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GiI THIU
CC TI BO CO TI HI NGH TIM MCH MIN TRUNG- TY NGUYN M RNG LN TH VI TI BUN MA THUT THNG 8 NM 2011
IEU TR TOAN DIEN ROI LOAN LIPID MAU PGS TS Trng Quang Bnh
PGS TS Trng Quang Bnh HYD TP HCM
Hypercoagulable states Life-style (e.g., Homocysteinaemia smoking, diet, Dyslipidaemia lack of exercise) Insulin resistance Diabetes Obesity Hypertension Genetics Infection?
Atherosclerosis
Age Gender
American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl 2):II 4II-6; Laurila et al. Arterioscler Thromb Vasc Biol 1997;17:2910-2913; Grau et al. Stroke 1997;28:1724-1729; Graham et al. JAMA 1997;277:1775-1781; Brigden. Postgrad Med 1997;101(5):249-262.
Dyslipidemia LDL-C
TG
HDL-C
Keech AC et al, Lancet 371:117-25, 2008
Secondary Prevention
20
15
10
LIPID - Rx CARE - Rx HPS - Rx TNT Atv10 PROVE-IT - Pra TNT Atv80 PROVE-IT Atv
tter e be r, th we e lo Th
LIPID - Pl CARE - Pl HPS - Pl 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2)
4S - Rx
0 40 (1.0) 60 (1.6)
Trial
% Risk Reduction
26 27 19 9 36 25
74 74 82 91 64 75
*Nonfatal MI/CHD death; AFCAPS also included unstable angina; weighted average
1. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383; 2. Sacks FM et al. N Engl J Med. 1996;335:1001; 3. Shepherd J et al. N Engl J Med. 1995;333:1301; 4. Downs JR et al. JAMA. 1998;279:1615; 5. The LIPID Study Group. N Engl J Med. 1998;339:1349; 6. HPS Collaborative Group. Lancet. 2002;360:7; 7. Shepherd J et al. Lancet. 2002;360:1623; 8. The ALLHAT Officers and Coordinators. JAMA. 2002;288:2998; 9. Sever P et al. Lancet. 2003;361:1149
LDL-C
% CV EVENTS
- Low HDL-C - High TG (Metabolic Syndrome, DM) + other risk factors
0
35%
65%
* bat ky mc
LDL-C, nong o HDL-C lien quan nghch vi nguy c CHD
3.0
Risk of CHD
2.0
* Qui luat
25 45 C 65 L- L) 85 D d
1.0
0.0
100
160
220
LDL-C (mg/dL)
Gordon T et al. Am J Med 1977;62:707-714.
H g/ (m
10
TNT
8 6 4 2 0
+64%
p=0.03
<37
57 473
55
35 544
from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest or fatal or nonfatal stroke Calculated from adjusted hazard ratio for Q5 (95% CI) = 0.61 (0.380.97)
Tin trin
1
Tin trin
-1
Thai trin
-2 0
People should think of both LDL and HDL as yin and yang, cant consider one without the other
-Dr. Peter Wilson Director of Laboratoires for the Framingham Study
PROCAM Study:
CHD Cases
5902 4256 7728 1994 7484 2674 4469 5689
N = 262,525
1.72 (1.56-1.90)
*Individuals in top vs bottom third of usual log-TG values; adjusted for at least age, sex, smoking status, and lipid concentrations; also adjusted for BP (in most studies). Sarwar N, et al. Circulation. 2007;115:450-458. 16
Elevated TG levels also increase the risk of a coronary event, despite LDL-C at goal
Despite achieving LDL-C <70 mg/dL with a high-dose statin, patients with TG 200 mg/dL have a 67% higher risk of coronary events*
PROVE IT-TIMI 22
25
30-day risk of death, MI or recurrent ACS (%)
20 15 10
+67%
20.3% 13.2%
p=0.001
5 0
(n=603)
200
(n=2,796)
<200
On-treatment TG (mg/dL)
*Death, myocardial infarction or recurrent acute coronary syndrome Calculated from adjusted hazard ratio of TG <200 mg/dL (95% CI) = 0.60 (0.45 0.81) Miller M et al. J Am Coll Cardiol. 2008;51:724-30.
Elevated TG and low HDL-C represent an even greater risk for patients with T2D
In patients with T2D, elevated TG and low HDL-C is associated with a 70% higher residual CV risk* despite achievement of LDL-C goal with a statin
ACCORD Lipid
18
16 14 12 10 8 6 4 2 0
17.3%
+70%
Mean LDL-C: 80 mg/dL
10.1%
*Major CV events defined as CV death, nonfatal MI and nonfatal stroke (primary endpoint) ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.
HDL
LDL
IDL
VLDL
Anti Atherogenic
lipoprotein gay x va
While LDL-C levels are improving, the problem of elevated TG and low HDL-C may be worsening
In the past 3 decades in the US, while the prevalence of normal LDL-C levels has increased, the prevalence of combined abnormal TG and HDL-C has more than doubled1,2
NHANES
80%
6% 5% 4% 3% 2%
HDL-C
24%
64%
4.8%
2.3-fold
40%
1% 0%
2.1%
1976-1980
1999-2006
Even with treatment, only 30% of patients currently achieve all lipid goals
61%
72%
69%
50%
30%
40%
19%
17%
15%
LDL-C goals: <100 mg/dL if 2 risk factors and Framingham risk >20% or prior CVD, T2D or chronic kidney disease (CKD), <130 mg/dL if 2 risk factors and Framingham risk 20%, <160 mg/dL if combined with 0 to 1 risk factors. NonHDL-C goals: <130 mg/dL if 2 risk factors and Framingham risk >20% or prior CVD, T2D or CKD, <160 mg/dL if 2 risk factors and Framingham risk 20%, <190 mg/dL if 0 to 1 risk factors. HDL-C normal levels: 40 mg/dL if male and 50 mg/dL if female. TG normal levels: <150 mg/dL Ghandehari H et al. Am Heart J. 2008;156:112-9.
xet phoi hp them fibrate vao ieu tr ha LDL cho BN nguy c cao co tang TG va giam HDL.1
++
Combining Fenofibrate with rosuvastatin further improved TG and HDL-C in patients with T2D
Lipanthyl-rosuvastatin combination therapy substantially improved TG and HDL-C levels over and above the effect of rosuvastatin alone
+6.4%
+11.7%
-31.3%
-47.1%
SAFARI: Combining fenofibrate with simvastatin improved all lipids vs. simvastatin alone
In patients with mixed dyslipidaemia, Fenofibrate improved the entire lipid profile over and above the effects of simvastatin
30 20
TG
VLDL-C
Non-HDL-C
LDL-C
HDL-C
18.6
9.7 %
-20.1%
-24.1%
26.1% -35.3%
-25.8% -31.2%
p<0.001 for all between-group comparisons
ACCORD Lipid evaluated adding Lipanthyl to a statin in patients with T2D at goal for LDL-C
The first trial to assess fibrate-statin combination therapy on macro and microvascular outcomes
Simvastatin 20-40 mg + Lipanthyl 160 mg** (n=2,765)
*According to patients LDL-C levels and CVD history **Bioequivalent to 200 mg micronised and 145 mg nanocrystal. Patients whose eGFR was 30-50 mL/min/1.73 m2 received a lower dose of Lipanthyl, corresponding to 1/3 of the normal daily dose ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.
Fenofibrate significantly reduced CV events in the elevated TG + low HDL-C subgroup by 31%
In patients with TG 204 mg/dL and HDL-C 34 mg/dL
18 16 14 12 10 8 6 4 2 0
17.3%
-31%
p=0.03
12.4% Number needed to treat (NNT) for 5 years to prevent one CV event
20
Simvastatin
Fenofibrate + Simvastatin
The primary endpoint of major CV events (CV death, nonfatal MI and nonfatal stroke) was not significantly reduced in the overall population (HR=0.92, 95% CI 0.79-1.08, p=0.32) There was a nonsignificant suggestion of heterogeneity when the subgroup of patients with elevated TGs and low HDL-C were compared with all the other patients (p=0.06 for interaction) ACCORD Study Group. N Engl J Med. 2010;362(17):1563-74. Elam MB et al. AHA 2010. Presentation 19724.
The ACCORD Lipid results are consistent with FIELD and other fibrate trials
Study (Treatment) HHS1,2 (Gemfibrozil) BIP3 (Bezafibrate) FIELD4,5 (Fenofibrate) HDL-C (mg/dL) Baseline Mean 47.1 Primary analysis: RRR (p value) -34% (0.02) Lipid subgroup criteria TG/HDL-C subgroup: RRR (p value) -71% (0.005)
34.6
-7.3% (0.24)
-39.5% (0.02)
42.5
-11% (0.16)
TG 204 mg/dL HDL-C <40 mg/dL for men, HDL-C<50 mg/dL for women TG 204 mg/dL HDL-C 34 mg/dL
-27% (0.005)
38.1
-8% (0.32)
-31% (0.03)
1. Frick MH et al. N Engl J Med. 1987;317:1237-45. 2. Manninen V et al. Circulation. 1992;85:37-45. 3. The BIP study group. Circulation. 2000;102:21-7. 4. FIELD Study Investigators. Lancet. 2005;366:1849-61. 5. Scott R et al. Diabetes Care. 2009;32:493-8. 6. ACCORD Study Group. N Engl J Med. 2010;362(17):1563-74. 7. Elam MB et al. AHA 2010. Presentation 19724.
Cons
Potential for increased adverse
effects
Increased costs
Number of reports of rhabdomyolysis per million prescriptions in combination with statin (excluding cerivastatin)
10
9 8 7 6 5 4 3 2 1 0
8.6
15-fold increase
6,641,000
prescriptions dispensed
3,419,000
prescriptions dispensed
Gemfibrozil
UGT1A1 & 1A3
Statins
Most statins use UGT1A1 & 1A3
fluvastatin & rosuvastatin metabolised by CYP2C9 Cerivastatin metabolised by CYP2C8 simvastatin & atorvastatin metabolised by CYP3A4
Gemfibrozil
UGT1A1 & 1A3
Statins
Most statins use UGT1A1 & 1A3
fluvastatin & rosuvastatin metabolised by CYP2C9 Cerivastatin metabolised by CYP2C8 simvastatin & atorvastatin metabolised by CYP3A4
The ACCORD Lipid results support guidelines that recommend adding a fibrate to statin therapy for elevated TG and/or low HDL-C
NCEP ATP III 20041 Fibrates may have an adjunctive role in the treatment of patients with high triglycerides/low HDL, especially in combination with statins. IDF 20052 Provide active management of the blood lipid profile () in addition to statin, fenofibrate where serum triglycerides are >2.3 mmol/L (>200 mg/dL), once LDL-C is as optimally controlled as possible. ESC/EASD 20073 In diabetic patients with hypertriglyceridemia >2 mmol/L (177 mg/dL) remaining after having reached the LDL-C target with statins, () combination therapy with fibrates, ezetimibe or nicotinic acid may be considered. ADA 20084 Combination therapy with a statin and a fibrate or statin and niacin, may be efficacious for treatment for all three lipid fractions. NICE 20095 If cardiovascular risk is high (as is usual in people with type 2 diabetes) consider adding a fibrate to statin therapy if TG levels remain in the range 2.3-4.5 mmol/L (200-400 mg/dL) despite statin therapy. Fenofibrate is recommended as the first-line fibrate.
1. 2. 3. 4. 5. Grundy SM et al. Circulation. 2004;110:227-39. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. 2005. ESC/EASD Guidelines. Eur Heart J. 2007;28:88-136. ADA. Diabetes Care. 2008;31(Supplement 1):S12-S54. NICE clinical guideline 87. March 2010.
Ket luan
Roi loan lipid mau hon hp ngay cang nhieu va chung ta phai tap trung giai quyet nhng yeu to quan trong khac ngoai LDL (nh HDL, TG).
Fenofibrate la thuoc co kha nang lam giam TG, tang HDL va cai thien c cac bien co tim mach Phoi hp ieu tr gia Statin va Fenofibrate se toi u hoa ieu tr RLLP