HDL的药物治疗
NCEP ATP-II Cutpoints for TG and HDL-C
Parameter mg/dL
Normal TG < 200
Borderline-high TG 200–400
High TG 400–1,000
Very high TG > 1,000
Low HDL-C < 35
High (protective) HDL-C ? 60
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:3015–3023
Effects of Lipid-Modifying Drugs on HDL-C Levels
Niacin ? 15–35%
Fibrates ? 10–15%
Estrogens ? 10–15%
Statins ? 5–10%
Belalcazar LM et al. Progr Cardiovasc Dis 1998;41:151–174
Drug Effects on HDL: Niacin
Liver
B
B
TG
CMR/IDL
C-II
CM/VLDL
LPL
A-I
CE
CE
FC
FC
LCAT
A-I
ABC1
Macrophage
Mature HDL
Nascent HDL
LDLR
HL
Intestine
NIACIN
NIACIN
*
*Inhibits uptake of apoA-I but not CE
Extended-Release Niacin for Treatment of Dyslipidemia
*Significant difference (P < 0.001) between dosage groups.
1. Morgan JM et al. Am J Cardiol 1998;82(12A):29U–34U
2. Capuzzi DM et al. Am J Cardiol 1998;82(12A):74U–81U
? Copyright 1998, with permission from Excerpta Medica Inc.
% change from baseline
Baseline (mg/dL):
-6
17
-15
23
-28
-20
28
-40
-30
-20
-10
0
10
20
30
40
TG
(156)
LDL-C
(197)
HDL-C
(44)
TG
(137)
LDL-C
(206)
HDL-C
(42)
TG
(174)
LDL-C
(195)
HDL-C
(45)
1,000 mg/d* (1)
(12 wk; n = 35)
2,000 mg/d* (1)
(12 wk; n = 31)
? 3,000 mg/d (2)
(96 wk; n = 225)
-21
-28
Fibrate Chemical Structures
Cl
C
O
O
CH3
CH3
C
COO
CH
CH3
CH3
Cl
Fenofibrate
Clofibrate
O
C
COOC2H5
CH3
CH3
C
COOH
CH3
CH3
CH2
O
CH2
CH2
CH2
CH3
CH3
Gemfibrozil
Drug Effects on HDL: Fibrates
Liver
B
B
TG
CMR/IDL
C-II
CM/VLDL
LPL
A-I
CE
CE
FC
FC
LCAT
A-I
ABC1
Macrophage
Mature HDL
Nascent HDL
LDLR
HL
FIBRATES
FIBRATES
Intestine
Fenofibrate for Treatment of Types IV and V Hyperlipoproteinemia
*Mean percentage changes, not percentage changes in means.
Goldberg AC et al. Clin Ther 1989;11:69–83.
14.5
19.6
-46.2
45.0
22.9
-54.5
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
Group A
(TG = 350–499 mg/dL)
Group B
(TG = 500–1,500 mg/dL)
% change from baseline*
LDL-C
(128.4)
HDL-C
(33.7)
LDL-C
(103.1)
HDL-C
(29.6)
Mean baseline
(mg/dL):
Total-TG
(432.0)
Total-TG
(725.6)
Trials of Agents That Increase HDL-C in Patients With Isolated Low HDL-C Randomized, Placebo-Controlled Studies
1. Vega GL, Grundy SM. JAMA 1989;262:3148–3153
2. Miller M et al. Am J Med 1993;94:7–12
3. Lavie CJ et al. Am J Cardiol 1992;69:1083–1085
4. King JM et al. Am J Med 1994;97:323–331
5. Miller M et al. Arterioscler Thromb Vasc Biol 1995;15:2151–2156
9
9
27
31
12
0
5
10
15
20
25
30
35
Vega (1)
(n = 22)
Miller (2)
(n = 14)
Lavie (3)
(n = 19)
King (4)
(n = 15)
Miller (5)
(n = 39)
Gemfibrozil
Niacin
Phenytoin
% increase in HDL-C
Trial:
Drug Effects on HDL: Estrogens
Liver
B
B
TG
CMR/IDL
C-II
CM/VLDL
LPL
A-I
CE
CE
FC
FC
LCAT
A-I
ABC1
Macrophage
Mature HDL
Nascent HDL
LDLR
HL
ESTROGENS
ESTROGENS
Intestine
Estrogen Versus Estrogen/Progestin in Postmenopausal Women Effect on Lipids
CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; cyc = cyclic administration (days 1 through 12 of each month);
con = administered daily for 1 month; MP = micronized progesterone
Writing Group for PEPI Trial. JAMA 1995;273:199–208
-2.9
-2.0
-3.2
-10.3
9.0
13.9
-12.9
2.4
13.5
-11.6
1.9
11.1
-10.9
6.5
13.7
-20
-15
-10
-5
0
5
10
15
20
LDL-C
HDL-C
TG
Placebo
CEE
CEE + MPA (cyc)
CEE + MPA (con)
CEE + MP (cyc)
(143.3) (140.6) (137.0) (141.7) (135.7)
% change from baseline
(61.4) (61.9) (64.8) (62.7) (62.6)
(99.0) (98.7) (94.3) (102.7) (97.5)
Baseline (mg/dL):
Statin Chemical Structures*
O
H
CH3
CH3
H3C
H3C
O
HO
Simvastatin
H3C
H
O
O
O
H
CH3
H
H3C
HO
OH
HO
Pravastatin
COONa
H
H
H3C
O
O
H
CH3
H
H3C
H3C
HO
Lovastatin
H
H3C
H
N
O*Na+
CH3
CH3
Fluvastatin
Cerivastatin
NHC
N
NHC
CH3OCH2
CH3
Naphthalene sub-class (hydronaphthalene ring in common)
Fluorophenyl sub-class (fluorophenyl ring in common)
*The clinical impact of these differences is not known.
Lennernas H et al. Clin Pharmacokinet 1997;32:403–423.
Atorvastatin
O
O*Na++
N
O* Ca++
O*
N
Drug Effects on HDL: Statins
Liver
B
B
TG
CMR/IDL
C-II
CM/VLDL
LPL
A-I
CE
CE
FC
FC
LCAT
A-I
ABC1
Macrophage
Mature HDL
Nascent HDL
LDLR
HL
STATINS
Intestine
STATINS
STATINS
?
Simvastatin in Mixed Hyperlipidemia Baseline Characteristics
Mean age (range): 53 y (21–70 y)
Sex (M/F): 68/62 (N = 130)
Baseline lipids:
LDL-C (mean) 156 mg/dL
HDL-C (mean) 39 mg/dL
TG (median) 389 mg/dL
Type-2 diabetes mellitus: n = 21 (16%)
Stein E et al. Am J Cardiol 2000;86:406-411
Simvastatin in Mixed Hyperlipidemia Changes in Lipids
Placebo
Simvastatin 40 mg
Simvastatin 80 mg
*Mean; ?median
n = 119–121 per treatment group
P ? 0.05 for between-treatment comparisons
Stein E et al. Am J Cardiol 2000;86:406-411
2
3
-4
-29
13
-28
-36
16
-33
-50
-40
-30
-20
-10
0
10
20
LDL-C*
HDL-C*
TG?
% change
Simvastatin in Mixed Hyperlipidemia Changes in Apolipoproteins
Placebo
Simvastatin 40 mg
Simvastatin 80 mg
n = 120–123 per treatment group
aS40 vs placebo: P < 0.001; bS80 vs placebo: P < 0.001; cS40 vs S80: P < 0.05; dS40 vs placebo: P < 0.005
Stein E et al. Am J Cardiol 2000;86:406-411
Simvastatin Versus Atorvastatin in Primary Hypercholesterolemia Study Design
Open-label, randomized, parallel, 12-week study
842 patients (42% female)
Treatments:
Simvastatin 40 mg and 80 mg
Atorvastatin 20 mg and 40 mg
LDL-C inclusion criteria:
CHD: ? 130 mg/dL
No CHD plus ? 2 risk factors: ? 160 mg/dL
No CHD plus < 2 risk factors: ? 190 mg/dL
TG ? 350 mg/dL
Crouse JR III et al. Am J Cardiol 1999;83:1476–1477
Simvastatin Versus Atorvastatin in Primary Hypercholesterolemia Changes in Lipids
Simvastatin 40 mg (n = 202)
Atorvastatin 20 mg (n = 210)
Simvastatin 80 mg (n = 215)
Atorvastatin 40 mg (n = 215)
*Mean; ?median
Crouse JR III et al. Am J Cardiol 1999;83:1476–1477
-60
-50
-40
-30
-20
-10
0
P = 0.04
P = 0.10
NS
P < 0.01
LDL-C*
TG?
% change
-42.7
-45.0
-49.2
-51.1
-23.0
-23.3
-25.2
-29.6
Simvastatin Versus Atorvastatin in Primary Hypercholesterolemia
Mean % change
P < 0.01
P < 0.001
NS
*N = 842; ?N = 113
Crouse JR III et al. Am J Cardiol 1999;83:1476–1477
0
2
4
6
8
10
12
14
16
18
HDL-C
ApoA-I
HDL-C
? 35 mg/dL
P < 0.001
NS
P = 0.002
All patients*
Subgroup analysis?
6.7
4.0
6.6
3.0
6.3
5.0
5.9
0
Simvastatin Atorvastatin HDL Study
Kastelein JJP et al. Am J Cardiol 2000;86:221-223.
? Copyright 2000, with permission from Excerpta Medica Inc.
% Change from Baseline
Weeks
6
12<