Non-HDL From A-to-Z

Non-HDL
cholesterol as a
therapeutic target
By
M.Wafaie Aboleineen,MD,FACC.

Residual Cardiovascular Risk in Major Statin Trials
40
Patients Experiencing
Major CHD Events, %
30
20
10
28.0
19.4
15.9
12.3
13.2
10.2
11.8
8.7
Placebo
Statin
7.9
5.5
10.9
6.8
0
4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/
TexCAPS 6
N 4444 9014 4159 20 536 6595 6605
∆ LDL-C -35% -25% -28% -29% -26% -25%
Secondary High Risk Primary
1
4S Group. Lancet. 1994;344:1383-1389.
2
LIPID Study Group. N Engl J Med. 1998;339:1349-1357.
3
Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
4
HPS Collaborative Group. Lancet. 2002;360:7-22.
5
Shepherd J, et al. N Engl J Med. 1995;333:1301-1307
6
Downs JR, et al. JAMA. 1998;279:1615-1622.

In ACS, elevated levels of triglycerides TGs ≥150 mg/dL;
predict risk even in those with LDL-C

Risk of CHD by TG Level
The Framingham Heart Study (30-Year Follow-Up)
Relative CHD Risk
3
2.5
2
1.5
1
Men
Women
N = 5127 patients
with no history of CHD
0.5
0
50 100 150 200 250 300 350 400
TG Level, mg/dL
Univariate analysis of data from the Framingham Heart Study, including 5127 patients aged 30
to 60 years without CHD, to determine the relationship between TGs and CHD.
Reprinted from Castelli WP. Am J Cardiol. 1992;70:3H-9H, with permission from Elsevier.

Association Between LDL-C, Non-HDL-C,
TGs, HDL-C and CHD Risk
Lipid Level
LDL-C 1 Each 1%
increase in LDL-C
Non-HDL-C 2 Each 1%
increase in Non-HDL-C
CHD Risk
1% increase in
the risk of CHD in women and
men
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.

Non-HDL Cholesterol
(Non-HDL Chol. = TC - HDL)
• sum of :
• LDL, Lp(a), IDL, and VLDL
• : All atherogenic apo B
containing lipoproteins
• Lipid Equivalent of “HbA1C”

Targets of Therapy
Copyright ©2010 American College of Cardiology Foundation. Robinson, Restrictions may J. apply. G. JACC 2010

CHD Across Fifths of Usual Lipids or Apolipoproteins
Copyright restrictions may apply. The Emerging Risk Factors Collaboration, JAMA 2009.

Factors Contributing to Cardiometabolic Risk
Brunzell, J. D. et al. JACC 2008
Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Mechanisms of DM Dyslipidemia
Fat Cells
FFA
Liver
IR X
Insulin
13 www.drsarma.in

Mechanisms of DM Dyslipidemia
Fat Cells
FFA
Liver
IR X
TG
Apo B
VLDL
VLDL
Insulin
14 www.drsarma.in

Mechanisms of DM Dyslipidemia
Fat Cells
Liver
FFA
CE
IR X
TG
Apo B
VLDL
VLDL
(CETP)
TG
HDL
(hepatic
lipase)
Apo A-1
Insulin
Kidney
15 www.drsarma.in

Mechanisms of DM Dyslipidemia
Fat Cells
FFA
Liver
CE
IR X
Insulin
TG
Apo B
VLDL
CE
VLDL
(CETP)
LDL
(CETP)
TG
TG
(lipoprotein or hepatic lipase)
16 www.drsarma.in
HDL
SD
LDL
(hepatic
lipase)
Apo A-1
Kidney

Drugs Affecting Lipoprotein Metabolism:
Lipid Lowering Drugs
Drug Class LDL–C HDL–C TG
Statins 30-60% 4-10% 15-20%
Bile Acid
Binders
18-25% 2-3% 10%
Ezitimibe 18% 3% 3%
Nicotinic
Acid
Fibrates 10%,
May or not change
15-30% 15-30% 20-30%
6-12% 30-50%
Fish Oil 5-10% 5% 35-45%

Change in Relative Risk of CHD Event
Robinson, J. G. et al. JACC2009
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

Specific Dyslipidemias:
Elevated Triglycerides
Non-HDL Cholesterol: Secondary Target
• Primary target of therapy: LDL cholesterol
• Achieve LDL goal before treating non-HDL cholesterol
• Therapeutic approaches to elevated non-HDL
cholesterol
– Intensify therapeutic lifestyle changes
– Intensify LDL-lowering drug therapy
– Nicotinic acid or fibrate therapy to lower VLDL

Lipid Management
Recommendations
I
I
IIa IIb III
IIa IIb III
If TG are 200-499 mg/dL, non-HDL-C should be < 130
mg/dL
Further reduction of non-HDL to < 100 mg/dL is
reasonable
Therapeutic options to reduce non-HDL-C:
More intense LDL-C lowering therapy I (B) or
Niacin (after LDL-C lowering therapy) IIa (B) or
Fibrate (after LDL-C lowering therapy) IIa (B)
I
IIa IIb III
If TG are > 500 mg/dL, therapeutic options to
prevent pancreatitis are fibrate or niacin before LDL
lowering therapy; and treat LDL-C to goal after TGlowering
therapy. Achieve non-HDL-C < 130 mg/dL,
if possible

NCEP ATP III LDL-C and
Non-HDL-C Goals
Risk category
CHD Risk Factors or
Equivalents
LDL-C Goal
(mg/dL)
Non-HDL-C
Goal (mg/dL)
Very high
High risk + recent acute coronary
syndrome, diabetes, smoking,
metabolic syndrome*
< 70 < 100
High
CAD or risk equivalent
< 100
< 130
(10-year risk > 20%)
(optional < 70)
Moderately high > 2 risk factors +
(10-year risk 10% to 20%)
< 130 < 160
Moderate > 2 risk factors +
(10-year risk < 10%)
< 130 < 160
Low 0 – 1 risk factor < 160 < 190
NCEP ATP III Final Report. Circulation. 2002;108:3143-3421; Grundy, SM et al. Circulation. 2004;110:227-239

2007 NLA Safety Task Force
Niacin/Statin Combination Therapy
• Clinical evidence does not support a
general myopathic effect of niacin either
alone or in combination with statins
• Niacin/Statin combination therapy improve
all atherogenic lipid abnormalities, slows
the progression and increases the
regression of coronary atherosclerosis, and
reduces residual CVD risk
Guyton JR et al. Am J Cardiol 2007;

Fibrate Mechanisms of Action
Fibrate
Fibrate
↑LDL Particle Size
↓Triglycerides
↑HDL Synthesis
PPARα
↓Inflammation
↑Reverse Cholesterol Transport

2007 NLA Safety Task Force
Fibrate/ Statin Combination Therapy
• Fibrate + statins are associated with
increased risk for myopathy and
rhabdomyolysis
• Fenofibrate has much less potential for
impairment of statin metabolism, and
reduced reports of myopathy compared
with gemfibrozil + statin.
Guyton JR et al. Am J Cardiol 2007

Efficacy of Fenofibrate and Omega-3
Fatty Acids on High TG
Efficacy Comparison in Patients with TG >500 mg/dL Relative
Difference vs Placebo
50%
Omega-3
50%
Fenofibrate
30%
30%
10%
10%
-10%
-30%
HDL-C
Chol
LDL-C
-10%
-30%
HDL-C
Chol
LDL-C
-50%
VLDL-C
-50%
-70%
TG
-70%
TG
VLDL-C
Harris WS et al. J Cardiovasc Risk 1997;4:385-391.
Goldberg AC et al. Clin Ther 1989;11:69-83.

A
Statin
LDL > target
Algorithm for LDL Therapy
(Dose per LDL level)
LDL < target
Non HDL < target
Monitor
LDL < target
Non HDL >target
Fish Oil
Follow Protocol B
LDL > target
Increase Statin
LDL target
LDL < target
Non HDL > target
Add Fenofibrate or Niacin
LDL < target
Non HDL< target
Monitor