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Gemfibrozil

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Dyslipidaemia

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Summary

Synopsis

Gemfibrozil is a lipid-regulating agent which is genetically classified as a flbric acid derivative, but which exhibits different pharmacological effects from other such drugs. Published data indicate that in patients with all types of dyslipidaemia (except type I) gemfibrozil 800 to 1200 mg/day is particularly effective in reducing total plasma triglyceride concentrations. The reduction in total plasma cholesterol is statistically significant with the most pronounced response occurring in patients with severe hypercholesterolaemia. Gemfibrozil also effectively increases high density lipoprotein cholesterol. In a 5- year double-blind prospective placebo-controlled study in over 4000 male patients with types IIa, IIb and IV primary dyslipidaemia (but without coronary symptoms), gemfibrozil 600mg twice daily significantly reduced the incidence of cardiac events (by 34%) compared with placebo, although overall mortality was not affected. In comparative studies with clofibrate similar reductions in plasma lipid levels have been observed, although these changes tend to be more favourable overall with gemfibrozil. Gastrointestinal symptoms and rash are the only side effects produced more frequently with gemfibrozil than with placebo. Although gemfibrozil is hepatotoxic in male rats, drug-induced pathological liver changes have not been reported in humans.

Thus, gemfibrozil is an effective drug indicated for the treatment of severe hypertrig-lyceridaemia, and in certain patients with severe hypercholesterolaemia who are unresponsive to other standard therapies. In addition, it would appear to reduce the risk of cardiac events in patients with dyslipidaemia, although its effects on overall mortality remain speculative.

Pharmacodynamic Properties

Gemfibrozil is a lipid-regulating agent, which is classified a fibric acid derivative. In chow-fed animals and those with hypertriglyceridaemia induced by fructose administration or a high fat diet, gemfibrozil reduces plasma triglyceride concentration. Total plasma cholesterol is usually unaffected by gemfibrozil in animals fed a normal chow diet but is reduced in those fed a high cholesterol diet. High density lipoprotein cholesterol is increased during gemfibrozil administration regardless of diet. Gemfibrozil prevents abnormal lipoprotein accumulation in animals fed a high cholesterol diet, shifting cholesterol from low to higher density lipoprotein such that the resultant lipid, lipoprotein and apolipoprotein profiles resemble those of animals fed a normal diet. In normolipidaemic subjects gemfibrozil significantly decreases triglycerides, causes some reduction in total cholesterol, and increases HDL cholesterol. In dyslipidaemic patients both HDL2 and HDL3 subfractions may increase, apolipoproteins AI and AII are increased, and apolipoprotein B is decreased in the VLDL fraction. In certain hypertriglyceridaemics the LDL fraction may be increased.

Unlike clofibrate which markedly reduces plasma fibrinogen, gemfibrozil has no effect, although prekallikrein and kininogen activities are increased. Spontaneous blood coagulation in vitro is unaffected by gemfibrozil but heparin thrombin clotting time and erythrocyte sedimentation rate are markedly increased. Thus, the hypothetical effects of gemfibrozil in the management of atherosclerosis may not be solely due to a correction of dyslipidaemia but might also be due to protection against the accelerated coagulation tendency seen in these patients.

In normolipidaemic subjects gemfibrozil increases the lithogenic index of bile, but the magnitude of this effect appears to be less than that induced by therapeutically equivaient dosages of clofibrate. Certain other pharmacological effects of gemfibrozil, such as increased biliary apolipoprotein A secretion, may inhibit the increased tendency to gallstone formation. At present, there is no clear evidence from tolerability data that gallstones are induced by gemfibrozil.

The fundamental mechanism of action of gemfibrozil is not well established. Lipoprotein lipase activity is increased and hepatic triglyceride production is decreased, but more significantly there is a marked increase in the clearance of triglycerides from plasma. Increased HDL cholesterol is associated with increased synthesis of the major HDL carrier apolipoproteins AI and AII. It is difficult to interpret which of the effects of gemfibrozil are primary or secondary drug effects.

In toxicology studies gemfibrozil induces hepatomegaly and hepatic peroxisome proliferation. These effects appear to be specific to male rats. Gemfibrozil is not mutagenic but in male rats it causes the dose-dependent induction of hepatic and Leydig’s cell tumours at dosages over 10 times greater than the equivalent human therapeutic dosage, although there is no evidence that these effects occur in man.

Pharmacokinetic Studies

The pharmacokinetic properties of gemfibrozil have been studied in healthy subjects, but the influence of different disease states on kinetics has not been thoroughly investigated. The drug is rapidly and completely absorbed following oral administration, and a peak plasma concentration of about 20 mg/L is attained 1 to 2 hours after a single 600mg dose. Steady-state is achieved in 7 to 14 days after the administration of gemfibrozil 600mg twice daily. The drug is extensively (97%) bound to serum albumin in vitro, and will displace warfarin from protein binding sites. Unchanged drug, and several minor metabolites, are excreted primarily as glucuronide conjugates in urine. The mean elimination half-life of gemfibrozil is 7.6 hours.

In open studies and controlled comparisons against placebo and clofibrate, gemfibrozil 800 to 1600 mg/day decreased plasma triglycerides (40 to 60%) and total cholesterol (up to 20%), and increased HDL cholesterol concentrations (15 to 20%) in patients with types IIa, IIb and IV dyslipidaemia. The magnitude of the lipid-lowering effect was proportional to the duration of therapy, dosage, and initial severity of the dyslipidaemia. In some studies the mean reduction in total cholesterol was not clinically significant (<10%), but some individuals, particularly those with severe hypercholesterolaemia, responded with significant decreases. Total and LDL cholesterol levels were usually reduced slightly although some studies showed an increase of up to 15% in type IV patients. The maximum therapeutic response to gemfibrozil may take several months to be manifest though this can be increased by increasing dosage from 800 to 1200 mg/day in many patients. Only a few patients show additional improvement by increasing the dosage to 1600 mg/day.

Gemfibrozil 800 to 1200 mg/day produces similar reductions in plasma triglyceride and total cholesterol concentrations to those seen with clofibrate 1500 to 2000 mg/day, and similar percentages of patients achieve target levels of lipid regulation (63 vs 71%, respectively). However, gemfibrozil appears to produce a greater increase in plasma HDL cholesterol concentration, and the drug may therefore be more potent in reducing atherogenic risk.

The improvement in lipid and lipoprotein profiles attained during short and medium term controlled trials of gemfibrozil was retained in several long term extensions for up to several years, and a few patients continued to show some additional improvement in their lipid profiles. Recently, the Helsinki Heart Study prospectively assessed the effects of long term therapy with gemfibrozil on coronary heart disease in patients with primary dyslipidaemia. Over a 5-year period, gemfibrozil 600mg twice daily was associated with significantly fewer cardiac end-point events than placebo (27.3 vs 41.4 per 1000 patients), although overall mortality rates were similar in both groups.

In a small number of patients with dyslipidaemia secondary to renal impairment, normal therapeutic dosages of gemfibrozil were as effective in uraemic patients as in patients with primary dyslipidaemia, although nephrotic patients showed more accentuated percentage lipid changes. The pharmacokinetics of gemfibrozil have been studied in renal impairment with no evidence of drug accumulation.

In patients with dyslipidaemia associated with diabetes treated by diet, oral hypoglycaemic agents or insulin, gemfibrozil produced a similar degree of lipid regulation as seen in patients with primary dyslipidaemia uncomplicated by diabetes. Gemfibrozil 1200 mg/day exerted a greater hypotriglyceridaemic effect than clofibrate 1500 mg/day in diabetic patients. Unlike clofibrate, gemfibrozil did not potentiate the hypoglycaemic effect of tolbutamide and chlorpropamide. Minor increases in insulin or oral hypoglycaemic dosage were required in some patients receiving gemfibrozil.

Side Effects

Gastrointestinal symptoms and rash are the only effects occurring more frequently than with placebo, although the Helsinki Heart Study results are suggestive that these adverse effects diminish with time. There have been no reports of serious adverse reactions which are definitely attributable to the drug. Although biliary lipid metabolism is influenced in a similar manner as with clofibrate, available evidence indicates that gemfibrozil does not induce gallstone formation. No clear pattern of drug-related toxicity is indicated by clinical laboratory tests. Thus, gemfibrozil appears to possess a particularly favourable side effect profile, but as with all drugs long term tolerability needs to be assessed continually.

Dosage and Administration

Patients with dyslipidaemia should be treated initially by non-pharmacological methods (reduction of excess bodyweight, dietary and alcohol control, and exercise), and contributory diseases should be looked for and treated appropriately. Only if these fail should drug therapy be considered; dietary and other methods should also continue if drug therapy is found to be necessary.

The recommended dosage of gemfibrozil is 600mg twice daily given 30 minutes before morning and evening meals. Some patients may respond to 900 mg/day, and a few may require 1500 mg/day. Gemfibrozil is indicated for adult patients with all types of dyslipidaemia (except type I), particularly those who present with very high serum triglyceride concentrations (>7.5 g/L) at risk of abdominal pain and pancreatitis. The drug can be used selectively in patients with a clearly defined risk due to severe primary hypercholesterolaemia and in patients with dyslipidaemia secondary to diabetes. Results of a long term prospective study suggest that gemfibrozil reduces the risk of cardiac events in asymptomatic men with all types of primary dyslipidaemia.

Contraindications include hepatic or renal dysfunction, gallbladder disease, and known hypersensitivity to gemfibrozil. The dosage of concomitant anticoagulant therapy needs to be reduced and in such patients prothrombin time needs to be monitored regularly until bleeding time is maintained and stabilised. Safety and efficacy have not been established in children, and gemfibrozil should only be used in pregnant or lactating women if the benefit clearly outweighs any potential risk.

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    Peter A. Todd & Alan Ward

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Various sections of the manuscript reviewed by: K. Berg, Institute of Medical Genetics, University of Oslo, Oslo, Norway; A. Eisalo, First Department of Medicine, University of Helsinki, Helsinki, Finland; O. Leiss, Medizinische Universitätsklinik, Bonn, West Germany; J.E. Lewis, Sunnyvale Medical Clinic, Sunnyvale, California, USA; V. Manninen, First Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; E.R. Nye, Dunedin Medical School, Dunedin, New Zealand; P. Samuel, Manhasset Hospital, Manhasset, New York, USA; K. von Bergman, Medizinische Universitätsklinik, Bonn, West Germany.

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Todd, P.A., Ward, A. Gemfibrozil. Drugs 36, 314–339 (1988). https://doi.org/10.2165/00003495-198836030-00004

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