DEMA-CVN.

COM
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

Ganh nang toan cau cua benh ly tim mach

D tnh vao nam 2020: T vong do benh tim mach se tang en 20 trieu/nam. Benh M vanh va ot qu :nguyen nhan gay t vong va thng tat hang au tren toan the gii

International Cardiovascular Disease Statistics 2005; AHA

Risk Factors for Atherothrombosis

Hypercoagulable states Life-style (e.g., Homocysteinaemia smoking, diet, Dyslipidaemia lack of exercise) Insulin resistance Diabetes Obesity Hypertension Genetics Infection?

Atherosclerosis

Age Gender

Atherothrombotic Manifestations (MI, Ischemic Stroke, Vascular Death)

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

Key Statin Trials and Spectrum of Risk

CHD/high cholesterol 4S CHD/average to high cholesterol LIPID CHD/low to average cholesterol PROVE-IT MI/low to average cholesterol CARE Increasing MI/low to average cholesterol IDEAL absolute CHD HPS CHD or diabetes/low to average cholesterol risk TNT CHD/low to average cholesterol CARDS Diabetes + 1 other risk factor/low to average cholesterol PROSPER CHD or risk factors/average cholesterol WOSCOPS no MI/high cholesterol ALLHAT-LLT some CHD/average cholesterol ASCOT-LLA >3 risk factors/low to average cholesterol AFCAPS/TexCAPS No CHD/average cholesterol JUPITER No CHD/low to normal cholesterol

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials

30 4S - Pl 25 Rx - Statin therapy Pl Placebo Pra pravastatin Atv - atorvastatin

Secondary Prevention

Event rate (%)

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)

LDL-C achieved mg/dL (mmol/L)

Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:1425-1435.

Trial

Events* in Major Prevention Studies

N # Events Control 2042 # Events Statin 1490 30,817 20,536 5804 10,355 10,305 77,817 1212 356 421 154 4185 898 292 380 100 3160

% Risk Reduction

% Events Not Avoided

4S / CARE / WOSCOPS / AFCAPS / LIPID15 HPS6 PROSPER7 ALLHAT-LLT8 ASCOT-LLA9 TOTAL

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

Cardiovascular Disease Prevention

100

LDL-C
% CV EVENTS
- Low HDL-C - High TG (Metabolic Syndrome, DM) + other risk factors
0

35%

65%

Time to Look Beyond LDL

S tng tac gia HDL-C va LDL-C

* 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

Tang HDL 1mg% se giam nguy c tim mach 2%

0.0

100

160

220

LDL-C (mg/dL)
Gordon T et al. Am J Med 1977;62:707-714.

H g/ (m

Framingham Heart Study

Low HDL-C levels contribute to residual risk, despite LDL-C at goal

Despite achieving LDL-C <70 mg/dL with a high-dose statin, patients with HDL-C <37 mg/dL have a 64% higher risk of a major CV event* than those with HDL-C 55 mg/dL

10

TNT

5-year risk of major CV events (%)

8 6 4 2 0

+64%
p=0.03

<37
57 473

37 to <42 42 to <47 47 to <55 Quintile of HDL-C level (mg/dL)

50 525 34 550 34 569

55
35 544

No. of events No. of patients *Death

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)

Barter P et al. N Engl J Med. 2007;357:1301-10.

Li ch ca vic h thp t l LDL-C:HDL-C trn x va ng mch

2

Tin trin
1

Tin trin

-1

Thai trin
-2 0

Thai trin 1,6

1 2 3

LDL-C:HDL-C during treatment

Nicholls S et al. JAMA 2007;297:499508

 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

MI-Incidence according to LDL-cholesterol and triglycerides

PROCAM Study:

TG Level Is Significant CVD Risk Factor: Recent Meta-Analysis of 29 Studies

Groups
Duration of follow-up 10 years <10 years Sex Male Female Fasting status Fasting Nonfasting Adjusted for HDL Yes No

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

CHD Risk Ratio* (95% CI)

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

Proportion with event (%)

16 14 12 10 8 6 4 2 0

17.3%

+70%
Mean LDL-C: 80 mg/dL

10.1%

Elevated TG (204 mg/dL) + low HDL-C (34 mg/dL) (n=456)

All others (n=2,284)

*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.

Lipids and CVD- Guidelines

Cholesterol Triglycerides

HDL

LDL

IDL

VLDL

Anti Atherogenic

Pro Atherogenic Lipoproteins

NCEP ATP III: TG-Rich Remnant Lipoproteins Are Atherogenic

Tang TG la tang cac

lipoprotein gay x va

VLDL-C = very low-density lipoprotein cholesterol.

NCEP ATP III. Circulation. 2002;106:3143-3421. 20

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%

Optimal or near optimal LDL-C

Proportion with abnormal TG and abnormal HDL-C
(<130 mg/dL)

6% 5% 4% 3% 2%

Proportion with optimal or near optimal LDL-C

(TG >150 mg/dL and <40 mg/dL)

Abnormal TG and HDL-C

HDL-C

70% 60% 50% 40% 30% 20% 10% 0%

1976-1980 1999-2006

24%
64%

4.8%

2.3-fold

40%

1% 0%

2.1%

1976-1980

1999-2006

1. Cohen JD et al. Am J Cardiol. 2010;106:969-75. 2. Cohen JD et al. Circulation. 2008;118(18Suppl):S108182. (Abstract).

Even with treatment, only 30% of patients currently achieve all lipid goals

NHANES: LMA-treated patients

85%

% of treated patients at target

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.

Treating Beyond LDL-C: Other Targets of Lipid-Lowering Therapy

NCEP ATP III 2004 update: Xem

xet phoi hp them fibrate vao ieu tr ha LDL cho BN nguy c cao co tang TG va giam HDL.1

1. Grundy SM, et al. Circulation. 2004;110:227-239. 23

Complementary lipid-altering effects of statins and fibrates

Statin LDL decrease TG-rich lipoprotein decrease HDL increase Post-prandial lipaemia decrease Improvement in LDL size profile Prevention of lipoprotein oxidation +++ + + + Fibrate + +++ ++ ++ ++

++

Farnier M. Am J Cardiovasc Drugs 2003;3:169-78.

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

% change from baseline to week 24

+6.4%

+11.7%

-31.3%

-47.1%

Durrington PN et al. Diabetes Res Clin Pract. 2004;64(2):137-51.

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

% change from baseline

10 0 -10 -20 -30 -40 -50 -60

-43.0% -49.1%
Simvastatin 20 mg/day (n=207) Simvastatin 20 mg/day + Lipanthyl 160 mg/day (n=411)

9.7 %

-20.1%

-24.1%

26.1% -35.3%

-25.8% -31.2%
p<0.001 for all between-group comparisons

Grundy SM et al. Am J Cardiol 2005;95:462-8.

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)

5,518 patients with T2D

Simvastatin 20-40 mg*

Simvastatin 20-40 mg + Placebo (n=2,753) Month 1 Mean 4.7-year follow-up

*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

Proportion with event (%)

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)

TG >204 mg/dL LDL-C/HDL-C >5.0 TG 200 mg/dL

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)

ACCORD Lipid6,7 (Fenofibrate)

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.

Fibrate-statin combination therapy versus monotherapy: Pros and cons

Pros
LDL-C, TG, HDL-C Decrease non-HDL-C LDL particle size Fibrinogen (fenofibrate) Reduce uric acid (fenofibrate) Likelihood of outcome benefit

Cons
Potential for increased adverse
effects

Increased costs

Rhabdomyolysis in combination therapy with statins other than cerivastatin

Low level of adverse events

reported to the FDA

Over 3.4 million prescriptions

Number of reports of rhabdomyolysis per million prescriptions in combination with statin (excluding cerivastatin)
10

Number of cases reported per million prescriptions

9 8 7 6 5 4 3 2 1 0

8.6

were dispensed for fenofibrate in combination with a statin

(excluding cerivastatin)

15-fold increase

6,641,000
prescriptions dispensed

3,419,000
prescriptions dispensed

0.58 Fenofibrate Gemfibrozil

Jones & Davidson. Am J Cardiol 2005;95:120-2.

Fibrates and statins can be metabolised via two different pathways

Pathways Enzymes used in glucuronidation Effect on oxidative metabolism (cytochrome P450) Fenofibrate
UGT1A9 & 2B7

Gemfibrozil
UGT1A1 & 1A3

Statins
Most statins use UGT1A1 & 1A3

Mild/Moderate inhibitor of CYP2C9

Potent inhibitor of CYP2C9 Potent inhibitor of CYP2C8

fluvastatin & rosuvastatin metabolised by CYP2C9 Cerivastatin metabolised by CYP2C8 simvastatin & atorvastatin metabolised by CYP3A4

UGT : uridine diphosphate-glucuronotransferase

Davidson MH. Expert Opin Drug Saf 2006;5(1):145-56.

Fibrates and statins can be metabolised via two different pathways

Pathways Enzymes used in glucuronidation Effect on oxidative metabolism (cytochrome P450) Fenofibrate
UGT1A9 & 2B7

Gemfibrozil
UGT1A1 & 1A3

Statins
Most statins use UGT1A1 & 1A3

Mild/Moderate inhibitor of CYP2C9

Potent inhibitor of CYP2C9 Potent inhibitor of CYP2C8

fluvastatin & rosuvastatin metabolised by CYP2C9 Cerivastatin metabolised by CYP2C8 simvastatin & atorvastatin metabolised by CYP3A4

UGT : uridine diphosphate-glucuronotransferase

Davidson MH. Expert Opin Drug Saf 2006;5(1):145-56.

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

Chan thanh cam n s theo doi cua quy v