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PubMed1993

Hypertriglyceridemia and lowered apolipoprotein C-II/C-III ratio in uremia: effect of a fibric acid, clinofibrate.

We examined the effects of a fibric acid, clinofibrate, on lipoprotein metabolism in 12 hyperlipidemic patients with uremia treated on continuous ambulatory peritoneal dialysis during a 24 week treatment. Daily dose of clinofibrate was 200 mg for the initial four weeks, 400 mg for the second four weeks, and 600 mg for the subsequent 16 weeks. Serum and very-low density lipoprotein (VLDL) triglyceride were decreased by 36% and 48%, respectively. Neither total cholesterol nor apolipoprotein B changed significantly, whereas cholesterol was decreased in VLDL and increased in low (LDL) and high density lipoprotein (HDL) fractions. Post-heparin plasma lipoprotein lipase (LPL) before treatment was not lower than the normal value, and we found no change in LPL activity following clinofibrate. Hepatic triglyceride lipase also did not change. Apolipoprotein (apo) C-II/C-III ratio was low as compared to the normal value before treatment, and the ratio was increased by 38% after the treatment. Decrease in VLDL triglyceride was associated with increase in apo C-II/C-III ratio in all the cases. Abnormal enrichment with triglyceride of LDL and HDL fractions was improved by clinofibrate. Although one patient had a transient and asymptomatic elevation of serum creatine phosphokinase, no patient had muscle pain. There was no accumulation of the drug in the 24 week trial. These results suggest that clinofibrate is an effective and safe approach to the management of dyslipidemia in CAPD patients.

Adult↗
PubMed1991

Influence of fibric acid derivatives on intermediate filament proteins in myocardiocyte cultures.

We analyzed desmin and vimentin accumulation in chick myocardiocyte cultures treated with the fibric acid derivatives bezafibrate, fenofibrate and gemfibrozil. The most noteworthy finding was the 50% decrease in the cytoplasmic desmin fraction in cells treated with gemfibrozil in comparison to control cultures, and the 19% increase in the cytoskeletal fraction in cultures treated with gemfibrozil and with bezafibrate. Vimentin accumulation by cells treated with bezafibrate was similar to that in control cultures, however the cytoskeletal vimentin fraction rose by 26% after treatment with gemfibrozil, and fell 13% after treatment with fenofibrate. No vimentin was found in the cytoplasmic fraction of cell treated with bezafibrate. Given the role of intermediate filaments in heart muscle contraction, fibric acid derivative- induced changes in the cytoplasmic and cytoskeletal concentrations of intermediate filament proteins may be related with the secondary effects of these drugs on heart rate.

Animals↗
PubMed1985

Influence of a fibric acid type of hypolipidemic agent on the oxidative metabolism of arachidonic acid by liver microsomal cytochrome P-450.

The regiospecificity of arachidonic acid oxygenation, catalyzed by rat liver microsomal fractions in the presence of NADPH, can be altered by animal pretreatment with a fibric acid type of hypolipidemic drug, ciprofibrate. While microsomal fractions isolated from either control or phenobarbital-treated animals oxygenate arachidonic acid to mainly epoxyeicosatrienoic acids (EETs), animal pretreatment with ciprofibrate results in an eightfold stimulation of omega and omega-1 oxidation, concomitant with a net decrease in the formation of both HETEs and EETs. The isomeric composition of the EETs and of the omega and omega-1 oxidation products formed is also dependent on the type of animal pretreatment. Associated decreases in the amounts of HETEs and the rate of hydrogen peroxide formation suggests a modification of the "uncoupler action" of arachidonic acid during the function of different cytochromes P-450.

8,11,14-Eicosatrienoic Acid↗
PubMed1987

Effects of fibric acid derivatives on biliary lipid composition.

Fenofibrate, a potent analogue of clofibrate, causes changes in biliary lipid composition similar to those seen with clofibrate and other derivatives of fibric acid, although there is a suggestion that the increase in cholesterol content may be accompanied by an increase in phospholipid content as well as a decrease in bile acid content. This may favor liquid crystal formation, and fenofibrate may have less propensity to cause gallstones than would other derivatives. Many other factors are also important in determining whether supersaturated bile will result in gallstone formation, and the use of this compound should be monitored in the future to determine the clinical importance of these findings.

Bezafibrate↗
PubMed1998

Clinical pharmacokinetics of fibric acid derivatives (fibrates).

Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein (a), fibrinogen and uric acid. As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment. The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate. Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.

Anticholesteremic Agents↗
PubMed1991

Effects of fibric acid derivatives on accumulation of actin in myocardiocytes.

We used sodium dodecylsulphate polyacrylamide gel electrophoresis and immunoblotting to analyze the effects of the fibric acid derivatives bezafibrate, fenofibrate and gemfibrozil on the accumulation of actin in the cytoplasmic and cytoskeletal fraction of cultured myocardiocytes. All three drugs tested modified cellular and subcellular actin in different ways, and the findings are thought to be related with the secondary effect of arrhythmia known to be caused by these drugs. Bezafibrate and gemfibrozil more markedly affected accumulation of actin by myocytes, while fenofibrate interfered less notably with the accumulation of this protein.

Actins↗
PubMed1998

Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia.

We have investigated the effects of two fibric acid derivatives, bezafibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross-over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), cholesteryl ester transfer activity (CETA), plasma fibrinogen, plasminogen activator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreased (P < 0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34 +/- 1.05 (mean +/- S.D.), gemfibrozil 7.70 +/- 1.23 and bezafibrate 7.8 +/- 1.37 mmol/l). Both drugs decreased the serum triglyceride concentration (both P < 0.001) (placebo 4.39 (3.13-5.75) (median (interquartile range)), bezafibrate 2.26 (1.89-3.89) and gemfibrozil 2.00 (1.30-3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P < 0.001) (placebo 1.18 (0.74-2.30), bezafibrate 0.59 (0.34-0.85) and gemfibrozil 0.48 (0.34-0.68) mmol/l). Discontinuous gradient ultracentrifugation (DGU) revealed that Sf 60-400 (large VLDL) decreased by more than 50% and Sf 20-60 (small VLDL) by more than 30% with each of the drugs (both P < 0.001), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12-20 lipoprotein (intermediate density lipoprotein; IDL) by 23% (P < 0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0-12 lipoproteins (low density lipoprotein, (LDL)). Both, however, significantly increased the quantity of free cholesterol in Sf 0-12 lipoproteins (P < 0.05). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU (Sf 0-12, Sf 12-20, Sf 20-60, Sf 60-400) on gemfibrozil treatment, but only in Sf 20-60 and Sf 60-400 on bezafibrate (all P < 0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15 +/- 0.29, bezafibrate 1.27 +/- 0.38 (P < 0.01) and gemfibrozil 1.26 +/- 0.49 (P < 0.05) mmol/l) and HDL3 cholesterol concentration (placebo 0.59 +/- 0.12, bezafibrate 0.72 +/- 0.23 (P < 0.001) and gemfibrozil 0.70 +/- 0.24 (P < 0.01) mmol/l). Serum apolipoprotein A1 (apo A1) was increased (P < 0.05) by bezafibrate compared to gemfibrozil (placebo 103 +/- 26, bezafibrate 111 +/- 28 and gemfibrozil 102 +/- 25 mg/dl) and CETA from HDL to VLDL and LDL was decreased (P < 0.05) by bezafibrate compared to placebo, but the apparent decrease with gemfibrozil did not achieve statistical significance (placebo 39.6 +/- 17.7, bezafibrate 32.3 +/- 14.7 and gemfibrozil 33.8 +/- 15.0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased (P < 0.05) by gemfibrozil (placebo 4.16 (3.38-4.71) and gemfibrozil 4.65 (4.05-5.77) g/l) and was significantly lower (P < 0.001) on bezafibrate (3.60 (3.18-4.54) g/l) than on gemfibrozil treatment. There was a significant (P < 0.05) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6-64.5), bezafibrate 50.5 (35.1-73.9) and gemfibrozil 48.5 (31.5-5.4 U/l). Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin:cholesterol acyl transferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12-20 lipoproteins and the triglycerides in Sf 12-20 and 0-12 lipoproteins. Bezafibrate, however, increased serum apo A1 concentration and significantly decreased CETA. The two drugs also had different effects on the plasma fibrinogen levels, which increased with gemfibrozil and tended to decrea

Adult↗
PubMed2002

Comparison in patients with type 2 diabetes of fibric acid versus hepatic hydroxymethyl glutaryl-coenzyme a reductase inhibitor treatment of combined dyslipidemia.

Patients with combined dyslipidemia are at greatly increased coronary heart disease (CHD) risk. The threat of rhabdomyolysis with dual pharmacologic treatment (hepatic hydroxymethyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors plus fibric acid derivatives) has tended to limit therapy in patients with combined dyslipidemia to a choice of one or the other drug. Judgment of the potential benefits of either agent has rarely taken into account their effect on the postprandial accumulation of highly atherogenic, triglyceride (TG)-rich, remnant lipoprotein particles (RLPs). Because this information could be of substantial clinical relevance, we addressed this question in patients with type 2 diabetes and combined dyslipidemia by comparing the effects of gemfibrozil versus HMG-CoA reductase inhibitors (statins) on both fasting and postprandial lipid and lipoprotein concentrations. For this purpose, 22 patients with type 2 diabetes and combined dyslipidemia were randomized to treatment with either a statin or gemfibrozil for 3 months. Glycemic control was similar in both groups at baseline and did not change in response to treatment. Baseline lipid and lipoprotein concentrations were also similar in the 2 treatment groups, but the responses to therapy were quite different. Statin-treated patients had a statistically significant decrease in low-density lipoprotein (LDL) cholesterol concentration (156 mg/dL to 96 mg/dL, P <.001), whereas there was no change in patients treated with gemfibrozil. In contrast, there was a statistically significant decrease (P <.05) in plasma TG concentrations (116 mg/dL) in gemfibrozil-treated individuals, without any change in subjects treated with statins. However, the decrease in total integrated postprandial plasma RLP response measured hourly from 8 AM to 4 PM was not different in patients treated with either gemfibrozil (-43%) or statins (-34%). These results indicate that statin treatment, in addition to its beneficial effect on hypercholesterolemia, was as effective as gemfibrozil in reducing postprandial accumulation of triglyceride-rich, atherogenic RLPs in patients with type 2 diabetes and combined dyslipidemia. As such, the clinical utility of statin monotherapy in the treatment of combined dyslipidemia may have been underestimated.

Cholesterol, HDL↗
PubMed2004

Profiling of hepatic gene expression in rats treated with fibric acid analogs.

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal beta-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARalpha activation, although signaling through other receptors (e.g. PPARgamma, RXR) or through non-receptor pathways cannot be excluded.

Animals↗
PubMed1999

Micronized fenofibrate: a new fibric acid hypolipidemic agent.

OBJECTIVE: To review the efficacy and safety of fenofibrate in the management of hyperlipidemias. DATA SOURCES: A MEDLINE search (1974-October 1998), Current Contents search, additional references from article bibliographies, and the package insert from the manufacturer were used to identify data for evaluation. Studies evaluating fenofibrate (peer-reviewed publications, package insert data) were considered for inclusion. Abstracts and data on file with the manufacturer were not considered for inclusion. STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, clinical use, and tolerability of fenofibrate. Data from animals and in vitro systems were included only when necessary to explain the drug's pharmacology. DATA SYNTHESIS: Micronized fenofibrate is a fibric acid derivative approved by the Food and Drug Administration (FDA) in February 1998 for the treatment of types IV and V hyperlipidemia. Data from the peer-reviewed literature also support the use of fenofibrate in types IIa, IIb, and III hyperlipidemias. Micronized fenofibrate 67-201 mg/d is useful as monotherapy or as an adjunct to other hypolipidemics and dietary therapy. In placebo-controlled clinical trials, regular formulation fenofibrate 300-400 mg/d lowered serum triglyceride (TG) concentrations by 24-55%, total cholesterol by 9-25%, low-density lipoprotein cholesterol (LDL-C) concentrations by 6-35%, and raised high-density lipoprotein cholesterol (HDL-C) concentrations by 8-38%. Few comparative data exist regarding fenofibrate versus clofibrate and gemfibrozil. In noncomparative and comparative clinical trials, fenofibrate appeared to be well tolerated. The most common causally related adverse events were digestive, musculoskeletal, and dermatologic in nature. Concurrent use of fenofibrate and a hydroxymethylglutaryl-coenzyme A inhibitor may increase the risk of myopathy and/or rhabdomyolysis, although recent data suggest that concurrent use of fenofibrate with low-dose simvastatin or pravastatin is safe. Fenofibrate may enhance the effect of oral anticoagulants. CONCLUSIONS: Fenofibrate reduces serum TG, total cholesterol, and LDL-C, and raises HDL-C to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb, and III hyperlipidemias as well. To this extent, it may be considered a broader-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function). Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Cost-effectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia. The need for dosage titration of the micronized preparation from 67 mg/d upward to a final dose of 200 mg/d is also not supported by peer-reviewed literature (except in the case of renal impairment). Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.

Clinical Trials as Topic↗
PubMed2004

Role of fibric acid derivatives in the management of risk factors for coronary heart disease.

Although elevated low-density lipoprotein (LDL)-cholesterol is a well established coronary heart disease (CHD) risk factor, the ability to adequately discriminate high-risk individuals by this risk factor alone is limited and other metabolic risk variables are known to modulate CHD risk. For instance, it has been reported that the cluster of metabolic disturbances observed among individuals with abdominal obesity, the so-called metabolic syndrome, is associated with a substantially increased risk of CHD. Among the features of the dyslipidaemic profile observed in these individuals, the high triglyceride-low high-density lipoprotein (HDL)-cholesterol dyslipidaemia is predictive of an elevated risk of CHD. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-cholesterol levels, with a limited but significant additional lowering effect on LDL-cholesterol levels. Although the clinical benefits of HMG-CoA reductase inhibitors (statins) have been well documented by primary and secondary prevention trials that justify their widespread use, it was not until the publication of the VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) that the relevance of identifying HDL-cholesterol as a therapeutic target to reduce the risk of recurrent CHD events was finally confirmed. The clinical benefits of fibrate therapy are especially important in the subpopulation of patients with low HDL-cholesterol levels with the metabolic syndrome, particularly in patients with type 2 diabetes mellitus or in abdominally obese, hyperinsulinaemic patients. Evidence also suggests that there is a 'fibrate effect' that mediates the reduction in CHD risk beyond the favourable impact of these agents on HDL-cholesterol levels. This last notion is consistent with the pleiotropic effects of fibrates which are known to be related to their mechanisms of action. Through peroxisome proliferator-activated alpha-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Fibrate therapy has been reported to decrease apo CIII levels (a powerful inhibitor of lipoprotein lipase) and increase apo AI levels, as well as to increase lipoprotein lipase activity. Such changes contribute to improve the catabolism of triglyceride-rich lipoproteins, leading to a substantial increase in HDL-cholesterol levels accompanied by a shift in the size and density of LDL particles (from small, dense LDL particles to larger, more buoyant cholesteryl ester-rich LDL). It is proposed that some of these pleiotropic effects could explain some of the clinical benefits of fibrate therapy beyond its HDL-raising properties, particularly among patients with abdominal obesity, hyperinsulinaemia or type 2 diabetes with both low HDL- and low/normal LDL-cholesterol levels.

Anticholesteremic Agents↗
PubMed2006

Nucleophilic group transfer reactivity for fibric acid derived drug molecules.

A novel group transfer reaction is reported in which a drug molecule undergoes a thermally induced 2-methyl-2-yl-propionic acid group transfer from one drug molecule to the carboxylic acid functional group of another. The resulting product, the 2-carboxy isopropyl ester of the parent compound, can itself participate in further reactions to yield a series of homologous products. The structural requirements and solvent dependence of this reactivity were investigated, and the resulting implications for the reaction mechanism were discussed. The experimental data is consistent with solvent-assisted nucleophilic substitution reaction mechanism, where the solvent is a small molecule or a second drug molecule. Hydrogen bonding appears to play an important role in both intramolecular activation of the leaving group, as well as intermolecular interaction with the attacking nucleophile. The reactivity is found to be intrinsic to the 2-arenoxy-2-methylpropionic acid structure, which is common to the extended class of fibrate PPAR drug molecules, suggesting that the potential for this reactivity exists for many of these drug molecules as well.

Chemical Phenomena↗
PubMed1987

Fibric acids: effects on lipids and lipoprotein metabolism.

The major effect of the fibrates on triglycerides is to promote triglyceride-rich lipoprotein catabolism through increased lipoprotein lipase activity. Fibrates also enhance lipolysis of plasma triglycerides by a means different from that of caloric restriction. Their effect on very low-density lipoprotein metabolism also differs from that of nicotinic acid. The effect of fibrate therapy upon low-density lipoprotein-cholesterol concentrations depends upon the patients' overall lipoprotein status. The responsible mechanisms are not understood. In hypertriglyceridemic patients, fibrates often reverse abnormal changes in low-density lipoprotein composition; low-density lipoprotein heterogeneity is reduced and small dense low-density lipoproteins are eliminated, apparently secondary to reduced levels of triglyceride-rich lipoproteins. Kinetic studies indicate that fibrates do not enhance low-density lipoprotein formation rates, thus contradicting the idea that fibrate therapy causes increased low-density lipoprotein cholesterol levels via increased conversion of very low-density lipoprotein to low-density lipoprotein. Though enhanced low-density lipoprotein catabolism in hypertriglyceridemia could occur via several mechanisms, the responsible factors are largely reversed by fibrate therapy. In non-hypertriglyceridemic patients, fibrates may actually enhance the fractional clearance of low-density lipoprotein and thus reduce low-density lipoprotein levels. Fibrate therapy reverses the typical high-density lipoprotein pattern of hypertriglyceridemic patients, producing more high-density lipoprotein2a and less high-density lipoprotein2b. Such treatment also increases high-density lipoprotein cholesterol levels in patients without definite hypertriglyceridemia. Synthesis rates of apolipoproteins AI and AII may be affected by fibrates. The fibrates' major effects on sterol metabolism are interference with cholesterol and bile acid synthesis and increased cholesterol secretion into bile. Although bile saturation increases in most patients, in only a relatively small percentage do gallstones actually develop; super-saturated bile is not sufficient to induce gallstone formation in most patients. Available data strongly imply that fibrates mobilized cholesterol out of tissue pools, perhaps by altering tissue cell membranes to allow cholesterol release from the cell surfaces.

Bezafibrate↗
PubMed1987

Comparative toxicity and safety profile of fenofibrate and other fibric acid derivatives.

It is estimated that there are approximately six million patient-years of clinical experience with fenofibrate among physicians outside of the United States. A review of the European literature and unpublished studies supplied by the manufacturer (Laboratoires Fournier, Dijon, France) has been compiled with the data recently reported from a double-blind, placebo-controlled study completed in the United States. In general, fenofibrate has been found to reduce serum triglyceride levels by 30 to 60 percent in patients with type II B and IV hyperlipoproteinemia. Serum cholesterol levels were also reduced by 20 to 25 percent in this group of hypertriglyceridemic patients. A similar reduction in serum cholesterol levels was also found in type II A patients (normal triglyceride levels). Low-density lipoprotein levels were usually reduced in those patients with elevated levels and high-density lipoprotein levels increased when baseline levels were low. Fenofibrate also produced a 10 to 28 percent reduction in uric acid that was sustained for years. The incidence of unwanted effects ranged from 2 to 15 percent in the open trials lasting from a few months up to six years. Gastrointestinal problems (abdominal discomfort, diarrhea, and constipation) are most common, occurring in approximately 5 percent of patients. Reports including fatigue, headache, loss of libido, impotence, dizziness, and insomnia were grouped as neurologic and occurred with a total incidence of 3 to 4 percent. In about 1 percent of patients, muscle tenderness developed, often accompanied by elevated creatine phosphokinase levels. These and the gastrointestinal problems occurred with a similar frequency in the placebo-treated cohort in controlled studies. In approximately 2 percent of patients, a skin rash developed, an incidence that appears significantly higher than that of placebo control groups. Liver changes in rodents have included marked peroxisome proliferation and increased hepatic carcinomas with very high doses. In humans, only a small increase in incidence of elevated levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase seems to be present and is not clearly different from that of the control groups. Alkaline phosphatase, gamma-glutamyl transferase, and bilirubin levels are often decreased with no known undesirable effects. Investigations into the lithogenicity of bile indicated a significant increase in five studies. However, there has been no evidence of a significant rise in the incidence of cholelithiasis in the clinical trials completed to date.

Animals↗
PubMed1988

Hypertriglyceridemia and hyperuricemia: effects of two fibric acid derivatives (bezafibrate and fenofibrate) in a double-blind, placebo-controlled trial.

The effects of bezafibrate and fenofibrate on serum lipoproteins and serum urinary uric acid were compared. In a double-blind, placebo-controlled, cross-over study, each drug was administered in random order for 6 weeks followed by a 3-week drug-free phase to ten men with primary hypertriglyceridemia. Serum triglyceride and cholesterol concentrations decreased significantly with both fenofibrate and bezafibrate, although no significant change in serum apolipoprotein B, serum low density lipoprotein (LDL) cholesterol or serum high density lipoprotein (HDL) cholesterol concentrations was apparent. Serum uric acid levels, which were elevated on placebo and bezafibrate, were significantly reduced by 20% by fenofibrate. This was associated with an increase in renal uric acid clearance of 30% during fenofibrate therapy. Because it seems likely that hypertriglyceridemia and hyperuricemia are linked by a common carbohydrate inducibility, we studied the acute hyperuricemic response to orally administered fructose. Fructose (50 g) caused the anticipated rise in serum urate reaching a peak between 60 and 90 minutes, which was quantitatively greater in the men with hypertriglyceridemia than in healthy controls. The serum uric response to fructose was unaffected by bezafibrate, but was converted to normal by fenofibrate. The hyperuricemic action of fenofibrate is of sufficient magnitude to be of therapeutic value in the management of patients whose hypertriglyceridemia is associated with gout.

Bezafibrate↗
PubMed1998

Effects of fibric acid derivatives and metformin on postprandial lipemia.

It was suggested that postprandial lipoproteins (PPLp) may play an important role in atherogenesis. We studied PPLp metabolism and its response to drugs in seven hypertriglyceridemic subjects, 23 men with isolated low HDL-C levels, and nine non-diabetic glucose intolerant subjects. Results were compared with those found in a group of 19 healthy normolipidemic individuals. We used the vitamin A-fat loading test which specifically labels PPLp with retinyl palmitate (RP). In the hypertriglyceridemics the areas under RP curves of the chylomicrons were 6.3-fold and those of non-chylomicrons 2.9-fold higher than in normals (P < 0.01). Gemfibrozil 1200 mg/day caused a dramatic decrease in chylomicrons 73% and nonchylomicrons 31%. In subjects with isolated low HDL-C, RP chylomicron curves were significantly higher than in normals (17.733+/-6.821 vs 13939+/-6217 microg/l per h, P < 0.005). Bezafibrate 400 mg/day reduced RP chylomicrons and nonchylomicron levels by 35% (P < 0.0001) in 15 responders with an increase in fasting HDL-C 35+/-3 to 40+/-22 mg/dl (P < 0.0001). No response was found in eight subjects. In the nine glucose intolerant subjects, metformin reduced postprandial insulin area under the curve from 389 to 245 mU/ml (P <0.01) chylomicron and nonchylomicron RP areas were 3.6- and 3-fold higher than in normals and were reduced by 56 and 32%, respectively. In conclusion gemfibrozil, bezafibrate and metformin were shown to be beneficial in the clearance of PPLp in hypertriglyceridemic patients, subjects with isolated low HDL-C levels and nondiabetic glucose intolerant subjects, respectively.

Bezafibrate↗