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Bezafibrate

An Update of its Pharmacology and Use in the Management of Dyslipidaemia

Drugs volume 52, pages 725–753 (1996)Cite this article

An Erratum to this article was published on 01 January 1997

Abstract

Synopsis

The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors.

Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels.

In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone.

The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages.

Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive.

Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate.

In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.

Overview of Pharmacological Properties

Bezafibrate markedly decreases triglyceride levels: by stimulating the activity of lipoprotein lipase, and to a lesser extent, hepatic triglyceride lipase, bezafibrate promotes the catabolism of triglyceride-rich lipoproteins. Levels of high density lipoprotein (HDL) cholesterol, especially the HDL3 fraction, are increased, as are those of the attendant lipoproteins apolipoprotein AI and AII Effects on other apolipoproteins are less well documented.

Low density lipoprotein (LDL) and total cholesterol levels are also reduced by bezafibrate, probably by enhanced clearance of receptor-bound LDL particles. Apolipoprotein B associated with LDL cholesterol is usually decreased during bezafibrate therapy but may rise in some patients with type IIb or IV dyslipidaemia. In some investigations, bezafibrate reduced levels of atherogenic LDL particles and increased resistance of LDL to oxidation in vitro.

Bezafibrate decreases lipoprotein (a) [Lp(a)] levels in patients with abnormally high baseline values. Furthermore, elevated plasma fibrinogen levels are consistently reduced with bezafibrate but generally not with HMG-CoAreductase inhibitors. Decreases are moderate to marked in patients with or without diabetes mellitus and, like those seen in Lp(a) levels, are related to baseline values. Plasma fibrinogen levels declined by 12% compared with placebo (p = 0.001) in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), a secondary prevention study in 81 young male survivors of myocardial infarction. Bezafibrate also reduces platelet aggregability and blood viscosity in vitro.

Metabolic control, as measured by levels of fasting glucose, insulin and glycosylated haemoglobin (HbA1C), has remained unaltered or has improved in patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipidaemia who received bezafibrate, enabling dosage reduction or discontinuation of oral hypoglycaemic agents in some patients. Free fatty acid levels have also decreased in a few instances.

Absorption of bezafibrate is near-complete and the drug does not accumulate after multiple doses. The bioavailability of the sustained-release tablet relative to the standard tablet is about 90% and the elimination half-life (t½β) is longer. Bezafibrate has an apparent volume of distribution of 17L; it is highly bound to plasma proteins (≈95%). Clearance is predominantly by renal metabolism and is therefore impaired by renal dysfunction. The t½β of bezafibrate, normally 1.5 to 2 hours, is lengthened to about 20 hours in patients undergoing peritoneal dialysis.

Clinical Efficacy

In patients with type IIa, IIb or IV dyslipidaemia, bezafibrate decreases total cholesterol levels by about 10 to 30%. The level of LDL cholesterol is also reduced (generally by at least 10%) in those with type IIa or IIb dyslipidaemia, but is unaffected or may increase slightly in patients with type IV dyslipidaemia. A striking feature of the drug’s profile is its ability to reduce triglyceride levels by 40 to 50% or more, with the greatest change apparent in patients with hyper-triglyceridaemia (mainly types IIb and IV). HDL cholesterol levels are increased by about 10 to 30%. The calculated risk of coronary events and myocardial infarction decreased by 50% or more during bezafibrate therapy in the 16-week, noncomparative SPIRIT study in 712 patients with hypercholesterolaemia or familial combined hyperlipidaemia. The incidence of atherosclerotic lesion progression was more than 50% lower with bezafibrate than in a control group in a 4-year trial.

Based on direct comparisons in patients with type IIa or IIb dyslipidaemia, significant differences in efficacy are few amongst the fibrates tested, although investigations are sparse and generally included small numbers of patients. Bezafibrate appears to be at least as efficacious as clofibrate and fenofibrate, and more so than gemfibrozil in reducing LDL and total cholesterol levels in the short, but possibly not long, term. It was less effective than ciprofibrate (except for effects on HDL cholesterol). Comparative data in patients with type IV dyslipidaemia are scant; available results have not shown consistent differences between bezafibrate and the other fibrates investigated.

Conversely, there are distinct dissimilarities between bezafibrate (and fibrates as a whole) and HMG-CoA reductase inhibitors (e. g. simvastatin, pravastatin, lovastatin, fluvastatin). Bezafibrate decreases triglyceride levels and, in general, increases HDL cholesterol levels by a larger amount than these drugs. On the other hand, bezafibrate-induced reductions in LDL and total cholesterol levels are smaller.

These differences in efficacy profile work in favour when combining bezafibrate with an HMG-CoA reductase inhibitor in patients with severe dyslipidaemia, particularly those with type IIb or familial combined hyperlipidaemia. LDL cholesterol and total cholesterol levels decrease significantly, triglycerides decline by about 20 to 40% and in most instances, HDL cholesterol levels rise by up to 20%. Thus, the lipid-modifying effects of combination therapy are generally superior to monotherapy with bezafibrate or an HMG-CoA reductase inhibitor in such patients.

Bezafibrate monotherapy was more beneficial than other classes of drug therapy (bile acid sequestrants, probucol) in limited investigations; combining bezafibrate with these drugs offset disadvantages such as further reductions in HDL cholesterol levels caused by probucol or, in the case of colestipol, elevations in LDL cholesterol induced by bezafibrate in patients with type III dyslipidaemia. In patients with isolated low HDL cholesterol levels, bezafibrate increased this parameter by about 30%; adding nicotinic acid raised it further.

Patients with NIDDM commonly have dyslipidaemia (especially hypertriglyceridaemia and low HDL cholesterol levels) and are at high risk of coronary heart disease (CHD). In this group, bezafibrate improves the lipid profile to a similar extent to that in patients without diabetes mellitus, although effects on HDL cholesterol levels are more variable. Additionally, bezafibrate can enhance glycaemic control (see Overview of Pharmacological Properties summary). Bezafibrate was at least as effective as acipimox and, predictably, reduced triglyceride levels more than simvastatin and lovastatin, which had a greater effect on LDL and total cholesterol levels.

Bezafibrate is also beneficial in patients with renal insufficiency, decreasing triglyceride levels by 30 to 40% and total cholesterol levels by up to 20%, and increasing HDL cholesterol levels by about 10 to 20% in individuals undergoing haemodialysis. Dosage must be adjusted in such patients (see Dosage and Administration summary).

In the BECAIT secondary prevention trial, young male survivors of myocardial infarction who received bezafibrate for 5 years experienced fewer coronary events (3 vs 11, p = 0.02) and a smaller reduction in mean minimum luminal diameter (treatment effect: 0.13mm) than placebo recipients. In a separate investigation, bezafibrate reduced the rate of early arterial lesion progression in 356 asymptomatic patients with hyperlipidaemia, regardless of dyslipidaemia type.

Bezafibrate reduced the rate of restenosis following coronary angioplasty in 1 trial. A small retrospective analysis has demonstrated increased exercise workload and exercise-induced vasodilation of normal and stenotic arteries in men who had undergone coronary angioplasty and had received bezafibrate for 7 months; serum total cholesterol levels were inversely correlated with the latter finding in normal arteries. Amongst patients undergoing other cardiac procedures, bezafibrate was superior to fish oil and similar to lovastatin in its effects on lipid profile in patients with heart transplants.

Pharmacoeconomic Considerations

Bezafibrate was the least costly of several fibrates and HMG-CoA reductase inhibitors as measured by annual drug acquisition cost per 10% reduction in serum cholesterol levels; however, the assumptions used in this calculation are questionable and results should be interpreted cautiously. Similarly, although bezafibrate and other fibrates were less cost effective than acipimox in a separate study when clinical parameters such as gallstones, myocardial infarction and claudication were used in the calculation of efficacy, no data from comparable clinical trials are available to support the assumptions made.

Tolerability

Few adverse events have been recorded in clinical trials of bezafibrate. Gastrointestinal symptoms and cutaneous reactions are most frequent, with headache, loss of libido and drowsiness reported less often. More serious events such as rhabdomyolysis and worsening renal impairment are uncommon. These occur mainly in patients with compromised renal function who receive excessive dosages of the drug. There has been one report of anaphylaxis during bezafibrate therapy. Patients with diabetes mellitus or previous cardiac surgery have tolerated the drug well.

Bezafibrate is as well tolerated as other fibrates and HMG-CoA reductase inhibitors, as shown in direct comparisons, and is better accepted than cholestyramine. Serum levels of creatine phosphokinase and transaminases have risen in a few instances with bezafibrate and the comparator agents, but not sufficiently to cause treatment withdrawal. Concern that fibrates as a class may cause cancer has not been substantiated. The combination of bezafibrate and HMG-CoA reductase inhibitors has not increased the incidence of myalgia in clinical trials, but ongoing monitoring is prudent in general practice.

Drug interactions with bezafibrate are few. The drug can enhance the effect of anticoagulant drugs.

Dosage and Administration

The recommended dosage of bezafibrate in patients with types IIa, IIb, III, IV or V dyslipidaemia is 400mg as a sustained release tablet once daily in conjunction with dietary management. A dosage of 200mg 2 or 3 times daily as a standard tablet may also be used. Dosage reduction is required in patients with mild to moderate renal dysfunction, depending on serum creatinine levels. Bezafibrate is contraindicated in the presence of severe renal failure. A dosage of 200mg every 3 days has been used successfully in clinical trials in patients undergoing dialysis. Patients with impaired renal function must be monitored for symptoms of worsening renal dysfunction or myositis/myalgia.

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    Karen L. Goa, Lee B. Barradell & Greg L. Plosker

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Additional information

Various sections of the manuscript reviewed by: F. Beil, Medizinische Kernklinik und Poliklinik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany; U. Goldbourt, Henry N. Neufeld Cardiac Research Institute, Sheba Medical Center, Tel Hashomer, Israel; R. Ikeuchi, The Third Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan; I. Inoue, The Fourth Department of Medicine, Saitama Medical School, Saitama, Japan; G. Pagano, Istituto de Medicina Interna, Turin, Italy; M.W. Stewart, Human Diabetes and Metabolism Research Centre, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, England; G. Weir, Research Division Joslin Diabetes Center, Harvard University, Boston, Massachusetts, USA.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03260134.

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Goa, K.L., Barradell, L.B. & Plosker, G.L. Bezafibrate. Drugs 52, 725–753 (1996). https://doi.org/10.2165/00003495-199652050-00008

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Keywords

  • Simvastatin
  • High Density Lipoprotein Cholesterol
  • Lovastatin
  • Fenofibrate
  • Cholesteryl Ester Transfer Protein