Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics...

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Dyslipidemia and Dyslipidemia and Atherosclerosis Atherosclerosis Eliot A. Brinton, M.D. Eliot A. Brinton, M.D. Associate Professor Associate Professor Cardiovascular Genetics Cardiovascular Genetics Division of Cardiology Division of Cardiology Department of Internal Medicine Department of Internal Medicine University of Utah School of University of Utah School of Medicine Medicine

Transcript of Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics...

Page 1: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Dyslipidemia and Dyslipidemia and AtherosclerosisAtherosclerosis

Eliot A. Brinton, M.D.Eliot A. Brinton, M.D.Associate ProfessorAssociate Professor

Cardiovascular GeneticsCardiovascular GeneticsDivision of CardiologyDivision of Cardiology

Department of Internal MedicineDepartment of Internal MedicineUniversity of Utah School of MedicineUniversity of Utah School of Medicine

Page 2: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

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0.9 0.95 1 1.05 1.1 1.15 1.2 1.25

Density

Dia

met

er (a

ngst

rom

s)

HDL2HDL2 HDL3HDL3

LDLLDLIDLIDL

VLDLVLDL

ChylomicronChylomicron

1.0061.006

plasmaplasmapre-pre-ββ HDL HDL

Lipoproteins by Size and DensityLipoproteins by Size and Density

Page 3: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 4: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 5: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Pre-β HDL

Page 6: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

AdiposeAdipose

HeartHeart

MuscleMuscle

Lipoprotein LipaseLipoprotein Lipase

HMG CoA ReductaseHMG CoA Reductase

Dietary CholesterolDietary Cholesterol100-500 mg/day100-500 mg/day

(40-50% absorbed)(40-50% absorbed)

Bile acids 300 mgBile acids 300 mgCholesterol 600 mgCholesterol 600 mg

Biliary Biliary Chol.Chol.

700 mg/day700 mg/day

Bile Bile Acids Acids

20 g/day 20 g/day 98.5% 98.5%

reabsorbedreabsorbed

TRIGTRIGketone bodiesketone bodies

COCO22, H, H22OO

OtherOtherTissuesTissues

intestine, skin, intestine, skin, adrenal, ovary, adrenal, ovary,

testes, testes, atheroma / atheroma /

macrophagesmacrophages

VLDLVLDL

Apo C’sApo B-100

Apo E

IDLIDL

Hepatic LipaseHepatic Lipaseapo Eapo E

LDLLDL

pre-pre-ββ11 HDL HDL

(two apo A-I)(two apo A-I)

pre-pre-ββ22 HDL HDL

(+PL=disc)(+PL=disc)

pre-pre-ββ33 HDL HDL

(+UC in disc)(+UC in disc)

HDLHDL33

PLPLFCFC

LCATLCAT

PLPLFCFC

““LDL Pathway”LDL Pathway”

LDL ReceptorsLDL Receptors

CETPCETPTGTG

CECE

HDLHDL2a2a

HDLHDL2b2b

Hepatic Hepatic LipaseLipase

CHOLCHOL

Dietary Fat Dietary Fat 60-100 g/day (98% absorbed)60-100 g/day (98% absorbed)

free fatty free fatty acidsacids

ChylomicronChylomicron

Apo B-48(Apo A-I)

Page 7: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Familial Familial Hypercholesterolemia Hypercholesterolemia

(FH)(FH)

Page 8: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

LDLLDL

AdiposeAdipose

HeartHeart

MuscleMuscle

Lipoprotein LipaseLipoprotein Lipase

Bile Bile Acids Acids

CHOLCHOL

ffaffa VLDLVLDL

TRIGTRIG

““LDL Pathway”LDL Pathway”

HMG CoA ReductaseHMG CoA Reductase

OtherOtherTissuesTissues

ketone bodiesketone bodies

COCO22, H, H22OO

IDLIDL

HDLHDL

FamilialFamilialHypercholesterolemiaHypercholesterolemia

(heterozygous)(heterozygous)

½ normal ½ normal LDL ReceptorsLDL Receptors

StatinsStatins

Page 9: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 10: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 11: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Non-Fatal CAD in FH (Utah) Non-Fatal CAD in FH (Utah) vs. General U.S. Populationvs. General U.S. Population

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FH Women

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Cu

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FH Men

Page 12: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

What FH May Mean for a What FH May Mean for a FamilyFamily

45 45 ♥♥334334

47 47 ♥♥

4242218218

38 38 ♥♥ 34 34 ♥♥347347

40 40 ♥♥373373

41 41 ♥♥ 34 34 ♥♥

1616284284

18189494

2020182182

4242180180

3131158158

1212132132

1717157157

1818285285

1919130130

2121311311

2222135135

66291291

1313344344

1414118118

1515255255

40 40 ♥♥373373

AffectedAffectedAge at MIAge at MITotal CholTotal Chol

KeyKey

Page 13: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

““Pure” HypercholesterolemiaPure” HypercholesterolemiaMonogenic SyndromesMonogenic Syndromes

Familial hypercholesterolemia (FH)Familial hypercholesterolemia (FH)• LDL receptor mutations (over 800 distinct types)LDL receptor mutations (over 800 distinct types)• 1/500 in general population (heterozygotes)1/500 in general population (heterozygotes)

Familial defective apo B (FDB) (Familial defective apo B (FDB) (minorityminority of FH) of FH)• Ligand defect Ligand defect notnot receptor defect receptor defect• Apo B mutations (3500, etc.)Apo B mutations (3500, etc.)

PCSK9PCSK9 mutations (rel mutations (rel rarerare, 1/50 FH families), 1/50 FH families)

Autosomal recessive hypercholest. (Autosomal recessive hypercholest. (v. rarev. rare))

Page 14: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

““Pure” HypercholesterolemiaPure” HypercholesterolemiaOther causesOther causes

Polygenic hypercholesterolemiaPolygenic hypercholesterolemia• Very Very CommonCommon• Genetics poorly definedGenetics poorly defined• Mechanisms poorly defined (likely includes Mechanisms poorly defined (likely includes

hyperabsorbers)hyperabsorbers)• Generally Generally milder milder than FHthan FH

Diet-inducedDiet-induced• Very Very commoncommon• Generally Generally much milder much milder than FHthan FH

““Secondary” causesSecondary” causes• Hypothyroidism—rel. Hypothyroidism—rel. common in elderly common in elderly but but ↑↑LDL LDL mildmild• Other (Other (rare rare hepatic and renal abn., etc.)hepatic and renal abn., etc.)

Page 15: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

VLDL overproductionVLDL overproduction

Associated Lipid Abnormalities:Associated Lipid Abnormalities:• Mild-moderate Mild-moderate ↑↑VLDL-C/Plasma TGVLDL-C/Plasma TG• Mild-moderate Mild-moderate ↓↓HDL-C HDL-C • Small, dense LDL (and HDL)Small, dense LDL (and HDL)• Mild Mild ↑↑LDL-CLDL-C

11oo mechanism of familial combined mechanism of familial combined hyperlipidemia (FCHL) and familial HTG hyperlipidemia (FCHL) and familial HTG (mechanism of (mechanism of difference undifference unclear)clear)

Strongly associated with central adiposity:Strongly associated with central adiposity:• Major mechanism for Major mechanism for ↑TC ↑TC and and ↑↑TG with aging TG with aging • Almost always helped by weight lossAlmost always helped by weight loss

Page 16: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 17: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Metabolic Syndrome

DM-2

FCHL

↑Apo B???

?

“Classic” DM-2

“Isolated” ↑Apo B

“Isolated” Metabolic Syndrome

Adapted from John Brunzell, personal communication, 2005Adapted from John Brunzell, personal communication, 2005

Overlap Among Metabolic Syndrome, Diabetes Mellitus-2, ↑Apo B and FCHL

Page 18: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Despite Elegant Science of Despite Elegant Science of Abnormalities Abnormalities

of Lipoprotein Metabolism,of Lipoprotein Metabolism,Treatment of Dyslipidemias Treatment of Dyslipidemias

is Nearly is Nearly AlwaysAlways Just Just According to Lipid Levels!According to Lipid Levels!

Page 19: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Atheroprevention in Diabetes

Mellitus

Page 20: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

Atherosclerosis in Diabetes

• ~80% of all diabetic mortality– 75% from coronary atherosclerosis– 25% from cerebral or peripheral vascular

disease

• >75% of all hospitalizations for diabetic complications

• >50% of patients with newly diagnosed type 2 diabetes already have CHD

Page 21: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic MenMultiple Risk Factor Intervention Trial (MRFIT)

Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic MenMultiple Risk Factor Intervention Trial (MRFIT)

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20

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00

1 2 3 4 5

Serum Cholesterol Quintile Bierman EL, Arteriosder Thromb, June 1992Based on data from J. Stamler

● ●

●●●●●

Page 22: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 23: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

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40

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Diabetes and glucose intolerance vs. cardiovascular mortality

MenWomen

Bedford Study, Keen, et al. Lancet. 2:505–508, 1965.

10 y

ear

CV

D m

orta

lity

(%)

Normal IGT DM Normal IGT DM

40-59 60+

Age (years)

Page 24: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

HBP Inflam, cytokines insulin Gluc/DM

(ox/glycox) TG Dense

LDLLow HDL Coag.

Endothelial dysfunction

Insulin Resistance

Interrelationship Between Obesity, Insulin Resistance, DM and Atherosclerosis

Obesity, etc.

Atherosclerosis

Page 25: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

ATP III: Insulin Resistance Syndrome (“The Metabolic” Syndrome* ICD9 277.7)

*3 risk factors = Insulin Resistance†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

<40 mg/dL<50 mg/dL

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

100 mg/dLFasting glucose

130/85 mm HgBlood pressure

HDL-C

150 mg/dLTG

Abdominal obesity† (Waist circumference‡)

Defining LevelRisk Factor

Page 26: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Insulin Resistance Syndrome Prevalence:NHANES III Data; ATP III Criteria

• 24% of total US Population (47 million pts)• 32% of US Hispanics• 26% higher Hispanic women vs. men• 57% higher in Black women vs. men• 43% of total population > 60 y old

Ford E, et al JAMA 287:356-9, 2002

Page 27: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Fredrickson Type III Fredrickson Type III (Familial Dysbetalipoproteinemia)(Familial Dysbetalipoproteinemia)

DefinitionDefinition

TGRL remnant (IDL) excessTGRL remnant (IDL) excess

VLDL-C/Plasma TG VLDL-C/Plasma TG 0.30, TG >150 mg/dl 0.30, TG >150 mg/dl

Apo E 2/2 + other abn (VLDL overprod?); Apo E 2/2 + other abn (VLDL overprod?); or or apo E deficiencyapo E deficiency

Palmar (flat and orange) and/or tuberoeruptive (elbow) Palmar (flat and orange) and/or tuberoeruptive (elbow) xanthomasxanthomas

Prevalence and Athero RiskPrevalence and Athero Risk

193 NIH referrals for TG >190 mg/dl and familial 193 NIH referrals for TG >190 mg/dl and familial lipids, 49 ( lipids, 49 (25%!25%!) ) had type III. had type III.

37% of these type III patients had CAD (average onset of 38 yo)37% of these type III patients had CAD (average onset of 38 yo)

Fredrickson DS, Morganroth J, Levy RI. Ann Intern Med 1975; 82:150-157Morganroth J, Levy RI, Fredrickson DS. Ann Intern Med 1975; 82:158-174

Page 28: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

TG and HDL vs. Risk of Premature CAD653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM,

cigarette smoking and LDL cholesterol

1.0

2.8

2.2

4.0

8.3

0 2 4 6 8 10

TG <200, HDL 40+

TG 200-799, HDL 40+ (p <0.000)

TG <200, HDL <40 (p <0.0001)

TG 200-799, HDL <40 (p <0.0001)

Definite Type III (p <0.0001)

Odds Ratio

Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.

Page 29: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

LDL-C at follow-up (mg/dL)

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Perc

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4S-PI

2° Prevention

1° PreventionWOSCOPS-PI

WOSCOPS-Rx

AFCAPS/TexCAPS-Rx

AFCAPS/TexCAPS-PI

GREACE-UC

GREACE-Rx

HPS 2o-Pl

CPPT-PlCPPT--Rx

POSCH-Pl

POSCH—Rx

HPS 2o-Rx

HPS 1o-Pl

HPS 1o-Rx

CHD Events vs. LDL-C: Statin and Non-Statin Trials

Page 30: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

NCEP ATP Update—2004 Risk Category Risk Factors LDL-C Goal Lower 0-1 RF <160Mod/Mod-High >2 RF, FRS <20% <130 High CVD alone or FRS >20% <100Very High CVD+DM, MS, ↑↑RF, ACS <70*

•In High and Very High Risk categories–Consider statin Rx even if already at goal–Consider combination Rx—statin + fibrate or niacin—if TG>200+NHDL-C>130 or HDL-C<40

•Statin Rx for 30-40% ↓LDL-C (R-5, A-10, S-20, F,L,P-40) in > mod. high risk vs. don’t use lower doses•65-80 yrs: 2o prev as younger; 1o prev+DM=high risk; other, use clinical judgment•Non-HDL-C: use if TG>200; goal as LDL-C+30

Grundy, et al. Implications of Recent Clinical Trials for NCEP ATP III. Circ. July 13, 2004;110:227-239.

*Therapeutic option: use clinical judgment

Page 31: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

More Aggressive Lipid Treatment“BEIGE”

• Broader use of treatment (TLC and meds)

• Earlier use of medications (may not wait for TLC)

• Increased intensity of Rx

• Getting to goal

• Evaluation of progress, follow-up (esp. compliance which is <50% at 1 year!!!)

Modified from AM Gotto AHA mtg 11/05

Page 32: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Factors Not Included in the Framingham Risk Score

• CVD (FRS designed for 1o prevention)

• Diabetes Mellitus (FRS not used in DM in ATP III)

• Metabolic Syndrome (TG, glucose, obesity, DBP)

• Family History of CHD

• Emerging risk factors

• Diet and exercise

• Higher risk in non-Caucasians

• Further risk increase above 79 years old

• Risk beyond 10 years in future (underestimates risk in young adults)

Page 33: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

May adjust the LDL-C goal from NCEP table

up or down by 30 mg/dl per:

1. Position within risk category (add if risk, subtract if ), or factors not in Framingham score (e.g. DM, IR)

2. Overall health (add if quality/ quantity, subtract if )

3. Patient’s wishes (add if fears Rx, subtract if fears

atherosclerosis)

Clinical Judgment for NCEP ATP Update—2004

(per Dr. E. A. Brinton)

Page 34: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Choice of HMG-CoA Reductase Inhibitors

(“Statins”)1. Lovastatin (Mevacor, Altoprev, generic)—events (1o prev.),

longer experience, generic and extended release available

2. Pravastatin (Pravachol)—v. good event data (1o and 2o prevention), safer in combo?

3. Simvastatin (Zocor)—best 2o prev. data, DM/2o prev. indication (any LDL-C), max efficacy, cost effective ( events)

4. Fluvastatin (Lescol)—athero and events, cost effective (low-mod lowering), safer in combo?

5. Atorvastatin (Lipitor)—good event data (A80 > P40 or A10, 2o prev), max effic., cost eff. (mid LDL-C), good CRP

6. Rosuvastatin (Crestor)—max efficacy, v. cost-effective ($17/mo for ½ of R40 qod), event data pending, safety = other statins, good CRP, better resp. to added ezet?

Page 35: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Diet (Medical Nutrition Therapy, MNT), and

Lifestyle (Therapeutic Lifestyle Change, TLC) for

Atheroprevention

Page 36: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Intensive Lifestyle Changes and Intensive Lifestyle Changes and CAD ReversalCAD Reversal (Ornish D, et al. JAMA 1998; (Ornish D, et al. JAMA 1998;

280:2001)280:2001)

42.3

51.9

37.340.7

38.5

41.3

30

35

40

45

50

55

Baseline 1 year 5 years

Dia

met

er S

teno

sis

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Control

Treament

-6.81

-3.01

-0.37

-8

-7

-6

-5

-4

-3

-2

-1

0

MostAdherent

(n=6)

MediumAdherent

(n=7)

LeastAdherent

(n=6)

Ch

ang

es i

n D

iam

eter

Ste

no

sis

(% i

n 5

y)

p = 0.02 p = 0.001p = 0.02 p = 0.001

Page 37: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

180

200

220

240

260

280

300

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

Year

Ser

um C

hole

ster

ol (m

g/dl

)

Hospital K

Hospital N

Finnish Mental Hospital StudyFinnish Mental Hospital Study

Study Design and Serum Study Design and Serum CholesterolCholesterol

Diet changed in Diet changed in hospital Nhospital N

Diets reversedDiets reversed

Data for males Data for males shown here. shown here. Total in each Total in each hospital about hospital about 3500. About 70-3500. About 70-75% remained 75% remained in hospital all 12 in hospital all 12 yearsyears

Miettinen M, et al. Lancet 1972; ii: 835Miettinen M, et al. Lancet 1972; ii: 835

Page 38: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Finnish Mental Hospital StudyFinnish Mental Hospital Study

Age-adjusted death-rates Age-adjusted death-rates (per 1000 (per 1000

person-years)person-years)

MalesMales FemalesFemales

CHDCHD TotalTotal CHDCHD TotalTotal

Hospital N, dietHospital N, diet 5.75.7 34.634.6 4.04.0 31.131.1

Hospital N, controlHospital N, control 13.013.0 38.838.8 7.77.7 32.132.1

Hospital K, controlHospital K, control 15.215.2 40.240.2 8.18.1 25.925.9

Hospital K, dietHospital K, diet 7.57.5 35.135.1 6.56.5 30.730.7

Pooled dietPooled diet 6.66.6 34.834.8 5.25.2 30.930.9

Pooled controlPooled control 14.114.1 39.539.5 7.97.9 29.029.0

Miettinen M, et al. Lancet 1972; ii: 835Miettinen M, et al. Lancet 1972; ii: 835

Page 39: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Non-Medical Treatments (TLC)for Dyslipidemias

Diet (MNT)• Low saturated fat (5-10% ↓LDL-C); low cholesterol?• Whole grains, fruits, vegetables, legumes, non-fat

dairy? hard water? (~5% ↓LDL-C)

• Supplements– Plant sterol/stanol ester margarine (5-10% ↓LDL-C)– Soluble fibers (~5% ↓LDL-C)– Red Yeast Rice/Cholestin (lovastatin + other statins?)—% ↓LDL-C & safety issues not

well documented– Niacin (Rx effective but AHA recommends against DS NA for lipids)– Fish oil (Rx effective but AHA and FDA against DS ω-3 at TG ↓doses, DS ok anti-plt)– Flaxseed oil (little conversion to EPA/DHA, few data, ok for vegans)– Phospholipids, garlic, biotin, etc. not well documented– Folate, B6, B12—↓Hcy but ↓CVD not seen yet

Page 40: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Non-Medical Treatments for Dyslipidemias (cont.)

Exercise• How? (aerobic, anaerobic, stretching all beneficial)• How often? (2/wk to constant)• What benefits?

– ↓Obesity, ↑mood/↓depression, ↓insomnia,– Plasma factors: ↓TG, ↑HDL-C, ↑ LDL size?, ↓Glucose, ↓CRP?– ↑Collateral vessels– ↓CVD (but protection not absolute)– ↑Longevity

Smoking Cessation• Will to quit essential• Non-medical treatment effective (hypnosis, behavior modif.)• Several good medications available

Page 41: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Atheroprevention Beyond LDL-C and

Statin Monotherapy: Non-Statin Treatment

Page 42: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

CHD Risk Prediction byHDL-C vs. LDL-C*

0.0

1.0

2.0

3.0

100 160 220 8565

4525

LDL-C (mg/dL)

HDL-C (mg/dL)

Adapted from and reprinted with permission from Castelli WP. Can J Cardiol. 1988;4(suppl A):5A.

RR of CHDAfter 4 yr

*Data represent men age 50–70 yr from the Framingham Study.

Patient 2:LDL-C: 100 mg/dLHDL-C: 25 mg/dL

Patient 1:LDL-C: 220 mg/dLHDL-C: 45 mg/dL

Page 43: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Univariate Regression

R2

N=44,170; total CHD events = 3869R2 denotes the proportion of variance. TC = total cholesterol.

Rx Changes HDL and TC/HDL are Best predictors of CHD Risk Reduction

0.45

0.53 0.55

0.65 0.65

0.86

0

0.2

0.4

0.6

0.8

1

TG LDL TC Non-HDL HDL TC/HDL

Alsheikh-Ali AA, et al. Increases in HDL-C are the strongest predictors of risk reduction in lipid intervention trials [poster]. AHA Scientific Sessions 2004; November; New Orleans, La.

Page 44: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Hypothesized Antiatherogenic Mechanisms of HDL

• Reverse cholesterol transport

• Antioxidant effects

• Anti-inflammatory effects

• Anti-thrombotic effects?

• Direct blocking of LDL effects?

• Other?

Page 45: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Reverse Cholesterol Transport

A-I

Liver CECE

UCPL&UCLCAT

UC

Bile

SR-BI

A-I

ABCA1

Macrophage

CE B

CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein

Adapted from C Cuchel et al. Art Thromb & Vasc Biol 2003;23:1710-12

LDL-R

VLDL/LDL

CETP

Mature HDLNascent HDL

CE

SR-A

Oxidation

PL

Page 46: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

12-Lipoxygenase12-Lipoxygenase

HPODEHPODEHPETEHPETE

Oxidized Oxidized LDLLDL

Page 47: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 48: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Medications which Raise HDL-C Levels

Agent HDL-C Effect

Nicotinic acid 15-35%

Fibrates 5-20%

Statins 5-15%

TZD’s (esp pio) 5-20%

Estrogens 10-25%

-blockers 10-20%

Alcohol 5-10%

Belalcazar LM et al. Progress in Cardiovascular Disease 1998;41:151-174.

Page 49: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Effect of Niaspan on Lipids and Glycemic Control in Effect of Niaspan on Lipids and Glycemic Control in Patients with Diabetes Mellitus (ADVENT)Patients with Diabetes Mellitus (ADVENT)

Fasting Blood Glucose*

0

50

100

150

200

250

Placebo Niaspan 1 gram Niaspan 1.5 grams

Glu

co

se

mg

/dL

Baseline Week 4 Week 8 Week 12 Week 16

Grundy et al, Arch Int Med 162:1568-76, 2002* median values

Page 50: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

0

5

10

15

20

<95 95-104 105-125

CDP at 6 yr: Nonfatal MI by Baseline FBG*

mg/dL

RelativeHazard 0.70 0.74 0.73 0.44

*Z for interaction = –0.35. Indicates homogeneity

Eve

nt

Rat

e (%

)

126

Placebo Niacin

Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.

Page 51: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Niacin Reduces MI Regardless of Increase in Fasting Glucose

Change in FPG (baseline to 1yr)CDP data. Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.

Page 52: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Maximizing Niacin Tolerability

• Niacin ER (Niaspan), or ERNL (Advicor), far less flushing than IR (?SR qd?)

• Take with – ASA 325mg (buffered, not enteric-coated) vs. Alka-Seltzer– Diphenhydramine (Benadryl) 25-50 mg– CaCO3 (Tum) vs. snack (vs. buffered ASA)

• Gradual uptitration (1 mo each at 500 and 1000 mg/d, re-do if off > 2 wks)

• Avoid with: EtOH, hot liquids, spicy foods• Consider dosing in am (vs. hs)• Watch glucose (also uric acid/gout, GI Sx if Hx)• Remind pt: flushing not harmful, niacin is a vitamin, D/C

antioxidants!

Page 53: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

No-Flush Niacins

Types• Niacinamide/Nicotinamide• Acipimox• Inositol HexaniacinateLipid Effects• Few or noneEvidence for CHD Prevention• None

Not recommended for atheroprevention!

Page 54: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

HDL- Clinical SummaryLevels--Basal vs. Intervention1. HDL is protective, but

2. Lowering it may not be bad (e.g. good diet), and

3. Raising it may not be good (data not definitive)

4. LDL/HDL ratio estimates risk but confuses Rx

Treatment (goal >40 mg/dl in men >50 in women)1. Not Diet (bad diet is bad, high mono unproven)

2. Not Ethanol (adverse events, bene. unproven)

3. Lifestyle: wt loss, exercise, smoking cessation

4. Meds: niacin (↑effective but ↑Sx), fibrates, statins or TZD’s (less effective but fewer Sx)

Use med Rx to ↑HDL only in 2o and high-risk 1o prev

Page 55: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

TG and HDL vs. Risk of Premature CAD653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM,

cigarette smoking and LDL cholesterol

1.0

2.8

2.2

4.0

8.3

0 2 4 6 8 10

TG <200, HDL 40+

TG 200-799, HDL 40+ (p <0.000)

TG <200, HDL <40 (p <0.0001)

TG 200-799, HDL <40 (p <0.0001)

Definite Type III (p <0.0001)

Odds Ratio

Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.

Page 56: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

0

10

20

30

40

50

60

70

80

90

100

20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 500

Phenotype APhenotype B

% Cumulativefrequency

TG (mg/dL)Austin M et al. Circulation. 1990;82:495-506.

LDL Phenotypes/Patterns A and B (B=SD LDL) vs. Plasma TG

Page 57: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Extra Atherogenicity of Small Dense LDL (pattern B)

EndothelialChemoattractants

FOAM CELL

Highly oxidizedSmooth

Muscle Cell

Mildly oxidized

Macrophage

LDL

LDLENDOTHELIUM Monocyte

Macrophage

Through endothelium easier

Stays on matrix longer

More readily oxidized

Associates w/ Metabolic Syndrome/DM:↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid.

↓LDL-R uptake, ↑ Levels & Modific.

And

Page 58: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

LDL-C Doubly Underestimates CHD Risk with Small-Dense LDL

• More particles/LDL-C →higher LDL particle # than suspected

– e.g. LDL-C 100 → ↑risk ≈ 120 mg/dl

• More atherogenic/LDL particle than large LDL

– e.g. LDL-C 120 ↑risk ≈ 140 mg/dl

LDL-C looks low but CHD risk is high

Page 59: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Test (method)

• Berkley Heart Lab (GGE), Lipo Print

• LipoProfile/ LipoScience (NMR)

• VAP/Atherotech (Ultracentrifugation)

Pro/Con• Established method, well

validated, rel. pricey ($99-$240 and up, a la carte)

• More affordable (~$120), new method but well validated, LDL particle #, no extras

• Established method, well validated, CDC std, very affordable ($45-$90), MetSynd, Lp(a)-chol gratis

Advanced Lipid Profiles—Which?

Page 60: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Rx of Small, Dense LDL

Increase LDL Size• Niacin• Fibrates• TZDsLower LDL-C• Statins• Niacin, CAI, BAS, fenofibrateRx Insulin Resistance• Diet, exercise, weight loss• TZD’s• Metformin? ACEI’s?

Page 61: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Non-Pharmacological Approaches to Hypertriglyceridemia

• Consider secondary causes (increased frequency)

– Poorly controlled diabetes mellitus

– Hypothyroidism

– Corticosteroids / Cushing’s

– Isotretinoin (Accutane) (rarely a problem)

• Weight loss, exercise

• Avoid sugar and high carbohydrate diet

• Fish and fish oil

• Little or NO ALCOHOL

• Change oral estrogen to patch or discontinue

Page 62: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Lipid Effects: Fenofibrate vs SimvastatinM

ean

(%)

chan

ge f

rom

bas

elin

e

Steinmetz A et al., J Cardiovasc Pharmacol 1996 Apr;27 Suppl:S63-70

Double-blind, randomized, controlled 12 week trial

Type IIa and IIb Patients

-50

-40

-30

-20

-10

0

10

20

Total Chol LDL TG HDL fibrinogen uric acid

fenofibrate 200mg mic. (n=66) simvastatin 20mg (n=64)

-20-25

-21

-35

-41

-17

+18+15

-10

+4

-25

0

P=0.05 P=0.001 P=0.001 P=0.015 P=0.001 P=0.001

Page 63: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Gemfibrozil (Lopid and generic) vs.

Fenofibrate (TriCor, Antara, Tryglide, generic)

Favor Gemfibrozil

• Cost (generic)

• Availability (generic)

• Better CHD event ↓ data (Helsinki & VA-HIT)

Favor Fenofibrate

• Statin compatibility

• Dosed qd w or w/o meal (ease & compliance)

• Better lipid effects (esp. ↑HDL, ↓LDL)

• ↓Fibrinogen

• ↓Atherosclerosis (DAIS)

• ↓Athero events (FIELD)

Page 64: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Niacin vs. Fibrates for Mixed Dyslipidemia, DM & Met. Synd.

Favoring Fibrates• Exc ↓TG

• OK ↑HDL

• OK ↓LDL (feno only)

• No flushing

• No increase in glucose levels

• No increase in gout/uric acid

• No increase in Hcy

• ↓CHD event data (gemfib, trend w/ feno)

• Some ↓Lp(a) (feno)

Favoring Niacin• Exc ↑HDL-C

• OK ↓LDL

• OK ↓TG

• Fewer GI Sx (N & V)

• Better Lp(a) lowering

• ↓CHD event data (CDP)

• Better ↓CHD event data in combo w/ statin and/or BAS

• ↓Total mortality

• Better compatibility w/ statin (vs. gemfib.)

• Statin combo tablet (ERNL, Advicor)

Page 65: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Efficacy Comparison in Patients with TG ≥ 500 mg/dLRelative Difference vs. Placebo

Source: Omacor® Prescribing Information; Antara® 130 mg Prescribing Information.

Omega-3 AEE Fenofibrate

Lipid Efficacy of Omega-3 AEE is Similar to Fenofibrate

-70%

-50%

-30%

-10%

10%

30%

50%TG HDL-C CHOL VLDL-C LDL-C

-70%

-50%

-30%

-10%

10%

30%

50%TG HDL-C CHOL VLDL-C LDL-C

Page 66: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Dose-Range of Omega-3 FA Effect on Triglycerides

TG 177-442 mg/dL at baseline; 8-week treatmentSource: Data on file at Pronova/Reliant.

---------Dose of O3AEEs ---------

-8.2% -12.0%

-30.0%-43.0%

-60%

-40%

-20%

0%

Placebo 2 g/d 4 g/d 8 g/d

% C

ha

ng

e T

G (

mg

/dL

)

Page 67: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

GISSI-Prevenzione TrialOmega-3 Acid Ethyl Esters

Reduce All-Cause and Sudden Death

Control Omacor® RR P-ValueAll-Cause Mortality 10.6% 8.4% 21% 0.0064Sudden Death 3.3% 1.8% 44% 0.0006

Days

1.00

0.99

0.98

0.97

0.96

0.95

Pro

bab

ilit

y

330210150600 90 180 27030 120 240 300 360

0.59 (95% CI 0.36-

0.97) P=0.037

Omega-3 AEE

Control

Marchioli R, et al., Circulation 2002;105:1897-1903.

Page 68: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Non-Lipid Atherosclerosis and Cardiac Effects of Omega-3 FA

• ↓Malignant ventricular arrhythmias (via cardiac membrane enrichment)

• ↑ICD triggering (malignant ventr. arrhythmias)

• ↓Heart rate and ↑HR variability (via ↑parasympathetic tone, altered cytokine levels?)

• ↑Endothelial relaxation (via ↑NO &↑NO independent mech.)

• ↓Blood Pressure

• Anti-proliferative effect/ ↓smooth-muscle cell proliferation

• Antithrombotic effects (↓platelet reactivity, ↓AA)

• ↓Plasma viscosity

• Anti-inflammatory effects

– ↓Inflammatory cytokines (interleukins, TNF)

– ↓Mitogens

– ↓Cell-adhesion molecule expression

– Altered eicosanoid synthesis (↓AA)

• ↑PON (antioxidant on HDL)

• ↓CHF?

• ↓Sudden Death

• ↓Total and CVD mortality

Holub BJ, CMAJ 2002;166(5):608-15.

Page 69: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Suggestions for Improving Omega-3 FA Tolerability

•Use O3-AEE’s – fewer capsules, fewer impurities

•Take at start of meal

•Freeze/refrigerate capsules (PI says no)

•Gradual uptitration

Page 70: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Mortality Effects of Lipid Rx

Rx # Trials

N % Δ Total

% Δ CVD

% Δ non-CVD

Statins 35 53K ↓13%* ↓22%* ↓3%

Omega-3 14 10K ↓23%* ↓32%* ↓3%

Fibrates 17 14K 0% ↓7% ↑13%*

*p<0.01. M Studer, et al. Arch Int Med 2005;165:725-36.

----------Mortality----------

Page 71: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Fibrates vs. Omega-3 to Rx HTG and Prevent Atherosclerosis

Favoring Fibrates• More conventional• ↓CVD• Better ↑HDL-C & ↓LDL-C • Non-lipid benefits?• Good statin compatibility

(feno only, FIELD)• More convenient (fewer

capsules)• No fishy burping

Favoring Omega-3• More natural• ↓CVD and ↓total mortality• Non-lipid benefits?• No transaminase

contraindic. • No precaution w/ statins• No warfarin interaction• Less nausea and vomiting

Bottom line: •Either is good as first-line •Both often needed in combination!

Page 72: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Hypertriglyceridemia Drug Treatment

When—After diet and Rx 2o factors• Treat all TG > 500 for pancreatitis & athero• Treat to <150 if 2o prevention, DM/IR or other athero

risk How• Gemfibrozil/Fenofibrate—easier, more effective• Niacin—cheap/easy, best if HDL-C and/or LDL-C • Statins—consider, especially if LDL-C• Omega-3 oils, effective in high doses• TZDs (pioglitazone > rosiglitazone)

Page 73: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Use Non-HDL-C Instead of LDL-C if TG > 200 (ATP III)

LDL-C Target Non-HDL-C Target

Patient Category (mg/dL) (mg/dL)

No CHD, 0-1 risk factors < 160 <190

No CHD, 2+ risk factors < 130 <160

CHD/CHD risk equivalent < 100 <130

CVD + DM/MS/Cigs/ACS < 70 <100

Non-HDL-C goal = LDL-C goal + 30 Rx to ↓Non-HDL-C:

•If TG <~400 Rx as LDL-C•If TG >~400 Rx as HTG

Page 74: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Hepatic Source of Inflammatory Markers: CRP, Fibrinogen, SAA

Rader. N Engl J Med 2000;343:1179.

CRPFibrinogen

SAA

Page 75: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 76: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Lp(a)—Summary• Pro-atherogenic/pro-thrombotic factor• Genetically determined • Not lowered by most treatments:

– Diet– Exercise– Weight loss– Statins, – Bile acid resins, – Gemfibrozil

• Rx options:– Lower Lp(a)

Niacin Estrogen Fenofibrate?

– Extra LDL-C lowering

Page 77: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Suggested Use of Emerging CHD Risk-Factor Tests

Blood Tests• SD LDL• Apo B vs. LDL # vs. Non

HDL-C• CRP (vs. Met. Synd.)• Lp(a)• Microalb’uria, GFR• Hcy• RLP-C • LpPLA2 (PLAC)Arterial Tests (1o Prev)• CAC by CT• Carotid US• Ankle Brachial Index (SBP

ankle/SBP arm <.9)

Why?

• Rx yes/no?

• More aggressive Rx?

• Specific Rx

When?

• 1o Prevention

– Intermediate-Risk

• 2o Prevention, CVD:

– W/ normal lipid profile

– Severe beyond risk factors

– Progression despite “adequate” Rx

Page 78: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Combination Therapy Statin + Other Med

Page 79: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

18

9.9

1314.4

11.29.4

7.9

16.6

0

5

10

15

20

25

% ofpatients

100 101- 111- 121- 131- 141- 151- >160 110 120 130 140 150 160

LDL-C (mg/dL) on-treatment

n = 1,460

L-TAP: Majority of CHD Patients

Do Not Reach NCEP LDL-C Goal

Pearson TA et al. Arch Intern Med. 2000;160:459-467.Other L-TAP data courtesy of TA Pearson.

Page 80: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Statin dose (mg)

LD

L-C

Example of Statin Titration and Failureto Attain Optimal LDL-C

Starting LDL-C 220 mg, 40% Lowering at Statin 10 mg

Optimal50

100

150

200

250

0 20 40 60 80 100

Page 81: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

20 mg includes pts on 40 mg (37%). This does not represent data from a comparative study. Data from prescribing information for atorvastatin, lovastatin, simvastatin.

Statin Titration: Potential for Side Effects at Maximum Dose

20 40 8010 20 40 800

0.5

1.0

1.5

2.0

2.5

Ele

vate

d t

ran

sam

inas

es(%

of

pat

ien

ts)

8040

1.7 4

2.3

20

Statin dose (mg)

Atorvastatin Lovastatin Simvastatin

Page 82: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

More vs. Less Aggressive LDL-C Lowering Rx

Study LDL-C LowRx

LDL-C HiRx

Add'lLDL↓

Add’lCHD↓

Safety

Prove-IT 95 mg/dl 62 mg/dl 35% 16% 3x ↑ALT

A to Z 81 mg/dl 66 mg/dl 18% 11% 9x ↑myop*

TNT 101 mg/dl 77 mg/dl 24% 22% 6x ↑ALT

IDEAL 103 mg/dl 82 mg/dl 20% 11% 2x ↑myalg 9x ↑ALT

Prove-IT: Prava 40 vs. Atorva 80. NEJM, 2004;350:1495-1504.A to Z: Simva 20 vs. Simva 80. JAMA, 2004;292:1307-1316.TNT: Atorva 10 vs. Atorva 80. NEJM, March 8, 2005.IDEAL: Simva 20-40 vs. Atorva 80. JAMA 2005; 294:2437-2445.

*Included patients w/ ARF, EtOH abuse and on meds interfering w/ statin metabolism.

Page 83: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Majority of CAD Events Occur Despite Statin Rx:

Need for Further Rx Improvement

Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383.

28

19

0

5

10

15

20

25

30

% w

ith

CA

D e

ven

t 30% ↓CAD w/ statin

70% CAD events not prevented

CAD Events in the 4S Trial

Placebo Simvastatin

Page 84: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

-100

-80

-60

-40

-20

0

Event Reduction With Monotherapy Versus Combination Therapy

-31 -36

ASCOT19341

WOSCOPS 6595

FATS (10 Y)176

4S 4444

Trial N

-72

-34 -25

HPS20,536

Red

uct

ion

in C

V

Eve

nts

(%

)

CARE4159

-24

1. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307; 2. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Sever PS, et al. Lancet. 2003;361:1149-58; 6. Brown BG, et al. Circulation. 1998;98(suppl I):I-635.

Page 85: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

3.9

-0.4

0.7

23.7

2.6

14.3

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Placebo S+N S+N+AV

HATS: Angiographic and Clinical Endpoints After 3 Years

Coronary Death, MI, Stroke, or Revascularization

Mea

n C

han

ge

in S

ten

osi

s, % C

om

po

site Even

t Rate, %

9 Proximal Lesions

25

20

15

10

5

0

*p<0.001 vs. placebo; †p<0.005 vs. placebo; ‡p=0.04 vs. placebo.Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.

HATS = HDL-C-Atherosclerosis Treatment Study; S = simvastatin; N = niacin; AV = antioxidant vitamins.

*

89% reduction

Page 86: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

PlaceboNiacin ER 1g/d

Page 87: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Ezetimibe + Atorvastatin 10 mg: Greater LDL-C Reduction vs. Atorvastatin 20 or 40 mg Alone

–54%

–45%–42%

–37%

–53%–60%

–50%

–40%

–30%

–20%

–10%

0%

Mean %Change in LDL-C

FromUntreated Baseline

P<0.01

Ezetimibe +Atorvastatin 10 mg

(n=65)10 mg(n=60)

20 mg(n=60)

40 mg(n=66)

80 mg(n=62)

Atorvastatin

Page 88: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

-46.1-44.3

-50.2-49.1

-55.6-52.5

-59.4

-37.2

-60

-50

-40

-30

-20

-10

0

% R

edu

cti

on

fro

mb

ase

line

at

wk

6

Ezetimibe/simvastatinAtorvastatin10 20 80 10/10 10/20 10/40 10/8040

**PP0.0010.001 vs atorvastatin at corresponding dose. vs atorvastatin at corresponding dose.

Ballantyne et al.Ballantyne et al. J Am Coll CardiolJ Am Coll Cardiol. 2004;43(suppl A):480A.. 2004;43(suppl A):480A.

**

**

Ezetimibe/Simvastatin vs. Atorvastatin Ezetimibe/Simvastatin vs. Atorvastatin LDL-C LoweringLDL-C Lowering

Page 89: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Ezetimibe With Fenofibrate in Hypercholesterolemia

-13.5

-22.3

-36.3

-10.1

-40

-35

-30

-25

-20

-15

-10

-5

0

Placebo(n=8)

Fenofibrate 200 mg(n=8)

Ezetimibe 10 mg(n=8)

Ezetimibe 10 mg +fenofibrate 200 mg(n=8)

Mea

n %

LD

L-C

re

du

ctio

n a

fter

14

d

*Ezetimibe is not yet indicated for combination use with fenofibrate or any other non-statin lipid agent. †P<0.03 vs placebo or either drug alone.Kosoglou et al. European Atherosclerosis Society Meeting, Glasgow, Scotland, 2001.

Page 90: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Statin Mono Rx vs. Combination Rx

Favoring Combo Rx

• Better LDL-C lowering

• Better non-LDL effects (HDL-C, TG, CRP, other?)

• Likely better CVD event reduction

• Complementary mechanisms

Favoring Statin Mono Rx

• Nearly comparable LDL-C↓ (esp. w/ rosuva.)

• Simpler (less AE risk)

• Less expensive (esp. rosuva.)

Page 91: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Atheroprevention in Postmenopausal Women

Page 92: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.
Page 93: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Incidence of Cardiovascular Events in Women Before and After the Menopause

Incidence of Cardiovascular Events in Women Before and After the Menopause

0

50

100

150

200

250

300

350

Inci

den

ce /

100

,000

Inci

den

ce /

100

,000

20-2420-24 25-2925-29 30-3430-34 35-3935-39 40-4440-44 45-4945-49 50-5450-54 55-5955-59 60-6460-64 >65>65

Age RangeAge RangeF. B. Hu et al. New Engl J Med, 2000; 343:530-7F. B. Hu et al. New Engl J Med, 2000; 343:530-7

Average Age Average Age at Menopauseat Menopause

In postmenopausal women, atherosclerosis is a disease of estrogen deficiencyIn postmenopausal women, atherosclerosis is a disease of estrogen deficiency

Page 94: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Risk of Cardiac Events/Death in Estrogen Users in 6 Large Observational Studies

0.00.0 0.50.5 1.01.0 1.51.5 2.02.0

Relative Risks andRelative Risks and 95%Confidence Intervals95%Confidence Intervals

Bush, T. L. et al., Lipid Research ClinicsFollow-up Study Circulation 75:1102, 1987Bush, T. L. et al., Lipid Research ClinicsFollow-up Study Circulation 75:1102, 1987

Grodstein, F. et al., Nurses Health StudyN Engl J Med 335:453, 1996Grodstein, F. et al., Nurses Health StudyN Engl J Med 335:453, 1996

Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988

Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992

Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990*Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990*

Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994

*Deaths from circulatory diseases*Deaths from circulatory diseases

Page 95: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Rationale for the Randomized HRT Trials

(HERS&WHI)

• Supposed to verify observational studies:–peri-menopausal start

• Instead studied– late post-menopausal start

Page 96: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

1 2 3 4 5 6+

Pe

rce

nt

CH

D E

ve

nts

*

CEE/MPA

Placebo

HazardYear Ratio

1 1.78

2 1.15

3 1.06

4 0.99

5 2.38

6+ 0.78

Year

WHI: Percent CHD Events by Year

P = NS for trend over time.

HR = 1.29

95% nCI = 1.02–1.63

95% aCI = 0.85–1.97

*Includes 8 silent MIs.

Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

Page 97: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Early vs. Late Estrogen Effects on the Natural History of Atherosclerosis

Adventitia

Media

Fatty Streak/Plaque

InternalElastic

Lamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

•Estrogen Effects in Atherogenesis LDL oxidation LDL atherogenicity LDL binding/accum lesion progression CAMs monocyte adhesion/

macrophage accumulation

MCP-1 and TNF SMC proliferation lesion progression Endothelial function vasodilation

•Estrogen Effects in Established Plaques MMP expression PQ instability/rupture Thrombosis Event # and severity

•Loss of Estrogen Benefits (when HRT started after prolonged estrogen deficiency) Expression of estrogen receptors Vascular responsivity

Benefits of estrogen early in atherogenesis

Adverse effects ofestrogen in vulnerable plaque

CAMs = cell adhesion molecules; SMC = smooth muscle cell; MMP = matrix metalloproteinase.

Page 98: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6. 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21. 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-7. 4Williams JK, et al. Arterioscler Thromb Vasc Biol. 1995;15:827-36.

Premenopause Postmenopause

Ovariectomy

70%Decrease1,2Healthy diet CEE + atherogenic diet

Plaque Area(Relative to Placebo)

50%Decrease3

Atherogenic diet

CEE + atherogenic diet

0%No change4

Healthy dietAtherogenic diet+ No CEE 2 years

Healthy Diet+ CEE

Timing of CEE Start vs. Anti-atherosclerosis Effect

(Nonhuman Primates)

***

*Like Obs. HRT trials

**Like HERS/WHI

Page 99: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6R

isk

Rat

io f

or

CV

D

0 5 10 15 20 25 30Years Postmenopause at Randomization

<10

10-19

≥ 20

*Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)*Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)

Zero-YearRR=0.62

Timing of HRT Start vs. Effects on CVD: Extrapolation of WHI Results (E+P Arm)

Page 100: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Nurses’ Health Study, 1980-1996

NeverNever

0.3 mg*0.3 mg*

0.625 mg*0.625 mg*

1.25 mg1.25 mg

1.01.0

0.580.58 (0.37-0.92) (0.37-0.92)

0.540.54 (0.44-0.67) (0.44-0.67)

0.70 (0.51-0.97)0.70 (0.51-0.97)

609609

1919

9999

4141

Hormone Use

Multivariate-adjustedRR (95% CI)

Cases(n)

Person-years of Follow-up

Grodstein F, et al. Ann Intern Med. 2000;133:933-41.

313,661313,661

19,96419,964

116,150116,150

39,02639,026

RR = relative risk for current vs. never users.

Effect of Estrogen Dose on Risk for CHD

Page 101: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Nurses’ Health Study, 1980-1996

NeverNever

0.3 mg*0.3 mg*

0.625 mg*0.625 mg*

1.25 mg1.25 mg

1.01.0

0.540.54 (0.28-1.06) (0.28-1.06)

1.351.35 (1.08-1.68) (1.08-1.68)

1.63 (1.18-2.26)1.63 (1.18-2.26)

290290

99

124124

4646

Hormone Use

Multivariate-adjustedRR (95% CI)

Cases(n)

Person-years of Follow-up

Grodstein F, et al. Ann Intern Med. 2000;133:933-41.

313,661313,661

19,96419,964

116,150116,150

39,02639,026

RR = relative risk for current vs. never users.

Effect of Estrogen Dose on Risk for Stroke

Page 102: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

“Because of the excellent study design of WHI there is now consensus that CEE+MPA should not be started in older women to prevent heart disease.”—Good for <10% of ERT

“Whether benefit would be seen if women initiated hormones …at… menopause was not addressed in the WHI.” —Nothing learned about >90% of ERT(!)

“We need new clinical trials to test the hypothesis not addressed by the WHI—that younger women who initiate hormones…at the time their own estrogen levels drop will eventually…have less heart disease.” —KEEPS under way

ML Stefanick, Kronos Longevity Kronicle 2004;3(7);6-11.

What to do while we await relevant RCT data? Choice A: Use best current evidence which is: early-start, long-term/lifetime

ERT/HRT benefits most women!Choice B: D/C ERT/HRT (assume WHI applies to all women)

WHI Scorecard: $600M Later…

Page 103: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

HRT in Postmenopausal Women:

State of the Art 2005• HRT is good in most women

– All perimenopausal women should be considered for HRT (early start) esp if estr. defic Sx present

– Low-dose oral CEE/MPA usually best (if tolerated); – Oral or patch estradiol are good alternatives– Continue life-long (unless/until adverse event—VTE, etc.)

• Current dogma (D/C of HRT after 1-5 y) is likely harmful • Late-start HRT usually bad

Caveat: HRT does not have FDA indication for CHD prevention

Page 104: Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

Factor Statins BAS CAI Fibrates Niacin

↓LDL-C +++ ++ ++ +/- ++

↑LDL size - ? ? ++ ++

↓TG ++ - + +++ ++

↓Remnant ++ - ++? +++ +++

↓Lp(a) - ? ? +/- +++

↑HDL + +/- + +/++ +++

Lipoprotein Effects of Major Lipid Rx Classes:

Summary