Fibrate and cardiovascular disease: Evident from meta-analysis

Fibrate and cardiovascular disease: Evident from meta-analysis

Thongchai Pratipanawatr

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“Statin era”

CURRENT ROLE OF FIBRATE

What are the roles of fibrate in statin era.Severe hypertriglyceridemiaAllergy to statinSide effect from statin

MyopathyGI : N/VHepatitis

Combination with statin in combined dyslipidemia

DRUG AFFECTING LIPOPROTEIN METABOLISM

Drug class Lipid effects Side effects Contraindications

Statin Decrease LDL Myopathy, increase liver enzyme

Active or chronic liver disease

Fibrate Decrease TG and increase HDL

Dyspepsia, gall stones, myopathy

Severe renal and hepatic disease

Bile acid sequestrants

Decrease LDL Gastrointestinal distress, constipation, decrease absorption of other drugs

Dysbetalipoproteinemia, Hypertriglyceridemia (TG>400 mg/dl)

Ecetimide Decrease LDL increase liver enzyme Hypertriglyceridemia(TG>400 mg/dl)

Nicotinic acid

Decrease LDL Flushing, hyperglycemia, hyperuricemia, hepatotoxicity

Chronic liver disease, severe gout

เราทําไมตองรักษาโรคไขมันสูง?1.ใหผูปวยอายุยืนยาว2. ใหผูปวยไมเจ็บไมปวย3. ใหผูปวยใหผูปวยมีความสุข

THREE CATEGORIES OF RISK THATMODIFY LDL CHOLESTEROL GOALS

Risk Category LDL Goal

CHD and CHD risk equivalents

< < 100(Optional <70)

Multiple (2+) risk factors <130<130

0-1 risk factor <160<160

CHD and CHD risk equivalents

CHDDMPeripheral artery diseaseAbdominal aortic aneurysmSymptomatic carotid artery disease

ATHEROSCLEROTIC RISK FACTORS

Age : male>45 female>55 yrsSmokingHypertensionLow HDL (<40 mg/l)Family history of premature CHD(male>55, female>45 yrs)

OBJECTIVES

Efficacy of fibrate onMyocardial infarctionCoronary artery revascularizationStrokeDeath

Safety of fibrate

LIPID METABOLISM

Small bowel

Bile

Chylomicron

CE

TGTG

TGTG

TG

Chylomicronremnant

CETG

TG

TG

Lipoprotein lipase

VLDL

CE

TGTG

TGTG

TG

IDL

CE

TG

TGTGCE

LDL

CE TGCE

Lipoproteinlipase

TG

TG

Peripheralcell

B

B

B

HMG coA reductase

CHOLESTEROL TRANSPORT SYSTEM

REVERSE CHOLESTEROL TRANSPORT SYSTEM

CEC

ABC-A1A-IC

A-I

CESR-B1

A-I

CE-depletedHDL

A-I

Kidney

VLDL/LDL

CE

CE

CETP

CE

C

Bile

LCAT

Nascent HDL

MatureHDL

Peripheralcell

PPRE (DR-1)

RXR

AGGTCA X AGGTCA

retinoicPPARα

Activation of PPAR alpha alters expression of specific genes

PPRE (DR-1)

PPARα RXR

AGGTCA X AGGTCA

Gene expression-Increase LPL, A I-Decrease C III

Fibrate retinoic

Activation of PPAR alpha alters expression of specific genes

Small bowel

Bile

Chylomicron

CE

TGTG

TGTG

TG

Chylomicronremnant

CETG

TG

TG

Lipoprotein lipase

VLDL

CE

TGTG

TGTG

TG

IDL

CE

TG

TGTGCE

LDL

CE TGCE

Lipoproteinlipase

TG

TG

Peripheralcell

B

B

BDecrease apo C III

CHOLESTEROL TRANSPORT SYSTEM

HMG coA reductase

REVERSE CHOLESTEROL TRANSPORT SYSTEM

CEC

ABC-A1A-IC

A-I

CESR-B1

A-I

CE-depletedHDL

A-I

Kidney

VLDL/LDL

CE

CE

CETP

CE

C

Bile

LCAT

Nascent HDL

MatureHDL

Peripheralcell

META-ANALYSIS:THE EFFECT OF FIBRATE ON CARDIOVASCULAR DISEASE

Search methodology

PUBMED SEARCH

#1. cardiovascular disease [ Mesh ] 63,052 papers#2. fibrate 74 papers#3. fibric acid 44 papers#4. gemfibrozil 316 papers#5. bezafibrate 185 papers#6. fenofibrate 1,256 papers#7. #1 OR #2 177 papers#8. #1 OR #3 115 papers#9. #1 OR #4 379 papers#10. #1 OR #5 230 papers#11. #1 OR #6 274 papers

INCLUDE STUDY

1. Randomized control trials2. Intervention :

fenofibrate, bezafibrate, gemfibrozil3. Outcome :

death, cardiovascular disease (CVD) death, myocardial infarction, stroke, side effects

4. Duration of study more than 6 month

META ANALYSIS OF FIBRATE STUDIES

Study year Treatment Control

Helsigki 1987 2051 2030

BECAIT 1997 42 39

SENDCAP 1998 81 83

VA HIT 1999 1264 1267

BIP 2000 1548 1542

DAIS 2001 207 211

Leader 2002 783 785

FIELD 2005 4895 4900

Total 10664 10644

META ANALYSIS OF FIBRATE STUDIES

Study year Treatment Control

Helsigki 1987 Gemfibrozil Primary

BECAIT 1997 Bezafibrate Secondary

SENDCAP 1998 Bezafibrate Primary

VA HIT 1999 Gemfibrozil Secondary

BIP 2000 Bezafibrate Secondary

DAIS 2001 Fenofibrate Mix

Leader 2002 Bezafibrate Primary

FIELD 2005 Fenofibrate Mix

Total 10664 10644

HETEROGENEITY

Statistic : chi2

Subgroup analysisPrimary vs secondaryDrugs

RESULTS

Myocardial infarction

Pratipanawatr T MD , unpublished

Study Treatment Control

Genfibrozil

Helsigki 51/2051 79/2030

VA HIT 219/1264 275/1267

Fenofibrate

DAIS 9/207 11/211

FIELD 158/4895 207/4900

Bezalifrate

BECAIT 3/42 11/39

SENDCAP 6/81 17/83

BIP 168/1548 189/1542

Leader 90/783 111/785

Total 10664 10644

0.72 (0.61-0.86)

0.76 (0.62-0.93)

1 2 5 10.5.20.1

Favours treatment Favours control

0.79 (0.66-0.94)

0.76 (0.68-0.84)

FATAL AND NON-FATAL MYOCARDIAL INFARCTION



Primary

Helsigki 51/2051 79/2030

SENDCAP 6/81 17/83

Leader 90/783 111/785

Secondary

BECAIT 3/42 11/39

BIP 168/1548 189/1542

VA HIT 219/1264 275/1267

Mix

DAIS 9/207 11/211

FIELD 158/4895 207/4900

Total 10664 10644

0.69 (0.55-0.86)

0.79 (0.68-0.91)

1 2 5 10.5.20.1


0.76 (0.62-0.93)

0.76 (0.68-0.84)

FATAL AND NON-FATAL MYOCARDIAL INFARCTION

CORONARY REVASCULIZATION



Genfibrozil

VA HIT 284/1264 320/1267

Fenofibrate

DAIS 19/207 31/211

FIELD 290/4895 364/4900

Bezalifrate

BIP 72/1548 77/1542

Total 7914 7920

0.86 (0.71-1.03)

0.77 (0.68-0.90)

1 2 5 10.5.20.1


1.05 (0.82-1.35)

0.84 (0.76-0.93)

OBJECTIVES


Safety of fibrate

“ Treatment with fibrate significantly reduced myocardial infarction (by 24%) and coronary artery revascularization (by 16%).”

Conclusions

Stroke

STROKE



Genfibrozil

Helsigki 6/2051 4/2030

VA HIT 64/1264 88/1267

Fenofibrate

Shiming et al 13/115 24/110

FIELD 158/4895 175/4900

Bezalifrate

BIP 72/1548 77/1542

Leader 60/783 49/785

Total 10664 10644

0.75 (0.54-1.03)

0.85 (0.69-1.05)

1 2 5 10.5.20.1


1.05 (0.82-1.35)

0.89 (0.77-1.02)



Primary

Helsigki 6/2051 4/2030

Leader 60/783 49/785

Shiming et al 13/115 24/110

Secondary

BIP 72/1548 77/1542

VA HIT 64/1264 88/1267

Mix

FIELD 158/4895 175/4900

Total 10656 10634

1.02 (0.73-1.41)

0.81 (0.65-1.03)

1 2 5 10.5.20.1


0.90 (0.72-1.12)

STROKE

0.89 (0.77-1.02)

OBJECTIVES


Safety of fibrate

“ Treatment with fibrate reduced incidence of stroke by 11%.”

Conclusions

Compared with statin:

MI, revascularization and Stroke

Cholesterol Treatment Trialists’ (CTT) Collaborators.Lancet 2005; 366: 1267–78



Genfibrozil

Helsigki 45/2051 42/2030

VA HIT 198/1264 220/1267

Fenofibrate

DAIS 6/207 9/211

FIELD 356/4895 323/4900

Bezalifrate

BIP 161/1548 152/1542

Leader 204/783 195/785

Total 10664 10644

0.92 (0.76-1.11)

1.10 (0.94-1.28)

1 2 5 10.5.20.1


1.06 (0.90-1.25)

1.04 (0.94-1.14)

TOTAL DEATH



Primary

Helsigki 45/2051 42/2030

Leader 204/783 195/785

Secondary

BIP 161/1548 152/1542

VA HIT 219/1264 275/1267

Mix

DAIS 6/207 9/211

FIELD 356/4895 323/4900

Total 10664 10644

1.07 (0.87-1.30)

0.96 (0.82-1.12)

1 2 5 10.5.20.1


1.10 (0.94-1.28)

TOTAL DEATH

1.04 (0.94-1.14)



Genfibrozil

Helsigki 14/2051 19/2030

VA HIT 93/1264 118/1267

Fenofibrate

FIELD 140/4895 127/4900

Bezalifrate

BIP 95/1548 88/1542

Leader 64/783 65/785

Total 10541 10541

0.77 (0.59-1.00)

1.11 (0.87-1.41)

1 2 5 10.5.20.1


1.04 (0.83-1.31)

0.97 (0.84-1.12)

CVD DEATH



Primary

Helsigki 14/2051 19/2030

Leader 64/783 65/785

Secondary

BIP 95/1548 88/1542

VA HIT 93/1264 118/1267

Mix

FIELD 140/4895 127/4900

Total 10541 10541

0.92 (0.67-1.27)

0.91 (0.74-1.11)

1 2 5 10.5.20.1


1.11 (0.87-1.41)

CVD DEATH

0.97 (0.84-1.12)

OBJECTIVES


Safety of fibrate

“ Fibrate did not reduce rate of death and cardiovascular death. However, gemfibrozil may reduce risk of cardiovascular death”

Conclusions


Death and CVD death


Microvascular complications

(FIELD tertiary endpoints)

Microvascular diseaseRetinopathy

Cum

ula

tive

ris

k (%

)

Years from randomization

HR = 0.7095% CI = 0.58–0.85p = 0.0003

4,900

4,895

4,775

4,792

4,664

4,701

4,573

4,618

4,472

4,502

2,518

2,529

Placebo

Fenofibrate835

841

10

8

6

4

2

0

0 1 2 3 4 5

Fenofibrate

Placebo

6

Number of patients still followed-up at the given year

FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

5.2%

3.6%

0

1

2

3

4

5

6

Placebo Fenofibrate

Perc

enta

ge

of pat

ieNeed for laser treatment

for retinopathy

“This effect cannot be explained by changes in HbA1c or concomitant

medications, or by the minor reduction in blood pressure in the fenofibrate group”

P=0.0003

-30%

Microvascular diseaseRetinopathy


Progression of microalbuminuria(baseline to study close)

Regression No change Progression

Placebo(n=4900)

400(8.2%)

3654(74.6%)

539(11.0%)

Fenofibrate(n=4895)

462(9.4%)

3583(73.2%)

466(9.5%)

Mann-Whitney test:P=0.002Albuminuria status categories:Normal: <3.5 mg/mmol; microalbuminuria:3.5-<35 mg/mmol;macroalbuminuria: > 35 mg/mol

“This effect cannot be explained by changes in HbA1c or concomitant medications, or by the minor reduction in blood pressure in the

fenofibrate group”


PATHOGENESIS OF PROLIFERATIVE DIABETIC RETINOPATHY

Retinal cell ischemia

Microvascular obstruction

Vascular Endothelium Growth Factor

Endothelium proliferation(Neovascularization)

POSSIBLE EFFECT OF FIBRATE ON DIABETIC RETINOPATHY

Retinal cell ischemia

Microvascular obstruction

Vascular Endothelium Growth Factor

Endothelium proliferation(Neovascularization)

Decrease lipotoxicity

Decrease lipid utility(14% less O2 consumption)

Decrease VEGF via inhibition of activate protein1(Grau R Biocehm J (2006) 395;81)

Safety results



Genfibrozil

Helsigki 11/2051 11/2030

VA HIT 126/1264 138/1267

Fenofibrate

DAIS 5/207 7/211

FIELD 393/4895 373/4900

Bezalifrate

BIP 161/1548 152/1542

Total 9965 9950

0.91 (0.71-1.16)

1.05 (0.91-1.22)

1 2 5 10.5.20.1


0.93 (0.68-1.26)

1.00 (0.89-1.12)

CANCER


Cancer




FIELD 11/4895 7/4900

BIP 4/1548 1/1542

Total 6443 6442

1 2 5 10.5.20.1


1.88 (0.8-4.43)

ELEVATED CK

Adverse event Placebo(n = 4,900)

Fenofibrate(n = 4,895)

ALT 3–5 × ULN 26 (< 1%) 11 (< 1%)

> 5 × ULN 12 (< 1%) 11 (< 1%)

CPK 5–10 × ULN 7 (< 1%) 11 (< 1%)

> 10 × ULN 3 (< 1%) 4 (< 1%)

Elevated creatinine (> 200 μmol/L) 48 (1%) 73 (2%)

Laboratory variable measurements occurring in < 2 % of patients

Abbreviations: ALT = alanine aminotransferase; CPK = creatine phosphokinase; ULN = upper limit of normal.


Adverse event Placebo(n = 4,900)

Fenofibrate(n = 4,895)

Deep-vein thrombosis 48 (1%) 67 (1%)

Pulmonary embolism 32 (0.7%) 53 (1%)

Pancreatitis 23 (0.5%) 40 (0.8%)

Myositis 1 (< 1%) 2 (< 1%)

Rhabdomyolysis 1 (< 1%) 3 (< 1%)

Renal disease requiring dialysis 21 (< 1%) 16 (< 1%)

Clinically important events occurring in < 2% of patients




Genfibrozil

Helsigki 225/2051 142/2030

VA HIT 505/1264 430/1267

Fenofibrate

DAIS 1/207 4/211

FIELD 975/4895 927/4900

Total 9965 9950

1.64 (1.32-2.04)

1.06 (0.96-1.71)

1 2 5 10.5.20.1


1.18 (1.09-1.28)

GI SIDE EFFECT

OBJECTIVES


Safety of fibrate

“ Fibrate did not increase incidence of cancer. However, it may increase incidence of myopathy”

Conclusions

THANK YOU

Fibrate and cardiovascular disease: Evident from meta-analysis

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