CORONARY EFFECT OF FIBRATES ON PROTEINS AND ENZYMES WHICH HYDROLYZE TRIACYLGLYCEROLS.

Clofibric acid derivatives called fibrates, are quite commonly used lipid-lowering drugs, so it is necessary to know beneficial and adverse effects of these compounds on the body. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that benefits of four fibrates such as: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil continue outweigh their risk in treatment of people with blood lipid disorders. According to recommendations of the CHMP fibrates should not be used as first-line drugs, except in patients with severe hypertriglyceridemia and patients who cannot use statins. In this paper, we focused on effect of clofibric acid derivatives on lipid metabolism, in particular on apoproteins and regulatory enzymes.

Fibrates: no ACCORD on their use in the treatment of dyslipidaemia.

PURPOSE OF REVIEW: New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. RECENT FINDINGS: Endpoint studies have been conducted with fibrates in coronary heart disease since 1971 and results have been contradictory. Fibrates have shown benefits in patients with low HDL-cholesterol and low LDL-cholesterol. Fibrates remain topical, given their actions on the lipid triad present in the metabolic syndrome and in diabetes. In the Fenofibrate Intervention in Endpoint Lowering in Diabetes study of mixed primary and secondary prevention cohorts, fenofibrate therapy resulted in an 11% reduction in coronary or cardiovascular events in monotherapy. Despite frequent use, there was little endpoint data on fibrate-statin combination therapy until recently. The Action to Control Cardiovascular Risk in Diabetes trial of fenofibrate added to baseline simvastatin therapy in diabetes showed a nonsignificant 8% reduction in cardiovascular events. The benefits were concentrated in men, and women did slightly worse with fibrate therapy. In post-hoc analysis, slight beneficial effects of fenofibrate were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-cholesterol (<0.88 mmol/l). The safety profile of fibrate-simvastatin combination was good. SUMMARY: Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes. They are safe in combination therapy with statins but add little endpoint benefit except possibly in patients with a significant degree of atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol). The benefits of fibrates on microvascular disease remain to be fully explored.

Lipid-lowering agents and new onset diabetes mellitus.

Statin treatment (and possibly niacin when given alone or in combination with statins) appears to be associated with a slightly increased risk of new onset diabetes mellitus (NODM). However, statin induced cardiovascular disease (CVD) risk reduction is greater in patients with DM than in non-diabetic patients in several survival studies. Thus, statin treatment outweighs any potential increase in CVD risk related to NODM and in high-risk Caucasian patients present clinical practice should not change. However, the risk/benefit ratio of treatment might not be as favourable in subjects with propensity to develop DM such as the elderly and in subjects of Asian ethnicity. Colesevelam was shown to improve both glycaemic control and lipid profile in inadequately controlled T2DM and might reduce the risk for NODM. There are no data on the incidence of NODM in fibrate-treated non-diabetic patients. Prospective studies are needed to clarify these issues.

[HDL and CETP in atherogenesis]. / HDL im Rahmen der Atherogenese und HDL-Steigerung durch CETP-Inhibition.

Despite optimal treatment of high low density lipoprotein (LDL) cholesterol with statins many cardiovascular events are not prevented. Additional therapeutic strategies are required to reduce the residual cardiovascular risk. Large epidemiological studies show an inverse correlation between the plasma concentration of high density lipoprotein (HDL) cholesterol and the incidence of cardiovascular events. Under physiological conditions, HDL is vasculoprotective and mediates the reverse cholesterol transport. However, new studies suggest that HDL particles represent a heterogeneous population. Under several pathophysiological conditions, HDL was shown to promote atherogenesis and inflammation. Interventional studies and metaanalyses examining the effect of increasing HDL cholesterol have reported mixed results. Inhibition of cholesteryl ester transfer protein (CETP) is a new and potent strategy to increase HDL concentrations. However, the first CETP-inhibitor torcetrapib increased blood-pressure and increased cardiovascular events despite increasing HDL. The blood-pressure increasing effects are not known for more recently developed CETP inhibitors such as dalcetrapib and anacetrapib nor in patients with genetic CETP deficiency. An increase of HDL cholesterol does not necessarily imply an improvement of the functional properties of HDL such as reverse cholesterol transport. An important open question remains the functional characterization of HDL generated by CETP inhibition. Important current clinical endpoint studies with new CETP inhibitors will elucidate whether increasing HDL by CETP inhibition leads to a reduction of cardiovascular events.

New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists with improved potency and reduced adverse effects on skeletal muscle function.

The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.

[Treatment of dyslipidemia in patients with metabolic syndrome and chronic kidney disease]. / Lécba dyslipidemie u pacientu s metabolickým syndromem a chronickým onemocnením ledvin.

Dyslipidemia, often present in patients with metabolic syndrome and chronic kidney disease, contributes to increased cardiovascular risk and progression of renal impairment. In these patients, the probability of death from cardiovascular complications is higher than death consequent to terminal renal failure. Positive neuroprotective effects ofstatins and fibrates are being attributed to hypolipidemic as well as other, lipid-unrelated, properties. Statins are able to slow down the decline in glomerular filtration rate and may decrease proteinuria. Nevertheless, conclusive evidence that statins decrease the incidence of cardiovascular complications in patients with advanced chronic kidney disease is still lacking. Through their effect on albuminuria, fibrates contribute to slowing down ofthe progression of diabetic nephropathy. Controlled trials and clinical practice have shown that monotherapy with statins as well as fibrates is safe. Management of combined dyslipidemia requires, apart from the selection of a suitable statin-fibrate combination, careful monitoring of potential adverse effects and treatment tolerability and compliance. The results of the Czecho-Slovakian pivot study KOLCHRI have demonstrated the efficacy and safety of fenofibrate combined with low dose statin in patients with metabolic syndrome and stage 2-4 chronic kidney disease.

Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine.

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

[Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. / Wirksamkeit und Sicherheit von Etofibrat bei Patienten mit nicht proliferativer diabetischer Retinopathie.

INTRODUCTION: Diabetic retinopathy is the leading cause of vision loss or blindeness in working-age adults in the developed and developing countries. No curative treatments are available for diabetic retinopathy and the most common symptomatic treatment, laser photocoagulation, provides only partial and temporary relief from the progressive vascular damage caused by this disease. Etofibrate (Lipo-Merz) is an orally-administered treatment for lipid disorders that combines fibrate and nicotinic acid in a slow-release formulation. PATIENTS AND METHODS: This report describes the results of a double-blind, randomised, placebo-controlled study, performed to evaluate the efficacy and safety of etofibrat in patients with type 2 diabetes mellitus and concomitant diabetic retinopathy. They received either placebo or 1000 mg/day etofibrate for up to 12 months. Efficacy analyses were based on visual acuity assessment and blinded expert ratings of ocular fundus pathology, as well as laboratory analyses of serum lipid parameters. RESULTS: The evaluable population comprised 296 patients, 148 in each treatment group, of whom 89% completed the study and 73% completed according to protocol. After 12 months of treatment, a significantly larger population of etofibrate-treated patients than placebo-treated patients showed improvements in ocular pathology (46% versus 32%, respectively, p < 0.001); similar findings were already apparent after 6 months of treatment (43% versus 31%, respectively p < 0.001). Etofibrate treatment also produced significant improvements in total cholesterol, LDL-cholesterol and HDL-cholesterol in comparison to the placebo treatment group. Safety evaluations (adverse events, laboratory parameters) did not reveal any clinically significant adverse effects of etofibrate in comparison to placebo. CONCLUSION: Etofibrate provides a safe and effective treatment for ocular pathology resulting from type 2 diabetes mellitus.

Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.

OBJECTIVE: Fibrates might represent a viable treatment option for patients who do not meet their target low-density lipoprotein levels on statins or who are resistant or intolerant to statins. New data from fibrate trials can be synthesized with the existing literature to better estimate their effects. METHODS: We systematically searched the literature to identify randomized, double-blind, placebo-controlled trials examining the effect of fibrates on lipid profiles or cardiovascular outcomes. We estimated the effect of fibrates on the incidence of nonfatal myocardial infarction and all-cause mortality using random effects models. RESULTS: Compared with placebo, fibrates were associated with greater reductions in total cholesterol (range: -101.3 mg/dL to -5.0 mg/dL) and triglycerides (range: -321.3 mg/dL to -20.8 mg/dL), and a greater increase in high-density lipoprotein (range: +1.1 mg/dL to +17.9 mg/dL) in all trials. Fibrates tended to be associated with a greater reduction in low-density lipoprotein (range: -76.3 mg/dL to +38.7 mg/dL) than placebo, although these results were not consistent across all trials. Fibrates were more efficacious than placebo at preventing nonfatal myocardial infarction (odds ratio=0.78; 95% confidence interval, 0.69-0.89), but not all-cause mortality (odds ratio=1.05; 95% confidence interval, 0.95-1.15). CONCLUSION: In addition to improving lipid profiles, fibrates are associated with an important decrease in nonfatal myocardial infarction, but do not substantially affect all-cause mortality. Potential applications include treatment for patients with statin resistance or isolated hypertriglyceridemia, or as an adjunct to other lipid-lowering therapies.

Myopathy with statin-fibrate combination therapy: clinical considerations.

Many patients who receive statin therapy for hyperlipidemia-such as patients with diabetes mellitus and metabolic syndrome--have residual cardiovascular risk. These patients often have dyslipidemia, including low levels of HDL cholesterol and elevated levels of triglycerides and small, dense LDL. For such patients, combination treatment with statins and fibrates is a potentially useful strategy to improve lipid and lipoprotein profiles and reduce cardiovascular risk. However, statin-fibrate combination regimens have potential adverse effects on skeletal muscle, including myopathy. To date, no large-scale, prospective, randomized, controlled trial has evaluated the safety and efficacy of statin-fibrate combination therapy; one such trial is underway but will not report data until 2010. Until then, clinicians need to consider pharmacokinetic, pharmacodynamic, metabolic, pathophysiologic and other factors that can increase the systemic exposure of statins and/or fibrates and hence heighten the risk of toxic effects on muscles, as well as data from clinical trials and recommendations of consensus panels to optimize the safety of such combination regimens. On the basis of currently available data, fenofibrate or fenofibric acid is the fibrate of choice when used in combination with a statin because each is, in theory, associated with a lower risk of myopathy than gemfibrozil.

[Fibrate-induced deterioration of renal function]. / Deterioro de la función renal inducido por fibratos.

INTRODUCTION: Fibrates represent one of the medications used to treat patients with hyperlipemia. Deterioration in renal function is not a very known adverse effect of fibric acid derivates. In the last 26 months we have detected thirteen patients with acute renal failure associated to fibrates in our outpatients' clinic. SUBJECTS AND METHODS: The aim of our study is to analyze our experience in deterioration in renal function associated to fibrates use. This is a retrospective charts review. RESULTS: From the thirteen patients (8 males/5 females) with mean age of 65.5 +/- 12.2 years, ten received Fenofibrate (FN), one Bezafibrate (BZ) and two Gemfibrozil (GF). Six cases had previously normal renal function and the seven remaining had mild chronic renal failure (CRF). The increase of serum Creatinine (Crs) value was higher than 74%. Acute renal failure was reversible in 9 patients (group 1), but the other 4 did not recover their previous renal function (group 2). The average of Crs before fibrate treatment was 1.33 +/- 0.36 mg/dl (Creatinine clearance 63.2 +/- 26.6 ml/min) and the highest average of Crs during the treatment was 2.22 +/- 0.49 mg/d (Creatinine clearance 37.3 +/- 11.9 ml/min). The average time until acute renal failure diagnosis was 6.7 +/- 5.8 months and the recovery of renal function was delayed an average of 3.8 +/- 3.5 months after fibrates withdrawn. Group 2 patients had a higuer Crs and longer time with fibrates than group 1 patients. CPK values were normal in all cases. In two patients renal biopsy was performed and no significant lesions were detected. CONCLUSION: The fibrate treatment can induce an acute renal failure. Four patients (30.8%) did not recover their basal renal function. When fibrate treatment begins a renal function should be monitored specially in patients with CRF.

Iatrogenic severe depression of high-density lipoprotein cholesterol.

The authors present 5 cases of paradoxical depression of high-density lipoprotein (HDL) cholesterol induced by fibrate drugs. In a 24-month review of all cases seen in one physician's practice at the Winnipeg Health Sciences Centre Lipid Clinic, 492 patients made a total of 1187 visits. Sixty-eight of them were given a fibrate drug (14%). Ten patients had HDL cholesterol levels that were less than 0.5 mmol/L (2%), and of these, 5 cases were due to exposure to fenofibrate (1%). These 5 cases comprised 7.4% of the 68 patients who were given any fibrate drug during that period. Mean levels were as follows: HDL cholesterol on fenofibrate 0.27, off fenofibrate 1.0 mmol/L and apo A1 on fenofibrate 0.41, off fenofibrate 1.17 g/L. A literature review revealed documented cases in 37 patients involving fibrates alone or in combination with other drugs known to cause decreased HDL cholesterol levels. In 13 patients, exposure was to fibrate therapy alone; in those exposed to combinations, the effect was clearly attributable to fibrates in 9; in 14, the nonfibrates (mostly rosiglitazone) were the attributable drugs; and in 1, it was impossible to tell. Thus, fibrate therapy should always be suspected as a cause of profoundly depressed HDL cholesterol.

Fibrates: where are we now?

UNLABELLED: Cardiovascular disease remains a leading cause of mortality worldwide. As dyslipidemia increases cardiovascular disease risk, proper management of dyslipidemia is one means by which to decrease cardiovascular disease risk. This review focuses on dyslipidemia treatment utilizing fibrate therapy, which targets high trigylcerides, low HDL, and high small, dense LDL, while contrasting fibrate therapy with statin therapy and combined therapy. Studies were obtained using electronic search strategies, such as Medline and Cochrane Library. Sources selected were limited to those that discussed fibrates, statins, and combined therapy, with specific emphasis placed on sources that focused on fibrates. Selected studies were then assessed for quality via analysis of the study's methodology, results, and data. RESULTS: of selected studies were then stratified using a rating system devised to determine the quality of results using the scientific evidence provided for them. Combination fibrate and statin therapy can be more effective in achieving optimal lipid levels than just fibrate or statin therapy alone without significant side effects as long as gemfibrozil is not used in therapy.

A case of rhabdomyolysis and thromboembolic event secondary to fibrate monotherapy.

Fibrates either alone or in combination with statins have been commonly used for the treatment of high non-HDL-cholesterol levels. In addition, this type of therapy is also associated with some adverse events like rhabdomyolysis. We present the first case in the literature describing the development of both rhabdomyolysis-induced acute renal failure and thromboembolic event under the treatment of fibrate monotherapy.

Therapeutic effects of fibrates in postprandial lipemia.

Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.

Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease.

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Fibrate therapy: an update.

Fibrates are a class of lipid-lowering medication primarily used as second-line agents behind statins. Acting via the peroxisome proliferators-activated receptor-alpha, their main lipoprotein effects are to lower serum triglyceride levels and to raise high-density lipoprotein-cholesterol, with modest effects on low-density lipoprotein-cholesterol. However, many clinical trials indicate that fibrates may have benefits beyond simply altering one's lipid profile. Several angiographic studies show retardation in the progression of atherosclerotic lesions in coronary vessels. Although clinical trials have failed to show a reduction in mortality with fibrates, several post hoc analyses indicate that there may be a mortality benefit in patients with features of the metabolic syndrome. Given that fibrates are often used as second-line agents, it is essential they are safe to be given in combination with other agents, particularly statins and ezetimibe. Although the side-effect profile of fibrates includes gastrointestinal symptoms, increased liver function tests, a reversible rise in creatinine and myositis, in general, fibrates seem to be safe to use in combination with other lipid lowering medications. Thus far, fibrates have not shown a mortality benefit in randomized clinical trials; as a result, they cannot be considered first-line medication for the primary or secondary prevention of coronary artery disease.

Use of statins and the risk of Parkinson's disease: a retrospective case-control study in the UK.

BACKGROUND: Case reports have related the use of HMG-CoA reductase inhibitors ('statins') to Parkinson's disease (PD). Paradoxically, however, statins may have potentially beneficial effects on neurodegenerative diseases due to their anti-inflammatory properties. OBJECTIVE: To explore the risk of the development of PD in association with untreated hyperlipidaemia and with hyperlipidaemia treated with lipid-lowering drugs in the UK primary care setting. METHODS: We conducted a case-control analysis using the UK-based General Practice Research Database (GPRD). Cases were incident PD cases > or =40 years of age between 1994 and 2005. One control was matched to each PD case based on age, sex, general practice and index date. Lipid-lowering drug use was assessed by exposure timing (current vs past use) and by exposure duration (1-9, 10-29 or > or =30 prescriptions) prior to the index date for both cases and controls. Odds ratios (OR) were calculated using conditional logistic regression, adjusted for body mass index, smoking and various cardiovascular, metabolic and psychiatric co-morbidities. RESULTS: We identified 3637 cases with an incident idiopathic PD diagnosis, and the same number of controls. Compared with patients without hyperlipidaemia, those with untreated hyperlipidaemia did not have an altered relative PD risk (adjusted OR 0.98, 95% CI 0.74, 1.30). The adjusted ORs for current use of > or =30 prescriptions for statins or fibrates compared with non-use of statins or fibrates were 1.06 (95% CI 0.75, 1.51) and 1.25 (95% CI 0.51, 3.06), respectively. CONCLUSIONS: In this observational study, the long-term use of statins or fibrates was not associated with a substantially altered relative risk of developing PD.

Fibrate-associated adverse effects beyond muscle and liver toxicity.

Fibrate derivatives have a 40-year history in the management of dyslipidemia. Although this class of drugs is generally well tolerated, several safety issues have arisen from their use. In the present article we review the literature describing side effects associated with the use of fibrates except for those that are liver and muscle related. These effects are less well known but are clinically relevant.