ΦENOΦΙΒΡΑΤΗ TO 2011.

ΦENOΦΙΒΡΑΤΗ TO 2011.. ΡΙΧΤΕΡ, MD, FESC, FAHA - ιευθυντής Καρδιολογικής Κλ. Ευρωκλινικής Αθηνών -Γενικός Γραμματέας της Ελληνικής Εταιρείας Λιπιδιολογίας - Μέλος Σ ΕΛΙΚΑΡ

ΦΙΒΡΑΤΕΣ Βεζαφιβράτη (BEZALIP 200,400mg, GETUP 200mg, VERBITAL 200mg) Γεμφιβροζίλη(LOPID 600,900mg, FIBROLIP,GEMLIPID,GEDIZIL ENTIANTHE 600mg) Σιπροφιβράτη (SAVILEN 100mg), Κλοφιβράτη (όπως βεζαφιβράτη)(atromid-s 500mg) Φαινοφιβράτη 100mg (όπως βεζαφιβράτη) (Lipanthyl, fagratyl, climax κ.τ.λ.) Σαν γενική αρχή, καμία φιβράτη δεν μειώνει τη ΧΟΛ όσο οι στατίνες ή το νικοτινικό οξύ. Το NCEP δεν τα θεωρεί μείζωνα φάρμακα. Προτιμούνται όμως σε υπερλιπ/μίες τύπου ΙΙΙ και σε ΤG Κίνδυνος μυοσίτιδας (ιδιαίτερα ΝΑ ή + στατίνες) και Cr Μολονότι όλες ανήκουν στην ίδια κατηγορία υπάρχουν σημαντικές μεταξύ τους διαφορές ( η κλοφιβράτη δεν βελτίωσε την πρόγνωση αντίθετα με την γεμιφροζίλη) H βεζαφιβράτη Glu. Προτίμηση για διαβητικούς.

ΜΗΧΑΝΙΣΜΟΣ ΔΡΑΣΗΣ ΦΙΒΡΑΤΩΝ Ο ακριβής μηχανισμός δράσης δεν έχει εξακριβωθεί. Εξαρτάται από τη φιβράτη. 1. Όλες αυξάνουν τη δραστηριότητα της LPL. Πιθανών: 2. Μειωμένη σύνθεση λιποπρωτεινών. 3. Αυξημένη δραστηριότητα υποδοχέων LDL 4. Μειωμένη λιπόλυση

Effect Effect of of lipid-lowering lipid -lowering therapies therapies on on lipids lipids Therapy Therapy Statins* Statins * Fibrates Gemfibrozil Fibrates Gemfibrozil TC TC Down 15 30% Down 15 30% Down 15% Down 15% LDL LDL Effect on Effect on HDL HDL Down Up 24 50% Down 6 12% Up 24 50% 6 12% Down Up 5 15% Down 20% Up 5 15% 20% TG TG Down 10 29% Down 10 29% Down 20 50% Down 20 50% Patient tolerability Patient tolerability Good Good Good Good Bile acid sequestrants Bile acid sequestrants Nicotinic Acid Nicotinic Acid Probucol Probucol Down 20% Down 20% Down 25% Down 25% Down 25% Down 25% Down 15 30% Down 15 30% Down 25% Down 25% Down 10 15% Down 10 15% Up 3 5% Up 3 5% Up 15 30% Up 15 30% Down 20 30% Down 20 30% Neutral or Neutral up or up Down 20 50% Down 20 50% Neutral Neutral Poor Poor Poor to reasonable Poor to reasonable Reasonable Reasonable TC-total cholesterol, LDL-low-density lipoprotein, HDL-high-density lipoprotein, TG-triglyceride. TC-total cholesterol, LDL -low-density lipoprotein, HDL -high-density lipoprotein, TG -triglyceride. * Daily dose of 40 mg of each drug (cerivastatin 0.3 mg) * Daily dose of 40 mg of each drug ( cerivastatin 0.3 mg) (Adapted from Yeshurun 1995, Knopp 1999) (Adapted from Yeshurun 1995, Knopp 1999)

HDL-C Response to Pharmacological Intervention

Treatment Algorithm for Low HDL-C

Classification of dyslipidaemias Fredrickson (WHO) classification Phenotype Lipoprotein Serum Serum Atherogenicity Prevalence elevated cholesterol triglyceride I Chylomicrons Normal to None seen Rare IIa LDL Normal +++ Common IIb LDL and VLDL +++ Common III IDL +++ Intermediate IV VLDL Normal to + Common V VLDL and Normal to + Rare chylomicrons LDL low-density lipoprotein; IDL intermediate-density lipoprotein; VLDL very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification). (Adapted from Yeshurun et al, 1995)

2

Weight reduction-increased increased physical activity

Εκρηκτική αύξηση του επιπολασμού της παχυσαρκίας στις αναπτυγμένες χώρες CMAJ 2004;171:240-2

Overweight (%) children 7-11 years 18 10 Equivalent to BMI>25 26 27 18 12 15 16 18 17 IOTF 2004. IOTF-Cole et al definition of overweight 34 19 22 36 26 17 12 18 32 31 34 35 33 27

MΣ και Στεφανιαία νόσος Οι στατιστικές είναι για τους άλλου

Declining HDL-C C in the Population >12,000 respondents to a biennial population survey in the Pawtucket Heart Health Program 1.5 1.4 1.3 1.2 1.1 0.0 Women Nonsmokers Smokers 1.3 1.2 1.1 1.0 0.0 Men Nonsmokers Smokers Between 1981 and 1993, 0.08 mmol/l (3.1 mg/dl) decline Adjusted for other risk factor changes HDL-C (mmol/l) 1.5 1.4 1.3 1.2 1.1 0.0 1.5 1.4 1.3 1.2 1.1 0.0 Alcohol No Alcohol 1.3 1.2 1.1 1.0 0.0 Alcohol No Alcohol BMI <22.9 1.3 1.2 1.1 1.0 0.0 BMI <24.5 BMI 27.6 BMI 27.9 Reprinted from Ann Epidemiol, Vol. 8, Derby CA et al., 84-91, copyright 1998, with permission from Elsevier. '81-82 '85-86 '89-90 '83-84 '87-89 '92-93 '81-82 '85-86 '89-90 '83-84 '87-89 '92-93

WHO CLOFIBRATE TRIAL(Lancet 1980) ΟΕΜ Μη-καρδιαγγειακή θνησιμότητα (47% κατά τη διάρκεια της μελέτης, 5% τέσσερα έτη μετά). Η μελέτη διακόπηκε.

ΦΙΒΡΑΤΕΣ Γεμιφροζίλη-Πρωτογενής πρόληψη Helsinki Heart Study (1987) 2000 φαινομενικά υγιείς άντρες με μετρίου βαθμού υπερχολ/μία, 5 έτη παρακολούθηση 600mg X 2, 12% HDL, ΤC + LDL 8-10%. TG CHD θανάτων, αλλά όχι συνολικής θνησιμότητας. Παρενέργειες: μικρό ποσοστό καταράκτη, λίθων στη χολή Αυξάνει τη βαρβαρίνη, κίνδυνος μυοπάθειας με στατίνες.

ΦΙΒΡΑΤΕΣ Γεμιφροζίλη-Δευτερογενής πρόληψη VAHIT-1999 2500 άντρες, ιστορικό ΣΝ, ηλικία <74 ετών, 5 έτη παρακ. Γεμιφροζίλη 1200mg/ημερησίως για 1 έτος 6% HDL, ΤC 4%+ LDL 0%. TG 31% 22% ΜΙ, CHD death, 60% TIA, Όχι μείωση συνολικής θνησιμότητας

Increases in HDL-C Directly Related to CAD Risk Reduction: VA-HIT

VAHIT

Raising HDL-C: Fibrates

ΦΙΒΡΑΤΕΣ Βεζαφιβράτη-Δευτερογενής πρόληψη BIP(Bezafibrate Infarction Prevention)- Circulation 2000 3000 ασθενείς με ΣΝ (στηθάγχη ή ΟΕΜ) TC 180-250, HDL<45, TG,300 LDL,180. Bezafibrate 400mg ή placebo HDL 18%, TG 21% Όχι μείωση νέου ΜΙ ή καρδιακού θανάτου Μόνο στην υποομάδα με υψηλά TG (>200) παρατηρήθηκε στατιστικά σημαντική μείωση συνολικής καθώς και μηκαρδιακής θνητότητας

Diabetes Atherosclerosis Intervention Study A multinational project conducted in co-operation with the World Health Organisation The first study designed a priori to examine specifically the effect of treating lipid abnormalities on coronary artery atherosclerosis in 418 men and women with type 2 diabetes DAIS examined by quantitative coronary angiography whether treatment with Lipanthyl results in decreased progression or regression of CAD

Fenofibrate treatment slowed the progression of coronary atherosclerosis mm -0.10 % Change 4.00 mm -0.10-0.08-40% -42% -0.08-25% Progression of CAD -0.06-0.04-0.02 2.00-0.06-0.04 p = 0.029 p = 0.020 p = 0.171-0.02 0.00 Minimum lumen diameter Fenofibrate Placebo 0.00 Percent stenosis 0.00 Mean Segment Diameter Angiographic changes from baseline Lancet 2001; 357: 905-910

Study DAIS The result observed in DAIS is consistent with findings from subgroup analyses of endpoint trials Features Regression trial in primary and secondary prevention patients, fenofibrate Subgroup analyses from primary and secondary prevention studies Event reduction in % 23% CARE Similar lipids, pravastatin 25% LIPID Similar lipids, pravastatin 19% 4S Higher LDL-C, lower TG, simvastatin 55% HPS Similar lipids, simvastatin 20% VA-HIT Lower LDL-C, lower HDL-C, gemfibrozil 24%

DAIS Clinical implications Lipid abnormalities contribute to the excess risk of CVD in diabetes Many patients with type 2 diabetes have an abnormal lipid profile which is characterized by: Low HDL-C Increased serum triglycerides Normal to mildly elevated LDL-C This lipid profile generally can be well treated with fenofibrate

FIELD Study

FIELD: Study Design

FIELD: Results

FIELD: Primary outcome End point CHD death/ nonfatal MI Placebo (n=4900), n (%) Fenofibrat e (n=4895), n (%) HR (95% CI) 288 (6) 256 (5) 0.89 (0.75-1.05) CHD death 93 (2) 110 (2) 1.19 (0.90-1.57) Nonfatal MI 207 (4) 158 (3) 0.76 (0.62-0.94) p 0.16 0.22 0.010 The FIELD study investigators. Lancet 2005

FIELD: Secondary outcomes End point Placebo (n=4900), n (%) Fenofibrate (n=4895), n (%) HR (95% CI) Total CV events 683 (14) 612 (13) 0.89 (0.80-0.99) CV mortality 127 (3) 140 (3) 1.11 (0.87-1.41) Total mortality 323 (7) 356 (7) 1.11 (0.95-1.29) Stroke 175 (4) 158 (3) 0.90 (0.73-1.12) Coronary revascularization 364 (7) 290 (6) 0.79 (0.68-0.93) All revascularization 471 (10) 380 (8) 0.80 (0.70-0.92) p 0.035 0.41 0.18 0.36 0.003 0.001 The FIELD study investigators. Lancet 2005

FIELD: Statin Initiation

FIELD: How Concomitant Therapy Affected the Results

Action to Control CardiOvascular Risk in Diabetes (ACCORD) Aim To determine whether intensive vs standard intervention can reduce the rate of major cardiovascular events in diabetic patients. Glycaemic, BP and lipid control are involved Study design Average follow-up of 5.5 years, multicenter, double blind, 3x2 factorial randomized trial 60 centres in the US (financed by NHLBI) Patient characteristics 10 000 type 2 diabetic patients (5800 randomized to the lipid arm) Men and women aged 50-75 years : 55 for caucasians and African Americans, > 50 for as/hisp. Lipid levels : LDL-C 170 mg/dl (4.4 mmol/l), HDL-C 50 mg/dl (1.3 mmol/l),tg 750 mg/dl (8.6 mmol/l)

Action to Control CardiOvascular Risk in Diabetes (ACCORD) Methodology Randomisation for glucose control (HbA1C, N = 10000) Conventional therapy: target 8.0% Intensive treatment: target 6.0% Randomisation for LDL control (N = 5800): Conventional treatment with simvastatin: target < 130mg/dl if no CHD; < 100 mg/dl if CHD Intensive treatment with simvastatin + fenofibrate: target < 100mg/dl if no CHD; < 75 mg/dl) if CHD Randomisation for control of hypertension (N = 4200) Conventional treatment: target SPB < 130 mmhg Intensive treatment: target SPB < 120 mmhg Primary endpoint: major CV events (CV deaths, non fatal MI, non fatal strokes) Timing: Study due to complete in 2009

Henry C. Ginsberg, MD College of Physicians & Surgeons, Columbia University, New York For The ACCORD Study Group

ACCORD Study Design Designed to independently test three medical strategies to reduce cardiovascular disease in diabetic patients Lipid Trial question: whether combination therapy with a statin plus a fibrate would reduce cardiovascular disease compared to statin monotherapy in people with type 2 diabetes mellitus at high risk for cardiovascular disease. Randomized, placebo-controlled, double-blind clinical trial conducted in 77 clinical sites in the U.S. and Canada

ACCORD Study Design Overall ACCORD Glycemia Trial: 10,251 participants Lipid Trial: 5,518 in Lipid Trial 2765 randomized to fenofibrate 2753 randomized to placebo Primary Outcome: First occurrence of a major cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death) 87% power to detect a 20% reduction in event rate, assuming placebo rate of 2.4%/yr and 5.6 yrs follow-up in participants without events.

ACCORD Lipid Trial Eligibility Stable Type 2 Diabetes >3 months HbA1c 7.5% to 11% High risk of CVD events = clinical or subclinical disease or 2+ risk factors Age (limited to <80 years after Vanguard) 40 yrs with history of clinical CVD (secondary prevention) 55 yrs otherwise Lipids 60 < LDL-C < 180 mg/dl HDL-C < 55 mg/dl for women/blacks; < 50 mg/dl otherwise Triglycerides < 750 mg/dl if on no therapy; < 400 mg/dl otherwise No contraindication to either fenofibrate or simvastatin

All participants on open-labeled simvastatin, 20 to 40 mg/day Simvastatin dose complied with lipid guidelines Patients randomized to double-blind placebo or fenofibrate, 54 to 160mg/day Dosing based upon egfr level Only blinded ACCORD trial Observed Follow-up: 4 to 8 years (mean 4.7 years)

Characteristic Mean or % Characteristic Mean or % Age (yrs) 62 Total Cholesterol (mg/dl) 175 Women % 31 LDL-C (mg/dl) 101 Race / Ethnicity HDL-C (mg/dl) 38 White % 68 Triglyceride (mg/dl)* 162 Black % 15 Blood pressure (mm Hg) 134/74 Hispanic % 7 Serum creatinine (mg/dl) 0.9 Secondary prevent % 37 Current smoking % 15 DM duration (yrs) * 9 On a statin % 60 A1c (%) * 8.3 On another LLA % 8 BMI (kg/m 2 ) 32 On Insulin % 33 * Median values

Mean Total Cholesterol Mean LDL-C 200 120 190 110 mg/dl 180 170 160 Feno Placebo mg/dl 100 90 80 Feno Placebo 150 70 140 0 1 2 3 4 5 6 7 Years Post- Randomization 60 0 1 2 3 4 5 6 7 Years Post- Randomization N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5483 5180 4988 4783 5250 3377 1668 491 Mean HDL-C Median Triglycerides 42 170 41 160 mg/dl 40 39 38 Feno Placebo mg/dl 150 140 130 120 Feno Placebo 37 0 1 2 3 4 5 6 7 Years Post- Randomization 110 0 1 2 3 4 5 6 7 Years Post- Randomization N = 5483 5180 4988 4783 5250 3377 1668 491 N = 5432 5180 4988 4783 5250 3377 1668 491

Adverse Experiences During Follow-up Fenofibrate Placebo Adverse events (no. (%)) (N=2765) (N=2753) P value Out of the ordinary severe muscle aches/pains: regardless of CK 1110 (40.1%) 1115 (40.5%) 0.81 plus CK > 5 X ULN 7 (0.3%) 8 (0.3%) 0.79 plus CK > 10 X ULN 1 (0.04%) 2 (0.07%) 0.56 Any nonhypoglycemic SAE 54 (2.0%) 43 (1.6%) 0.27 Any Myopathy/Myositis/ Rhabdomyolysis SAE 4 (0.1%) 4 (0.1%) 1.00 Any Hepatitis SAE 3 (0.1%) 0 (0.0%) 0.18 Any SAE attributed to lipid meds 27 (1.0%) 19 (0.7%) 0.24

Lab Measures During Follow-up Fenofibrate Placebo Laboratory Measures (no. (%)) (N=2765) (N=2753) P value ALT ever > 3X ULN 52 (1.9%) 40 (1.5%) 0.21 ALT ever > 5X ULN 16 (0.6%) 6 (0.2%) 0.03 CK ever > 5X ULN 51 (1.9%) 59 (2.2%) 0.43 CK ever > 10X ULN 10 (0.4%) 9 (0.3%) 0.83

Lab Measures During Follow-up Fenofibrate Placebo Laboratory Measures (no. (%)) (N=2765) (N=2753) P value ALT ever > 3X ULN 52 (1.9%) 40 (1.5%) 0.21 ALT ever > 5X ULN 16 (0.6%) 6 (0.2%) 0.03 CK ever > 5X ULN 51 (1.9%) 59 (2.2%) 0.43 CK ever > 10X ULN 10 (0.4%) 9 (0.3%) 0.83 Serum creatinine elevation 235 (27.9%) 157 (18.7%) <0.001 698 (36.7%) 350 (18.5%) <0.001 Post randomization incidence of microalbuminuria ( > 30 to < 300 mg/g*) 1050 (38.2%) 1137 (41.6%) 0.01 Post randomization incidence of macroalbuminuria ( > 300 mg/g*) 289 (10.5%) 337 (12.3%) 0.03

Primary Outcome Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event N of Events Placebo (N=2753) Rate (%/yr) 310 2.41

Primary Outcome Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event Fenofibrate (N=2765) N of Rate Events (%/yr) Placebo (N=2753) N of Rate Events (%/yr) 291 2.24 310 2.41

Primary Outcome Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event Fenofibrate Placebo (N=2765) (N=2753) N of Rate N of Rate Events (%/yr) Events (%/yr) HR (95% CI) P Value 291 2.24 310 2.41 0.92 (0.79 1.08) 0.32

Prespecified Secondary Outcomes Outcome Primary + Revasc + hospitalized CHF Fenofibrate Placebo (N=2765) (N=2753) N of Rate N of Rate Events (%/yr) Events (%/yr) HR (95% CI) P Value 641 5.35 667 5.64 0.94 (0.85 1.05) 0.30 Major Coronary Event 332 2.58 353 2.79 0.92 (0.79 1.07) 0.26 Nonfatal MI 173 1.32 186 1.44 0.91 (0.74 1.12) 0.39 Total Stroke 51 0.38 48 0.36 1.05 (0.71 1.56) 0.80 Nonfatal Stroke 47 0.35 40 0.30 1.17 (0.76 1.78) 0.48 Total Mortality 203 1.47 221 1.61 0.91 (0.75 1.10) 0.33 Cardiovascular Death 99 0.72 114 0.83 0.86 (0.66 1.12) 0.26 Fatal/Nonfatal CHF 120 0.90 143 1.09 0.82 (0.65 1.05) 0.10

Primary Outcome By Treatment Group and Baseline Subgroups

Primary Outcome By Treatment Group and Baseline Subgroups

Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > 5.0-71% BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -39.5% FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% ACCORD (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31%

Conclusion (1) ACCORD Lipid does not support use of the combination of fenofibrate and simvastatin compared to simvastatin alone to reduce CVD events in the majority of patients with T2DM who have HDL- C and TG levels that are close to the normal range

Conclusion (2) Subgroup analyses suggesting heterogeneity in response to combination therapy by gender and by the presence of significant dyslipidemia require further investigation