Non-HDL-C

Current Targets and Treatment
Gaps in Lipid Therapy: Focus
on HDL-C
Prof. Dr. Tarek El-Zawawy
Prof. Cardiology and Angiology
Faculty of Medicine,
Alex. University

Log-linear Relationship Between LDL-C Levels and
Relative Risk for CHD
3.7
Relative
Risk
for
Coronary
Heart
Disease
(Log Scale)
2.9
2.2
1.7
1.3
1.0
40 70 100 130 160 190
LDL-Cholesterol, mg/dL
• This relationship is consistent with a large body of epidemiological data and with data
available from
clinical trials of LDL-lowering therapy
• These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is
changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C 40 mg/dL.
Grundy S, et al. Circulation. 2004;110:227-239

Fasting and Nonfasting TG:
Equally Predictive of CHD Risk*
Fasting
Nonfasting
Cumulative Probability of Death
20
15
10
5
0
HR † : 1.41
(1.12-1.79)
P = 0.004
TG ≥200 mg/dL
TG

Non–HDL-C Is Superior to LDL-C
in Predicting CHD Risk
• Within non–HDL-C levels, no
association was found between
LDL-C and the risk for CHD
2.5
• In contrast, a strong positive and
graded association between non–
HDL-C and risk for CHD occurred
within every level of LDL-C
• Non–HDL-C is a stronger
predictor of CHD risk than LDL-C
Relative CHD Risk
2
1.5
1
0.5
0

Role of Low HDL-C
in Residual
Cardiovascular Risk

Low HDL-C and
Cardiovascular Risk
An Independent Frequent Risk Factor
4.0
3.0
4.0
Controls Cases
Risk Factor (N=601) (N=321)
Cigarette smoking
29% 67%*
HDL-C 150/90 mmHg)
21% 41%*
LDL-C ≥160 mg/dL 26% 26%*
Diabetes mellitus 1% 12%*
1.0
1.0
0
0.65 1.17 1.68
HDL-C (mmol/L)
Kannel WB. AJC 1983; 52: Framingham Study;
Genest JJ et al. Am J Cardiol 1991; 67:1185–1189

Association Between LDL-C, Non-HDL-C, TGs,
HDL-C and CHD Risk
Lipid Level
LDL-C 1 Each 1%
increase in LDL-C
CHD Risk
1% increase in
the risk of CHD in women and
men
Non-HDL-C 2 Each 1%
increase in Non-HDL-
C
1% increase in
the risk of CHD in women and
men
TG 3
Each 1 mmol/L
(89 mg/dL)
increase in TG
37% increase in
the risk of CVD in women and
14% increased risk in men
HDL-C 4
Each 1 mg/dL
increase in HDL-C
2% decrease in CVD death in
men and 3% decrease in CVD
death in women
1 Grundy S, et al. Circulation. 2004;110:227-239.
2 Liu J, et al. Am J Cardiol. 2006;98:1363-1368.
3 Hokanson JE, et al. J Cardiovasc Risk. 1996;3:213-219.
4 Gordon DJ, et al. Circulation. 1989;79:8-15.

Does the HDL level matter if
the LDL-C is reduced by
statins and is very low

CHD risk predicted by HDL and LDL in the
Framingham Heart Study
CAD Relative Risk
4
3
2
1
0
100 160 220
85
65
45
25
LDL-C (mg/dL)
AJC 2001; 88(suppl): 9N-13N

TNT: Events in HDL-C and
LDL-C Quintiles
16
14
5-year K-M incidence
of MCVE (%)
12
10
8
6
4
2
0
1
(

New CV events in MI patients with
normal cholesterol levels
80
75%
New CV events
(% Patients)
60
40
20
45%
0
HDL < 35
mg/dl
HDL > 35 mg/dl
AJC 2001; 88(suppl): 9N-13N

Results from the statin trials have established
that interventions leading to lower LDL levels
produced a significant reduction in
CHD.However, the extent of this reduction is
incomple.
The decrease in the rate of coronary events
was only 30% to 35%. This implies that a
greater improvement could be achieved
through further interventional measures,
including therapy that modifies lipids other
than LDL”
Poulter NR, Dept of Clinical Pharmacology, Imperial School of Medicine, London
Am J Cardiol 2001;88(suppl):1N-2N

Percentage of patients reaching ADA lipid
targets
Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg + Fenofibrate 200 mg
% of patients reaching ADA goals
120
100
80
60
40
20
0
80
97.5
92.5
100
75
30
17.5
5
LDL TG HDL
60
Diabetes Care

Percent probability for MI within the next 10 years
as estimated with the PROCAM CAD calculator
25
21.6
20
15
10
7.5
10.9
5
4.2
0
Baseline Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg +
Fenofibrate 200 mg
Diabetes Care 2002;25:1198-1202

IS THERE AN ASYMPTOTIC
LIMIT FOR LDL AT WHICH
CARDIOVASCULAR EVENT
RATES APPROXIMATE
ZERO

The LDL level at which cardiovascular event
rate may approach ZERO is estimated to be
60mg/dl for primary prevention and
30 mg/dl for secondary prevention
1. McKenney. Am J Ther. 2004;11:54-59; 2. Jones et al for the STELLAR Study Group. Am J Cardiol.
2003;92:152-160; 3. Olsson et al. Am Heart J. 2002;144:1044-1051; 4. Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

CAD risk can be reduced to a maximum of
approximately 35% with current statin and/or fibric
acid derivates
Leaving 65% risk reduction to be gained, HDL-C
increasing strategies are becoming increasingly
important 1 1
Duffy & Rader Circulation 2006; 113

Time to move beyond LDL

Should both HDL-C and LDL-
C be targets for lipid therapy

HDL-C Increase and LDL-C Decrease
Additive
% Absolute change in LDL+HDL
% CV event RRR
0
10
20
30
40
50
60
70
0 10 20 30 40 50 60 70 80
VA HIT
DAIS
BIP
LIPID
HHS
CDP
WOSCOPS
ASCOT
ALLHAT
PROSPER
CARE, HPS
AFCAPS/
TexCAPS
4S
FATS F/U
80
90
HATS
FATS
100
LDL-C lowering
LDL-C lowering
+ HDL-C increase
Brown, 2004

Should HDL Raising Be a
Target for Lipid Therapy"

Meta-analysis of 4 large
prospective studies
For every 1 mg/dl
increase in HDL,
the incidence of
coronary events
decreases by
2% in men and
3% in women.
Am J Cardiol 2001;88(suppl):9N-1

Recommendations for
management of dyslipidemia

Modified ATP III LDL-C Guidelines
Low
(20%)
Very High
(ACS)

NCEP ATPIII, AHA, and ADA:
Recommended Lipid Goals
Parameter ATP III 1 AHA Women 2 (for adults
ADA Position 3
with diabetes)
LDL-C
- Very high risk

NCEP ATP III Guidelines
For all patients, including patients with high TG, or Low
HDL), the primary target of therapy is LDL-C.
Statin is the first line therapy
Non HDL-C should be a secondary target of therapy
when TG > 200 mg/dl. Two approaches:
- Increase the dose of LDL-lowering drug (statin)
- Add fibrate or nicotinic acid
If isolated low HDL, TG are < 200 mg/dl, drugs for HDL
raising (fibrates or nicotinic acid) can be considered in
high risk patients. Niacin in the first choice
Third report of NCEP expert panel of detection, evaluation and treatment of high
blood cholesterol in adults (ATP III). Circulation 2002; 106: 3143-421.

NCEP ATP III Guidelines (Cont.)
If TG >500 mg/dl, the initial aim is to prevent
pancreatitis through TG lowering.
- Fibrates are the drug class of choice
- Nicotinic acid or fish oils may be considered in
case of intolerance or failure of fibrates
- Only after TG lowered to < 500 mg/dl, should
attention turn to LDL lowering.
Third report of NCEP expert panel of detection, evaluation and treatment of high
blood cholesterol in adults (ATP III). Circulation 2002; 106: 3143-421.

Priorities of Diabetic
dyslipidemia management
• First, lower LDL cholesterol.
• Second, raise HDL cholesterol.
• Third, lower Triglyceride levels.
Diabetes:
The 2007 Guidelines

American Diabetes Association
Standards of Medical Care in Diabetes:
Dyslipidemia Management
LDL-C Lowering
Goal: 40 mg/dL †
TG Lowering
Goal:

Target Levels
Risk Level
Initiate treatment if:
High Consider treatment in all patients
CAD,PVD
Atherosclerosis
Most Pts with Diabetes
FRS>20%
RRS>20%
Primary
LDL-C

Target Levels
Risk Level
Initiate treatment if:
High Consider treatment in all patients
CAD,PVD
Atherosclerosis
Most Pts with Diabetes
FRS>20%
RRS>20%
Moderate (strive towards )
FRS 10-19% LDL-C>3.5 mmol/L
TC/HDL >5.0
hsCRP >2
men 50+, women 60+
Family history and hsCRP modulate risk
Primary
LDL-C

Target Levels
Risk Level
Initiate treatment if:
High Consider treatment in all patients
CAD,PVD
Atherosclerosis
Most Pts with Diabetes
FRS>20%
RRS>20%
Moderate (strive towards )
FRS 10-19% LDL-C>3.5 mmol/L
TC/HDL >5.0
hsCRP >2
men 50+, women 60+
Family history and hsCRP modulate risk
Primary
LDL-C

Conclusion
Non pharmacological strategies to
increase HDL-C include exercise, diet,
weight loss, and smoking cessation.
Patients who are at increased risk for
coronary disease with low HDL benefit
from niacin and statin therapy

Thank You
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