Update on Fenofibrate

Transcription

1 Cardiovascular Drug Reviews Vol. 20, No. 4, pp Neva Press, Branford, Connecticut Update on Fenofibrate David R. P. Guay College of Pharmacy, University of Minnesota and Division of Geriatrics, HealthPartners Inc., Minneapolis, MN, USA Key words: Atherosclerosis Cholesterol Diabetes mellitus Fenofibrate Fibrates Procetofen Triglycerides. ABSTRACT Fenofibrate is a fibric acid derivative that has been marketed since the mid-1970 s (1998 in the United States). Its active metabolite, fenofibric acid, is responsible for the primary pharmacodynamic effects of the drug: reductions in total plasma cholesterol, lowdensity lipoprotein cholesterol, triglycerides, and very low-density lipoprotein concentrations and increases in high-density lipoprotein cholesterol and apolipoproteins AI and AII concentrations. These effects are mediated by activation of peroxisome proliferator-activated receptor-á (PPAR á ). The drug has broad spectrum utility, with documented efficacy in Fredrickson types IIa, IIb, III, IV, and V hyperlipidemias. Fenofibrate is well tolerated, with digestive and musculoskeletal side effects similar to those of other fibrates. Results of the initial cardiovascular morbidity/mortality outcomes study with fenofibrate (known as DAIS [Diabetes Atherosclerosis Intervention Study]) were encouraging vis-à-vis slowing of atherosclerotic progression in the coronary vasculature of type II diabetics. The results of other ongoing outcome trials are eagerly awaited. These results will help to establish the overall place of fenofibrate in the hypolipidemic armamentarium. INTRODUCTION Fibric acid derivatives (fibrates) play an important role in the management of hypertriglyceridemia, combined hyperlipidemia, primary hypercholesterolemia, diabetic dyslipidemia, and nephrotic syndrome and transplant dyslipidemias, either as monotherapy or as a component of combination therapy (20,23,24,26,29,31,38,41). Address correspondence and reprint requests to: David R. P. Guay, Pharm. D. University of Minnesota, College of Pharmacy, Weaver-Densford Hall 7 115C, 308 Harvard Street SE, Minneapolis, MN 55455, USA. Tel: +1 (612) , Fax: +1 (612) , guayx001@umn.edu 281

2 282 D. R. P. GUAY Although available in many parts of the world since the mid-1970 s, fenofibrate (in a micronized formulation to improve bioavailability) has only been available in the United States since 1998 (Tricor, Abbott Laboratories). A comprehensive review of the product was published in late 1999 (33). The current paper will update this review, covering the pharmacology, pharmacokinetics, clinical efficacy, tolerability, drug interactions, pharmacoeconomics, and dosing recommendations of fenofibrate. The current paper will emphasize those studies appearing in the English language literature since the October 1999 review, as identified by computerized database searches and review of bibliographies of identified papers. PHARMACODYNAMICS Fenofibrate acts as a prodrug, being rapidly hydrolyzed in vivo to form the active fenofibric acid metabolite. This metabolite is responsible for the primary pharmacodynamic effects of reductions in total plasma cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and very low-density lipoprotein (VLDL) concentrations and increases in high-density lipoprotein cholesterol (HDL-C) and apolipoproteins (Apo) AI and AII concentrations (33). The lipid-modifying effects of fenofibrate are largely mediated by its ability to activate peroxisome proliferator-activated receptors (PPARs). hese PPARs are ligand-activated transcription factors that control gene expression by interacting with response elements located upstream. PPAR á controls a number of genes involved in lipid metabolism, including those encoding for apo-ciii, apo-ai, and apo-aii. Activated PPAR á reduces the nuclear content of the positive transcription factor hepatic nuclear factor-4 and displaces any hepatic nuclear factor-4 bound to the apo-ciii promotor site. This results in reduced plasma apo-ciii which, in turn, leads to increased lipoprotein lipase activity. The enhanced catabolism of VLDL in the capillaries bordering muscle cells produces remnants that are taken up by the muscle cells, transferred to HDL and returned to the liver. Increases in PPAR á -mediated synthesis of apo-ai and AII further augment HDL production. Fenofibrate also promotes â-oxidation of hepatic and smooth muscle cell fatty acids by inducing acyl coenzyme A carboxylate synthesis and other genes involved in mitochondrial and peroxisomal â-oxidation, thereby reducing hepatic secretion of VLDL. Fenofibrate favors the reduction of small, dense LDL particles while also reducing, to a lesser extent, large buoyant LDL particles, often resulting in a shift from pattern B to pattern A (33). In addition, fenofibrate may exert an antiinflammatory effect. Activation of human aortic smooth muscle cells is inhibited by fenofibrate-mediated PPAR á activation. Fenofibrate also inhibits the increased gene expression of cyclooxygenase-2 induced by IL-1â and reduces plasma concentrations of acute phase reactants such as C-reactive protein and fibrinogen (33). One of the most interesting developments of recent years has been the hypothesis that infectious agents may play a role in atherosclerosis via a pro-inflammatory effect. Chlamydia pneumoniae is the most plausible candidate pathogen. However, to date, prospective studies have failed to confirm this association. Further research, including two ongoing randomized controlled trials of antichlamydia antimicrobials (WIZARD, ACES),

3 FENOFIBRATE 283 may give a more definitive answer regarding infection as a risk factor for atherosclerosis (4,22,27). In 2002, results of a study examining the effect of fenofibrate on Chlamydia pneumoniae antibody concentrations were published. In the study (detailed in Table 2), 200 mg of micronized fenofibrate was administered once daily for three weeks in open-label fashion to 20 patients with coronary artery disease. Statistically-significant reductions from baseline were noted in C. pneumoniae IgA (mean 5.1%) and IgG (mean 7.6%) concentrations (49). The etiology and clinical significance of these findings are as yet unclear. Numerous clinical trials and two formal studies in healthy volunteers (as reviewed in ref. 33) have documented that fenofibrate therapy induces significant reductions in serum uric acid through a uricosuric effect. An additional paper published in 2001 examined the effect of fenofibrate on the urinary clearance of purine bases (hypoxanthine, xanthine, uric acid) and oxypurinol (the active metabolite of the xanthine oxidase inhibitor allopurinol). In 5 healthy volunteers, fenofibrate 150 mg thrice daily was administered for 3 days followed by a single 300 mg dose of allopurinol administered four hours after the last fenofibrate dose. The urinary excretion of uric acid was enhanced an average of 22% by fenofibrate but those of oxypurines or oxypurinol were not altered. The fractional clearances of xanthine, uric acid, and oxypurinol were increased by 41, 101, and 51%, respectively, over baseline while their respective plasma concentrations fell by 46, 46, and 19%, probably due to activity on common renal pathways. No effect was noted on hypoxanthine or creatinine. The authors felt that the effect of combination fenofibrate-allopurinol therapy on plasma uric acid may be less than additive due to the enhancement of oxypurinol urinary excretion (69). PHARMACOKINETICS After oral administration of fenofibrate, no parent compound is detectable in plasma due to the rapid cleavage by esterases to produce fenofibric acid. Oral bioavailability is incomplete, being approximately 30 percent for the regular (non-micronized) formulation. Micronization enhances the bioavailability substantially, such that 67 mg of the original micronized capsule formulation is bioequivalent to 100 mg of the regular release formulation based on peak plasma concentration (C max ) and area under the plasma concentration time curve (AUC) data. Administration with food enhances drug bioavailability by approximately 35% (i.e., from 30 to 65%) (33). Fenofibric acid is over 99% bound to serum proteins, mainly albumin. Fenofibric acid is extensively metabolized by carbonyl reduction and glucuronidation. Apparent oral clearance of fenofibric acid is approximately 1.9 L h while its terminal disposition halflife (t 1 2 ) ranges from 21 to 26 h in subjects with normal renal function. Gender, race and aging do not appear to exert significant effects on fenofibrate disposition while renal impairment substantially impedes fenofibric acid elimination (t 1 2 ranging from h in non-dialysis subjects with serum creatinine concentrations ranging from 1.7 to 12.9 mg dl) (33). Since 1999, two new liquid chromatographic analytical procedures for fenofibric acid in biological fluids have been published (47,60). In addition, a new superbioavailable

4 284 D. R. P. GUAY micronized preparation of fenofibrate has been developed (34). This tablet preparation exhibits much faster dissolution than the previous micronized capsule preparation (extents of dissolution within 10 min were 80% [new micronized], 48% [original micronized], and 11% [non micronized]). As a result, this new preparation is 25% more bioavailable than the original micronized preparation, thus 160 mg of the new tablet preparation is bioequivalent to 200 mg of the old capsule preparation. Also, intersubject variability in pharmacokinetic parameters is lower with the new versus original micronized preparations (e.g., C max variability is reduced by 24%, bioavailability variability during high- and low-fat meals is reduced by 26%). In the United States, only the superbioavailable tablet formulation is available. THERAPEUTIC USE The review published in 1999 presented the results of 53 noncomparative and 26 comparative trials involving regular release and micronized fenofibrate published between 1976 and Of interest, despite this extensive trial experience, relatively few comparative studies were available involving other fibrates available in the US (clofibrate, gemfibrozil) and other commonly available hypolipidemics (eg. resins, nicotinic acid, HMG- CoA reductase inhibitors or statins). Table 1 illustrates the mean (range) of significant alterations from baseline in lipid parameters by type of hyperlipidemia in the noncomparative and comparative trials reviewed in 1999 (33). In the comparative trials of fenofibrate and statins in primary and mixed hyperlipidemias (types IIa and IIb, respectively), fenofibrate was significantly superior in reducing TG, lipoprotein (a), fibrinogen, and VLDL-TG and increasing HDL-C while the statins were superior in reducing TC, VLDL-C, LDL-C, and apo-b (33). Since 1999, numerous nonrandomized and randomized (placebo, active comparator) trials of fenofibrate have been published (Tables 2 [6,13,18,21,37,40,44,49,55,62,70] and 3 [2,3,12,14,16,17,25,28,30,32,39,42,43,45,48,51,58,61,66,68], respectively). The results in Table 2 mirror those obtained in the previously-published review (33), demonstrating significant reductions in TC, LDL-C, TG, apo-b, fibrinogen, uric acid, and serum insulin and increases in HDL-C and apo-ai during fenofibrate therapy as compared to baseline. The results in Table 3 mirror those obtained in the previously published review (33). They demonstrates the same spectrum of lipid effects as described previously as well as the ability of fenofibrate to effect a change in LDL subtype distribution towards larger, less atherogenic particles, and to reduce the concentrations of acute-phase reactants (e.g., C-reactive protein), implying an antiinflammatory effect. With micronized fenofibrate, at doses in excess of 200 mg once daily, there appears to be no dose-response effect (42). Fenofibrate does not appear to affect left ventricular function at rest or during exercise (14). A recent comparative trial involving micronized fenofibrate, 200 mg once daily, and gemfibrozil, 900 mg once daily, demonstrated significantly greater effects of fenofibrate than of gemfibrozil on TC, LDL-C, and uric acid (39). An effective approach to the management of mixed or combined hyperlipidemia is a statin-fibrate combination. However, this regimen has not been widely adapted due, mainly, to concern regarding the myopathic side effects reported with the lovastatin-gemfibrozil combination. This effect has not been observed with other statin-fibrate combina-

5 FENOFIBRATE 285 tions, including statin-fenofibrate (vide infra). Use of combination therapy takes advantage of the complementary lipid nonlipid effects of the two drug classes. Recent and previously reviewed data support the use of such combinations in diabetic and nondiabetic patients (2,25,40). Combination therapy is generally safe provided that appropriate clinical and laboratory (creatinine phosphokinase levels) monitoring is done. Fibrate-induced additional, but moderate, LDL-C concentration reduction, substantial reduction in TG concentration, significant enhancement of HDL-C concentration, and shift in the size and density distribution of LDL particles should enhance the effects of combination therapy. Monotherapy with gemfibrozil or bezafibrate was effective in the secondary prevention of coronary artery disease (63,67). In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), 2531 men with coronary heart disease, HDL-C concentration less than 40 mg dl, and LDL-C concentration less than 140 mg dl were randomized to gemfibrozil 1200 mg d or placebo. Median follow-up was 5.1 years. At one year, mean HDL-C, TG, and TC concentrations were increased by 6, reduced by 31, and reduced by 4%, respectively, in the gemfibrozil compared to the placebo group. A primary event (nonfatal myocardial infarction [MI] or death from any coronary cause) occurred in 21.7 and 17.3% of placebo and gemfibrozil recipients, respectively (relative risk reduction Type of Hyperlipidemia TABLE 1. Mean (range) percentage alterations in lipid parameters with fenofibrate therapy in noncomparative and comparative clinical trials a Noncomparative trials IIa 24 (19 29) IIb 20 (13 28) III 42 (37 48) IV 18 (11 24) Comparative trials IIa 20 (17 28) IIb 20 (14 25) III 24 (NA) IV 14 (NA) Lipid Parameter TC TG HDL-C LDL-C VLDL-C LDL-TG VLDL-TG 29 (16 45) 44 (30 67) 58 (56 60) 51 (33 68) 33 (24 38) 46 (41 53) 51 (NA) 53 (NA) 18 (14 26) 29 (19 39) 50 (36 61) 24 (NA) 35 (18 52) (15 21) (8 43) (33 63) (26 34) (52 61) 27 (25 28) NA NA NA NA (12 23) ( 9 38) (39 53) (NA) (34 62) 12 (10 15) 20 (8 34) 21 (NA) 15 (14 15) 26 (20 24) 23 (6 35) NA 6 ( 9 20) 44 (38 61) NA 51 (48 53) NA 63 (NA) NA 60 (56 63) NA 34 (NA) 52 (NA) 58 (NA) 61 (59 63) Abbreviations: HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LDL-TG, low density lipoprotein triglycerides; NA, not available; TC, total cholesterol; TG, triglycerides; VLDL-C, very low density lipoprotein cholesterol; VLDL-TG, very low-density lipoprotein triglycerides. a This table was generated using mean significant change from baseline data from individual study data detailed in Tables 1 and 2 of ref. 33.

6 Reference Mark et al. (2002) (49) Dierkes et al. (2001) (18) Yong et al. (1999) (70) de la Serna and Cadarso (1999) (13) Idzior-Walus et al. (2000) (37) Kiortisis et al. (2000) (40) TABLE 2. Nonrandomized clinical studies of fenofibrate in hyperlipidemia N (breakdown by hyperlipidemia type) Regimen Results 20 (CAD) 200 mg qd 3w 29 (hyperlipidemic males) 22 males (low HDL-C dyslipidemicsyndrome) 80 (67 pure hypercholesterolemia, 13 mixed dyslipidemia) 37 (syndrome X) 200 mg qd 12 w 12 (severe mixed dyslipidemia) 200 mg d 6w fenofibrate 300 mg d 6mo SR fenofibrate 250 mg qd 2yr baseline to week mg qd 6w atorvastatin 40 mg qd 6w combination 6w Mean sign. changes from baseline to end of therapy: TC 18%, HDL-C 17%, LDL-C 18%, TG 38%, apo-ai 12%, apo-b 18%, fibrinogen 16%, C. pneumoniae IgA 5.1%, C. pneumoniae IgG 7.6% Mean sign. changes from baseline to end of therapy: thcy 31%, TG 25%, TC 7%, LDL-C 97%, HDL-C 10%, creatinine 14%, urea 12% mean sign. changes from baseline to end of therapy: SBP 6%, DBP 10%, TC 13%, TG 34%, HDL-C 55%, LDL-C 18%, FBG 11%, fasting serum insulin 28%, 2nd h serum insulin 46% (OGTT), insulin AUC sign. (OGTT) but% not stated Mean sign. Changes from baseline to 3 mo: fibrinogen 13%, TC 25%, LDL-C 30%, HDL-C 12%, TG 35%, uric acid 23% Mean sign. Changes from baseline to 1 yr: fibrinogen 19%, TC 20%, LDL-C 25%, HDL-C 16%, TG 36%, uric acid 18% Mean sign. Changes from baseline to 2 yr: fibrinogen 11%, TC 17%, LDL-C 21%, HDL-C 10%, TG 24%, uric acid 20% Mean sign. Changes from TC 12%, TG 34%, HDL-C 10%, LDL-C 12%, uric acid 16% LDL-C HDL-C ratio 19% Mean sign. Changes from baseline to week 8: TC 14%, TG 39%, HDL-C 10%, LDL-C 10%, LDL-C HDL-C ratio 19% Mean sign. Changes from baseline to week 12: uric acid 22%, TC 11%, TG 31%, HDL-C 12%, LDL-C 12%, LDL-C HDL-C ratio 21% Mean systolic and diastolic BP fell as well at 4, 8, and 12 w. (p < 0.05) and insulin response to oral glucose load was sign. reduced by feno. (insulin AUC 19%) Mean sign. Changes from baseline with feno alone: TC 15%, TG 39%, LDL-C 9%, HDL-C 25%, apo-b 8%, apo-ai 17%, fibrinogen 11% Mean sign. Changes from baseline with ator alone: TC 35%, TG 28%, LDL-C 37%, HDL-C 14%, apo-b 24%, apo-ai 9% Mean sign. Changes from baseline with combination: TC 42%, TG 46%, LDL-C 42%, HDL-C 29%, apo-b 28%, apo-ai 20%, fibrinogen 12% (differences between combo and feno alone were sign. for TC, TG, LDL-C, apo-b and between combo and ator alone for TC, TG, LDL-C, HDL-C, apo-b, apo-ai) Adverse events (No. patients) no AE data provided no AE data provided no data provided re AE no data provided except for stat. sign but clin. insign. in transaminases and serum creatinine no AE data were provided no AE data were provided 286 D. R. P. GUAY

7 Reference Tanetal. (2001) (62) Elisaf et al. (1999) (21) Brisson et al. (2002) (6) Ramjattan et al (2002) (55) le Roux et al. (2002) (44) N (breakdown by hyperlipidemia type) Regimen Results 35 (LDL mg dl and type 2 DM with HgA1c <9%) 25 (mixed dyslipidemia, hypertensive, hyperuricemic) 292 (TG > 2.0 mmol L) 364 (N = 152 type IIa, N = 192 type IIb, N = 20 type IV) 65 (lipid clinic patients, 18% had DM or IGT) 200 mg qd 6mo 200 mg qd 4w 200 mg qd + losartan 50 mg qd, each 4w 3 mo (regimen not specified) 160 mg d 12 w fenofibrate 267 mg d (no details given regarding duration of therapy before sampling) with without atorvastatin (no details given regarding statin regimen) TABLE 2 (continued) Mean sign. Changes from baseline to end of study: TG 33%, HDL-C 11%, apo-b 8%, LDL 1 93%, LDL 2 83%, LDL 3 43% (and in LDL subfractions refer to changes in subfraction proportional distributions, not changes in absolute concentration of each LDL subfraction) mean sign. changes from baseline to 4 w: TC 10%, HDL-C 11%, LDL-C 13%, TG 33%, apo-ai 11%, apo-b 20%, fibrinogen 16%, uric acid 26% mean sign. changes from baseline to 8 w: TC 13%, HDL-C 13%, LDL-C 14%, TG 34%, apo-ai 17%, apo-b 14%, fibrinogen 17%, uric acid 36% (only for uric acid did the effect of the combination exceed that of fenofibrate alone) Mean sign. Changes from baseline to end of therapy: TG 64%, TC 28%, HDL-C 19%, TC HDL-C ratio 45%, LDL-C 13% Mean sign. Changes from baseline to end of therapy type IIa: TC 14%, LDL-C 21%, HDL-C 11%, TG 28%, TC HDL-C ratio 21%, LDL-C HDL-C ratio 27%, fibrinogen 10% type IIb: TC 14%, LDL-C 13%, HDL-C 16%, TG 46%, TC HDL-C ratio 22%, fibrinogen 14%, type IV: HDL-C 12%, TG 40%, fibrinogen 8% Mean sign. Changes from baseline to end of therapy: fenofibrate alone (N = 29): TC 20%, HDL-C 9%, TG 53% fenofibrate + atorvastatin (N = 36): TC 15%, HDL-C 4%, TG 45% Adverse events (No. patients) GI irritation in 1 subject who withdrew early No AE data provided no data provided re AE Premature D C due to AE in 10 patients 1 AE in 32% of patients in 10% of patients, AE were considered to be possibly drug-related) majority of AE were referable to body as a whole or GI tract. 1 feno alone recipient D C due to AE (muscle pain) Abbreviations: CAD, coronary artery disease; micro, micronized; qd, once daily; TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TG, triglycerides; apo, apolipoprotein; Ig, immunoglobulin; thcy, total homocysteine; AE, adverse event; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; OGTT, oral glucose tolerance test; S sustained release; AUC, area under the concentration-versus-time curve; ator, atorvastatin; D C, discontinuation; GI, gastrointestinal; DM, diabetes mellitus; IGT, impaired glucose tolerance. FENOFIBRATE 287

8 Reference Vakkilainen et al. (2002) (66) Okopien et al. (2001) (51) Stulc et al. (2001) (61) Sebestjen et al. (2002) (58) N (breakdown by hyperlipidemia type) TABLE 3. Randomized clinical studies of fenofibrate in hyperlipidemia Regimen 46 (type 2 diabetics) 200 mg d for 3yr(N = 25) or placebo for 3yr(N = 21) 30 (type IIb) 200 mg qd 1mo(N = 14) or micro ciprofibrate 100 mg qd 1mo(N = 16) 22 (CH) 200mgqdfor9w(N =11) or 200 mg qd + folic acid 10mgeodfor9w(N =11) 38 (CH) fenofibrate 250 mg daily 3mo(N = 19) or cerivastatin 0.2 mg qd (N =9) ( to 0.4 mg qd if LDL-C 3.0 mmol L at week 6, N = 10) 3mo Study Design AB, DB, Results mean sign. differences at end of study (feno vs. placebo): LDL size 3%, TG 41%, TC 14%, LDL-C 12%, TC HDL-C ratio 18%, LPL 17% in feno group, change in TG (r = 0.57, p = 0.003) and HDL-C (r = 0.49, p = 0.012) correlated with change in LDL diameter mean sign. changes from baseline to end of therapy: fenofibrate: TC 22%, TG 56%, LDL-C 18%, HDL-C 6%, fibrinogen 19%, PAI-1 20% ciprofibrate: TC 20%, TG 45%, LDL-C 13%, HDL-C 6%, fibrinogen 20% (no intergroup statistical analysis was done) plasma folic acid 138% (p < 0.001) in folate-supplemented group and 20% (NS) in fenofibrate alone group although thcy sign. in both groups over the course of the study, the in the fenofibrate alone group was over 3-fold higher than that in the fenofibrate + folate group (6.85 vs mmol L, p = 0.014) pooled results: TC 20%, TG 40%, fibrinogen 12%, uric acid 27% (all p < 0.05 vs. baseline) serum creatinine rose sign. in both groups (by 29% in fenofibrate alone group and 15% in fenofibrate + folate group, intergroup difference p = 0.029) mean sign. changes from baseline to end of therapy: feno, week 6: TC 12%, a HDL-C 20%, a TG 41%, a oxidized LDL 8%, apo-b 16%, NTG-mediated brachial artery dilatation (flow 24%) a feno, week 12: TC 14%, a LDL-C 12%, a HDL-C 20%, a TG 41%, a oxidized LDL 18%, apo-b 15%, NTG-mediated brachial artery dilatation (flow 45%) a ceriv, week 6: TC 21%, a LDL-C 29%, a oxidized LDL 19%, apo-b 22%, NTG-mediated brachial artery dilatation (flow 89%) a Adverse events (No. patients) no AE data provided tolerance was good and no serious side effects were observed in subjects (otherwise, no data provided) treatment was well tolerated; no serious side effects were noted throughout treatment (otherwise no details re AE were provided) no data provided re AE 288 D. R. P. GUAY

9 TABLE 3 (continued) Reference N (breakdown by hyperlipidemia type) Regimen Study Design Results ceriv, week 12: TC 24%, a LDL-C 31%, a TG 23%, a oxidized LDL 31%, apo-b 24%, NTG-mediated brachial artery dilatation (flow 107%) a Adverse events (No. patients) Malik et al. (2001) (48) Giral et al. (2001) (32) Frost et al. (2001) (30) 29 (CH) 200 mg qd 10 w and atorvastatin 10 mg qd 10 w (no washout) 53 (CH) 200 mg qd 6mo(N = 29) or atorvastatin 10 mg qd 6mo(N = 24) 13 (type 2 diabetics, CH) 200 mg qd 6w and atorvastatin 10 mg qd 6w (6-w washout period) SB, CO CO Mean sign. Changes from baseline to end of therapy: fenofibrate: TC 12%, a TG 50%, a HDL-C 13%, a non-hdl-c 17%, a apo-ai 17%, CRP 51%, a thcy 36%, a serum insulin 13%, uric acid 26% a atorvastatin: TC 28%, a TG 32%, a LDL-C 34%, a non-hdl-c 33%, a apo-ai 12%, apo-b 23%, a fibrinogen 17% a vascular reactivity: feno sign. peak blood flow mean 20% while atorvastatin sign. peak blood flow and blood flow increase by means of 27 and 35%, respectively (NS intertreatment differences) sign. correlation of in CRP and in serum insulin with improvement in vascular reactivity during feno treatment (r range of 0.48 to 0.60, p value range of to 0.014) mean sign. changes from baseline to end of therapy: fenofibrate: TC 14%, a VLDL-C 40%, LDL-C 12%, a HDL-C 14%, TG 42%, a apo-ai 9%, a apo-b 14%, a thcy 36%, a cysteine 18%, a cysteinglycine 4%, uric acid 23%, a creatinine 13% a atorvastatin: TC 29%, a VLDL-C 38%, LDL-C 35%, a HDL-C 9%, TG 28%, a apo-ai 4%, a apo-b 28%, a uric acid 6%, a creatinine 5% a in fenofibrate group, in thcy correlated with in HDL-C (r = 0.39, p < 0.05) and in creatinine correlated with in cysteine (r = 0.39, p < 0.05) Mean sign. Changes from baseline to end of therapy: fenofibrate: TC 16%, HDL3-C 20%, TG 39%, VLDL-TG 53%, VLDL-C 51%, apo-b 20%, small dense LDL 32%, fibrinogen 15%, Hct 2%, plasma viscosity 3%, shear rate 8 sec 6% (native and stand.), native red cell aggreg. shear rate 3 sec 13%, stand. red cell aggreg. stasis 15%, shear rate 3 sec 14% abdominal pain in 2 pts. when receiving atorvastatin, requiring short-term D C (2 and 3 days) no data provided regarding AE 1 pt. withdrew due to mild muscle pain (feno). no other data provided regarding AE. FENOFIBRATE 289

10 Reference Feher et al. (1999) (28) Krempf et al. (2000) (42) N (breakdown by hyperlipidemia type) 32 (hypercholesterolemic type 2 diabetics) 319 (hypercholesterolemic or CH subjects) Regimen 200 mg qd 3mo(N = 16) or placebo 3mo(N = 16) 200 mg qd (N = 63) or 267 mg qd (N = 66) or 340 mg qd (N = 61) or 400 mg qd (N = 63) or placebo qd (N = 66) all treatments lasted 3 mo Study Design Results atorvastatin: TC 24%, LDL-C 29%, HDL-C 10%, apo-b 28%, intermed. dense LDL 28%, small dense LDL 25%, large buoyant LDL 31% atorvastatin did not alter LDL subtype distribution while fenofibrate resulted in relative reduction in small dense LDL (fractions 5, 6, 7 18%, 25%, 22% p < 0.05) and increase in intermed. dense LDL (fractions 3, 4 45, 54%; p < 0.01) (no intertreatment statistical analysis was done) DB, DB, TABLE 3 (continued) mean sign. changes from baseline to end of therapy: fenofibrate: TC 17%, a LDL-C 22%, a HDL-C 20%, TC/HDL-C ratio 27%, TG 44%, a apo-b 18%, a uric acid 31%, a fibrinogen 18%, a LDL I mass 44%, LDL II mass 27%, a LDL III mass 48% a placebo: TC HDL-C ratio 10%, a TG 21%, a apo-b 9% a mean sign. changes from baseline to end of therapy: micro feno 200 mg: LDL-C 32%, TC 25%, a TG 27%, apo-b 27% micro feno 267 mg: LDL-C 33%, TC 27%, TG 35%, apo-b 28% micro feno 340 mg: LDL-C 39%, TC 32%, a TG 41%, apo-b 35% micro feno 400 mg: LDL-C 36%, TC 29%, TG 29%, apo-b 31% lipid effects reached max. by end of 1 mo on therapy. no evidence of dose-response effect. Adverse events (No. patients) 1 fenofibrate recipient had transient LFTs. no other data re AEs treatment-related AE occurred in 9, 4, 13, 23, and 13% of placebo, feno 200, feno 267, feno 340, and feno 400 mg recipients, respectively (no statistical eval. done). no sign. difference between groups in premature D C rates. AE mainly referable to GI tract and elevated hepatic and renal function test results 290 D. R. P. GUAY de Lorgeril et al. (1999) (14) 64 (type 2 hypercholesterolemic with previous confirmed Q-wave MI) 200 mg qd 12w(N = 32) or simvastatin 20 mg qd 12w(N = 32) DB, mean sign. changes from baseline to end of therapy: fenofibrate: TC 18%, a LDL-C 22%, a TG 43%, a fibrinogen 17% a simvastatin: TC 26%, a LDL-C 37%, a ubiquinone 19%, a LVEF at rest 6%, LVEDV at rest 8% transient dyspepsia in 3 fenofibrate and 1 simvastatin recipient

11 TABLE 3 (continued) Reference N (breakdown by hyperlipidemia type) Regimen Study Design Results except for above, neither treatment sign. affected LV function at rest or during exercise and neither had any effect on exercise ability (bicycle ergometry) Adverse events (No. patients) Deighan et al. (2001) (12) DAIS (2001) (17) Westphal et al. (2001) (68) 12 (proteinuric renal disease and hyperlipidemia) 418 (type 2 diabetics) 22 (hypertriglyceridemic males) 200 mg qd 2mo and cerivastatin 0.1 mg qd 1mo 0.2 mg qd 1mo (1 mo washout period) 200 mg qd 3yr(N = 207) or placebo 3yr(N =211) 200 mg qd 6w and gemfibrozil 900 mg d 6w (6-w washout period) CO AB, CO mean sign. changes from baseline to end of therapy: fenofibrate: serum creatinine 14%, a TC 19%, TG 41%, a VLDL-C 52%, a HDL-C 19%, a apo-b 27%, apo-cii 29%, a apo-ciii 26%, a apo-e 32%, total VLDL 55%, a VLDL 1 57%, a LDL I conc. 47%, a LDL 60%, a LDL III conc. 49% cerivastatin: TC 21%, TG 14%, a LDL-C 23%, apo-b 21% apo-cii 10%, a apo-ciii 7%, a apo-e 20%, total VLDL 26%, a total LDL conc. 18%, a LDL III conc. 27% a for fenofibrate, TG correlated with in VLDL 1 (r 2 = 0.705, p < 0.001) and LDL III conc. (r 2 = 0.675, p < 0.001). Also, RLP correlated with in VLDL 1 (RLP-C: r 2 = 0.607, p < 0.004; RLP-TG: r 2 = 0.683, p < 0.002) and in TG (RLP-C: r 2 = 0.582, p < 0.005; RLP-TG: r 2 = 0.555, p < 0.005). Also, LDL III correlated with both in RLP-C (r 2 = 0.446, p < 0.02) and in RLP-TG (r 2 = 0.350, p = 0.05). fenofibrate sign. TC, LDL-C and TG and HDL-C compared to placebo (figure only) fenofibrate (compared to placebo) treatment was associated with 40% less progression in minimum lumen diameter (p = 0.029), 42% less progression in percentage diameter stenosis less progression in mean segment diameter (p = 0.171). statistical power was insufficient to detect differences in clinical end points (6 deaths feno, 9 deaths placebo; 9 vs. 12 MI; 5 vs. 13 angioplasties; 14 vs. 18 CABG) mean sign. changes from baseline to end of therapy: fenofibrate: TG 35%, HDL-C 14%, thcy 35%, a creatinine 20%, a cystatin C 21%, a B6 2% a gemfibrozil: TG 47%, HDL-C 23% myalgias occurred in 1 pt. taking ceriv 0.2 mg d (resolved with dose reduction to 0.1 mg d). one pt. developed abnormal LFTs and CK while on fenofibrate (resolved with D C). no sign. intergroup differences in AE rates no data provided re AE FENOFIBRATE 291

12 Reference Levin et al. (2000) (45) Farnier et al. (2000) (25) Bairaktari et al. (1999) (3) Insua et al. (2002) (39) N (breakdown by hyperlipidemia type) 28 (renal dyslipidemia, TG > 200 mg dl or LDL HDL 5) 102 (severe primary hypercholesterolemia) 91 (primary mixed hyperlipidemia) 21 (N = 16 type IIa, N = 5 type IIb) Regimen mg qd or placebo, each for 6 mo (dose titration at mo 2 and 4, depending on response) 200 mg qd 16 w or 200 mg qd + fluvastatin 20 mg qd 16 w or 200 mg qd + fluvastatin 40 mg qd 16 w open 20 w extension with micro fenofibrate 200 mg qd mg qd fluvastatin 200 mg qd and atorvastatin 10 mg qd, each for 16 w 200 mg qd 6 w and gemfibrozil 900 mg qd 6w (4-w washout) Study Design DB DB CO DB, CO TABLE 3 (continued) Results 63% of feno pts. had a therapeutic response (30% in TG from baseline or LDL HDL ratio < 5) compared to 17% of placebo pts. (p = 0.015). feno produced a sign. in TG (mean 34%) and in HDL-C (mean 20%). at end of study, feno doses were 67 mg d (N = 6), 134 mg d (N = 7) and 201 mg d (N = 3). mean sign. changes from baseline to end of therapy: feno monotherapy feno + low dose fluva feno + high dose fluva were: TC %, LDL-C %, HDL-C %, TG %, apo-b % (pairwise statistical comparisons not provided) mean changes from baseline to end of therapy: fenofibrate: TC 16%, a LDL-C 18%, a HDL-C 17%, a TG 26%, a apo-ai 15%, a apo-b 19%, a fibrinogen 20% a atorvastatin: TC 25%, a LDL-C 35%, a HDL-C 5%, a TG 13%, a apo-ai 4%, a apo-b 30%, a fibrinogen 3% a Mean sign. Changes from baseline to end of therapy: fenofibrate (pooled): TC 22%, a LDL 27%, a TG 54%, HDL-C 9% apo-b 23%, fibrinogen 13%, uric acid 17% a gemfibrozil (pooled): TC 15%, a LDL 16%, a TG 47%, HDL-C 9%, apo-b 16%, fibrinogen 8%, uric acid 1% a fenofibrate (type IIb): TC 26%, a TG 67%, HDL-C 23% gemfibrozil (type IIb): TG 62%, HDL-C 20% Adverse events (No. patients) epigastric pain in 1 feno pt. led to premature D C after 1 mo. no other AE details provided. AE profiles of the 3 treatments were similar similar in types and frequencies no AE data provided 5 26 prematurely D C due to AE (3 feno: headache in 1, nausea abdominal pain in 1, rash in 1; 2 gemfib: diarrhea epigastric pain in 1, epigastric pain alone in 1). asymptomatic LFTsin4 subjects (2 while on feno, 1 while on gemfib, 1 while on both). no other details provided re AE. 292 D. R. P. GUAY

13 TABLE 3 (continued) Reference N (breakdown by hyperlipidemia type) Regimen Study Design Results Adverse events (No. patients) Lemieux et al. (2002) (43) Despres et al. (2002) (16) 79 (type IIa) 200 mg d for 16 w (N = 36) or pravastatin 20 mg d for 16w(N = 43) (at end of 8 w, if response to latter unsatisfactory, could to 40 mg d for final 8 w) 165 (low HDL-C, LDL-C > 125 mg dl, TG < 400 mg dl) 200 mg d for 12 w (N = 79) or atorvastatin 10 mg d for 12 w (N = 86) Mean sign. Changes from baseline to end of therapy: no data provided re AE fenofibrate: TC 18%, LDL-C 24%, HDL-C 13%, TC HDL-C ratio 27%, TG 26%, apo-b 26%, LDL peak particle size 1%. sign. correlations occurred between changes in LDL-C and apo-b (r = 0.84, p < ), changes in TG and changes in LDL peak particle size (r = 0.54, p < 0.001), and LDL size on treatment and TG at week 16 (r = 0.47, p < 0.005). pravastatin: TC 21%, LDL-C 28%, HDL-C 5%, TC HDL-C ratio 24%, TG 7%, apo-b 23%. sign. correlation existed between change in LDL-C and apo-b (r = 0.92, p < ). Mean sign. Changes from baseline to end of therapy: fenofibrate: HDL-C 13%, a TC 15%, a TC HDL-C ratio 24%, a LDL-C 16%, a TG 30%, a apo-ai 10%, a apo-aii 44%, a apo-b 17%, a fibrinogen 4%. a change in HDL-C correlated with change in TG (r = 0.28, p < 0.01). atorvastatin: HDL-C ratio 5%, a TC 28%, a TC HDL-C ratio 31%, a LDL-C 39%, a TG 15%, a apo-ai 5%, a apo-aii 23%, a apo-b 28%, a fibrinogen 25%. a change in HDL-C correlated with change in TG (r = 0.41, p < 0.01). proportion of pts. achieving HDL-C conc. 40 or 45 mg dl favored fenofibrate over atorvastatin in all cases 49 AE reported in 30.9% of atorvastatin recipients and 52 AE reported in 31.0% of fenofibrate recipients. 17% of atorvastatin recipients and 10% of fenofibrate recipients experienced 1 AE possibly or probably study treatment-related. premature withdrawal due to AE in 6 atorvastatin recipients (abdominal pain in N = 2; dyspepsia, nausea + headache + myalgia, leg cramps, leg cramps + abdominal pain in N =1 each) and 3 fenofibrate recipients (migraine, dizziness + nausea + headache, headache + dizziness + myalgia in N = 1 each) FENOFIBRATE 293

14 Reference Athyros et al. (2000) (2) N (breakdown by hyperlipidemia type) 120 (type 2 DM, TC > 220 mg dl, LDL-C > 130 mg dl, TG mg dl, HDL-C < 40 mg dl, apo-b > 150 mg dl) Regimen 200 mg d 24w(N = 40) or atorvastatin 20 mg d 24w(N = 40) or 200 mg d + atorvastatin 20 mg d 24w(N = 40) Study Design TABLE 3 (continued) Results mean sign. changes from baseline to end of therapy: fenofibrate: TC 16%, TG 41%, LDL-C 15%, apo-ai 6%, apo-b %, fibrinogen 21% atorvastatin: TC 31%, TG 30%, LDL-C 40%, HDL-C 9%, apo-b % combination: TC 37%, TG 50%, LDL-C 46%, HDL-C 22%, apo-ai 12%, apo-b %, fibrinogen 19% sign. intergroup differences occurred for HDL-C and fibrinogen (combination therapy vs. atorvastatin) and for TC, TG, LDL-C, apo-ai, and apo-b-100 (combination vs. both monotherapies) % of patients achieving ADA LDL-C, TG, and HDL-C targets for fenofibrate, atorvastatin, and the combination were %, %, and %, respectively (intergroup differences were sign. for atorvastatin vs. fenofibrate for all 3 lipid moieties and for combination vs. both monotherapies for all 3 lipid moieties) % 10-year probability for MI (baseline = 22%) for fenofibrate, atorvastatin, and the combination were %, respectively (all 3 treatments vs. baseline, atorvastatin vs. fenofibrate, and combination vs. both monotherapies were sign. different) Adverse events (No. patients) no significant AE were reported. Abbreviations: micro, micronized; randomized; AB, angiographer blinded;, parallel group; LDL, low density lipoprotein; TG, triglycerides; TC, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; LPL, lipoprotein lipase; feno, fenofibrate; AE, adverse event; PAI-1, plasminogen activator inhibitor-1; CH, combined hyperlipidemia; eod, every other day; NS, not significant; thcy, total homocysteine; DB, double-blind; NTG, nitroglycerin; ceriv, cerivastatin; SB, single blind; CRP, C-reactive protein; ator, atorvastatin; D C, discontinuation; VLDL-C, very low density lipoprotein cholesterol; Hct, hematocrit; LFT, liver function test; GI, gastrointestinal; MI, myocardial infarction; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end diastolic volume; CO, crossover; RLP, remnant lipoproteins; CK, creatinine phosphokinase; CABG, coronary artery bypass grafting; DM, diabetes mellitus; ADA, American Diabetes Association adenotes sign. intergroup intertreatment differences. 294 D. R. P. GUAY

15 FENOFIBRATE 295 = 22%, p = 0.006). In the combined endpoint of death from any coronary cause, nonfatal MI or stroke, gemfibrozil therapy was associated with a 24% risk reduction (p < 0.001) (67). In the Bezafibrate Infarction Prevention (BIP) study, 3090 patients with a prior MI or stable angina were randomized to receive bezafibrate, 400 mg d or placebo and were followed for a mean of 6.2 years. Their TC levels ranged from 180 to 250 mg dl, HDL-C levels were less than or equal to 45 mg dl, TG levels less than or equal to 300 mg dl, and LDL-C levels less than or equal to 180 mg dl. Bezafibrate increased HDL-C levels by 18% and reduced TG levels by 21%. The frequency of the primary endpoint (fatal or nonfatal MI or sudden death) was not significantly different between groups (bezafibrate 13.6%, placebo 15.0%) and the reduction in the cumulative probability of the endpoint was only 7.3% (p = NS). In a post hoc analysis in the subgroup with high baseline TG level ( mg dl), the reduction in the cumulative probability of the primary endpoint was significant (39.5%, p = 0.02) (63). There is no reason a priori to believe that fenofibrate therapy would not have at least equivalent results and such studies are currently underway. Several studies of the use of fenofibrate in the management of the hyperlipidemia of highly-active antiretroviral therapy (HAART) (specifically with protease inhibitors) have been published recently (8,15,64). In one trial, 69 HIV-seropositive individuals with hypertriglyceridemia of at least 6 months duration (unresponsive to at least 3 months of diet and exercise therapy) were randomized to fenofibrate 200 mg once daily (N = 22), bezafibrate 400 mg once daily (N = 25), or gemfibrozil 600 mg twice daily (N = 22). Among these patients, 18 also had hypercholesterolemia and 41 had lipodystrophy. Pooled analyses revealed mean decreases in TG and TC of 41 and 23%, respectively, at 6 months. These effects were maintained at 12 months (mean TG decrease = 41%, TC decrease = 22%; also LDL-C decrease = 23% and HDL-C increase = 20%). Sixty-four and 61% attained normal TG and TC concentrations at 1 year, respectively. There were no changes in the lipodystrophy. The authors suggested that the three fibrates were similar in their effects on TG and TC, although no numerical data were provided. The agents also appeared similar in their adverse event profiles, with mild gastrointestinal events occurring in 9% of subjects (8). Nine HAART recipients with hypertriglyceridemia due to protease inhibitors were treated with micronized fenofibrate 201 mg d for 3 months. Mean glucose and TG fell 23 and 73%, respectively, while TC, transaminases, viral RNA, and CD4 count were not significantly altered (15). Lastly, two HAART recipients with hypertriglyceridemia were treated with 268 mg d of fenofibrate, resulting in 77 and 84% reductions in TG after 10 months of therapy (64). In addition to hyperlipidemia, fenofibrate has been suggested as an adjunct to allopurinol in the management of hyperuricemia and gout (36). TOLERABILITY Although generally well-tolerated, fenofibrate has been associated with the following adverse events which may be causally related: hepatitis, cholelithiasis, cholecystitis, hepa-

16 296 D. R. P. GUAY tomegaly, myalgias, myasthenia, rhabdomyolysis, photosensitivity, eczema, and allergic pulmonary alveolitis. These events all occur in fewer than 10% of recipients (33). Fenofibrate enhances cholesterol gallstone formation, just as do other fibrates, by altering biliary composition and increasing the lithogenic index. Preexisting gallbladder disease is a contraindication to fenofibrate therapy (33). The safety of fenofibrate in pregnant and lactating women has not been established. It is classified in FDA pregnancy category C and use during breast feeding is discouraged as well (33). Since 1999, relatively few data have appeared in the medical literature regarding the safety of fenofibrate. A search of the literature revealed only three case reports of adverse events since Case reports have documented acute necrotizing pancreatitis (N = 1) (50), major allergic reaction (N = 1) (54), and rhabdomyolysis (N = 2 patients with endstage renal disease on dialysis given inappropriately high initial doses) (11). An epidemiologic study was conducted in France examining the relationship of fibrates and statins to gallstone development, using gallbladder ultrasonography. Eight hundred thirty of 5466 townspeople were randomly selected to participate. Fibrates were 80% fenofibrate, 15% bezafibrate and 5% ciprofibrate while statins were 64% pravastatin and 36% simvastatin. On univariate analysis, risk factors for gallstones included female gender (relative risk [RR] = 1.52), age >50 years (RR = 3.75) and use of fibrates (RR = 2.1). On multivariate analysis, the same three risk factors remained significantly associated (female gender RR = 1.9, age >50 years RR = 3.7, fibrates RR = 1.7). In contrast, statins had no effect on galbladder disease (9). Several studies have evaluated the effect of fibrates on renal function (7,46,57,65). A retrospective chart review was conducted on 10 patients demonstrating a reduction of renal function on fibrate therapy. All patients were male (37 71 years old) with a history of chronic renal insufficiency. Six were renal transplant recipients (5 6 on cyclosporine). Seventeen courses of fibrate therapy were evaluated (13 with fenofibrate, 3 with gemfibrozil, 1 with bezafibrate). Serum creatinine rose during all courses (as expected as this was the main inclusion criterion) from 2.1 ± 0.1 mg dl (mean ± S.E.M.) to an on-therapy peak of 2.8 ± 0.2 mg dl (35 ± 3% increase) and then fell to 2.1 ± 0.1 mg dl post-therapy. No changes were noted in cyclosporine concentrations and all CPK values were within normal limits. The rapid and complete reversibility suggested a renal hemodynamic mechanism. The actual frequency of this effect could not be ascertained from the data provided. Also, whether these data can be extrapolated to the general population is not known (46). In another study of similar design, a chart review was conducted of 27 patients developing renal impairment after starting fibrate therapy (25 with fenofibrate, 1 each on bezafibrate and ciprofibrate). Nineteen of 27 patients were solid organ transplant recipients. Serum creatinine and BUN rose a mean of 40 and 36%, respectively, after fibrate initiation (i.e., mean creatinine 1.60 mg dl at baseline and 2.29 mg dl after drug initiation) and returned to baseline after discontinuation in patients. The 6 patients with a permanent rise in serum creatinine were all transplant recipients. Again, overall frequency of this event could not be ascertained due to the study design (7). A small case series documented elevated serum creatinine concentrations in 6 patients upon initiation of fenofibrate. The mean ± S. D. percentage elevation was 35 ± 14 (range 13 58)% (i.e., mean 1.23 mg dl at baseline and 1.65 mg dl after drug initiation). In 2 patients, the elevation was dose-related. In 4 of the 6 patients, institution of gemfibrozil did not have the same effect (57).

17 FENOFIBRATE 297 Lastly, a retrospective review of fibrate recipients was conducted in a lipid clinic in Greece. This review avoided using patients with any other drugs conditions possibly affecting renal function. The mean elevations in serum creatinine upon initiation of fenofibrate (N = 60), ciprofibrate (N = 55) and gemfibrozil (N = 15) were 12% ( mg dl), 17% ( mg dl), and 6% ( mg dl), respectively (no statistical analysis provided). Similar alterations in BUN concentrations occurred as well. The authors hypothesized that the differences between the agents in their ability to inhibit PPAR á (with a resulting difference in production of vasodilatory prostaglandins) may have accounted for the lesser effect of gemfibrozil (gemfibrozil has no effect on PPAR á ) (65). With increasing evidence that elevation in plasma homocysteine is a risk factor for atherosclerotic cardiovascular disease (10,53,56,59), much interest has surrounded the effect of various antihyperlipidemics on the homocysteine pathway, including the fibrates. A randomized, placebo-controlled, double-blind, crossover trial was conducted in 20 males with documented coronary artery disease or at least two cardiovascular risk factors who also had hypertriglyceridemia and low HDL-C and needed fibrate therapy. The effect of micronized fenofibrate on plasma homocysteine was evaluated in a post-hoc analysis. After a four week diet stabilization phase, subjects were randomized to eight weeks of either placebo or micronized fenofibrate 200 mg once daily. At the end of the trial an 8-h postprandial lipemia study was conducted (fat load = 1 g fat kg body weight with 35% cream). After a five week washout phase, subjects crossed over to eight weeks of treatment with the agent not used pre-washout at the end of which the postprandial lipemia study was repeated. Fenofibrate therapy resulted in a 40.4 ± 20.5% (range %) rise in total plasma homocysteine (from 10.3 ± 3.3 to 14.1 ± 3.8 mmol L, p.001) in the fasting state. Hyperhomocysteinemia (defined as a plasma concentration 14 mmol L) occurred in 10% of placebo and in 45% of fenofibrate treated patients (p = 0.034). In the postprandial state, the increase in total plasma homocysteine was statistically-significant in placebo (mean 14%, p < 0.001) and fenofibrate (mean 21%, p < 0.001)-treated patients (no statistical comparison of placebo vs. fenofibrate effect was provided). Fenofibrate treatment also significantly increased plasma methionine, cysteine, threonine, and proline levels. However, in fasted patients there were no significant differences between the two treatments in their effects on plasma folate, vitamin B 6, vitamin B 12, or creatinine levels (5). In another study (Table 3), long-term micronized fenofibrate, 200 mg once daily, therapy was associated with significant elevations in total plasma homocysteine (mean 36%) and cysteine (mean 18%) while long-term atorvastatin 10 mg once daily had no effect. Plasma homocysteine increased in (90%) and decreased in 3 29 (10%) of fenofibrate recipients. In yet another study (also described in Table 3), six weeks of micronized fenofibrate, 200 mg once daily, significantly increased total plasma homocysteine (mean 35%) and decreased vitamin B 6 (mean 2%) while six weeks of gemfibrozil 900 mg once daily had neither effect (68). The effect of fenofibrate and bezafibrate on total plasma homocysteine was evaluated in 20 hypertriglyceridemic males. Ten received 6 weeks of micronized fenofibrate 200 mg once daily while the other ten received bezafibrate 400 mg once daily. The treatments significantly differed in the mean increase in total plasma homocysteine (fenofibrate 44%,

18 298 D. R. P. GUAY bezafibrate 18%) but did not in terms of changes in plasma folate, cobalamin, or vitamin B 6 (19). Lastly, a randomized, double-blind, placebo-controlled, crossover study was conducted in 29 hypertriglyceridemic males to evaluate the effect of vitamin supplementation on the plasma homocysteine response to fenofibrate. After a six week run-in phase, patients were randomized to 6 weeks of treatment with either placebo or folic acid 650 ìg plus vitamin B ìg plus vitamin B 6 5 mg per day orally (all patients received 200 mg once daily of micronized fenofibrate). After an eight week washout phase, patients received the treatment which they had not received pre-washout, again for six weeks. A significant difference occurred in plasma homocysteine elevation after placebo (44 ± 47%) and vitamin supplementation (13 ± 25%, p = 0.02) (18). From the above information, it does appear that fenofibrate elevates plasma homocysteine to a significant degree. However, this elevation can be largely mitigated by coadministration of a combination of folic acid, vitamin B 12 and vitamin B 6 orally. DRUG INTERACTIONS Fenofibrate does not alter the pharmacokinetics of cyclosporine but does enhance the hypoprothrombinemic effect of oral anticoagulants by an as yet unknown mechanism. The latter was seen with the other fibrates. A low but finite risk (3 5% for the combination of lovastatin plus gemfibrozil) of myopathy has been suggested for statin-fibrate combination therapy. The myopathy may progress to rhabdomyolysis and renal failure. The propensity for myopathy may differ with specific statin-fibrate combination. Combination low-dose statin plus fenofibrate therapy is infrequently associated with this side effect (33). Since 1999, a case report has been published of a 79-year-old male warfarin recipient who developed an elevated international normalized ratio (INR) (18.0) and rectal bleed one month after being switched from gemfibrozil to fenofibrate (1). In addition, a drug interaction study conducted in 23 healthy volunteers has documented absence of any interaction between fenofibrate and pravastatin (52). PHARMACOECONOMICS In 2000, a clinical outcomes model was developed using US data estimating the ability of fibrates (fenofibrate, gemfibrozil) and statins (lovastatin, pravastatin at 2 dose levels, simvastatin, fluvastatin, and atorvastatin) to reduce relative and absolute risks of developing coronary heart disease (CHD) in diabetics. A meta-analysis of 83 studies was conducted to evaluate the efficacy of these agents in lowering lipid levels. Framingham Offspring Study, San Antonio Heart Study, and Third NHANES data were used to determine median lipid values in type 2 diabetics with dyslipidemia. Predictions of relative and absolute risk reduction in CHD as a function of lipid level were assessed using Framingham Heart Study data. The cost of cardiovascular disease (CVD) was estimated using a de-