epidemiology of hdl and its evolution into a therapeutic

www.lipid.orgwww.lipid.org

EPIDEMIOLOGY OF HDL AND ITS EVOLUTION INTO A THERAPEUTIC TARGET

Peter P. Toth, MD, PhD, FAAFP, FNLA, FAHA, FCCP, FACCDirector of Preventive Cardiology

Sterling Rock Falls ClinicSterling, Illinois

Professor of Clinical Family and Community MedicineUniversity of Illinois School of Medicine

Peoria, Illinois


WHAT DIFFERENTIATES HDL PARTICLES FROM OTHER

LIPOPROTEINS?

IT APPEARS TO BE PRIMARILY ANTIATHEROGENIC.


Potential Antiatherogenic Actions of HDL

Chapman MJ, et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G, et al. Annu Rev Med. 2003;53:321-341.

Antioxidative Activity

AntithromboticActivity

Anti-infectious Activity

EndothelialRepair

AntiapoptoticActivity

ReverseCholesterolTransportCellular

CholesterolEfflux

Anti-inflammatoryActivity

VasodilatoryActivity

HDL

Apo A-I

Apo A-II


WHERE ARE HDL PARTICLES PRODUCED?


HDL BIOGENESIS

www.lipid.orgwww.lipid.orgZhang, Y. et al. Circulation 2010;121:1347-1355.

Because adipose inflammation is a hallmark of central obesityand type 2 diabetes mellitus, loss of adipocyte lipidation of HDL may

contribute directly to lower HDL-C levels in these inflammatory,insulin-resistant states


Early case-control studies (1950s) in the US and Israel showed that patients with CAD tend to have lower HDL levels than controls

The Tromso Heart Study showed that CAD patients have HDL levels 35% lower than controls and that patients with low HDL are 3 times more likely to develop CAD than those with elevated LDL

Low HDL is associated with significant disability and the loss of ability to execute daily living activities among patients over 65 years of age. Among the elderly, low HDL predicts risk for future MI and stroke better than LDL.

CAD, coronary artery disease; LDL, low-density lipoprotein; MI, myocardial infarction.

HDL as CAD Risk Factor


Increased risk for MI and CAD mortality1

Stroke in the elderly2

Sudden death3

Restenosis after angioplasty4

Severe premature atherosclerotic disease in the proximal left main coronary artery5

Increased risk for retinopathy in diabetic patients6

For every 1 mg/dL drop in HDL-C, risk for NIDDM increases 4%7

Low HDL Portends

1. Goldbourt U et al. Arterioscler Thromb Vasc Biol 1997;17:107-13.2. Qeverling-Rijnsburger AWE et al. Arch Intern Med 2003;163:1549-54.3. Burke AP et al. JAMA 1999;281:921-6.4. Shah P et al. Circulation 1992;85:1279-85.5. Pearson T et al. Am J Epidemiol 1979;109:285-95.6. Sasongko et al. Diabetes care 2011; 34: 474-479.7. Stern MP et al. Ann Intern Med 2002;136:575-581.


AdjustedNonadjustedControls (N = 601)Risk Factor

–12%*1%Diabetes mellitus

34%*26%26%LDL-C 160 mg/dL

–41%*21%Hypertension

57%*63%*19%HDL-C 35 mg/dL

–67%*29%Cigarette smoking

*Significantly different from controls (P < 0.001).CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Frequency of Low HDL-C Compared with Other Risk Factors in Men with Premature CHD

Genest JJ et al. Am J Cardiol. 1991;67:1185-1189.


EPIDEMIOLOGY OF HDL‐C


5-9 10-14 15-19 20-24 25-29 30-34 35-39

HDL-C (mg/dL)

0

2

4

6

8

10

12

14

16

% o

f the

Pop

ulat

ion Men

Women

Miller M & Zahn M. Curr Opin Cardiol 2004;19:380-384.

<20 mg/dL occurs in 1/200 men & 1/400 women

<10 mg/dL occurs in ~ 1/20,000

< 40/50 mg/dL men/women are the bottom tertile of population

National Health And Nutrition Examination Survey III: Distribution of Low HDL-C Bottom Tertile of

Population

www.lipid.orgwww.lipid.orgBruckert E Eur Heart J Suppl 2006;8:F17-F22.

Mean HDL-cholesterol in mmol/L (M) by country and prevalence (P) of low HDL-cholesterol adjusted for eight confounding factors by country;

low HDL-cholesterol was defined as <1.03 mmol/L (40 mg/dL) in men and <1.29 mmol/L (50 mg/dL) in women.


Prevalence (%) of different severities of obesity in the Pan-European Survey of low HDL-cholesterol (excludes 3% of the overall population

for whom obesity status was not recorded)

Bruckert E Eur Heart J Suppl 2006;8:F17-F22.


Prevalence of low HDL-cholesterol, hypertriglyceridaemia, or both according to receipt or not of lipid-modifying treatment in the Pan-

European Survey of low HDL-cholesterol.

Bruckert E Eur Heart J Suppl 2006;8:F17-F22.

www.lipid.org

0.00

5.00

10.00

15.00

20.00

25.00

30.00

HDL 1 HDL 2 HDL 3 HDL 4 HDL 5

≤ 2%3‐4%5‐9%≥ 10%

CVD

Morta

lity R

ate (p

er 10

00 pe

rson y

ears)

0.73 0.50 0.360.39 0.30

6.52

3.891.60 3.08

2.26

9.87

5.31 5.053.69

3.22

24.69

28.84

23.32

17.0915.74

SCOR

E Ca

tegor

y

www.lipid.org

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

< 1.291.3 ‐ 1.6

> 1.6

Age < 55Age 55‐65Age > 65

HDL Tertiles

CVD

Morta

lity R

ate (p

er 10

00 pe

rson y

ears)

0.370.22

0.20

3.3

2.01.7

13

11

8

www.lipid.org

0.002.004.006.008.00

10.0012.00

14.00

16.00

18.00

< 1.091.09 ‐ 1.34

> 1.34

Age < 45Age 45‐55Age 55‐65Age > 65

HDL Tertiles

CVD

Morta

lity R

ate (p

er 10

0 per

son y

ears)

0.800.55

0.36

4.0

2.82.7

9.6

6.4

4.9

17

15

13

www.lipid.org

0.000.501.001.502.002.503.003.504.004.505.00


TC 1TC 2TC 3TC 4TC 5

HDL Quintile

CVD

Morta

lity R

ate (p

er 10

00 pe

rson y

ears)

0.9

0.2 0.2 0.50.2

1.21.0

0.80.3 0.7

2.2

1.41.1

0.7 0.4

2.7

1.81.4

1.2 1.2

4.94.7

2.1 2.11.7

www.lipid.org

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00


TC 1TC 2TC 3TC 4TC 5

HDL Quintile

CVD

Morta

lity R

ate (p

er 10

00 pe

rson y

ears)

2.8

1.9

1.21.8

1.2

3.7

2.62.4

2.11.9

5.7

2.93.5

2.5 2.7

5.7

4.63.9

3.52.9

7.3

5.4 5.55.0

4.4


Relative risk of CHD for sex-specific lipid factor quintiles with adjustment for age and race in ARIC women and men N=12,339, 10-

year follow-up, 725 events

Sharrett AR, et al. Circulation. 2001;104:1108-1113.

Women Men

mg/dL 39 48 56 65 81 31 38 43 49 62 HDL-C Cholesterol (mmol/L) HDL-C Cholesterol (mmol/L)

Rel

ativ

e R

isk

HDL-C Provides Substantial CHD Prediction: ARIC Study


Significant association found between incidence of CHD and HDL‐C levels after adjustment for other risk factors (P<0.001)12

Incidence of CHD Per 1000 SubjectsOver a 6-year Period According to HDL-C Level12

*PROCAM: Prospective Cardiovascular Münster study.The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

PROCAM* Results at 6 Years of Follow-up12Levels of LDL-C and Percent Change in HDL-C

www.lipid.orgwww.lipid.orgCastelli WP. Can J Cardiol. Jul 1988;4 Suppl A:5A-10A.

Framingham Heart StudyRisk of Coronary Artery Disease in Men Aged 50-70 by

LDL and HDL Cholesterol Levels

www.lipid.orgwww.lipid.orgAbbott RD, et al. Arteriosclerosis. May-Jun 1988;8(3):207-211.

23-46 47-55 56-66 67-1390

10

Rat

e pe

r 100

/12

year

s

267-412

Cholesterol (mg/dL)

238-266

212-237

124-211

HDL-C(mg/dL)

12 Year Incidence of Myocardial InfarctionFramingham Cohort-Women


Objectives To evaluate if apoB and apoA-I add predictive

information of cardiac risk - fatal myocardial infarction - up and above TC, TG, and LDL-C

Subjects 98,722 males and 76,831 females, <20 – >80 years consecutively referred 1985–1996, no diagnosis or

treatment known, 67 months mean follow up Fatal myocardial infarction males 864, females 359

24

AMORIS


0.92 1.28

HDL-cholesterol (mmol/L)

Ris

k ra

tio

0.30

0.6

0.8

0.4

1.0

1.91 2.251.20 1.57 1.81

Men Women

1.52

§

0.5

0.7

0.9

0.30.4

1.0

0.5

0.7

0.90.8

0.6

*§

§

§‡

AMORIS, Fatal Myocardial Infarction


1.12 1.30

Apolipoprotein A-I (g/L)

Ris

k ra

tio

0.30

0.6

0.8

0.4

1.0

1.64 1.831.24 1.43 1.57

Men Women

1.43

§ §§

0.5

0.7

0.9

0.30.4

1.0

0.5

0.7

0.90.8

0.6

**

§


www.lipid.org

4.03.6

2.3

1.7

4.1

3.1

1.8 1.72.31.6

1.1 1.21.4

0.8 1.1 1.0

0.0

1.0

2.0

3.0

4.0

5.0

1.12 1.30 1.42 1.65

0.901.10

1.391.80

Men <70 years

Ris

k ra

tio

ApoA-I (g/L)

ApoB (g/L)


www.lipid.org

9.1

5.76.7

3.9

8.7

5.1

2.5

5.17.0 7.0

3.85.2

5.8

4.3 4.5

1.0

0.0

2.0

4.0

6.0

8.0

10.0

1.24 1.43 1.57 1.83

0.811.06

1.281.71

Women 70 years

Ris

k ra

tio

ApoA-I (g/L)

ApoB (g/L)


www.lipid.orgwww.lipid.orgMcQueen M et al. Lancet 2008;372:224-233.

Odd

s ra

tio (9

5% C

I)

Decile Median (SD distance from overall median)

-1 0 1 21.00

2.00

4.00

8.00 ApoB/ApoA-ITC/HDL-C

1 2 3 4 5 6 7 8 9 10ApoB/ApoA-I 0.43 0.53 0.60 0.66 0.72 0.78 0.85 0.93 1.04 1.28TC/HDL-C 2.74 3.37 3.82 4.23 4.64 5.08 5.58 6.21 7.15 9.20

Risk of MI for increasing decile medians (adjusted for age, sex

and region) of ratios of apoB/ApoA-I and TC/HDL-C

TC/HDL-C

ApoB/ApoA-I

Lipids, Lipoproteins & Apolipoproteins as Markers of risk of MI in52 Countries in The INTERHEART Study

www.lipid.org

Risk factor Odds ratio adjusted for age, sex, and smoking (99% CI)

Odds ratio adjusted for all (99% CI)

ApoB/ApoA-1 (fifth quintile compared with first)

3.87 (3.39-4.42) 3.25 (2.81-3.76)

Current smoking 2.95 (2.72-3.20) 2.87 (2.58-3.19)Diabetes 3.08 (2.77-3.42) 2.37 (2.07-2.71)Hypertension 2.48 (2.30-2.68) 1.91 (1.74-2.10)Abdominal obesity 2.22 (2.03-2.42) 1.62 (1.45-1.80)Psychosocial 2.51 (2.15-2.93) 2.67 (2.21-3.22)Vegetable and fruits daily 0.70 (0.64-0.77) 0.70 (0.62-0.79)Exercise 0.72 (0.65-0.79) 0.86 (0.76-0.97)Alcohol intake 0.79 (0.73-0.86) 0.91 (0.82-1.02)All combined 129.2 (90.2-185.0) 129.2 (90.2-185.0)

Yusuf S. European Society of Cardiology Congress 2004; August 28-September 1, 2004; Munich, Germany.

INTERHEART: Risk of Acute MI Associated with Risk Factorsin the Overall Population


Characteristic Men with event (n=97) Men w/o event (n= 837) P-value

BMI (kg/m2) 27.6 27.6 n.s.Total cholesterol (mg/dl) 259.6 243.3 0.001HDL cholesterol (mg/dl) 46.8 51.8 0.0037

TC/HDL-Ratio§ 5.66 4.83 < 0.0001Systolic BP (mmHg) 139.0 136.6 n.s.Diastolic BP (mmHg) 84.9 84.5 n.s.Regular smoker % 53.9 28.0 <0.0001Physical activity % 25.7 35.6 0.05Diabetes % 8.4 3.1 0.0096Education (<12 years) % 74.2 73.7 n.s.Lp-PLA 2 (ng/ml) 292.3 263.4 0.0013C-reactive protein§ (mg/L) 2.49 1.54 < 0.0001

§ geometric means calculated from the log-transformed distributionKoenig et al. AHA 2003.

Age-Adjusted Baseline Characteristics of 934 men, Aged 45-64 YearsParticipating in the MONICA Augsburg Survey 1984/85

With Follow-up 1998


1.63 0.91 0.78

18.32

11.75

3.29

<35 35-44 45+HDL Cholesterol (mg/dL)

0

5

10

15

20

Dea

ths/

1000

per

son-

yr CVD at BaselineAbsent (n=1940)Present (n=471) Trend p<0.001

Pekkanen J, Linn S, Heiss G, et al. N Engl J Med. Jun 14 1990;322(24):1700-1707.

11.2

CHD Mortality and HDL CholesterolLRC Men 10 Year Follow up

www.lipid.org

HDL-C = high-density lipoprotein cholesterol; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; RR = relative risk; CI = confidence interval.aRelative risks are adjusted for age at baseline as a continuous variable using Cox proportional hazards models.bHigher Χ2 values indicated better prediction of CVD mortality by that lipid level when added to age-only model.*Measured by an increase of 0.78 mmol/L (30 mg/dL).†Measured by an increase of 0.26 mmol/L (10 mg/dL).

Risk for CHD based on Lipid Fractions: Lipid Research Clinics Program Study

Cui Y et al. Arch Intern Med. 2001;161:1413-1419..

Comparison of lipid levels in predicting CVD mortality in men and womenRR (95% CI)a Χ2 for addition to modelb

MenNon-HDL-C* 1.19 (1.13 to 1.26) 24.3LDL-C* 1.11 (1.02 to 1.22) 5.0TC 1.16 (1.08 to 1.23) 14.4HDL-C† 0.77 (0.69 to 0.86) 23.2

WomenNon-HDL-C 1.15 (1.06 to 1.25) 8.3LDL-C 1.08 (0.96 to 1.22) 1.8TC 1.10 (0.99 to 1.22) 2.8HDL-C 0.77 (0.69 to 0.88) 18.5


Hazard Ratio for Ischemic Heart Disease (IHD) as a Function of High-Density Lipoprotein (HDL) Cholesterol in

Quintiles in the Copenhagen City Heart Study

Frikke-Schmidt, R. et al. JAMA 2008;299:2524-2532.


Hazard Ratios for Coronary Heart Disease Across Fifthsof Usual Lipids or Apolipoproteins

Di Angelantonio E, Sarwar N, Perry P, et al. JAMA. Nov 11 2009;302(18):1993-2000.

Quintile Mean (SD Distance From Overall Mean)

Haz

ard

Rat

io


Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quintiles of Usual Triglyceride, HDL-C, and Non–HDL-C Levels

Coronary Heart DiseaseHDL-CTriglyceride Non-HDL-C

HDL-CTriglyceride Non-HDL-CIschemic Stroke

Haz

ard

Rat

io

Usual Mean Level, mg/dLH

azar

d R

atio

Usual Mean Level, mg/dL

Haz

ard

Rat

io


Haz

ard

Rat

io


Haz

ard

Rat

io


Haz

ard

Rat

io




Hazard Ratios for Coronary Heart Disease Across Fifths of Non-HDL-Cby Levels of HDL-C and Fifths of HDL-C by Levels of Non-HDL-C

Haz

ard

Rat

io

Haz

ard

Rat

io

Usual Mean Non-HDL-C Level, mg/dL Usual Mean HDL-C Level, mg/dL

Non-HDL-C by levels of HDL-C HDL-C by levels of Non-HDL-C


www.lipid.orgwww.lipid.orgShahar, E. et al. Stroke 2003;34:623-631.

Multivariable-adjusted risk functions of incident ischemic stroke among men in relation to LDL-C, HDL-C, apoB, and triglycerides (TG)

www.lipid.orgwww.lipid.orgWilley, J. Z. et al. Arch Neurol 2009;66:1400-1406.

HRs and 95% CIs for Lipid Parameters as Continuous Variables and Risk of Ischemic Stroke


Cooperative Lipoprotein Phenotyping Study Western Collaborative Group Study Israeli Ischemic Heart Disease Study Belgian Interuniversity Research on Nutrition

and Health Honolulu Heart Study

The following other observational studiesalso confirm low HDL as an importantindependent CAD risk factor:

HDL as CAD Risk Factor


*95% confidence intervals for adjusted proportional hazards regression coefficients.

CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol

% C

hang

e in

Ris

k pe

r In

crem

ents

(1 m

g/dL

)in

HD

L-C

*

FHS LRCF CPPT MRFIT FHS LRCF

CHD IncidenceMen Women

Coronary Heart Disease Incidence Is Related toHDL-C Levels in Various Clinical Trials

-10

-8

-6

-4

-2

0

Gordon DJ, et al. Circulation. 1989;79:8-15.

www.lipid.orgwww.lipid.orgFoody, J. M. et al. Circulation 2000;102:III-90-III-94.

Survival and HCL-C. Adjusted for age, HTN, DM, body mass index,TC, TG, LVEF, disease extent, and ITA use


Event-free survival and HDL-C. Adjusted for age, HTN, DM,body mass index, TC, TG, LVEF, disease extent, and ITA use

Foody, J. M. et al. Circulation 2000;102:III-90-III-94.


0.0

3.83.0

11.3

0

3

5

8

10

13

15 High HDL-Cc

Low HDL-Cd

N = 1032a98% of patients were discharged on 40 mg atorvastatin with mean LDL-C of 105 mg/dLbTarget lesion revascularization or major cardiac eventcMean HDL-C of 55 mg/dL (>40 mg/dL in men and >45 mg/dL in women)dMean HDL-C of 32 mg/dL (<40 mg/dL in men and <45 mg/dL in women)

Wolfram RM. Am J Cardiol. 2006;98:711-717.

Patie

nts,

%

0 to 30 Days >30 Days to 1 Year

Post Drug-Eluting Stent Implantationa

50

60

70

80

90

100

Surv

ival

Pro

babi

lity,

%

60 120 180 240 300 360

Days

P<.001 P<.001

P=.033

HDL-C 1 mg/dL Eventsb by 4%

High HDL-Cc

Low HDL-Cd

Eventb-Free Survival Death

0

Impact of Low HDL-C on Clinical Outcomes

www.lipid.org

Rel

ativ

e R

isk

of C

HD

HDL-C (mg/dL)

Low

High

Low High25 45 65

1

2

3

4

Higher the Level of HDL-C, Lower the Risk of CHD


ARE THERE COMPLICATIONS/EXCEPTIONS TO THE RULE THAT WHEN IT COMES TO HDL, HIGHER IS BETTER?


Unadjusted Rates of the Combined Primary End Point

deGoma, E. M. et al. J Am Coll Cardiol 2008;51:49-55.

All-cause mortalityMyocardial injury orIHD hospitalization

Even

t rat

e (%

)


Adjusted Odds Ratios for the Combined Primary End Point

All-cause mortalityMyocardial injury orIHD hospitalization

Adj

. Odd

s R

atio

Mor

e E

vent

sFe

wer

Eve

nts

deGoma, E. M. et al. J Am Coll Cardiol 2008;51:49-55.

www.lipid.orgwww.lipid.orgWim A. van der Steeg, et al. J Am Coll Cardiol 2008;51:634–42.

European Prospective Investigation into Cancer and

Nutrition - Norfolk Study (EPIC-Norfolk)

Incremental Decrease in End Points Through Aggressive Lipid Lowering

(IDEAL)

1 2 3 40 5 6 8 9 1 2 3 40 5 6 8 9

<8.60

8.60-9.05

9.05-9.53

9.53-9.85

9.85-10.07

>10.07

Adjusted for apoA-I & apoB

OR for MCE

HD

L S

ize

(nm

)

RR for MCE

HD

L-C

(m

g/dL

)

<40

40-49

50-59

60-69

70-79

>80

Adjusted for apoA-I & apoB

NMR measured particle size

The data suggest that very high values of plasma HDL-C and HDL particle size can confer increased risk of atherosclerotic disease. Although this epidemiological observation parallels the findings of some previous animal studies , there is no clear biological explanation of how HDL can become pro-atherogenic.

www.lipid.orgwww.lipid.orgRobins, S. J. et al. Arterioscler Thromb Vasc Biol 2011;31:1208-1214.

The Prevalence of IR by the 4th Quartile of HOMA-IR is Shown across Quartiles of Fasting Plasma HDL-C and across Quartiles of Fasting

Plasma Triglycerides for Men and Women


Unadjusted Kaplan-Meier Curves Showing the Cumulative Incidence of CHD Events in the Entire Study Sample (N=2910) with and without IR

and with Lower or Higher Values of Fasting Plasma HDL-C (A) and with Lower or Higher Values of Plasma Triglycerides (TG) (B)

Robins, S. J. et al. Arterioscler Thromb Vasc Biol 2011;31:1208-1214.


Plasma TG (mmol/L)0.0 1.0 2.0 3.0 4.0 5.0

0.0

0.5

1.0

1.5

2.0

2.5H

DL-

C (m

mol

/L)

R = -0.48; P < 0.001.

Quebec Cardiovascular Study

Sniderman AD et al. Am J Cardiol. 2001;87:792-793.


Cholesterol/HDL-C

0.0

3.0

4.0

5.0

T1< 4.97

T24.97–6.37

T3 637

< 50th< 1.56

> 50th 1.56

1.0

2.0

TG

IHD, ischemic heart disease.

Quebec Cardiovascular Study

Sniderman AD et al. Am J Cardiol. 2001;87:792-793.


Atherogenicity of Triglycerides and Etiology of Abnormal Lipid Metabolism

Adapted from Bays H, et al. Expert Opin Pharmacother. 2003;4:1901-1938.

Liver

VLDLTG

HDL

LDL

TG CECETP

CETPTG CE

Renal Clearance

TG

Lipases

Small, denseHDL-P

TG

Small, denseLDL-P

Lipases

HDL-C

VisceralAdiposopathy

FFA

Elevated TG

TG

VLDL-C

? LDL-C Non–HDL-C

Apo B

LDL P #

Apo A-I Apo A-I

Apo A-I

Apo B Apo B

Apo B


Framingham Offspring Study

1000

1200

1400

1600

1800

20 40 60 80 100

100

120

140

160

180

0 100 200 300 400

100

120

140

160

180

1000

1200

1400

1600

1800

LDL

Part

icle

s (n

mol

/L)

LDL

Cho

lest

erol

(m

g/dL

)

HDL Cholesterol (mg/dL) Triglycerides (mg/dL)

LDL Particles

LDL Cholesterol

LDL Particles

LDL Cholesterol

Otvos et al., Amer J Cardiol 2002;90:22i-29i.

Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides


01020304050607080

Downs JR et al. JAMA 1998;279:1615-1622.

HDL-C Levels

Placebo

Lovastatin

<34 mg/dl 35–39 mg/dl >40 mg/dl

71

40

68

41 4435

44% RR 40%

RR

20% RR

AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at Baseline


0.30

0.25

0.20

0.15

0.10

0.05

0HDL-C 35 mg/dL HDL-C 35 mg/dL

Dec

reas

e in

min

imum

lum

en

diam

eter

(mm

)

P = 0.09

P = 0.0004

Fluvastatin

Placebo

P for interaction = 0.01

Ballantyne CM et al. Circulation 1999;99:736–743.

-0.065

-0.274

-0.036

-0.083

Lipoprotein and Coronary Atherosclerosis Study (LCAS) Benefit of Statin Therapy in Patients With Low HDL-CLRC Men 10 Year Follow up


29.9

20.922.6

17

0

5

10

15

20

25

30

35

Placebo

Simvastatin

Mean LDL = 131 mg/dL.

HDL-C LevelBelow Tertile*(< 35 mg/dL)

HDL-C LevelAbove Tertile*( 42 mg/dL)

Abs

olut

e Ev

ent R

ate

(%)

*P < 0.05

25% 18.7%

CHD Event Rate and HDL-C Levels in the Heart Protection Study (HPS)

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.


*CHD death, nonfatal MI, and stroke.

0.4 0.6 0.8 1 1.2 1.4 1.6

LDL-C

HDL-C

mg/dL

43

53

Interaction Pvalue

43–53 0.007

Pravastatin Better Placebo Better

1320.88

132–159 0.70.88

1590.77

0.64

0.93

1.09

Primary End Point* by Tertiles of LDL-C and HDL-C in PROSPER

Shepherd J et al. Lancet. 2002;360:1623-1630.


• Patients with stable coronary disease (N=143) received gemfibrozil + niacin + cholestyramine or placebo

– Baseline LDL-C 128 mg/dL• Group with greatest HDL-C increase had greatest chance of being CV event

free– HDL-C increase was a significant predictor of event-free survival even after

adjustment for LDL-C changes (p<0.01)

Devendra GP, et al. J Cardiovasc Pharmacol Ther. Dec 2010;15(4):380-383.

Post-hoc Analysis of AFREGS


Angiographic Effects of Lipid Drug Classes Meta‐Analysis, 12 Trials

%s = 3.0 – 0.076 (%HDL-C) + 0.06 (%LDL-C) R2 = 0.96; P<.004

S+N=simvastatin + niacinHATS (HDL - Atherosclerosis Treatment Study) data not shown in original study.

ASTEROID

Brown BG, et al. Curr Opin Lipidol. 2006;17:631–636.


LDL-C <87.5 mg/dL HDL-C >7.5%

Nicholls SJ, et al. JAMA. 2007;297(5):499-508.

Regression of Coronary Atherosclerosis Associated with On-Treatment Levels of LDL-C and

Percent Change in HDL-C


Percentage increase in HDL-C and percentage relative risk reduction in CHD: data from 17 prospective, randomized trials combining a total of 44,170 patients and 3,869 CHD events

Alsheikh-Ali AA, et al. AHA Scientific Sessions, 2004.

HDL-C and CHD Risk: Meta Analysis

www.lipid.orgwww.lipid.orgBarter P, et al. N Engl J Med. 2007;357:1301-1310.

Low HDL-C was Associated with Higher CV Events in Patients with LDL-C < 70 mg/dL

Post-hoc Analysis of TNT

www.lipid.orgwww.lipid.orgJafri H, et al. Ann Intern Med. 2010;153:800-808.

Black circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control.

Associations Between HDL-C and Cardiovascular Outcomes: Statin Treatment Does Not Alter Inverse Relationship


Incidence rates per 100 person years of exposure for the JUPITER primary endpoint according to on-treatment concentrations of HDL-C and on treatment concentrations of ApoA1

ApoA1HDL-C

Ridker PM, Genest J, Boekholdt SM, et al. Lancet. Jul 31 2010;376(9738):333-339.

HDL-C and Risk Reduction in JUPITER


• Electronic medical record study of 1,512 high-risk patients

• Low HDL-C present in 66% of overall patients

– Most prevalent (79%) in patients with LDL-C 70 mg/dL

Alsheikh-Ali AA, et al. Am J Cardiol. 2007;100:1499-1501.

Low HDL-C defined as 40 mg/dL in men and 50 mg/dL in women

Prevalence of Low HDL-C in Patients with Documented CHD

Or CHD Risk Equivalents and Controlled LDL-C


WHEN IT COMES TO THE GENETICS OF HDL, PUZZLE PIECES DO NOT ALWAYS FIT TOGETHER NEATLY


Tangier disease (deletion of nucleotides 3283 & 3284) produces a premature stop codon, resulting in the expression of a nonfunctional molecule1

Up to one half of the cases of familial hypoalphalipoproteinemia are due to a mutation in the gene for ABCA11

The R219K variant of ABCA1 is associated with increased ABCA1 expression, higher mean serum HDL levels, and lower frequency of CAD in Dutch men2

ABCA1 Mutations

1. Remaley et al. Proc Natl Acad Sci USA 1999;96:12685-90.2. Clee SM et al. Circulation 2001;103:1198-205.


Table 2. Summary of Data Available on CETP Genotypes, CETP Phenotypes, Lipid Levels, and Coronary Outcomesa.


Characteristics of Participants of Danish Descent in the3 Studies Conducted in Copenhagen, Denmark


Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the

Copenhagen General Population Study



Risk of Ischemic Heart Disease as a Function ofABCA1 Mutations in the 3 Different Studies



APOPROTEIN A1


ApoA-INichinan significantly decreases the ability of apoA-I to bind fibroblasts and promote lipid efflux1

ApoA-IZavalla results in about a 4-fold reduction of serum HDL and increased risk for premature CAD2

Patients with apoA-I(Lys 0) have low HDL due to enhanced catabolism3

ApoA-I (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature CAD4

Apoprotein A-I Mutations

1. Huang W et al. Arterioscler Thromb Vasc Biol 2000;20:210-6.2. Miller M, et al. Arterioscler Thromb Vasc Biol 1998;18:1242-7.3. Tilly-Keisi M et al. Arterioscler Thromb Vasc Biol 1997;17:873-80.4. Hovingh GK et al. J Am Coll Cardiol 2004;44:1429-35.


Effect of APOA1 genotype and genotype combinations on HDL cholesterol levels and theoretically predicted and observed risks of

IHD and MI

Haase, C. L. et al. J Clin Endocrinol Metab 2010;95:E500-E510.


Effect of APOA1 genotype and genotype combinations onapoA-I levels and theoretically predicted and observed risks of

IHD and MI

Haase, C. L. et al. J Clin Endocrinol Metab 2010;95:E500-E510.


Intravenous injections of HDL and apoA-I prevent atherogenesis in rabbits fed high-cholesterol diets1,2

Intravenous injection of HDL in rabbits with established atherosclerotic disease results in significant slowing in rates of disease progression and can stimulate regression of established plaques3

Transgenic apoE-deficient mice overexpressing human apoA-I have elevated serum HDL levels and resistance to atherosclerosis4,5,6

Mice with an LDL receptor deficiency fed an atherogenic diet experience a dramatic 70% decrease in aortic atheromatous plaque burden within 4 weeks after being injected with an adenovirus that contains the human apoA-I gene7

The residual plaque in treated animals also has fewer foam cells, has a lower density of macrophages, and is more fibrotic, possibly rendering it more stable.

Apoprotein A-I and Atherosclerosis

1. Badimon J et al. J Clin Invest 1990;85:1234-41.2. Miyazak et al. Arterioscler Thromb Vasc Biol 1995;15:1882-8.3. Badimon J et al. Circulation 1992;86(suppl III):86-94.4. Plumb A et al. Proc Natl Acad Sci USA 1994;91:9607-11.5. Paszty C et al. J Clin Invest 1994;94:899-903.6. Benoit P et al. Circulation 1999;99:105-10.7. Tangirala R et al. Circulation 1999;100:1816-22.


Apo B

Total Cholesterol (mg/dl)

LDL Cholesterol

HDL CholesterolTriglyceridesApo A-I

Age (y)

nA-IM Carriers

103 ±35

189 ±50

132 ±35

20 ±10

186 ±107

78 ±28

42 ±17

21Controls

90 ±28

215 ±56

143 ±46

49 ±20

120 ±61

132 ±27

42 ±17

42

97 ±20

191 ±33

133 ±29

27 ±6

142 ±49

97 ±13

Low-HDL

44 ±17

21

A-IMilano Cardiovascular Study

Sirtori CR, et al. Circulation. Apr 17 2001;103(15):1949-1954.


0.5

0.6

0.7

0.8

0.9

1.0

0.5

1.0

1.5

2.0

Aver

age

IMT

(mm

)

Max

imum

IMT

(mm

)

Mean ±SEM

A-IMCarriers

ControlsLow-HDL A-IMCarriers

ControlsLow-HDL

A-IMilano Cardiovascular StudyCarotid Intima-Media Thickness

Sirtori CR, et al. Circulation. Apr 17 2001;103(15):1949-1954.


N C

Apo-AI

Cys

N C

Apo-AIMilano monomer

Cys-

N

Cys

N

Apo-AIMilano dimer

www.lipid.orgwww.lipid.orgRoma P, Gregg RE, Meng MS, et al. J Clin Invest. Apr 1993;91(4):1445-1452.

A-IM Dimer Has A Long Half-Life


AIM INFILTRATION INTO THE CORONARY WALLREDUCES STENT RESTENOSIS

Control

AIMPROXIMALSEGMENT

DISTAL SEGMENT

Kaul S, et al. Circulation. May 27 2003;107(20):2551-2554.

www.lipid.orgwww.lipid.orgNissen SE, et al. JAMA. Nov 5 2003;290(17):2292-2300.

Overall r Apo A-I Milano ( ETC-216 ) produced 4.5 % net regression of coronary atheroma volume in

6 Weeks

N=47 patients with ACS

Baseline Post-Rx

-1.06

0.14

-1.5

-1

-0.5

0

0.5

-14.1

-2.9

-20

-15

-10

-5

0

(N=36) (N=11) (N=36) (N=11)

Mean Change in Atheroma Volume (%)

Mean Change in Total Atheroma Volume

(mm3)

P<0.02

P<0.97

(P<0.001)

P<0.97

A-Im A-ImPlacebo Placebo

10 mm coronary segments with the largest plaqueshowed 11 % net regression: Nichols JACC 2006

Rapid Regression of Human Coronary Plaque after 5 Weekly Intravenous Injections of Recombinant rApo A-Imilano (ETC-216)


CHOLESTEROL ESTER TRANSFER PROTEIN AND CETP INHIBITION


Reverse Cholesterol Transport

Toth PP. Am J Cardiol. Nov 7 2005;96(9A):50K-58K; discussion 34K-35K.


No evidence of premature atherosclerosis in any of the 10 homozygotes.Trend toward longevity in 2 families with a 100 year old heterozygote.

Lipid Profile of 5 Families With HALP

Group

Homozyg.(10)

Heterozyg.(20)

Unaffected(10)

Age (yr)

58(51-68)

49(19-100)

48(20-71)

Total

271*

195

189

HDL

164*(209%)

66(25%)

53

LDL

77*(-44%)

111(-5%)

117

A-I B

0.54*(-31%)

0.66(-15%)

0.78

2.13*(72%)

1.49*(20%)

1.24

CETP(g/mL)

0*

1.4*(0.3)

2.3

Cholesterol (mg/dL) Apoproteins(mg/mL)

Are CETP Gene Mutations Atheroprotective?

Inazu et al. N Engl J Med. 1990;323:1234-1238.

*Significant difference from unaffected P<0.05; numbers in parentheses are % difference from unaffected controls.


CETP Mutation:

Curb JD, et al. J Lipid Res. May 2004;45(5):948-953.

HDL-C <60 mg/dl HDL-C 60 mg/dl

CH

D In

cide

nce

(rat

e/10

00 p

erso

n-ye

ars)

171/1713*

31/509**5/76

2/42

*Number of CHD events/men at risk

**Significantly lower risk compared to men with HDL-C <60 mg/dl and without a CETP mutation (p<0.05)

absentpresent

18

15

12

9

6

3

0

Age-Adjusted 6-Year CHD/CVD Rates for Elderly Japanese American Men With and Without CETP Mutations



Thompson, A. et al. JAMA 2008;299:2777-2788.



Figure 2. Associations of CETP Genotypes With CETP Phenotypesand Lipid Levels



Figure 4. CETP Genotypes and Coronary Risk, Grouped by Recorded Study Characteristics



Figure 5. Observed Per-Allele Odds Ratios for Coronary Disease With CETP Variants vs Odds Ratios Derived From Available Prospective

Studies of HDL-C Levels


www.lipid.orgwww.lipid.orgRidker P M et al. Circ Cardiovasc Genet 2009;2:26-33.

Figure 2. Distribution of HDL-C (left), ApoA1 (middle), and Kaplan Meier estimates of cumulative incidence of myocardial infarction (right)

according to the genotype of SNPs at the CETP locus

www.lipid.orgwww.lipid.orgCopyright ©2009 American Heart Association

Vasan, R. S. et al. Circulation 2009;120:2414-2420.

Kaplan-Meier curves showing survival free from CVD over the follow-up period in individuals above vs below the median plasma CETP activity


Multivariable-adjusted relations of plasma CETP activity (continuous variable) to the incidence of CVD on follow-up

Copyright ©2009 American Heart Association

Vasan, R. S. et al. Circulation 2009;120:2414-2420.


Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot

* Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina


LIPOPROTEIN LIPASE


Ser447(stop) in LPL was found to increase HDL levels in Dutch men, possibly from increased lipolytic activity1

Gly188→Glu in LPL develop hypertriglyceridemia and low HDL/apoA-I and have increased risk for developing ischemic heart disease2

The Asn291→Ser in LPL is a key contributor to the development of low HDL and premature CAD. The Copenhagen City Heart Study found that this mutation increases the risk for CAD and ischemic cerebrovascular disease 2-fold in women3,4

Lipoprotein Lipase Mutations

1. Kuivenhoven J et al. Arterioscler Thromb Vasc Biol 1997;17:595-9.2. Nordestrgaard B et al. Circulation 1997;96:1737-44.3. Reymer P et al. Nat Genet 1995;10:28-34. 4. Wittrup HH et al. Circulation 2000;101:2393-7.


Associations between plasma high density lipoprotein (HDL) cholesterol and triglyceride levels and 6 polymorphisms of the

lipoprotein lipase gene, grouped by various study characteristics using a dominant genetic model (carriers vs. noncarriers).

Sagoo G S et al. Am J Epidemiol. 2008;168:1233-1246.


Meta-analyses of studies of coronary heart disease and 7 polymorphisms of the lipoprotein lipase gene, grouped by various

study characteristics using a dominant genetic model(carriers vs. noncarriers).

Sagoo G S et al. Am J Epidemiol. 2008;168:1233-1246.


HEPATIC LIPASE


Allelic variation in the gene for HL gives rise to 25% of the interindividual differences in serum HDL levels1,2

G250A in the promoter decreases HL activity, raises HDL2, and increases the concentration of large, buoyant LDL3

In the Familial Atherosclerosis Treatment Study, combination therapy with either niacin and colestipol or lovastatin and colestipolwas associated with decreased hepatic lipase activity and coronary artery plaque regression as a result of elevations in LDL particle buoyancy and serum HDL2 concentrations4

C480T in the promoter significantly decreases HL activity, and is associated with elevations in apoA-I and HDL5

C514T increases the size of HDL2 fraction but has no effect on LDL particle size6

Hepatic Lipase Mutations

1. Cohen et al. J Clin Invest 1994;94:2377-84. 2. Guerra R et al. Proc Natl Acad Sci USA 1997;94:4532-7.3. Zambon A et al. Aterioscler Thromb Vasc Biol 1998;18:1723-29.4. Zambon A et al. Circulation 1999;99:1959-64.5. Murtomaki S et al. Aterioscler Thromb Vasc Biol 1997;17:1879-84.6. Couture P et al. Arterioscler Thromb Vasc Biol 2000;20:815-22.


HDL FUNCTIONALITY


SAA1

PON1ApoA-I

SAA2

ApoHApoA-IV

C3

C4A

C4B

VTN

ApoA-II

ApoL-1

ApoDSAA4

ApoC-IV

ApoC-III

ApoC-II

ApoC-ILCATCETPPLTP

ApoM

ApoF

ApoE

HRP SERA1

KNG1

ORM2

AGT

AHSG AMP

SERF2 SERF1

Clusterin

PON3

C9

Lipid Metabolism

ITIH4TTR RBP4 TFFGA

HPX

Proteinase Inhibitor

ComplementRegulation

Acute Phase Response

Gene Ontology Analysis of HDL Proteins

Slide from J Heinecke.

www.lipid.orgwww.lipid.orgAssmann G et al. Ann Rev Med 2003;54:321-341.

The antioxidative effects of HDL are related to presence

of α-tocopherol and other antioxidants including apoA-I and apoJ. These scavenge

ROS and prevent lipid peroxides (LOOX) and oxidized CE (CE-OOX).

LDL

Phospholipids Fatty Acids

Oxidized Phospholipids

(POVPC, PGPC)

LDL-oxO2- , OH-

HDL12-lipooxygenase

HODE HETE

Oxidized phospholipids on LDL are deleterious. These are

generated by seeding molecules like HPODE and

HPETE as catalysts generated by 12-liopoxygenase and lipid

peroxides (LOOX) and oxidized CE (CE-OOX).

HPODE = Hydroperoxyoctadecadienoic acid HPETE = Hydroperoxycicosatetraenoic acid

HDL overtakes seeding molecules and degrades them using paraoxonase

(PON), PAF-AH or glutathione peroxidase

(GPX)

A-I, J

α-TOC PON, PAF-AH

GPX

HDL: Anti-inflammatory Activity

www.lipid.orgwww.lipid.orgFogelman AM Nature Medicine 2004;10:902-903.

A-I A-I

Anti-inflammatory HDL

Pro-inflammatory HDL

A-I

Myeloperoxidase damages apoA-I at the tyrosine molecules

Nitrotyrosine

Chlortyrosine

↓apoA-I ↓ Paraoxonase, other factors ↑ Proinflammatory factors,

other factors

In inflammatory states HDL can change its

properties and become pro-inflammatory

HDL Inflammatory Activity


A-I

A-I

A-I

A-IIA-I

A-I

J

J

A-I ApoAI

A-II ApoAII

PON1 Paraoxonase

LCAT Lecithin:cholesterol acyltransferase

CETP Cholesteryl ester transfer protein

PLTP Phospholipid transfer factor

J ApoJ

sPLA2 Secretory phospholipase A

SAA Serum Amyloid A

Normal HDL

APR HDL

Rohrer M et al. Curr Opin Lipidol 2004;15:269-278.

Acute Phase Reaction (APR) and HDL


Coronary Artery Disease Status According to Quartile of Efflux Capacity


Odds Ratios for Coronary Artery Disease According to Efflux Capacity

and Selected Risk Factors


CONCLUSIONS• HDL‐C is consistently shown to be an independent risk factor for CHD based on observational studies around the world in both men and women•Meta‐analyses and multivariate regression support the hypothesis that raising HDL‐C reduces risk for CVD•HDL particles have a complex proteosome that confers diverse protective and potentially toxic functionality •Polymorphisms in components of the HDL proteosome do not always impact risk for CHD as predicted•A variety of approaches to HDL therapy are being tested prospectively in randomized trials

epidemiology of hdl and its evolution into a therapeutic

Documents