Drug Treatment for Hypercholesterolaemia

Abstract

In Britain hypercholesterolaemia is common, and roughly a quarter of the adult population have plasma cholesterol levels greater than 6.5 mmol/1. Such levels are widely accepted as being associated with an appreciable risk of coronary heart disease. The risk appears to be directly related to the concentration of low density lipoprotein (LDL) cholesterol which is usually reflected in the total plasma cholesterol measurement [1]. High density lipoprotein (HDL) cholesterol is inversely related to coronary heart disease [1-3] but controversy remains as to whether it is an independent risk factor [4], The majority of people with a raised plasma cholesterol level have polygenic hypercholesterolaemia which is likely to respond to dietary modification (optimised calorie intake, reduction in saturated fat intake, an increase in the ratio of polyunsaturated to saturated fatty acids, and an increase in food containing soluble fibre). However, patients with a number of monogenic inherited disorders such as familial hypercholesterolaemia and familial combined hyperlipidaemia, have a particularly high risk of coronary heart disease and often show an inadequate response to diet changes alone. At least one in 500 people have familial hypercholesterolaemia, which in many adults is characterised by tendon xanthomas, xanthalasma and early corneal arcus, and is inherited in an autosomal dominant manner. The higher plasma concentration of LDL and total cholesterol is due to the fact that the cells of affected individuals have reduced numbers of the receptors responsible for LDL uptake. Untreated, these people have an estimated 50 per cent risk of dying from coronary heart disease before they reach 60 [5], and a significant number die or are disabled in their thirties and forties. Homozygotes, who are fortunately rare, seldom survive beyond the age of 25. Recent studies showing a reduction in the incidence and mortality from coronary heart disease associated with lowering of plasma cholesterol levels in people with primary hypercholesterolaemia [6, 7] have resulted in renewed interest in drug therapy for people who do not respond adequately to dietary modification. Coronary heart disease appears to be reduced irrespective of the type of hypercholeste rolaemia, but the potential benefit is likely to be particularly great in people with familial hypercholesterolaemia because their risk is so high if they are untreated. A number of different forms of lipid-lowerin g medication are available. For most patients with hypercholesterolaemia and normal, or near normal, plasma triglyceride concentration, an anion exchange resin such as cholestyramine or colestipol is the first line of treatment. These resins are not absorbed but act in the intestine by binding bile salts and reducing their enterohepatic circulation. This results in increased hepatic synthesis of bile salts from cholesterol. The dose of cholestyramin e required may vary from 4 to 28 g per day and the plasma cholesterol level can usually be reduced by at least 15 to 25 per cent. LDL cholesterol