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Case Study “SK”

ApoE‐OM3FA Interaction

KIF6

LDL Subclasses

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Dmitri Vasin MDDrew Garcia PA‐C

Atherosclerosis Regression Clinic Bremerton WA, USA

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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



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



Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega‐3 FA


Presenter

Presentation Notes

ATP III panel is clearly within acceptable range. Can we tell patient that “mission is accomplished” and his risk of CV event is very low? Should statin dose be decreased or Atorvastatin changed to generic statin, e.g. Pravastatin 40 mg q. hs? Should he continue on 4 g of OM3FA?


Standard of Care?

• NCEP ATP III lipid panel guidelines Failed to identify

75% of patients under 55 (n=222) who had first MI

Akosah A. 8th World Congress on Heart Failure. JACC 2003, Vol. 41, No. 9



Residual Cardiovascular Risk in Major Statin Trials

Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

62%69%73%75%

62%

75%

0

20

40

60

80

100

4S LIPID CARE HPS WOS AFCAPS /TexCAPS

ΔLDLN 4444 4159 20 536 6595 66059014

-36% -28% -29% -26% -27%-25%

Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

Maj

or C

oron

ary

Even

ts, %

Presenter

Presentation Notes

Residual Cardiovascular Risk in Major Statin Trials. In all of these major statin trials, significant residual cardiovascular risk remains even after reducing LDL-C. According to Libby, in the best of circumstances, the decrease in cardiovascular events due to statin treatment still allows two-thirds of cardiovascular events to occur. Libby concludes, “To address the majority of cardiovascular events that still occur despite our most powerful existing therapies, we must combine lifestyle change and evaluate new pharmacological strategies that will move us toward the goal of eradicating cardiovascular disease in the future.” Reference Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.


Looking Beyond the Numbers

● Vulnerable bloodAdvanced CVD Profile plus Apo E

● Vulnerable plaque/arteryLp‐PLA2

● Vulnerable myocardiumNT‐proBNP

Assessment Directs Comprehensive Therapy

Naghavi et al. Circulation. 2003;108


Presenter

Presentation Notes

This is slightly modified Berkeley’s slide illustrating their approach. BHL offers single blood testing platform for comprehensive evaluation of CV risk factors that have practical, actionable applications in care for individual patients. First step is to widen the clinicians scope from just looking at lipids for CV risk reduction to more comprehensive view of the situation. Nowadays we also add KIF6 to Vulnerable blood Carotid IMT, specifically looking for soft plaque to “vulnerable plaque”, we also using serial CIMTs to document regression of atherosclerosis – in our view ultimate guarantee that “vulnerable plaque” problem has been remediated ECHO for “vulnerable myocardium” if NT-pro-BNP is elevated and recommend use of RAAS inhibitors (usually ramipril/perindopril in combination with small dose spironolactone) regardless of ECHO results.

8

Subclasses Better Predictors of CVD

Biomarker Cutpoint n Sensitivity Patients NOTDetected by Biomarker

TRIG ≥ 150 mg/dL 1,723 39% 61%

HDL-C ≤ 40 mg/dL 1,768 40% 60%

TCHOL ≥ 200 mg/dL 1,015 23% 77%

LDL-C ≥ 130 mg/dL 481 11% 89%

%-HDL 2b ≤ 20 % 3,065 70% 30%

%-LDL IIIa+b ≥ 15% 4,036 92% 8%

BHL Internal Study 2006

30% had TG < 100 mg/dl

Presenter

Presentation Notes

Speaking of Vulnerable Blood: clearly traditional ATP III markers fail to identify majority of patients with CVD. Even though clearly not an interventional study, this one helps to identify high risk patients and concentrate additional effort on this population. Intuitively, treatments that improve abnormal subfractions should be favored, after outcome/evidence based treatment options are exhausted.

Inflammation Markers — How to Use?

Inflammation indicates that the process ofarteriographic progression may be occurring

• Key is to treat identified disorders more aggressively• Test for elevated levels of Lp-PLA2, hs-CRP, and Fibrinogen

Presenter

Presentation Notes

As you see here inflammation with associated risk of plaque rupture and acute events starts BEFORE plaques calcify. Thus it is possible, at least in theory, to die from MI with no calcium in the arteries and “normal” EBCT Ca score. Also this figure explains why majority of CV events occur on angiographically “not critical” ,- eccentric plaques with this fibrous caps, and not so much on “critical” concentric plaques covered with thick fibrous cap PLA2, hs-CRP and fibrinogen all are useful as inflammatory markers; however clinical context become paramount in interpretation of the results. PLA2 is probably the most specific marker of unstable plaques and, at least anecdotally, more sensitive too. In our clinic where majority of population are older, with metabolic syndrome or diabetes as well as chronic kidney disease Fibrinogen is elevated in majority of the patients, and we also feel we had too many elevated hs-CRPs not related to vascular inflammation.

Lp‐PLA2 – initiation and progression of atherosclerosis

Blood levels are significantly elevated in advanced plaque stages

Presenter

Presentation Notes

PLA2 seems to be plaque-specific inflammatory marker. Other, less specific inflammatory mediators can and had been used to discriminate between patients with and witout high inflammatory plaque burden: hs-CRP, Fibrinogen, etc. Imaging modalities from coronaroscopy to finding of soft plaque on CIMT (or ulcerated plaque on carotid US)

1. Ridker PM, et al, Circulation. 19982. Ridker PM, et al. New Engl J Med. 19973. Ridker PM, et al, Circ. 2001

4. Carpenter Keri LH, et al. FEBS Lett. 20015. Macphee CH, et al. Expert Opin Ther Targets. 20026. Packard CH, et al. New Engl J Med. 2000

Lp-PLA2 and CRP: Independent and distinct inflammatory markers

CRP Lp-PLA2

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

Presenter

Presentation Notes

This table provides a summary comparison of two inflammatory markers (CRP and Lp-PLA2) CRP is an acute phase reactant produced by the liver in response to inflammatory reactions, whereas Lp-PLA2 is an enzyme produced by macrophages and other cells involved in the inflammatory process that are associated with atherosclerotic plaque development While the specific role of CRP in CHD is unclear, it appears that Lp-PLA2 has a specific role in the vascular inflammatory process Since CRP is elevated in patients with a wide range of inflammatory conditions, it has limitations as a specific marker for CHD Lp-PLA2 is not affected by systemic inflammation and, due to its minimal biovariability, it can be used as a specific marker for CHD Because Lp-PLA2 is an enzyme that appears to be directly involved in the vascular inflammatory process, it is a potential target for therapeutic intervention Ridker PM, Glynn RJ, Hennekens CH. Circulation. 1998;97:2007-2011 Ridker PM, Cushman M, Stampfer MJ, et al. New England Journal of Medicine. 1997;336:973-979 Ridker PM, Rifai N, Lowenthal SP. Circulation. 2001;103:1191-1193 Ridker PM, Rifai N, Pfeffer SP. Circulation. 1999;100:230-235 Carpenter Keri LH, Dennis IF, Challis IR, et al. FEBS Lett. 2001;505:357-363 Macphee CH, Suckling KE. Expert Opin Ther Targets. 2002;6:309-314 Packard CJ, O’Reilly DSJ, Caslake MJ, et al. New Engl J Med. 2000;343:1148-1155

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

Presenter

Presentation Notes

This table provides a summary comparison of two inflammatory markers (CRP and Lp-PLA2) CRP is an acute phase reactant produced by the liver in response to inflammatory reactions, whereas Lp-PLA2 is an enzyme produced by macrophages and other cells involved in the inflammatory process that are associated with atherosclerotic plaque development While the specific role of CRP in CHD is unclear, it appears that Lp-PLA2 has a specific role in the vascular inflammatory process Since CRP is elevated in patients with a wide range of inflammatory conditions, it has limitations as a specific marker for CHD Lp-PLA2 is not affected by systemic inflammation and, due to its minimal biovariability, it can be used as a specific marker for CHD Because Lp-PLA2 is an enzyme that appears to be directly involved in the vascular inflammatory process, it is a potential target for therapeutic intervention Ridker PM, Glynn RJ, Hennekens CH. Circulation. 1998;97:2007-2011 Ridker PM, Cushman M, Stampfer MJ, et al. New England Journal of Medicine. 1997;336:973-979 Ridker PM, Rifai N, Lowenthal SP. Circulation. 2001;103:1191-1193 Ridker PM, Rifai N, Pfeffer SP. Circulation. 1999;100:230-235 Carpenter Keri LH, Dennis IF, Challis IR, et al. FEBS Lett. 2001;505:357-363 Macphee CH, Suckling KE. Expert Opin Ther Targets. 2002;6:309-314 Packard CJ, O’Reilly DSJ, Caslake MJ, et al. New Engl J Med. 2000;343:1148-1155




Presenter

Presentation Notes

ATP III panel is clearly within acceptable range. Can we tell patient that “mission is accomplished” and his risk of CV event is very low? Should statin dose be decreased or Atorvastatin changed to generic statin, e.g. Pravastatin 40 mg q. hs? Should he continue on 4 g of OM3FA?




Presenter

Presentation Notes

Besides clearly abnormal LDL subclasses patient also has multiple other risk factors, independent of ATP III panel risks. Apo E ¾ is a risk factor and major modifier to diet and lifestyle recommendations as well as pharmacologic therapy. We will discuss it shortly. Hyperinsulinemia is present. He had normal HbA1c, but declined 2 hour glucose tolerance test. In any case it is an additional risk factor for CV events Note that high fibrinogen is present while hs-CRP and PLA2 (performed later) are “normal”. Niacin and fibrates decrease fibrinogen level and increase in Niacin dose may be warranted NT-pro-BNP is yet another CV risk factor and reflects the presence of “vulnerable myocardium” which we already know, in some way, from the results of the nuclear stress test. It probably reflects “total accumulated damage” to myocardium from variety of factors: HTN, vascular disease, valvular disease, etc. As a bottom line this patient who would have been congratulated on great looking ATP III panel and let go with yearly follow ups (until next CV event, symptomatic PVD or heart failure) in reality needs significant modification in his lifestyle, diet and medications.

Apo E Genotype Effects on Plasma Lipids

Apo E3 has “normal” lipid metabolism - no genotype impactApo 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

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

1. Dallongeville J, Lussier-Cacan S, Davignon J Lipid Res 1992 April;33(4):447-54.

2 Schaefer EJ, Lamon-Fava S, Johnson S et al. Arterioscler Thromb 1994 July;14(7):1105-13.

3. 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.

6. Wilson PW, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ. JAMA 1994 December 7;272(21):1666-71.

Apo E Genotype and CVD Risk

Apo E2 Response Apo E3 Response Apo E4 Response

Genotype 2/2 2/3 3/3 2/4 3/4 4/4

Population Frequency 1% 10% 62% 2% 20% 5%

CVD Risk Intermediate Normal Highest Risk ( ↑ 42%)

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

Apo E Genotype Correlation to Treatment Response


Genotype 2/2 2/3 3/3 2/4 3/4 4/4


Low Fat Diet1,2 ↓ LDL↑ small dense LDL

↓↓ LDL↔ small dense LDL

↓↓↓ LDL↓ small dense LDL

Moderate Fat Diet2 ↔ LDL↔ small dense LDL

↓ LDL↓ small dense LDL

↓ LDL↑↑ small dense LDL

Moderate Alcohol3 ↑ HDL ↓ LDL ↑ HDL ↓ HDL ↑ LDL

Effective Statin Response Beneficial No distinction Limited

1. Am J Clin Nutr 2003; 77: 1098-111 2. 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

Apo E Genotype Correlation to Treatment Response


Genotype 2/2 2/3 3/3 2/4 3/4 4/4


Soluble Fiber1 ↓↓ LDL ↓ LDL ↓ LDL

Fish Oil2↓↓ TG

↓ small dense LDL↑ HDL

↓ TG↓ small dense LDL

↑ HDL

↓ TG↓↓ small dense LDL

↓ HDL ↑↑ LDL

Plant Sterols3 ↓ LDL↓ Apo B

↓ LDL↓ Apo B

↓ LDL↓ Apo B

Soy Protein4 ↓ Apo B ↓ Apo B ↓ Apo B

1. a) Am J Clin Nutr 1997 Sep; 66 (3): 584-90 b) Metabolism 1993 (42): 585-932. Arterioscler Thromb Vasc Biol 2000 Aug; 20 (8): 1990 -73. Nutrition 2002 Jul-Aug: 18 (7-8): 561-54. Nutr Metab Cardiovasc Dis 2000 Dec: 10 (6): 315-22

Apo E Genotype Response Treatment Summary

Apo E Genotype Treatment Surrogate Markers Response

Apo E2

♦ Statin

♦ Moderate Alcohol

♦ Low Fat Diet

♦ ↓ LDL

♦ ↓ LDL / ↑ HDL

♦ ↑ Small Dense LDL / limited ↓ LDL

♦ Beneficial

♦ Beneficial

♦ Not Recommended

Apo E4

♦ Statin

♦ Moderate Alcohol

♦ Low Fat Diet

♦ Limited ↓ LDL

♦ ↑ LDL / ↓ HDL

♦ ↓ LDL / ↓ TG / ↓ small dense LDL

♦ Limited

♦ Not Recommended

♦ Beneficial

↑ Increases ↓ decreases

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

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

● Pharmaceutical Recommendation● Diet Recommendation● Alcohol Recommendation

…..allowing personalization of:


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



Case Study “SK”: Apo E 3/4LDL gels On 4g/d and 1 g/d ofOmega‐3 FA

4g/d OM3FA

Off OM3FA


Presenter

Presentation Notes

The only real change between these two LDL gels is discontinuation of OM3FA. Dramatic drop in most atherogenic LDL IV is noted. This is not what you would be predicted in previous (BHL) slides, but the difference is dramatic and clearly negative (with worse numbers associated with treatment with OM3FA). Note that BHL has also Q-LDL calculated. It is expressed as mg/dl, rather than %. This is done to adjust for drop (sometimes very dramatic) in total LDL with lipid lowering therapy


Case Study “SK”: Apo E 3/4LDL gels On 4g/d and 1 g/d ofOmega‐3 FA

4g/d OM3FA

Off OM3FA


Presenter

Presentation Notes

The only real change between these two LDL gels is discontinuation of OM3FA. Dramatic drop in most atherogenic LDL IV is noted. This is not what you would be predicted in previous (BHL) slides, but the difference is dramatic and clearly negative (with worse numbers associated with treatment with OM3FA). Note that BHL has also Q-LDL calculated. It is expressed as mg/dl, rather than %. This is done to adjust for drop (sometimes very dramatic) in total LDL with lipid lowering therapy


Case Study “SK”: Apo E ¾HDL gels On 4g/d and 1 g/d of Omega‐3 FA

Off OM3FA

4g/d OM3FA

Presenter

Presentation Notes

Discontinuing OM3FA also resulted in dramatic improvement in HDL profile with HDL 2b increasing from 23 to 30 % while total HDL increased as well, albeit no so dramatically.


Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega‐3 FA


Presenter

Presentation Notes

Other changes between 3/25/08 and 7/15/08 presented here and on the following slide. Most of them are as predicted by the response tof discontinuing OM3FA in Apo E ¾ patient. 11/26/08 labs reflect patient doubling Niaspan to 2 g a day, losing 30 lbs of weight and vigorous exercise program. As you see, HDL changes, as well TG, and Insulin reflect this. Also note “rebound” in LDL subclasses despite weight loss and decrease in fasting insulin. It probably reflects patient increasing consumption of OM3FA a day (more fish). Increase in HDL and HDL2b most likely reflects effect of weight loss, exercise and increase in Niaspan dose. Note downward trend in PLAC (PLA2) and NT-pro-BNP. Repeat carotid IMT is not performed yet.

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Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega‐3 FA

Presenter

Presentation Notes

Same trends are seen in QLDL.


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)

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

Presenter

Presentation Notes

In July 2008 KIF6 genotype determination became commercially available. Our patient had Arg/Arg genotype. Let look into practical implications of this test.

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

Previous Genetic Studies of KIF6 719ArgRisk of CHD in 5 Prospective Studies

● Carriers of the KIF6 719Arg variant (60% of Caucasians) are at greater risk of coronary events compared with noncarriers

● More than 49,000 participants

Patients with prior MI

Patients with LDL-C >178mg/dL

Men and women of ≥65 years old

Middle-aged Americans

Initially healthy middle-aged women

ARIC

WHS

CHS

Placebo arm of WOSCOPS

Placebo arm of CARE

Adjusted Risk Ratios

WHS: Shiffman et al. J Am Coll Cardiol 2008; 51:444ARIC: Bare et al. Genet Med. 2007; 10:682CHS: Shiffman et al. Arterioscler Thromb Vasc Biol. 2008; 1:173

Presenter

Presentation Notes

KIF6 Arg is clearly a risk factor. Risk is only useful if it is addressable. In 5 large prospective studies carriers of the KIF6 Arg variant (representing 60% of Caucasians) were at greater risk for coronary events compared with noncarriers. We should ask next whether this risk can be addressed by specific intervention

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)

0

2

4

6

81.4%

Carriers Non-carriers

CARE WOSCOPS

Non-carriersCarriers

3.5% 4.9%*

P = 0.005 P < 0.0001

Absolute Risk Reduction (%)

3.5% 5.5%* 0.1%

All All

Presenter

Presentation Notes

Need to run this slide in Presentation mode of Powerpoint to see other bars. Benefits of statin are clearly more impressive (if not exclusively limited – at least for primary prevention) to KIF6 Arg carriers.

38

Coronary Events According to KIF6 719Arg Carrier Status in PROSPER Patients with Prior Vascular Disease

HR=0.66 HR=0.94

719Arg Carriers Noncarriers

Pravastatin

Placebo

● 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

Months of follow up Months of follow upFatal or nonfatal CHD

P=0.002 P=0.64

CH

D d

eath

or m

ajor

CH

D e

vent

s (%

)

Presenter

Presentation Notes

Another trial, this time secondary prevention in patients over 70 years old.

39

LDL-C Lowering by Pravastatin Therapy In the Elderly with Prior Vascular Disease

● 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

PROSPER Study

LDL

Cho

lest

erol

(mm

ol/L

)

KIF6 CarriersNoncarriers

Pravastatin

Placebo

1.0

2.0

3.0

4.0

Baseline 3 6 12 24 36Months of follow-up

Presenter

Presentation Notes

No difference in LDL in either placebo or Pravastatin group in carriers vs. non-carriers of KIF6 Arg. Will return to this issue few slides down the line.

Statin Intensity and CHD Event ReductionAccording to KIF6 719Arg Carrier Status

● 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

Dea

th o

r maj

or C

V ev

ents KIF6 Carriers Noncarriers

Months of follow-up Months of follow-up

p≤0.001P=1.0

Pravastatin

Atorvastatin

Pravastatin

Atorvastatin

PROVE IT—TIMI22

Presenter

Presentation Notes

“weaker” vs. “stronger” statin, secondary prevention. Clearly no benefit from “upgrade” to full dose Atorvastatin. At most, non-carriers should take 40 mg generic pravastatin., while carriers should be upgraded to 80 mg atorvastatin, if affordable.

LDL-C Lowering by Statin TherapySimilar Reduction in KIF6 Carriers and Noncarriers

120

100

80

60

40

20

LDL

(mg/

dL)

Baseline 30 Days 4 Mo 8 Mo 16 Mo

KIF6 CarriersNoncarriers

Pravastatin

Atorvastatin

Time of Visit

PROVE IT

● Similar reduction of LDL-C levels in carriers and noncarriers

● However, event reduction was significantly greater in carriers

Presenter

Presentation Notes

Clearly KIF6 effect has nothing to do with LDL reduction, which is probably just a neutral gage of the potency of the statins and their potential to neutralize risk carried by KIF6 Arg variant. Note, the above statement only relates to CORONARY events and may or may not be related to effect of statins on progression of (non-inflammatory) atherosclerosis, effect on strokes, CHF, renal disease, porteinuria, and other pleotropic effects of statins. It may be prudent in patient with above conditions to keep them on statins, even stronger statins if the tolearance and cost are acceptable until above issues are clarified.

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

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

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


Presenter

Presentation Notes

Primary prevention in patients >70 years old with statins is of questionable (really NO) benefit, according to PROSPER study and raises some very interesting and complicated issues. We are planning to develop this topic in one of the future presentations.

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 notreflect position of Celera and/or contributing authors**Limit to 1g qd for ApoE ¾ or 4/4 genotype


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 effectiveMonitoring Apo B, LDL IIIa+b, LDL IVb, and HDL2b are key to monitoring the patient’s progress


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



Final Comment

48

“If you aren’t confused, you don’t know what’s going on.”Jack WelshFormer CEO General Electric


Documents

Case Study “OC” - renalremission.comrenalremission.com/uploads/presentations/Case Study OM3FA ApoE KIF6...Case Study “SK ” ApoE‐OM3FA ... 猀漀昀琀 瀀氀愀焀甀攀

Case Study “OC” - renalremission.comrenalremission.com/uploads/presentations/Case Study OM3FA ApoE KIF6...Case Study “SK ” ApoE‐OM3FA ... 猀漀昀琀瀀氀愀焀甀攀