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Current Targets and Treatment<br />

Gaps in Lipid Therapy: Focus<br />

on <strong>HDL</strong>-C<br />

Prof. Dr. Tarek El-Zawawy<br />

Prof. Cardiology and Angiology<br />

Faculty of Medicine,<br />

Alex. University


Log-linear Relationship Between LDL-C Levels and<br />

Relative Risk for CHD<br />

3.7<br />

Relative<br />

Risk<br />

for<br />

Coronary<br />

Heart<br />

Disease<br />

(Log Scale)<br />

2.9<br />

2.2<br />

1.7<br />

1.3<br />

1.0<br />

40 70 100 130 160 190<br />

LDL-Cholesterol, mg/dL<br />

• This relationship is consistent with a large body of epidemiological data and with data<br />

available from<br />

clinical trials of LDL-lowering therapy<br />

• These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is<br />

changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C 40 mg/dL.<br />

Grundy S, et al. Circulation. 2004;110:227-239


Fasting and <strong>Non</strong>fasting TG:<br />

Equally Predictive of CHD Risk*<br />

Fasting<br />

<strong>Non</strong>fasting<br />

Cumulative Probability of Death<br />

20<br />

15<br />

10<br />

5<br />

0<br />

HR † : 1.41<br />

(1.12-1.79)<br />

P = 0.004<br />

TG ≥200 mg/dL<br />

TG


<strong>Non</strong>–<strong>HDL</strong>-C Is Superior to LDL-C<br />

in Predicting CHD Risk<br />

• Within non–<strong>HDL</strong>-C levels, no<br />

association was found between<br />

LDL-C and the risk for CHD<br />

2.5<br />

• In contrast, a strong positive and<br />

graded association between non–<br />

<strong>HDL</strong>-C and risk for CHD occurred<br />

within every level of LDL-C<br />

• <strong>Non</strong>–<strong>HDL</strong>-C is a stronger<br />

predictor of CHD risk than LDL-C<br />

Relative CHD Risk<br />

2<br />

1.5<br />

1<br />

0.5<br />

0<br />


Role of Low <strong>HDL</strong>-C<br />

in Residual<br />

Cardiovascular Risk


Low <strong>HDL</strong>-C and<br />

Cardiovascular Risk<br />

An Independent Frequent Risk Factor<br />

4.0<br />

3.0<br />

4.0<br />

Controls Cases<br />

Risk Factor (N=601) (N=321)<br />

Cigarette smoking<br />

29% 67%*<br />

<strong>HDL</strong>-C 150/90 mmHg)<br />

21% 41%*<br />

LDL-C ≥160 mg/dL 26% 26%*<br />

Diabetes mellitus 1% 12%*<br />

1.0<br />

1.0<br />

0<br />

0.65 1.17 1.68<br />

<strong>HDL</strong>-C (mmol/L)<br />

Kannel WB. AJC 1983; 52: Framingham Study;<br />

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


Association Between LDL-C, <strong>Non</strong>-<strong>HDL</strong>-C, TGs,<br />

<strong>HDL</strong>-C and CHD Risk<br />

Lipid Level<br />

LDL-C 1 Each 1%<br />

increase in LDL-C<br />

CHD Risk<br />

1% increase in<br />

the risk of CHD in women and<br />

men<br />

<strong>Non</strong>-<strong>HDL</strong>-C 2 Each 1%<br />

increase in <strong>Non</strong>-<strong>HDL</strong>-<br />

C<br />

1% increase in<br />

the risk of CHD in women and<br />

men<br />

TG 3<br />

Each 1 mmol/L<br />

(89 mg/dL)<br />

increase in TG<br />

37% increase in<br />

the risk of CVD in women and<br />

14% increased risk in men<br />

<strong>HDL</strong>-C 4<br />

Each 1 mg/dL<br />

increase in <strong>HDL</strong>-C<br />

2% decrease in CVD death in<br />

men and 3% decrease in CVD<br />

death in women<br />

1 Grundy S, et al. Circulation. 2004;110:227-239.<br />

2 Liu J, et al. Am J Cardiol. 2006;98:1363-1368.<br />

3 Hokanson JE, et al. J Cardiovasc Risk. 1996;3:213-219.<br />

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


Does the <strong>HDL</strong> level matter if<br />

the LDL-C is reduced by<br />

statins and is very low


CHD risk predicted by <strong>HDL</strong> and LDL in the<br />

Framingham Heart Study<br />

CAD Relative Risk<br />

4<br />

3<br />

2<br />

1<br />

0<br />

100 160 220<br />

85<br />

65<br />

45<br />

25<br />

LDL-C (mg/dL)<br />

AJC 2001; 88(suppl): 9N-13N


TNT: Events in <strong>HDL</strong>-C and<br />

LDL-C Quintiles<br />

16<br />

14<br />

5-year K-M incidence<br />

of MCVE (%)<br />

12<br />

10<br />

8<br />

6<br />

4<br />

2<br />

0<br />

1<br />

(


New CV events in MI patients with<br />

normal cholesterol levels<br />

80<br />

75%<br />

New CV events<br />

(% Patients)<br />

60<br />

40<br />

20<br />

45%<br />

0<br />

<strong>HDL</strong> < 35<br />

mg/dl<br />

<strong>HDL</strong> > 35 mg/dl<br />

AJC 2001; 88(suppl): 9N-13N


Results from the statin trials have established<br />

that interventions leading to lower LDL levels<br />

produced a significant reduction in<br />

CHD.However, the extent of this reduction is<br />

incomple.<br />

The decrease in the rate of coronary events<br />

was only 30% to 35%. This implies that a<br />

greater improvement could be achieved<br />

through further interventional measures,<br />

including therapy that modifies lipids other<br />

than LDL”<br />

Poulter NR, Dept of Clinical Pharmacology, Imperial School of Medicine, London<br />

Am J Cardiol 2001;88(suppl):1N-2N


Percentage of patients reaching ADA lipid<br />

targets<br />

Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg + Fenofibrate 200 mg<br />

% of patients reaching ADA goals<br />

120<br />

100<br />

80<br />

60<br />

40<br />

20<br />

0<br />

80<br />

97.5<br />

92.5<br />

100<br />

75<br />

30<br />

17.5<br />

5<br />

LDL TG <strong>HDL</strong><br />

60<br />

Diabetes Care


Percent probability for MI within the next 10 years<br />

as estimated with the PROCAM CAD calculator<br />

25<br />

21.6<br />

20<br />

15<br />

10<br />

7.5<br />

10.9<br />

5<br />

4.2<br />

0<br />

Baseline Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg +<br />

Fenofibrate 200 mg<br />

Diabetes Care 2002;25:1198-1202


IS THERE AN ASYMPTOTIC<br />

LIMIT FOR LDL AT WHICH<br />

CARDIOVASCULAR EVENT<br />

RATES APPROXIMATE<br />

ZERO


The LDL level at which cardiovascular event<br />

rate may approach ZERO is estimated to be<br />

60mg/dl for primary prevention and<br />

30 mg/dl for secondary prevention<br />

1. McKenney. Am J Ther. 2004;11:54-59; 2. Jones et al for the STELLAR Study Group. Am J Cardiol.<br />

2003;92:152-160; 3. Olsson et al. Am Heart J. 2002;144:1044-1051; 4. Expert Panel on Detection,<br />

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


CAD risk can be reduced to a maximum of<br />

approximately 35% with current statin and/or fibric<br />

acid derivates<br />

Leaving 65% risk reduction to be gained, <strong>HDL</strong>-C<br />

increasing strategies are becoming increasingly<br />

important 1 1<br />

Duffy & Rader Circulation 2006; 113


Time to move beyond LDL


Should both <strong>HDL</strong>-C and LDL-<br />

C be targets for lipid therapy


<strong>HDL</strong>-C Increase and LDL-C Decrease<br />

Additive<br />

% Absolute change in LDL+<strong>HDL</strong><br />

% CV event RRR<br />

0<br />

10<br />

20<br />

30<br />

40<br />

50<br />

60<br />

70<br />

0 10 20 30 40 50 60 70 80<br />

VA HIT<br />

DAIS<br />

BIP<br />

LIPID<br />

HHS<br />

CDP<br />

WOSCOPS<br />

ASCOT<br />

ALLHAT<br />

PROSPER<br />

CARE, HPS<br />

AFCAPS/<br />

TexCAPS<br />

4S<br />

FATS F/U<br />

80<br />

90<br />

HATS<br />

FATS<br />

100<br />

LDL-C lowering<br />

LDL-C lowering<br />

+ <strong>HDL</strong>-C increase<br />

Brown, 2004


Should <strong>HDL</strong> Raising Be a<br />

Target for Lipid Therapy"


Meta-analysis of 4 large<br />

prospective studies<br />

For every 1 mg/dl<br />

increase in <strong>HDL</strong>,<br />

the incidence of<br />

coronary events<br />

decreases by<br />

2% in men and<br />

3% in women.<br />

Am J Cardiol 2001;88(suppl):9N-1


Recommendations for<br />

management of dyslipidemia


Modified ATP III LDL-C Guidelines<br />

Low<br />

(20%)<br />

Very High<br />

(ACS)<br />


NCEP ATPIII, AHA, and ADA:<br />

Recommended Lipid Goals<br />

Parameter ATP III 1 AHA Women 2 (for adults<br />

ADA Position 3<br />

with diabetes)<br />

LDL-C<br />

- Very high risk<br />


NCEP ATP III Guidelines<br />

For all patients, including patients with high TG, or Low<br />

<strong>HDL</strong>), the primary target of therapy is LDL-C.<br />

Statin is the first line therapy<br />

<strong>Non</strong> <strong>HDL</strong>-C should be a secondary target of therapy<br />

when TG > 200 mg/dl. Two approaches:<br />

- Increase the dose of LDL-lowering drug (statin)<br />

- Add fibrate or nicotinic acid<br />

If isolated low <strong>HDL</strong>, TG are < 200 mg/dl, drugs for <strong>HDL</strong><br />

raising (fibrates or nicotinic acid) can be considered in<br />

high risk patients. Niacin in the first choice<br />

Third report of NCEP expert panel of detection, evaluation and treatment of high<br />

blood cholesterol in adults (ATP III). Circulation 2002; 106: 3143-421.


NCEP ATP III Guidelines (Cont.)<br />

If TG >500 mg/dl, the initial aim is to prevent<br />

pancreatitis through TG lowering.<br />

- Fibrates are the drug class of choice<br />

- Nicotinic acid or fish oils may be considered in<br />

case of intolerance or failure of fibrates<br />

- Only after TG lowered to < 500 mg/dl, should<br />

attention turn to LDL lowering.<br />

Third report of NCEP expert panel of detection, evaluation and treatment of high<br />

blood cholesterol in adults (ATP III). Circulation 2002; 106: 3143-421.


Priorities of Diabetic<br />

dyslipidemia management<br />

• First, lower LDL cholesterol.<br />

• Second, raise <strong>HDL</strong> cholesterol.<br />

• Third, lower Triglyceride levels.<br />

Diabetes:<br />

The 2007 Guidelines


American Diabetes Association<br />

Standards of Medical Care in Diabetes:<br />

Dyslipidemia Management<br />

LDL-C Lowering<br />

Goal: 40 mg/dL †<br />

TG Lowering<br />

Goal:


Target Levels<br />

Risk Level<br />

Initiate treatment if:<br />

High Consider treatment in all patients<br />

CAD,PVD<br />

Atherosclerosis<br />

Most Pts with Diabetes<br />

FRS>20%<br />

RRS>20%<br />

Primary<br />

LDL-C<br />


Target Levels<br />

Risk Level<br />

Initiate treatment if:<br />

High Consider treatment in all patients<br />

CAD,PVD<br />

Atherosclerosis<br />

Most Pts with Diabetes<br />

FRS>20%<br />

RRS>20%<br />

Moderate (strive towards )<br />

FRS 10-19% LDL-C>3.5 mmol/L<br />

TC/<strong>HDL</strong> >5.0<br />

hsCRP >2<br />

men 50+, women 60+<br />

Family history and hsCRP modulate risk<br />

Primary<br />

LDL-C<br />


Target Levels<br />

Risk Level<br />

Initiate treatment if:<br />

High Consider treatment in all patients<br />

CAD,PVD<br />

Atherosclerosis<br />

Most Pts with Diabetes<br />

FRS>20%<br />

RRS>20%<br />

Moderate (strive towards )<br />

FRS 10-19% LDL-C>3.5 mmol/L<br />

TC/<strong>HDL</strong> >5.0<br />

hsCRP >2<br />

men 50+, women 60+<br />

Family history and hsCRP modulate risk<br />

Primary<br />

LDL-C<br />


Conclusion<br />

<strong>Non</strong> pharmacological strategies to<br />

increase <strong>HDL</strong>-C include exercise, diet,<br />

weight loss, and smoking cessation.<br />

Patients who are at increased risk for<br />

coronary disease with low <strong>HDL</strong> benefit<br />

from niacin and statin therapy


Thank You<br />

45

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