5.pgs.quangbinh rllipid mau

8/4/2019 5.Pgs.quangbinh Rllipid Mau

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DEMA-CVN.COMGiI THIU

CC TI BO CO TI HI NGHTIM MCH MIN TRUNG- TY

NGUYN M RNG LN TH VI TIBUN MA THUT THNG 8 NM 2011


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PGS TS Trng Quang BnhPGS TS Trng Quang Bnh

HYD TP HCMHYD TP HCM

IEU TR TOANIEU TR TOAN

DIEN ROI LOANDIEN ROI LOANLIPID MAULIPID MAU


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Ganh nang toan cau cuaGanh nang toan cau cuabenh ly tim machbenh ly tim mach

D tnh vao nam 2020:D tnh vao nam 2020:

T vong do benh tim mach se tang enT vong do benh tim mach se tang en20 trieu/nam.20 trieu/nam.

Benh M vanh va ot qu :nguyenBenh M vanh va ot qu :nguyennhan gay t vong va thng tat hangnhan gay t vong va thng tat hangau tren toan the giiau tren toan the gii

International Cardiovascular Disease Statistics 2005; AHA


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Risk Factors for Atherothrombosis

AtherosclerosisAtherosclerosis

Atherothrombotic ManifestationsAtherothrombotic Manifestations(MI, Ischemic Stroke, Vascular Death)(MI, Ischemic Stroke, Vascular Death)

AgeAgeObesityObesity

DiabetesDiabetes

DyslipidaemiaDyslipidaemia

Hypercoagulable statesHypercoagulable states

HypertensionHypertension

GeneticsGenetics

Infection?Infection?

HomocysteinaemiaHomocysteinaemiaLife-style (e.g.,Life-style (e.g.,smoking, diet,smoking, diet,lack of exercise)lack of exercise)

GenderGender

American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl 2):I

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.

Insulin resistancInsulin resistanc


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Dyslipidemia

Keech AC et al, Lancet 371:117-25, 2008

LDL-CTG

HDL-C


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Key Statin Trials andSpectrum of Risk

CHD/high cholesterol

CHD/average to high cholesterol

CHD/low to average cholesterol

MI/low to average cholesterol

MI/low to average cholesterol

CHD or diabetes/low to average cholesterol

CHD/low to average cholesterol

Diabetes + 1 other risk factor/low to average cholesterol

CHD or risk factors/average cholesterolno MI/high cholesterol

some CHD/average cholesterol

>3 risk factors/low to average cholesterol

No CHD/average cholesterol

No CHD/low to normal cholesterol

Increasingabsolute CHDrisk

4SLIPID

PROVE-ITCAREIDEALHPSTNT

CARDS

PROSPERWOSCOPSALLHAT-LLTASCOT-LLA

AFCAPS/TexCAPSJUPITER


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

Rosenson RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med2005;352:1425-1435.

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

4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

CARE - Pl

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

E v e n

t r a t e

( % )

Secondary PreventionRx - Statin therapyPl PlaceboPra pravastatinAtv - atorvastatin

200(5.2)

PROVE-IT - Pra

PROVE-IT Atv

TNT Atv10TNT Atv80The

lower,thebetter


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Events* in Major

Prevention Studies

*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

Trial N # EventsControl

# EventsStatin

% RiskReduction

% EventsNot Avoided

4S / CARE / WOSCOPS/AFCAPS / LIPID15

30,817 2042 1490 26 74

HPS6 20,536 1212 898

27 74PROSPER7 5804 356 292 19 82

ALLHAT-LLT8 10,355 421 380 9 91

ASCOT-LLA9 10,305 154 100 36 64

TOTAL 77,817 4185 3160 25 75


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Cardiovascular Disease Prevention

100

0

35%

+ other risk factors

- Low HDL-C

- High TG

(Metabolic Syndrome, DM)

LDL-C

65%

% CVEVENTS


10/36Time to Look Be ond LDLTime to Look Beyond LDL


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S tng tac gia HDL-C vaLDL-C

Gordon T et al. Am J Med1977;62:707-714.

* bat ky mcLDL-C, nong oHDL-C lien quannghch vi nguy cCHD

* Qui luat Tang HDL 1mg%

se giam nguyc tim mach 2%R

isk

ofCHD

LDL-C(mg/dL)

0.0

1.0

2.0

3.0

100 160 220 8565

45

25

HDL-C

(mg/dL)

Framingham Heart Study


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

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

Despite achieving LDL-C


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

Nicholls S et al. JAMA 2007;297:499508

2

1

0

-1

-2

LDL-C:HDL-C during treatment

0 1 2 3

Tin trin

Thai trin 1,6

Tin trin

Thai trin


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People should think of

both LDL and HDL as yinand yang, cant considerone without the other

-Dr. Peter Wilson

Director of Laboratoires

for the Framingham Study


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PROCAM Study:MI-Incidence according to LDL-cholesterol and

triglycerides


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16

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

Sarwar N, et al. Circulation. 2007;115:450-458.

*Individuals in top vs bottom thirdof usual log-TG values; adjusted for at least age,sex, smoking status, and lipid concentrations; alsoadjusted for BP (in most studies).

CHD Risk Ratio* (95% CI)

1.72 (1.56-1.90)

21

Duration of follow-up10 years 5902


17/36Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

Despite achieving LDL-C


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Elevated TG and low HDL-C represent an evengreater risk for patients with T2D

In patients with T2D, elevated TG and low HDL-C is associated with a70% higher residual CV risk* despite achievement of LDL-C goal with astatin

ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.

Mean LDL-C:80 mg/dL

*Major CV events defined as CV death, nonfatal MI and nonfatal stroke (primary endpoint)

17.3%

0

2

46

8

10

12

14

16

18

10.1%

All others(n=2,284)

Elevated TG (204 mg/dL) + lowHDL-C (34 mg/dL)

(n=456)

Proportionwithevent

(%)

+70%

ACCORD Lipid


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LDL

Cholesterol

HDL IDL VLDL

Triglycerides

Lipids and CVD-Guidelines

Pro Atherogenic Lipoproteins

Anti

Atherogenic


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20

NCEP ATP III: TG-Rich RemnantLipoproteins Are Atherogenic

Tang TG la tang caclipoprotein gay x va

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

VLDL-C = very low-density lipoprotein cholesterol.


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0%

10%

20%

30%

40%

50%

60%

70%

80%

1. Cohen JD et al.Am J Cardiol. 2010;106:969-75.2. Cohen JD et al. Circulation. 2008;118(18Suppl):S1081-82. (Abstract).

While LDL-C levels are improving, the problem ofelevated TG and low HDL-C may be worsening

In the past 3 decades in the US, while the prevalence of normal LDL-C levelshas increased, the prevalence of combined abnormal TG and HDL-C hasmore than doubled1,2

Propo

rtionwithoptimal

ornear

optimalLDL-C

NHANES

1999-2006

Proportionw

ithabnormalTGand

abnormalHD

L-C

0%

1%

2%

3%

4%

5%

6%Optimal or near optimal LDL-C(150 mg/dL and HDL-C


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

Ghandehari H et al.Am Heart J. 2008;156:112-9.

%

oftreated

patientsat

target

NHANES: LMA-treated patients

85%

72%

19%

50%

40%

69%

17% 15%

LDL-C goals: 20% or prior CVD, T2D or chronic kidneydisease (CKD),


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23

Treating Beyond LDL-C: Other Targetsof Lipid-Lowering Therapy

NCEP ATP III 2004 update: Xem xet phoi

hp them fibrate vao ieu trha LDL cho BN nguy c cao cotang TG va giam HDL.1

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


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Statin

LDL decrease

TG-rich lipoprotein decrease

HDL increase

Post-prandial lipaemia decrease

Improvement in LDL size profile

Prevention of lipoprotein oxidation

Complementary lipid-alteringeffects of statins and fibrates

+++

+

+

+

++

+

+++

++

++

++

Fibrate

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


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Combining Fenofibrate with rosuvastatin furtherimproved TG and HDL-C in patients with T2D

Lipanthyl-rosuvastatin combination therapy substantially improved TGand HDL-C levels over and above the effect of rosuvastatin alone

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

%

changef r

om

baselinetoweek

24

-47.1%

-31.3%

+6.4%+11.7%


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Grundy SM et al.Am J Cardiol2005;95:462-8.

SAFARI: Combining fenofibrate with simvastatinimproved all lipids vs. simvastatin alone

In patients with mixed dyslipidaemia, Fenofibrate improved the entire

lipid profile over and above the effects of simvastatin

p


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ACCORD Lipid evaluated adding Lipanthyl to astatin in patients with T2D at goal for LDL-C

The first trial to assess fibrate-statin combination therapy on macroand microvascular outcomes

ACCORD Study Group. N Engl J Med. 2010; 362(17):1563-74.

5,518 patientswith T2D

Mean 4.7-year follow-up

Simvastatin 20-40 mg + Placebo

(n=2,753)

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/1.73m2 received a lower dose of Lipanthyl, corresponding to 1/3 of the normal daily dose

Month 1

Simvastatin 20-40mg*


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Fenofibrate significantly reduced CV eventsin the elevated TG + low HDL-C subgroup by

31%

ACCORD Study Group. N Engl J Med. 2010;362(17):1563-74.Elam MB et al. AHA 2010. Presentation 19724.

The primary endpoint of major CV events (CV death, nonfatal MI and nonfatal stroke) wasnot 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 withelevated TGs and low HDL-C were compared with all the other patients (p=0.06 forinteraction)

17.3%

12.4%

0

2

4

6

8

10

12

14

16

18

Proportio

nwithe

vent(%)

Simvastatin Fenofibrate + Simvastatin

-31%p=0.03

Number needed totreat (NNT) for 5 years

to prevent one CVevent

20

In patients with TG 204 mg/dL and HDL-C 34 mg/dL


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The ACCORD Lipid results are consistentwith FIELD and other fibrate trials

Study(Treatment)

HDL-C(mg/dL)Baseline

Mean

Primary analysis:RRR (p value)

Lipid subgroup criteria TG/HDL-C subgroup:RRR (p value)

HHS1,2

(Gemfibrozil)47.1 -34% (0.02) TG >204 mg/dL

LDL-C/HDL-C >5.0-71% (0.005)

BIP3(Bezafibrate)

34.6 -7.3% (0.24) TG 200 mg/dL -39.5% (0.02)

FIELD4,5

(Fenofibrate)42.5 -11% (0.16) TG 204 mg/dL

HDL-C


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Potential for increased adverseeffects

Increased costs

LDL-C, TG, HDL-C

Decrease non-HDL-C

LDL particle size

Fibrinogen (fenofibrate)

Reduce uric acid (fenofibrate)

Likelihood of outcome benefit

Fibrate-statin combinationtherapy versus monotherapy:

Pros and consPros Cons


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Low level of adverse eventsreported to the FDA

Over 3.4 million prescriptionswere dispensed for fenofibratein combination with a statin(excluding cerivastatin)

Number of reports of rhabdomyolysis permillion prescriptions in combination with statin(excluding cerivastatin)

0.58

8.6

Fenofibrate Gemfibrozil

Numberofcasesrepo

rted

permillion

prescription

s

0

10

5

1

2

3

4

6

7

8

9

6,641,000prescriptionsdispensed

3,419,000prescriptionsdispensed

Rhabdomyolysis in combination therapywith statins other than cerivastatin

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

15-foldincrease

Fibrates and statins can be


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Fibrates and statins can bemetabolised via two different pathways

Pathways Fenofibrate Gemfibrozil Statins

Enzymes used in

glucuronidation

UGT1A9 & 2B7 UGT1A1 & 1A3 Most statins use UGT1A1& 1A3

Effect on oxidativemetabolism(cytochromeP450)

Mild/Moderateinhibitor of CYP2C9 Potent inhibitor ofCYP2C9

Potent inhibitor ofCYP2C8

fluvastatin & rosuvastatinmetabolised by CYP2C9

Cerivastatin metabolisedby CYP2C8

simvastatin & atorvastatinmetabolised by CYP3A4

UGT : uridine diphosphate-glucuronotransferase

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

Fibrates and statins can be


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Fibrates and statins can bemetabolised via two different pathways

Pathways Fenofibrate Gemfibrozil Statins

Enzymes used in

glucuronidation

UGT1A9 & 2B7 UGT1A1 & 1A3 Most statins use UGT1A1& 1A3

Effect on oxidativemetabolism(cytochromeP450)

Mild/Moderateinhibitor of CYP2C9 Potent inhibitor ofCYP2C9

Potent inhibitor ofCYP2C8

fluvastatin & rosuvastatinmetabolised by CYP2C9

Cerivastatin metabolisedby CYP2C8

simvastatin & atorvastatinmetabolised by CYP3A4

UGT : uridine diphosphate-glucuronotransferase

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


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The ACCORD Lipid results support guidelinesthat recommend adding a fibrate to statintherapy 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 serumtriglycerides 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 theLDL-C target with statins, () combination therapy with fibrates, ezetimibe or nicotinic acid may beconsidered.

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. Grundy SM et al. Circulation. 2004;110:227-39.2. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. 2005.

3. ESC/EASD Guidelines. Eur Heart J. 2007;28:88-136.4. ADA. Diabetes Care. 2008;31(Supplement 1):S12-S54.5. NICE clinical guideline 87. March 2010.


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Roi loan lipid mau hon hp ngaycang nhieu va chung ta phai tap trunggiai quyet nhng yeu to quan trongkhac ngoai LDL (nh HDL, TG).

Fenofibrate la thuoc co kha nanglam 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

Ket luan


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