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Ezetimibe - A New Class of Lipid-Lowering Drugs

Author: Pharma, Posted on Monday, May 10 @ 03:32:26 IST by RxPG  

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Pharmacology

Introduction

Statins are among the best-studied drugs for the primary and secondary prevention of atherosclerosis, and particularly of coronary heart disease. Their tolerability is generally very good. Their lipid-lowering effect is species and dose dependent, and the maximum lowering of the LDL cholesterol level can be up to 55%. The lowering of the LDL cholesterol is curvilinear, and each doubling of the dose leads to a 6% reduction of the LDL cholesterol (‘rule of six’). This rule also applies to the side effects, which most often involve the liver enzymes and the musculature. Raised liver values are found in 0.5–2.0% of the patients, and the incidence of myopathy is 0.1–1.0%. Higher incidences occur under combined therapies with other drugs. Rhabdomyolysis has been observed in 0.01– 0.1% of the patients treated [1, 2]. These side effects and other unwanted effects such as headache and gastrointestinal symptoms sometimes lead to intolerance of statins or to intolerability when the dose is increased. The facts that the target LDL cholesterol values cannot always be reached with statin monotherapy, that particular patients do not tolerate statins and that combinations with fibrates increase the risk of myopathy has led to the search for new lipid-lowering substances. Ezetimibe is an interesting new lipid-lowering substance with a new mechanism of action and – up till now – good tolerability.

Pharmacology

Ezetimibe was discovered by Schering-Plough, as the first selective intestinal cholesterol absorption inhibitor . There is evidence that it blocks the specific cholesterol receptors in the small intestine, but these findings still have to be confirmed. Mainly active in this respect is the glucuronidised substance, ezetimibe, which is recirculated in the enterohepatic circulation and inhibits the absorption of both endogenous and exogenous cholesterol. It is calculated that the endogenous cholesterol synthesis amounts to about 800 mg/day, while the diet provides approximately a further 400 mg of exogenous cholesterol. Normally, about 800 of these 1,200 mg of cholesterol per day are re-absorbed in the ileum (enterohepatic circulation). Under ezetimibe treatment, the excretion of cholesterol in the faeces is increased by about 400 mg per day. Dose-effect studies have shown that ezetimibe exerted its maximum lipid-lowering effect in trial subjects even at the dose of 10 mg; the effect was independent of the time of day that the drug was taken (once-daily dosage). Ezetimibe showed no interaction with the metabolism of simvastatin; in combination with gemfibrozil, increases in the gemfibrozil concentration were observed in some trial subjects. Impaired renal function has no influence on the pharmacokinetics of ezetimibe.

Clinical Studies of Monotherapy and Combined Therapy with Statins

The first investigations carried out were comparative studies versus placebo in patients with mild hypercholesterolaemia, in which it was shown that the LDL cholesterol was lowered on average by 17.4%, while HDL cholesterol increased by 2.6% in comparison with the placebo group and the triglyceride level decreased by 7.7%.

Under the combination of simvastatin 10 mg with ezetimibe 10 mg, the lowering of the LDL cholesterol was the same (44%) as that obtained with 80 mg of simvastatin alone. Also, the lowering of the LDL cholesterol obtained with 10 mg of atorvastatin in combination with 10 mg of ezetimibe was similar to that obtained with 80 mg of atorvastatin alone (53 and 54%, respectively). It therefore seems that even with low doses of statins, pronounced effects of ezetimibe are to be observed, and that with high levels of HMG-CoA reductase inhibition, the effect of ezetimibe is relatively more pronounced. The increase in HDL cholesterol obtained with combinations with various different statins was 1–3% in comparison with statin monotherapy, while with the addition of ezetimibe, the lowering of the triglyceride level was 7–9% more pronounced. An ‘add-on’ study in almost 1,000 patients using various statins showed that ezetimibe lowered the LDL cholesterol by 21% on average, while the HDL cholesterol increased by 2% and the triglyceride level was lowered by an additional 11%.
Side Effects

The incidence of side effects was as high under the combination of ezetimibe with statins as with statins alone. Ezetimibe should be used with caution or not at all in children under the age of 10 years, during pregnancy and in patients with moderate to severe impairment of liver function.

Clinical Indications of Ezetimibe

Ezetimibe is indicated particularly in co-administration with statins in severe cases of hypercholesterolaemia, especially familial hypercholesterolaemia (heterozygous LDL receptor defect). A further therapeutic indication is in patients who do not tolerate statins or who tolerate them only in small doses. In any case, the attempt should be made to combine low doses of statins with ezetimibe.

Rare Indications

Individual observations in homozygous familial hypercholesterolaemia, a rare genetic disease which is caused by the total absence of LDL receptors and which can already cause severe manifestations of atherosclerosis in children, have shown that ezetimibe is apparently also effective in this condition. Also, in homozygous sitosterolaemia, a lowering of the sitosterol and campesterol levels with ezetimibe has been observed in isolated cases.

Conclusions

Ezetimibe is an interesting new cholesterol-lowering drug; its synergistic effect with statins makes it particularly attractive. Unlike cholestyramine, ezetimibe is a systemically metabolised drug; however, its safety cannot be evaluated conclusively on the basis of the data that are available at the present time. Also, there are no long-term studies or cases available with hard end points (cardiovascular morbidity, mortality). For these reasons, ezetimibe is at present not a ‘first-line drug’ in the treatment of hypercholesterolaemia.



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