HDL as a Therapeutic Target Daniel J. Rader, M.D.
100
160
220
Risk of CHD
Low HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is Low
HDL-C (mg/dL)
LDL-C (mg/dL)
25
Gordon T et al. Am J Med 1977;62:707-714.
45
65
85
ATP III: New Definition of Low HDL-C
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Low HDL-C was redefined as <40 mg/dL
ATP III: The Metabolic Syndrome
Diagnosis is established when ?3 of these risk factors are present.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Is HDL-C Simply a Marker of Increased Cardiovascular Risk?
Smoke
Are sedentary
Are obese
Are insulin resistant or diabetic
Have hypertriglyceridemia
Have chronic inflammatory disorders
Low HDL-C levels are commonly found in patients who:
Production of Apo A-I by Liver and Intestine
A-I
A-II
Liver
Intestine
HDL
A-I
HDL
Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits
Regression of pre-existing atherosclerosis in animals
Increased Apo A-I Production is Antiatherogenic in Animals
Increase apo A-I production
Promote reverse cholesterol transport
Delay catabolism of HDL
HDL Metabolism as a Therapeutic Target: Potential Strategies
Small molecule upregulation of apo A-I gene transcription
Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano)
Administration of peptides based on apo A-I sequence
Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells)
Approaches to Increasing Apo A-I Production
Increase apo A-I production
Promote reverse cholesterol transport
Delay catabolism of HDL
HDL as a Therapeutic Target: Potential Strategies
HDL and Reverse Cholesterol Transport
Liver
CE
CE
FC
LCAT
FC
Bile
SR-BI
ABCA1
Macrophage
Mature HDL
Nascent HDL
FC
Regulation of Cholesterol Efflux in the Macrophage
FC
FC
oxysterols
LXR/RXR
ABCA1
PPARs
Pharmacologic Manipulation of Cholesterol Efflux
LXR/RXR
PPARs
Fibrates, TZDs, new agents
New agents
FC
ABCA1
Increase apo A-I production
Promote reverse cholesterol transport
Delay catabolism of HDL
HDL as a Therapeutic Target: Potential Strategies
Antioxidant effects
Inhibition of adhesion molecule expression
Inhibition of platelet activation
Prostacyclin stabilization
Promotion of NO production
Mechanisms Other Than Reverse Cholesterol Transport by Which HDL May be Antiatherogenic
Liver
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
ABCA1
Macrophage
A-I
TG
CE
HDL Metabolism: Intravascular Remodeling of HDL
Kidney
PL
FC
PL
Liver
HL
A-I
TG
CE
HDL Metabolism: Role of Hepatic Lipase
Kidney
PL
HDL2
Liver
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
ABCA1
Macrophage
HDL Metabolism: Role of CETP
FC
Kidney
LDLR
CE TG
CETP
B
VLDL/LDL
HDL Metabolism in CETP Deficiency
CE
FC
FC
LCAT
ABCA1
Macrophage
A-I
CE
FC
CE TG
CETP
B
VLDL/LDL
Delayed catabolism
X
Okamoto H et al. Nature 2000;406:203-207.
Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantly Reduced Aortic Atherosclerosis
% Aortic Lesion
Control
Simvastatin
JTT-705
HDL Metabolism: Influence of CETP Inhibition
Liver
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
ABCA1
Macrophage
FC
LDLR
CE TG
CETP
B
VLDL/LDL
X
Weight reduction and increased physical activity
LDL-C is primary target of therapy
Non-HDL-C is secondary target of therapy (if triglycerides ?200 mg/dL)
Consider nicotinic acid or fibrates
Management of Low HDL-C
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Therapeutic lifestyle changes
Smoking cessation
Regular aerobic exercise
Weight loss
Alcohol use?
Management of Low HDL-C
Therapeutic lifestyle changes
Pharmacologic therapy
Statins
Management of Low HDL-C
Patients with Events (%)
Scandinavian Simvastatin Survival Study Group. Lancet 1995;345:1274-1275.
4S: Major Coronary Events by HDL-C Subgroup
HDL-C (mg/dL)
Placebo
Simvastatin
?38
39–44
45–52
?53
RR=0.67
RR=0.71
RR=0.57
RR=0.70
Patients with Events (%)
LIPID Study Group. N Engl J Med 1998;339:1349-1357.
LIPID: CHD Events by HDL-C Subgroups
HDL-C
Placebo
Pravastatin
?39 mg/dL
<39 mg/dL
25%
24%
Patients with Events (%)
Sacks FM et al. N Engl J Med 1996;335:1001-1009.
CARE: CHD Events by HDL-C Subgroups
HDL-C
Placebo
Pravastatin
>37 mg/dL
?37 mg/dL
P = 0.008
P < 0.001
Events (%)
Downs JR et al. JAMA 1998;279:1615-1622.
AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at Baseline
HDL-C Levels
Placebo
Lovastatin
<34 mg/dl
35–39 mg/dl
>40 mg/dl
71
40
68
41
44
35
44% RR
40% RR
20% RR
Therapeutic lifestyle changes
Pharmacologic therapy
Statins
Fibrates
Management of Low HDL-C
VA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo Groups
Cumulative Incidence (%)
0
Rubins HB et al. N Engl J Med 1999;341:410-418.
Copyright ?1999, Massachusetts Medical Society. All rights reserved.
1
2
3
4
5
6
Year
Placebo
Gemfibrozil
–22% reduction
P = 0.006
VA-HIT: Lipid Concentrations According to Year of Study and Treatment Group
TC (mg/dL)
Year
LDL-C (mg/dL)
Year
HDL-C (mg/dL)
Year
TG (mg/dL)
Year
Placebo
Gemfibrozil
–4%, P<0.001
No change
Gemfibrozil & Placebo
Placebo
Gemfibrozil
+6%, P<0.001
Placebo
Gemfibrozil
–31%, P<0.001
Rubins HB et al. N Engl J Med 1999;341:410-418.
Copyright ?1999, Massachusetts Medical Society. All rights reserved.
VA-HIT: Changes in Plasma Lipids during Treatment as Predictors of Coronary Events
Robins SJ et al. JAMA 2001;285:1585-1591.
Copyright ?2001, American Medical Association.
Therapeutic lifestyle changes
Pharmacologic therapy
Statins
Fibrates
Niacin
Management of Low HDL-C
Efficacy of Extended-Release Niacin
Change from Baseline
2500 mg
3000 mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
2000 mg
1500 mg
1000 mg
500mg
HDL-C
LDL-C
Lp(a)
TG
–9%
–14%
–22%
–21%
–17%
29.5%
30%
26%
22%
15%
10%
–28%
–35%
–44%
–39%
–11%
–5%
–26%
–3%
–12%
–30%
–24%
–17%
Lifestyle changes and secondary causes
Pharmacologic therapy
If LDL-C elevated: statin
If TG elevated: fibrate
If isolated low HDL-C: niacin
Combination therapy
Management of Low HDL-C
Change (%)
Wolfe ML et al. Am J Cardiol 2001;87:476-479.
Copyright ?2001, Excerpta Medica Inc. Reprinted with permission.
Addition of Extended-Release Niacin to a Statin because of Persistently Low HDL-C
TC
LDL-C
HDL-C
TG
CV Events
E