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Case Study “SK”

Case Study “SK”. ApoE-OM3FA Interaction KIF6 LDL Subclasses. Dmitri Vasin MD Drew Garcia PA-C Atherosclerosis Regression Clinic Bremerton WA, USA. Doctors Are Not Scientist.

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Case Study “SK”

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  1. Case Study “SK” ApoE-OM3FA Interaction KIF6 LDL Subclasses Dmitri Vasin MD Drew Garcia PA-C Atherosclerosis Regression Clinic Bremerton WA, USA Downloaded from www.atheroregression.com

  2. Doctors Are Not Scientist • “Some doctors are scientists – just as some politicians are scientists – but most are not… [Scientists are] the kind of people who brush their teeth on only one side of their mouth to see whether brushing your teeth has any benefit”. • “In their methods of working [doctors] are more like jazz musicians than scientists”. Richard Smith, M.D. Editorial. BMJ June 14, 2004;328:doi:1136 Downloaded from www.atheroregression.com

  3. Case Study “SK” • 67 y.o. wm 6’2”, 225 lbs, BMI 29 • Diagnosed with CAD by Nuclear stress test; small areas of reversible ischemia; normal EF on ECHO; medical Tx recommended • Meds: Atorvastatin 80 mg q. hs, Niaspan 1,000 mg q. hs, OM3FA 4 g a day, Perindopril 8 mg q.d., ASA 325 mg q.hs, Meotprolol XL 50 mg q.d. • LDL decreased 80% on Atorvastatin Downloaded from www.atheroregression.com

  4. Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega-3 FA Downloaded from www.atheroregression.com

  5. Standard of Care? Akosah A. 8th World Congress on Heart Failure. JACC 2003, Vol. 41, No. 9 NCEP ATP III lipid panel guidelines Failed to identify 75% of patients under 55 (n=222) who had first MI Downloaded from www.atheroregression.com

  6. Residual Cardiovascular Risk in Major Statin Trials Patients Experiencing Major Coronary Events, % N 4444 9014 4159 20 536 6595 6605 LDL -36% -25% -28% -29% -26% -27% Secondary High Risk Primary Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

  7. Looking Beyond the Numbers • Vulnerable blood • Advanced CVD Profile plus Apo E • Vulnerable plaque/artery • Lp-PLA2 • Vulnerable myocardium • NT-proBNP Assessment Directs Comprehensive Therapy Naghavi et al. Circulation. 2003;108 Downloaded from www.atheroregression.com

  8. Subclasses Better Predictors of CVD 30% had TG < 100 mg/dl 8 BHL Internal Study 2006

  9. Inflammation Markers — How to Use? Inflammation indicates that the process of arteriographic progression may be occurring • Key is to treat identified disorders more aggressively • Test for elevated levels of Lp-PLA2, hs-CRP, and Fibrinogen

  10. Lp-PLA2 – initiation and progression of atherosclerosis Blood levels are significantly elevated in advanced plaque stages

  11. Lp-PLA2 and CRP: Independent and distinct inflammatory markers Lp-PLA2 CRP • Marker of systemic inflammation • Produced by liver in response to inflammatory reactions – acute phase reactant • May enhance late stage plaque progression promoting plaque instability • Most useful in otherwise healthy individuals • A potentially useful tool for the pharmacological management of CHD patients • Marker of vascular inflammation • An enzyme produced by inflammatory cells • Appears to be involved in the initiation of the early stage of the vascular inflammatory process • Minimal biovariability; Not affected by other inflammatory conditions • A specific target for pharmacologic intervention for the treatment of CHD • Ridker PM, et al, Circulation. 1998 • Ridker PM, et al. New Engl J Med. 1997 • Ridker PM, et al, Circ. 2001 4. Carpenter Keri LH, et al. FEBS Lett. 2001 5. Macphee CH, et al. Expert Opin Ther Targets. 2002 6. Packard CH, et al. New Engl J Med. 2000

  12. Lp-PLA2 and CRP: Independent and distinct inflammatory markers • Lp-PLA2 is an independent predictor of risk from CRP and should be ordered in conjunction with CRP as part of comprehensive risk profile in order to deliver a complete snapshot of the inflammatory process. • Additionally, when both Lp-PLA2 and CRP are elevated to the highest tertile levels, there is a multiplicative impact on risk. CRP Lp-PLA2 Plaque Formation Acute, non-specific Stroke or Progression Inflammation Risk - + + - + + - - + + + + + + ++ +++ +++ +++ +++ +++ Important guides in determining intensity of therapy

  13. Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega-3 FA Downloaded from www.atheroregression.com

  14. Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega-3 FA Downloaded from www.atheroregression.com

  15. Apo E Genotype Effects on Plasma Lipids • Apo E3 has “normal” lipid metabolism - no genotype impact • Apo E2 versus Apo E4 - opposing effects on plasma lipids • Apo E2 associated with slow conversion of IDL to LDL • Decreases plasma cholesterol and increases triglycerides • Apo E4 limits HDL-binding - inhibits normal cholesterol clearance process (reverse cholesterol transport or RCT) • Increases total cholesterol, LDL, and TG and decreases HDL Mamotte C, Sturm M, Foo J, van Bockxmeer F, Taylor R. Am J Physiol 1999 March;276(3 Pt 1):E553-E557

  16. Therapeutic Implications of Apo E • Interactions between Apo E gene polymorphism, abnormal lipid profiles, and diet and drug therapy have been documented • Therapy targeting the lipid abnormalities resulting from the phenotypic expression of certain Apo E genotypes in response to environmental “stress” factors can mediate their impact on CVD • Wilson PW, Myers RH, Larson MG, • Ordovas JM, Wolf PA, Schaefer EJ. • JAMA 1994 December 7;272(21):1666-71. • Dallongeville J, Lussier-Cacan S, Davignon • J Lipid Res 1992 April;33(4):447-54. • Schaefer EJ, Lamon-Fava S, Johnson S et al. • Arterioscler Thromb 1994 July;14(7):1105-13. • Sing CF, Davignon J. • Am J Hum Genet 1985 March;37(2):268-85. • 4. Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. • Circulation 1995 January 15;91(2):265-9. • 5. Wang XL, McCredie RM, Wilcken DE. • Arterioscler Thromb Vasc Biol 1995 August;15(8):1030-4.

  17. Ann Intern Med 2004 July 20: 141(2): 137-47

  18. Am J Clin Nutr 2003; 77: 1098-111 • J Nutr 2004 134: 2517-2522 3. a)Am J Clin Nutr 2001 Apr; 73 (4): 736-45 b)Obes Res 2003 Oct; 11 (10) 1200-6 c)Atherosclerosis 2004 Mar: 173 (1); 79-87 d)J Neural Trans 2003 Apr: 110 (4) : 401-11 e)Proc Nutri Soc 2004 (65) 5-10 f)Art Thromb Vasc Biol 2002: AMy 1: 22 (5) 824-31

  19. a) Am J Clin Nutr 1997 Sep; 66 (3): 584-90 b) Metabolism 1993 (42): 585-93 • 2. Arterioscler Thromb Vasc Biol 2000 Aug; 20 (8): 1990 -7 • Nutrition 2002 Jul-Aug: 18 (7-8): 561-5 • Nutr Metab Cardiovasc Dis 2000 Dec: 10 (6): 315-22

  20. Increases decreases

  21. Therapeutic Implications of Apo E • When managed with treatment algorithms based on the routine CVD analytes supported by consensus guidelines (without Apo E genotype), a significant percentage of patients will be: • sub-optimally treated • managed in a limited way with a “one diet, standard drug therapy regimen fits all” approach • Conditions for which an Apo E genotype is applicable to make treatment decisions to reduce progression of vascular disease in patients with known hyperlipidemia and/or vascular disease include: • Pharmaceutical recommendation • Diet Recommendation • Alcohol recommendation

  22. Apo E Genotype and CVD Management Heterogeneity of gene-environment interaction Heterogeneity of therapeutic response to “accepted” treatments Establish Apo E genotyping as an important adjunct to an aggressive, targeted, and effective cardiovascular disease management program …..allowing personalization of: • Pharmaceutical Recommendation • Diet Recommendation • Alcohol Recommendation

  23. Apo E ¾ Implications for “SK” • A LOT of exercise • Low (really low) fat diet, including avoidance of OM3FA, unless indicated for non-lipid effects • Imperative target to lose waist size/weight to optimal • Avoidance of alcohol Downloaded from www.atheroregression.com

  24. Case Study “SK”: Apo E 3/4LDL gels On 4g/d and 1 g/d ofOmega-3 FA 4g/d OM3FA Off OM3FA Downloaded from www.atheroregression.com

  25. Case Study “SK”: Apo E 3/4LDL gels On 4g/d and 1 g/d ofOmega-3 FA 4g/d OM3FA Off OM3FA Downloaded from www.atheroregression.com

  26. Case Study “SK”: Apo E ¾HDL gels On 4g/d and 1 g/d of Omega-3 FA 4g/d OM3FA Off OM3FA

  27. Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega-3 FA Downloaded from www.atheroregression.com

  28. Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega-3 FA Downloaded from www.atheroregression.com

  29. Case Study “SK”Summary of OM3FA and Apo E interactions • LDL (total and subclasses) trended parallel with dose of OM3FA, with high dose of OM3FA associated with NEGATIVE changes • HDL (total and especially subclasses) trended reciprocal to dose of OM3FA, with higher dose associated with NEGATIVE changes • OM3FA are used in SK for its non-lipid effects, i.e. to decrease in CV mortality (GISSI, GISSI-HF trials)

  30. KIF6 Trp719Arg and CHD • Up to 50% increased risk of CHD in carriers of a common KIF6 variant • KIF6 719Arg is the risk variant • ~60% of Caucasians carry one or two risk variant of the gene • KIF6 encodes a kinesin, a molecular motor protein • Statin therapy can provide substantial and significant benefit in carriers

  31. KIF6 Trp719Arg and CHD • Up to 50% increased risk of CHD in carriers of a common KIF6 variant • KIF6 719Arg is the risk variant • ~60% of Caucasians carry one or two risk variant of the gene • KIF6 encodes a kinesin, a molecular motor protein • Statin therapy can provide substantial and significant benefit in carriers

  32. Previous Genetic Studies of KIF6 719ArgRisk of CHD in 5 Prospective Studies Placebo arm of CARE Patients with prior MI Placebo arm of WOSCOPS Patients with LDL-C >178mg/dL CHS Men and women of ≥65 years old Middle-aged Americans ARIC Initially healthy middle-agedwomen WHS Adjusted Risk Ratios • Carriers of the KIF6 719Arg variant (60% of Caucasians) are at greater risk of coronary events compared with noncarriers • More than 49,000 participants WHS: Shiffman et al.J Am Coll Cardiol 2008; 51:444 ARIC: Bare et al.Genet Med. 2007; 10:682 CHS: Shiffman et al.Arterioscler Thromb Vasc Biol. 2008; 1:173

  33. CHD Event Reduction by PravastatinAccording to KIF6 719Arg Carrier Status • Carriers of the 719Arg risk allele received significant benefit from pravastatin therapy • In WOSCOPS, risk reduction was significantly greater in carriers than in noncarriers (Pinteraction = 0.003) WOSCOPS CARE Non-carriers All Non-carriers All Carriers Carriers Absolute Risk Reduction (%) 1.4% 3.5% 4.9%* 3.5% 5.5%* 0.1% P = 0.005 P < 0.0001

  34. Coronary Events According to KIF6 719Arg Carrier Status in PROSPER Patients with Prior Vascular Disease Noncarriers 719Arg Carriers Placebo HR=0.66 HR=0.94 P=0.64 P=0.002 CHD death or major CHD events (%) Pravastatin Months of follow up Months of follow up Fatal or nonfatal CHD • Among patients with prior vascular disease, carriers of KIF6 719Arg risk allele received substantial and significant reduction of coronary events, whereas noncarriers did not • 34% relative risk reduction in carriers • Among patients without prior vascular disease, no significant event reduction 38

  35. LDL-C Lowering by Pravastatin Therapy In the Elderly with Prior Vascular Disease PROSPER Study Placebo 4.0 3.0 LDL Cholesterol (mmol/L) 2.0 Pravastatin KIF6 Carriers 1.0 Noncarriers Baseline 6 12 24 36 3 Months of follow-up • In PROSPER, substantial and significant difference in reduction of events between carriers and noncarriers was observed despite similar reduction of LDL-C levels • A similar observation was made in PROVE IT–TIMI 22 • An indication of the pleiotropic effect of statins among 719Arg carriers 39

  36. KIF6 Carriers Noncarriers Pravastatin Pravastatin P=1.0 p≤0.001 Death or major CV events Atorvastatin Atorvastatin Months of follow-up Months of follow-up Statin Intensity and CHD Event ReductionAccording to KIF6 719Arg Carrier Status PROVE IT—TIMI22 • KIF6 carriers received greater benefit from 80mg atorvastatin, compared with 40mg pravastatin, than did noncarriers • NNT for atorvastatin vs pravastatin: • 10 for KIF6 carriers • 125 for noncarriers

  37. PROVE IT Pravastatin 120 100 KIF6 Carriers Noncarriers 80 LDL (mg/dL) 60 Atorvastatin 40 20 Baseline 30 Days 4 Mo 8 Mo 16 Mo Time of Visit LDL-C Lowering by Statin TherapySimilar Reduction in KIF6 Carriers and Noncarriers • Similar reduction of LDL-C levels in carriers and noncarriers • However, event reduction was significantly greater in carriers

  38. KIF6 Variant: Carriers and Noncarriers Carriers • Carriers of the deleterious gene variant might benefit from aggressive treatment of modifiable CHD risk factors Noncarriers • The absence of significant benefit from intensive statin therapy in noncarriers does not preclude the possibility that a portionof noncarriers do benefit from statin therapy • But it does suggest that noncarriers may be treated with standard statin therapy and also with other lipid-modifying drugs or by strategies that target other risk factors such as hypertension, diabetes, or smoking

  39. KIF6 719Arg Variant and CHDSummary • Associated with risk of CHD in 5 prospective studies • ARIC, WHS, CHS, CARE, and WOSCOPS • Carriers at up to 50% higher risk • Risk estimate unchanged after adjustment for traditional risk factors • 60% of Caucasians carry the risk allele • Carriers received significant event reduction from statin therapy • Standard-dose pravastatin vs placebo • High-dose atorvastatin vs standard-dose pravastatin

  40. Our Take* Primary Prevention and KIF6 • Age <70 • KIF6 AA or AT: maximal dose potent statin (Atorva 80 or Rosuva 20-40) • KIF6 TT: non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA), statin as 3rd or 4th line therapy • Age >70 • Regardless of KIF6 status: • non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA), statin as 3rd or 4th line therapy *Represents current position of Atherosclerosis Regression Clinic *May or may not reflect position of Celera and/or contributing authors Downloaded from www.atheroregression.com

  41. Our Take* Secondary Prevention and KIF6 • KIF6 AA or AT • maximal dose potent statin (Atorva 80 or Rosuva 20-40) • non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA**) • KIF6 TT • non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA**) • statin as 3rd or 4th line therapy: Pravastatin 20-40 mg QHS *Represents current position of Atherosclerosis Regression Clinic ;May or may not reflect position of Celera and/or contributing authors **Limit to 1g qd for ApoE ¾ or 4/4 genotype Downloaded from www.atheroregression.com

  42. Risks of Not Using Berkeley • May miss a lipid disorder or other risk biomarker • Can’t target intervention or degree of aggressiveness, i.e.; • 1,000 mg of niacin or 1,500 mg, 2,000 mg…? • 10 mg/d of statin or 40 mg? • Combination drug therapy (statin / niacin / fenofibrate) ? • Aggressiveness of goal setting? • When is it imperative to initiate medication (rather than lose weight)? • Can’t monitor patient responsiveness to treatment and determine whether to continue to optimize treatment • You need greater discrimination to determine if the treatment plan is effective • Monitoring Apo B, LDL IIIa+b, LDL IVb, and HDL2b are key to monitoring the patient’s progress

  43. Case Study “SK”Summary • Multiple risk factors were still present despite “optimal” ATP III panel • OM3FA were clearly associated with adverse changes in LDL and HDL subclasses, as expected with Apo E ¾ genotype • Even small dose (1 g/d) of OM3FA was associated with adverse lipid effects • ApoE genotyping can help in individualizing lipid lowering therapy choices (as well as diet, EtOH, and exercise recommendations) • KIF6 genotyping allowed to optimize statin brand/dose recommendations Downloaded from www.atheroregression.com

  44. Final Comment “If you aren’t confused, you don’t know what’s going on.” Jack Welsh Former CEO General Electric Downloaded from www.atheroregression.com

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