Fibrate and cardiovascular disease: Evident from meta-analysis Thongchai Pratipanawatr
??? ย คห นใหม ย คห นกลาง ย คห นเก า
?? Statin era? ย คห นใหม ย คห นกลาง ย คห นเก า
CURRENT ROLE OF FIBRATE What are the roles of fibrate in statin era. Severe hypertriglyceridemia Allergy to statin Side effect from statin Myopathy GI : N/V Hepatitis Combination with statin in combined dyslipidemia
DRUG AFFECTING LIPOPROTEIN METABOLISM Drug class Lipid effects Side effects Contraindications Statin Decrease LDL Myopathy, increase liver enzyme Fibrate Bile acid sequestr ants Decrease TG and increase HDL Decrease LDL Dyspepsia, gall stones, myopathy Gastrointestinal distress, constipation, decrease absorption of other drugs Active or chronic liver disease Severe renal and hepatic disease 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
เราท าไมต องร กษาโรคไขม นส ง? 1.ให ผ ป วยอาย ย นยาว 2. ให ผ ป วยไม เจ บไม ป วย 3. ให ผ ป วยให ผ ป วยม ความส ข
THREE CATEGORIES OF RISK THAT MODIFY LDL CHOLESTEROL GOALS Risk Category LDL Goal CHD and CHD risk equivalents < 100 (Optional <70) Multiple (2+) risk factors <130 0-1 risk factor <160
CHD and CHD risk equivalents CHD DM Peripheral artery disease Abdominal aortic aneurysm Symptomatic carotid artery disease
ATHEROSCLEROTIC RISK FACTORS Age : male>45 female>55 yrs Smoking Hypertension Low HDL (<40 mg/l) Family history of premature CHD(male>55, female>45 yrs)
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
LIPID METABOLISM
CHOLESTEROL TRANSPORT SYSTEM Bile HMG coa reductase VLDL CE TG TG TG TGTG B TG IDL CE TG CE TG TG B Lipoprotein lipase LDL CE TG CE B TG Peripheral cell Chylomicron remnant CE TG TG Lipoprotein lipase Chylomicron CE TG TG TG TGTG TG Small bowel
REVERSE CHOLESTEROL TRANSPORT SYSTEM VLDL/LDL CE Bile CE C CE SR-B1 A-I CE Mature HDL A-I CETP LCAT A-I C Nascent HDL A-I ABC-A1 C CE Peripheral cell CE-depleted HDL Kidney
Activation of PPAR alpha alters expression of specific genes PPARα RXR retinoic AGGTCA X AGGTCA PPRE (DR-1)
Activation of PPAR alpha alters expression of specific genes Fibrate PPARα RXR retinoic Gene expression -Increase LPL, A I -Decrease C III AGGTCA X AGGTCA PPRE (DR-1)
CHOLESTEROL TRANSPORT SYSTEM Decrease apo C III Bile HMG coa reductase VLDL CE TG TG TG TGTG B TG IDL CE TG CE TG TG B Lipoprotein lipase LDL CE TG CE B TG Peripheral cell Chylomicron remnant CE TG TG Lipoprotein lipase Chylomicron CE TG TG TG TGTG TG Small bowel
REVERSE CHOLESTEROL TRANSPORT SYSTEM VLDL/LDL CE Bile CE C CE SR-B1 A-I CE Mature HDL A-I CETP LCAT A-I C Nascent HDL A-I ABC-A1 C CE Peripheral cell CE-depleted HDL Kidney
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 trials 2. Intervention : fenofibrate, bezafibrate, gemfibrozil 3. 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 analysis Primary vs secondary Drugs
RESULTS
Myocardial infarction
FATAL AND NON-FATAL MYOCARDIAL INFARCTION 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 Favours treatment Favours control 0.72 (0.61-0.86) 0.76 (0.62-0.93) 0.79 (0.66-0.94) 0.76 (0.68-0.84) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
FATAL AND NON-FATAL MYOCARDIAL INFARCTION Study Treatment Control 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 Favours treatment Favours control 0.69 (0.55-0.86) 0.79 (0.68-0.91) 0.76 (0.62-0.93) 0.76 (0.68-0.84) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
CORONARY REVASCULIZATION Study Treatment Control Genfibrozil VA HIT 284/1264 320/1267 Fenofibrate DAIS 19/207 31/211 FIELD 290/4895 364/4900 Bezalifrate BIP 72/1548 77/1542 Favours treatment Favours control 0.86 (0.71-1.03) 0.77 (0.68-0.90) 1.05 (0.82-1.35) Total 7914 7920 0.84 (0.76-0.93) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
Conclusions Treatment with fibrate significantly reduced myocardial infarction (by 24%) and coronary artery revascularization (by 16%).
Stroke
STROKE Study Treatment Control 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 Favours treatment Favours control 0.75 (0.54-1.03) 0.85 (0.69-1.05) 1.05 (0.82-1.35) Total 10664 10644 0.89 (0.77-1.02) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
Study Treatment Control 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 STROKE FIELD 158/4895 175/4900 Favours treatment Favours control 1.02 (0.73-1.41) 0.81 (0.65-1.03) 0.90 (0.72-1.12) Total 10656 10634 0.89 (0.77-1.02) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
Conclusions Treatment with fibrate reduced incidence of stroke by 11%.
Compared with statin: MI, revascularization and Stroke Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366: 1267 78
Death
TOTAL DEATH Study Treatment Control 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 Favours treatment Favours control 0.92 (0.76-1.11) 1.10 (0.94-1.28) 1.06 (0.90-1.25) Total 10664 10644 1.04 (0.94-1.14) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
Study Treatment Control Primary Helsigki 45/2051 42/2030 Leader 204/783 195/785 Secondary BIP 161/1548 152/1542 VA HIT 219/1264 275/1267 Mix TOTAL DEATH DAIS 6/207 9/211 FIELD 356/4895 323/4900 Favours treatment Favours control 1.07 (0.87-1.30) 0.96 (0.82-1.12) 1.10 (0.94-1.28) Total 10664 10644 1.04 (0.94-1.14) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
CVD DEATH Study Treatment Control 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 Favours treatment Favours control 0.77 (0.59-1.00) 1.11 (0.87-1.41) 1.04 (0.83-1.31) Total 10541 10541 0.97 (0.84-1.12) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
Study Treatment Control Primary Helsigki 14/2051 19/2030 Leader 64/783 65/785 Secondary BIP 95/1548 88/1542 VA HIT 93/1264 118/1267 Mix CVD DEATH FIELD 140/4895 127/4900 Favours treatment Favours control 0.92 (0.67-1.27) 0.91 (0.74-1.11) 1.11 (0.87-1.41) Total 10541 10541 0.97 (0.84-1.12) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
Conclusions Fibrate did not reduce rate of death and cardiovascular death. However, gemfibrozil may reduce risk of cardiovascular death
Compared with statin: Death and CVD death Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366: 1267 78
Microvascular complications (FIELD tertiary endpoints)
Microvascular disease Retinopathy 10 Cumulative risk (%) 8 6 4 2 HR = 0.70 95% CI = 0.58 0.85 p = 0.0003 Placebo Fenofibrate 0 0 1 2 3 4 5 6 Years from randomization Placebo Fenofibrate 4,900 4,895 4,775 4,792 4,664 4,701 4,573 4,618 4,472 4,502 2,518 2,529 835 841 Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Microvascular disease Retinopathy Need for laser treatment for retinopathy Percentage of patie 6 5 4 3 2 1 5.2% -30% 3.6% P=0.0003 This effect cannot be explained by changes in HbA 1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group 0 Placebo Fenofibrate FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
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=0.002 Albuminuria 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 HbA 1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
PATHOGENESIS OF PROLIFERATIVE DIABETIC RETINOPATHY Endothelium proliferation (Neovascularization) Microvascular obstruction Vascular Endothelium Growth Factor Retinal cell ischemia
POSSIBLE EFFECT OF FIBRATE ON DIABETIC RETINOPATHY Endothelium proliferation (Neovascularization) Decrease lipotoxicity Microvascular obstruction Decrease VEGF via inhibition of activate protein1 (Grau R Biocehm J (2006) 395;81) Vascular Endothelium Growth Factor Retinal cell ischemia Decrease lipid utility (14% less O2 consumption)
Safety results
CANCER Study Treatment Control 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 Favours treatment Favours control 0.91 (0.71-1.16) 1.05 (0.91-1.22) 0.93 (0.68-1.26) Total 9965 9950 1.00 (0.89-1.12) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
Compared with statin: Cancer Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366: 1267 78
ELEVATED CK Study Treatment Control Favours treatment Favours control FIELD 11/4895 7/4900 BIP 4/1548 1/1542 Total 6443 6442 1.88 (0.8-4.43) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
Laboratory variable measurements occurring in < 2 % of patients 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%) Abbreviations: ALT = alanine aminotransferase; CPK = creatine phosphokinase; ULN = upper limit of normal. FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Clinically important events occurring in < 2% of patients 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%) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
GI SIDE EFFECT Study Treatment Control Genfibrozil Helsigki 225/2051 142/2030 VA HIT 505/1264 430/1267 Fenofibrate DAIS 1/207 4/211 FIELD 975/4895 927/4900 Favours treatment Favours control 1.64 (1.32-2.04) 1.06 (0.96-1.71) Total 9965 9950 1.18 (1.09-1.28) ratipanawatr T MD, unpublished 0.1.2.5 1 2 5 10
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
OBJECTIVES Efficacy of fibrate on Myocardial infarction Coronary artery revascularization Stroke Death Safety of fibrate
Conclusions Fibrate did not increase incidence of cancer. However, it may increase incidence of myopathy
THANK YOU