al, Pharmacogenomics J. 2013 Aug 27.
    26. 26. SLCO1B1 and rechallenging statins • Builds on statin specific effects of SLCO1B1 and myopathy • Simastatin >> prava/rosuva • Hypothesis: Patient knowledge of their individualized risk for myopathy and a tailored intervention • Carriers of variant  prava/rosuva • Noncarrier  retry any statin no tried before
    27. 27. Self-reported statin use p<0.001 LDL-c Li et al, J. Pers. Med. 2014, 4(2), 147- 162
    28. 28. Statin adherence summary • 1 gene associated with adherence • SLCO1B1* • Providing individualized information to patients about their specific risks/benefits of statin therapy may improve statin adherence • SLCO1B1* • KIF6* (underlying biology has been questioned, though) * = Clinically available genetic tests
    29. 29. Statin Pharmacogenetics Summary 29
    30. 30. SLCO1B1 CPIC Guideline • “If you had a SLCO1B1 genetic test result, what should you do with it?”
    31. 31. CPIC SLCO1B1 algorithm

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