Transcript Statins

Prevention of CV Disease
with Statins
葉宏一
MD, PhD
馬偕醫學院 醫學系 教授兼主任
台北醫學大學 醫學科學研究所 兼任教授
馬偕紀念醫院 內科部 副主任
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Framingham: HDL-C vs LDL-C
as a predictor of CHD risk
Risk of CAD over 4
years of follow-up*
CHD RR
3
2.5
2
1.5
25 mg/dL
45 mg/dL
65 mg/dL
85 mg/dL
1
0.5
0
100 mg/dL160 mg/dL220 mg/dL
LDL-C
*Men aged 50–70
Gordon, Castelli et al. Am J Med 1977;62:707–714
Elevated Cholesterol Levels are Associated
with an Increased Risk of CHD Death
Death rate per 1000 men
18
16
n=12866, follow-up mean 7 years
14
12
10
8
6
4
2
0
3.62
(140)
4.14
(160)
4.65
(180)
Data from MRFIT study.
Martin MJ et al. Lancet 1986;ii:933–936.
5.17
(200)
5.69
(220)
6.21
(240)
6.72
(260)
Serum Total-C, mmol/L (mg/dL)
7.24
(280)
7.75
(300)
Correlation Between Total-C and CHD
Mortality in Men from Seven Countries
CHD mortality rates (%)
35
Northern Europe
30
Southern Europe,
Mediterranean
United States
25
20
15
Serbia
10
Southern Europe,
Inland
Japan
5
0
2.60
(100)
3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05
(125) (150) (175) (200) (225) (250) (275) (300) (325) (350)
Serum Total-C, mmol/L (mg/dL)
Data are from the Seven Countries Study of 12,467 men from Southern European Countries, the USA and Japan.
Verschuren WM et al. JAMA 1995;274:131–136.
INTERHEART
Population Attributable Risk for 1st MI by Region and Overall
NON-LIFESTYLE RISK FACTORS
Region
HTN %
Diab %
Abd Obes %
All PS%
Lipids %
All 9 RF
W. Europe
E/C Europe
Middle East
Africa
S. Asia
China
S.E. Asia
Australia/NZ
S. America
N. America
22.0
24.5
9.7
29.9
19.4
22.1
38.4
22.8
32.8
18.9
14.9
9.1
15.5
17.1
12.1
10.0
21.0
7.2
12.8
7.9
63.6
28.0
26.7
58.3
37.0
5.5
58.0
61.6
45.4
59.6
38.9
4.9
41.6
40.0
15.9
35.6
26.7
28.9
35.6
51.4
44.6
35.0
70.5
74.1
58.7
43.8
67.7
43.4
47.6
50.5
94.0
72.5
95.0
97.4
89.4
89.9
93.7
89.5
89.4
98.7
Overall 1
23.4
12.4
33.7
28.8
53.8
90.4
Overall 2
17.9
9.9
20.1
32.5
49.2
90.4
Yusuf et al. Lancet, 2004
高總膽固醇比例
Prevalence of Hypercholesterolemia
in Taiwan
Age
Data from Taiwan 3H survey
Definition: total cholesterol > 240 mg/dl or taking lipid-lpwering
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Atherosclerosis and Thrombosis
PHASE I: Initiation
PHASE II: Progression
PHASE III: Complication
Disease progression
Development of an Atheroma
Lumen
lipid + inflammation
LDL, β-VLDL, Lp(a)
Monocyte
Adhesion
VCAM-1
ICAM-1
P-selectin
E-selectin
Intima
Induction of adhesion
molecules and chemotaxis
oxidation
Differentiation
(GM-CSF)
CD36
SR-A
Migration
MCP-1
CCR-2
oxLDL
Endothelial
cells
Cytokines
MMPs
Endothelin-1
T lymphocyte
CD40
IFN-gamma
Foam cell
Macrophage
Adapted from Fan J, Watanabe T. J Atheroscler Thromb. 2003;10:63–71.
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Impact of Existing Drug Therapies on
Lipid Parameters
Drug class/agents
HDL-C
effect
LDL-C
effect
Triglyceride
effect
Bile acid sequestrants1
↑ 3–5%
↓ 15–30%
No change
or increase
Ezetimibe*2
↑ 1%
↓ 18%
↓ 8%
Fibric acids1
↑ 10–20%
↓ 5–20%
↓ 20–50%
Nicotinic acid1
↑ 15–35%
↓ 5–25%
↓ 20–50%
Probucol3
↓ up to 40%
↓ 10–17%
No change
Statins1
↑ 5–15%
↓ 18–55%
↓ 7–30%
*Selective inhibitor of intestinal cholesterol absorption
Adapted from 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA.
2001;285:2486–2497. 2. Ezetrol (ezetimibe) product information. WPC 072005. Merck Sharp and Dohme. NSW,
Australia. 2006. 3. Nippon Rinsho. 1994 Dec;52(12):3279-84.
Cholesterol Biosynthesis Pathway
Dolichol
HMG-CoA
reductase
Acetyl
CoA
HMGCoA
Mevalonate
Ras
protein
Farnesyl
Squalene
pyrophosphate
Farnesyltransferase
Cholesterol
E,E,E-Geranylgeranyl
pyrophosphate
Farnesylated GeranylgeranylatedUbiquinones
proteins
proteins
HMG-CoA Reductase inhibitirors
RhoA
TXA2
t-PA
PAI-1
Thrombotic
effect
Rac1
Macrophage growth
MMPs
TF
Platelet
activatin
ET-1
+
Plaque
stability
hs-CRP
Adhesion molecule
Vascular
inflammation
ROS
SMC
hypertrophy
Atherosclerosis
RhoA
AT1 receptor
N0
Endothelial
dysfunction
SMC
proliferation
Vasoconstriction
Hypertension
Cardiovascular
Diseases
Takemoto and Liao, 2001
Double dose of statins results in ~6%
reduction of LDL
The STELLAR Trial
Change in LDL-C From Baseline (%)
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
10
mg
*
20
mg
**
10
mg
20
mg
10
mg
10
mg
20
mg
20
mg
-50
40
mg
40
mg
-55
-60
40
mg
†
40 80
mg mg
80
mg
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
STELLAR = Statin Therapies for Elevated Lipid Levels
Compared Across Doses to Rosuvastatin.
*P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg.
**P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg.
†P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg.
Adapted from Jones et al. Am J Cardiol 2003;92:152–160.
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
ATP III: Lipid-Lowering Treatment Guidelines
Risk factors: FHx, HTN, smoking, male ≥45, female ≥55, HDL-C <40 mg/dL
Reimbursement guidelines from BNHI, Taiwan
血脂異常之
起步治療準則
有*
同
心 時
血或予
以
管糖非
疾尿藥
物
病病治
患 療
者
血脂濃度
≧2個危險因子 TC/HDL-C>5或
治療目標
(如附註二) HDL-C<40mg/dl
≧200mg/dl
×
×
<160mg/dl
(87/7/1)
LDL-C ≧130mg/dl
×
×
≦100mg/dl
(87/7/1)
TG ≧200mg/dl (需
同時合併有
TC/HDL-C>5或是
HDL-C <40mg/dl)
×
ˇ
< 150mg/dl
(87/7/1)
TC
* 冠狀動脈粥狀硬化, 腦血管病變, 周邊血管粥狀硬化
(ˇ)需符合此項條件
(×)不需符合此項條件
周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者
全民健保降血脂藥物給付規定（畫線部分為
91/9/1後適用）
血脂異常之
起步治療準則
有
下
心︵列
血如情
況
管附之
疾註一
時
病一
，
患︶應
無
者
給
予
血脂濃度
TC
三
至
六
個
月
非
藥
物
治
療
LDL-C
≧2個危險因子*
TC/HDL-C>5或
(如附註二)
HDL-C<40mg/dl
治療目標
≧200mg/dl
ˇ
×
<200mg/dl
≧240mg/dl
×
×
<240 mg/dl
≧130mg/dl
ˇ
×
<130mg/dl
≧160mg/dl
×
×
<160mg/dl
×
ˇ
<200mg/dl
(87/4/1)
TG ≧200mg/dl
(需同時合併有
TC/HDL-C>5或是
HDL-C<40mg/dl)
高血壓,
糖尿病, 男≧45歲, 有早發性冠心病家族史, 女≧55歲或停經沒有雌激素療法, 吸菸
*
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Statin Clinical Trials
Comparators
 Statin vs placebo
- statin alone
- combined with non-statin
 Statin vs statin
- different statins
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
Statin Clinical Trials
Comparators
 Statin vs placebo
- statin alone
- combined with non-statin
 Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
On-treatment LDL-C & CHD Events in Statin Trials
30
NCEP
2004
NCEP 2001
Eur Joint 2003
4S - PBO
Secondary Prevention
4S - Rx
20
LIPID - PBO
CARE - PBO
LIPID - Rx
HPS - PBO
CARE - Rx
10
TNT - ATV10
HPS - Rx
TNT - ATV80
PROVE-IT - PRA
PROVE-IT - ATV80
Primary Prevention
WOSCOPS - PBO
AFCAPS - PBO
WOSCOPS - Rx
ASCOT - PBO
AFCAPS - Rx
ASCOT - Rx AFCAPS - Rx
0
40
(1.0)
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
LDL-C achieved mg/dL (mmol/L)
Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269;
LaRosa J et al, N Engl J Med, 2005;352:1425
180
(4.7)
200
(5.2)
Cholesterol Treatment Trialists’ Collaboration
• randomised trials involving at least 1000 participants and
at least 2 years’ treatment duration
• more versus less intensive statin regimens (5 trials; 39612
individuals; median follow-up 5.1 years)
• statin versus control (21 trials; 129526 individuals;
median follow-up 4.8 years).
Lancet Vol 376 November 13, 2010
Cholesterol Treatment Trialists’ Collaboration
MVE per 1.0 mmol/L reduction in LDL-C, by
baseline prognostic factor
Cause-specific mortality per 1.0 mmol/L
reduction in LDL-C
Site-specific cancer incidence per 1.0 mmol/L
reduction in LDL-C
On-treatment LDL-C & CHD Events in Statin Trials
30
NCEP
2004
NCEP 2001
Eur Joint 2003
4S - PBO
Secondary Prevention
4S - Rx
20
LIPID - PBO
CARE - PBO
LIPID - Rx
HPS - PBO
CARE - Rx
10
TNT - ATV10
HPS - Rx
TNT - ATV80
PROVE-IT - PRA
PROVE-IT - ATV80
Primary Prevention
WOSCOPS - PBO
AFCAPS - PBO
WOSCOPS - Rx
ASCOT - PBO
AFCAPS - Rx
ASCOT - Rx AFCAPS - Rx
0
40
(1.0)
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
LDL-C achieved mg/dL (mmol/L)
Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269;
LaRosa J et al, N Engl J Med, 2005;352:1425
180
(4.7)
200
(5.2)
Tx based on hsCRP level
JUPITER
Comparators
Statin vs placebo
- statin alone
- combined with non-statin
Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
JUPITER
Justification for the Use of Statins in Primary Prevention:
an Intervention Trial Evaluating Rosuvastatin
• a randomized, double-blind, placebocontrolled primary prevention trial (26
countries)
• studied over 17,802 patients (men>= 50 yrs;
women>= 60 yrs; 6,801 women; 5,577 with
metabolic syndrome) without evidence of
cardiovascular disease and low to normal
LDL-C (<130 mg/dl, median 108 mg/dl), but
elevated C-reactive protein (hs-CRP ≧2 mg/L).
• rosuvastatin (20 mg) vs placebo
ACC 2008
JUPITER
Ridker et al NEJM 2008
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
0.08
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Placebo 251 / 8901
0.04
0.06
- 44 %
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
Number Needed to Treat (NNT5) = 25
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
0.06
Placebo
HR 1.0 (referent)
LDL > 70 mg/dL
and / or
0.04
hsCRP > 2 mg/L
HR 0.64 (0.49-0.84)
LDL < 70 mg/dL
0.02
Cumulative Incidence
0.08
JUPITER
Dual Target Analysis: LDLC<70 mg/dL, hsCRP<2 mg/L
and
0.00
hsCRP < 2 mg/L
HR 0.35 (0.23-0.54)
0
Number at Risk
Rosuvastatin 7,716
Placebo
7,832
1
2
3
4
Follow-up (years)
7,699
7,806
7,678
7,777
6,040
6,114
3,608
3,656
1,812
1,863
1,254
1,263
913
905
508
507
145
168
P < 0.0001
Anti-inflammatory effects of LDL-C
reducion on hsCRP
• >90% of the reduction in CRP was directly associated with the
magnitude of LDL cholesterol reduction, with no difference
between high-dose statins or statin-ezetimibe combinations
Kinlay S. JACC 2007
ANDROMEDA – reduction in hsCRP in patients with
baseline CRP ≥2 mg/L
8 weeks
0
RSV 10 mg
n=120
Median
16 weeks
ATV 10 mg
n=121
RSV 20 mg
ATV 20 mg
n=115
n=112
–20
change
from
baseline
(%)
–32
–40
‡
–43
–44
–60
*
‡
–52
‡
‡
ANDROMEDA=A raNdomised, Double-blind, double-dummy, multicentre, phase IIIb, parallel-group study to compare the
efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in patiEnts with type II DiAbetes
mellitus; hsCRP=high-sensitivity C-reactive protein; RSV=rosuvastatin; ATV=atorvastatin
*p<0.05 vs ATV at same time point; ‡p<0.001 vs baseline
Betteridge DJ et al. Am J Cardiol 2007 in press ;Betteridge DJ et al. Atheroscler Suppl 2005; 6: 102 Abs W16-P-007
Betteridge DJ et al. EAS April 2005. Poster presentation
The history of JUPITER
•
•
•
•
•
•
2008 Nov, AHA:
JUPITER (paper in NEJM)
2009 Feb, ISC :
Stroke (09 Dec. paper in circulation)
2009 Mar, ACC:
VTE / Dual treatment target
•
2009 Dec, news: FDA voted
2009 Sep, ESC: Elderly
2009 Sep: NNT (Circulation Cardiovascular Quality and Outcomes. 2009)
2009 Nov, AHA:
Women / IFG /
Very low LDL-C
Venous thromboembolism
JUPITER
Total Venous Thromboembolism
Glynn et al NEJM 2009
0.015
Placebo 60 / 8901
0.005
0.010
- 43 %
Rosuvastatin 34 / 8901
0.000
Cumulative Incidence
0.020
0.025
HR 0.57, 95%CI 0.37-0.86
P= 0.007
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,648
8,652
8,447
8,417
6,575
6,574
3,927
3,943
1,986
2,012
1,376
1,381
Ridker PM et al on behalf of the JUPITER Trial Study Group N Engl J Med 2009;360
1,003
993
548
556
161
182
Systolic Heart Failure
CORONA and GISSI-HF
Comparators
 Statin vs placebo
- statin alone
- combined with non-statin
 Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
CORONA
Rosuvastatin in older patients with systolic heart failure
• Patients (≥ 60 yr; n=5011)
with systolic heart failure
of ischemic cause (EF <
0.4, NYHA II-IV)
• 10 mg rosuvastatin daily
• LDL-C  45%; hsCRP 
37%
• Median follow-up of 32.8
months
• Primary outcome: death
from CV causes, non-fatal
MI, and nonfatal stroke
NEJM 2007
GISSI-HF / Statin
Rosuvastatin in patients with chronic heart failure
• Patients (68±11 yr;
n=4631) with heart
failure (NYHA II-IV)
• 10 mg rosuvastatin daily
• LDL-C  32% (1st yr),
27% (2nd yr); hsCRP 
16%
• Median follow-up of 3.9
yrs, average EF < 0.4,
• Primary outcome: death
• Secondary outcome:
death + CV
hospitalization
LANCET 2008
Death
Death + CV
Hospitalization
Stroke / TIA
SPARCL
Comparators
Statin vs placebo
- statin alone
- combined with non-statin
Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
SPARCL
The Stroke Prevention by
Aggressive Reduction in
Cholesterol Levels

4731 patients who with a
stroke or TIA within 1-6
months before study entry

LDL-C 100 to 190 mg/dl

No known coronary heart
disease

80 mg of atorvastatin per
day or placebo
NEJM. 2006
High-Dose Atorvastatin after Stroke
or Transient Ischemic Attack (SPARCL)
129 mg/dl
73 mg/dl
NJEM. 2006
Chronic Kidney Disease
4D, AURORA, SHARP
Comparators
 Statin vs placebo
- statin alone
- combined with non-statin
 Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
4D: primary endpoint
(cardiac death, nonfatal MI, and stroke)
20 mg
RR = 0.92 (95% CI 0.77-1.10)
P=0.37
NEJM 2005
AURORA: primary endpoint
Time to first major CV event
(cardiac death, nonfatal MI, stroke)
40
Placebo
35
30
Cumulative
incidence of
primary
endpoint
(%)
Rosuvastatin
10 mg
25
20
15
10
HR=0.96 (95% CI 0.84–1.11)
P=0.59
5
0
0
No. at risk:
Rosuvastatin
Placebo
1390
1384
1
3
4
2
Years from randomization
1152
1163
962
952
826
809
551
534
5
148
153
NEJM 2009
Statin in Diabetic Hemodialysis
Patients- post hoc analysis of the AURORA
32%
P=0.008
J Am Soc Nephrol. 2011 May 12. [Epub ahead of print]
SHARP: major atherosclerotic events
CKD grade 3-5
Proportion suffering event (%)
25
Risk ratio 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
20
Placebo
15
Eze/simv
10
5
0
0
1
2
3
Years of follow-up
4
5
CKD in TNT
CKD grade 2-4
CKD vs. non-CKD
HR=1.35 (95% CI 1.18 –1.54)
P<0.0001
Hypolipidemic therapy in prevention of non-fatal MI
and coronary revascularization in CKD patients
Lancet 2011
Non-fatal non-hemorragic and non-fatal
hemorrhagic stroke
Lancet 2011
Cumulative Incidence of CV End Points in CKD patients
from JUPITER Study
Primary End Point*
Cumulative Incidence
0.15
CKD, placebo
0.10
No CKD, placebo
CKD, rosuvastatin
0.05
No CKD, rosuvastatin
0.00
0
No. at Risk
CKD
No CKD
Rosuvastatin
Placebo
Rosuvastatin
Placebo
1638
1629
7259
7269
1
2
3
Follow-up (years)
1574 1538
1281
871
550
1557 1510
1234
838
516
7054 6871
5256
3020 1407
7061
6840
5272
3033 1447
4
352
345
1000
988
247
243
736
712
129
131
409
400
39
40
118
134
*Primary end point: non-fatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or CV death
Ridker PM et al. J Am Coll Cardiol. 2010;55(12):1266-1273.
Studies using surrogate marker
Comparators
 Statin vs placebo
- statin alone
- combined with non-statin
 Statin vs statin
- different statin
- same statin, different dose
- combined with non-statin
End points
 Disease outcome
 Surrogate marker
REVERSAL: Primary end point: %
change in total atheroma volume
P=0.02
Change in TAV (%)
3
2.7*
2
1
0
-0.4†
-1
Pravastatin
Atorvastatin
Significant atherosclerotic
progression from baseline
No significant change from
baseline; atherosclerotic
progression was stopped
*Progression vs baseline (P=0.001); †No change vs baseline (P=0.98)
JAMA. 2004
Example of regression of atherosclerosis with
rosuvastatin in ASTEROID, measured by IVUS
Baseline
IVUS
Atheroma Area
10.16 mm2
Lumen Area
6.19 mm2
Follow-up
IVUS
24 months
rosuvastatin
Atheroma Area
5.81 mm2
Lumen Area
5.96 mm2
Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print
METEOR primary endpoint:
Placebo
+0.0131 mm/yr
(n=252)
+0.02
P<0.0001
(CRESTOR vs. placebo)
+0.01
1
0.00
-0.01
Rosuvastatin 40 mg
-0.0014 mm/yr
(n=624)
2
Time
(years)
P=NS
(CRESTOR vs. zero slope)
Regression
+0.03
Progression
Change in IMT of 12 carotid sites (mm)
Rate of change of maximum IMT at 12 carotid sites
Rosuvastatin vs placebo
Placebo; Change in CIMT (95% CI)
Rosuvastatin 40 mg; Change in CIMT (95% CI)
Crouse JR, et al. JAMA 2007;297:(doi:10.1001/jama.297.12.joc70024)
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
Statins – Therapeutic Ratio
Adverse Effects
Therapeutic
Effects
Cardiovascular
protection
Muscle
Liver
Drug interactions
Rhabdomyolysis and % LDL-C Reduction
JACC 2007
Muscle effects - Benefit:Risk
Occurrence of CK >10 × ULN (%)
CK >10 x ULN: Frequency by LDL-C Reduction
3.0
Rosuvastatin (10, 20, 40 mg)
Atorvastatin (10, 20, 40, 80 mg)
2.5
Simvastatin (40, 80 mg)
2.0
Pravastatin (20, 40 mg)
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
1.5
1.0
0.5
0.0
20
30
40
50
LDL-C reduction (%)
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
60
70
↑Liver Enzymes and % LDL-C Reduction
JACC 2007
Rate of Elevated Liver Enzymes by Statin
Dose Category
JACC 2007
CYP450
Relative Importance of P450s in Drug Metabolism
CYP2E1
CYP1A2
CYP2C
CYP3A4
CYP2D6
Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.
Potential Drug Interactions
3A4
•
•
•
•
•
•
•
•
•
•
•
•
2C9
Simvastatin
• Fluvastatin
Atorvastatin
• Phenytoin
Lovastatin
• Fluconazole
Diltiazem
Clopidogrel
Amiodarone
Cimetidine
Ery/clarithromycin
Ketoconazole
Carbamazepine
St John’s wort
Grapefruit juice
• Warfarin
• Rosuvastatin
No clear difference between statins in terms
of diabetes risk
Lancet, Published Online February 17, 2010
Statins and risk of incident diabetes:
a collaborative meta-analysis
•
one additional case of
diabetes per 255
patients taking statin
therapy for 4 years
(12·23 cases per1000 patientyears with statin treatment and
11·25 cases per 1000 patientyears with control therapy).
•
Re reduction in major
coronary events
(coronary heart disease death and
non-fatal myocardial infarction) of
5·4 events per 255
patients treated for 4
years compared with control
therapy for a 1 mmol/L reduction
in LDLcholesterol concentration.
Lancet 2010; 375: 735–42
Content
• Epidemiology
• Pathophysiology
• Pharmacological Treatment
• Guidelines
• Statin clinical trials
• Adverse effects
• Real world practice
REALITY Asia Study: Objectives
•
To evaluate lipid-lowering
therapy prescribing patterns
and cholesterol goal
achievement in patients
with and without CHD and
other risk factors in the “real
world” setting in 6 major
Asian countries
Adapted from REALITY Study Protocol.
Cholesterol Goal Attainment in the Real World:
Results: Comparison of Overall Goal Attainment in Europe and Asia
Finland
Hungary
Spain
Germany
Italy
Norway
Switzerland
Netherlands
UK
France
Sweden
Overall EU
Korea
Thailand
Malaysia
Taiwan
Singapore
Overall Asia
54%
27%
27%
24%
14%
33%
29%
32%
55%
26%
30%
41%
42%
51%
54%
24%
58%
45%
0%
10%
20%
30%
40%
50%
60%
70%
Cholesterol Goal Attainment in the Real World: The REALITY ASIA Study
Results: Cholesterol Goal Attainment by Risk and Country
All Patients
100.0%
87.5%
83.2%
80.0%
80.9%
74.1%
66.7%
63.3%
64.2%
61.7%
60.0%
52.9%
42.5%
40.0%
84.4%
80.8%
42.4%
36.5%
32.4%
34.9%
31.5%
15.9%
20.0%
0.0%
Singapore
Taiwan
CHD/diabetic Patients
Thailand
Malaysia
nonCHD with 2 or more risk factors
Korea
Overall
nonCHD with less than 2 risk factors
Approximately 84% of CHD/diabetic patients
and 76% of patients overall failed to attain goal.
Curr Med Res Opin. 2008
Pan-Asian CEPHEUS (Pan Asian survey on
undertreatment of hypercholesterolemia)
Eur J Cardiovasc Prev Rehabil. 2011
LDL goals of patients
LDL Goals of Patients
60%
% of Patients
50%
49.1%
40%
32.1%
30%
18.5%
20%
10%
0.3%
0%
<70 mg/dl (n=3,557)
<100 mg/dl (n=2,325)
<130mg/dl (n=1,343)
<160 mg/dl (n=25)
• Half the patients (49.1%) in the study fulfilled the criteria for the very high risk category (< 70 mg/dl) when
stratified as per the 2004 updated NCEP ATP III guidelines.
79
Proportion of patients attaining their 2004 updated
NCEP ATP III-recommended LDL-C goals
% of Patients attaining their 2004 updated NCEP ATP III* guidelines recommended LDL-C goals
• Overall 49.1% LDL-C goal attainment rate among all patients surveyed across Asia.
• Proportion of patients attaining their respective LDL-C goal decreased with increasing cardiovascular risk.
Percentage of Patients at LDL-C goals
recommended by the 2004 updated NCEP ATP
% of Patients at LDL-C goalsIII*
recommended
by 2004 updated NCEP ATP III* guidelines
guidelines
• For patients in Hong Kong the treatment goal attainment rate was 82.9% while patients in other countries
had very low LDL-C attainment rate (31.3 – 52.7%).
81
Changes in the lipid-lowering drug since first
prescribed a drug
Changes in the lipid-lowering drug since first prescribed a drug
23.9
8.5
3.5
Same drug (n=4562)
64.1
same drug but dose
increased (n=607)
Changed drug once or
twice (n=1702)
Changed drug several
times (n=246)
• For 64.1% of patients, initial treatment remained the same.
82
Achievement of LDL-C goals among patients
Achievement of LDL-C goals among patients
Prevention
Metabolic Syndrome
• Rate of LDL-C goal attainment was similar in primary and secondary prevention patients.
83
Comparison of Pan-Asian CEPHEUS
with Pan-European CEPHEUS
Point of Comparison
Proportion of patients
achieving NCEP ATP III
targets for LDL-C
Mean baseline LDL-C
concentrations
Proportion of patients on
statins
84
Pan-European
CEPHEUS
Pan-Asian CEPHEUS
57.4%
49.1%
105±36 mg/dl
144.5 ±45.6 mg/dl
90.3%
85.1%
Why Only about 50% of patients with high
LDL-C achieve goal ?
• Only about 50% of patients with high
LDL-C achieve goal on current lipid lowering
therapies
– Non-compliance
– Lack of effective treatment
– Fear of high dose titration
• More effective cholesterol-lowering
agents are needed to attain LDL-C goals1,2
1
Kotseva, K, Wood D, de Backer, G et al. 2001
Pearson T et al. 2000
2
Unmet Need
• Even with current therapies, many patients,
especially those considered at high and very
high risk, are not achieving the goals
• Special populations, such as those FH and other
forms of severe hypercholesterolemia, do not
achieve even old goals
• Perhaps the largest need, however, is for the
growing number of patients who are statin
adverse
Statin Adverse
Primo study (7924 hyperlipidemic patients)
a
Percentage values relative to the total number of patients who had or
did not have muscular symptoms.
b Odds ratios were calculated using pravastatin as the reference.
c P values were determined by Pearson’s Chi-square test.
Cardiovasc Drugs Ther 2005
Conclusion
• The beneficial effect of statin is mainly in
prevention of CHD caused by atherosclerosis
• Statin is not effective in reducing CV events in
patients with systolic HF
• Statin is effective in reducing atherosclerotic
CV events in patients with CKD
• Hypercholesterolemia is prevalent in Taiwan;
however, cholesterol goal attainment is not
satisfactory
• A substantial number of patients with
hypercholesterolemia can not tolerate statins
Mackay Medical College
馬偕醫學院
Thanks for your attention