Since relatively few deaths will occur in a group of middle-aged subjects, approximately 20000 high-risk patients need to be studied for at least 5 years in a prevention trial to demonstrate whether treating hypercholesterolaemia produces a reduction in death rate. No such large well-designed trial has been performed. During a 5-10 year period of follow-up many more middle-aged subjects will develop non-fatal cardiovascular disease than will die. Thus if cardiovascular endpoints, and not death, are used in cholesterol-lowering trials, much smaller numbers of patients (approximately 4000) need be recruited to have a reasonable chance of showing a real effect if one exists. The two best controlled primary intervention studies (the Helsinki Heart Study and the Lipid Research Clinics Trial) each used different drug therapies in 4000 patients in two different countries and both demonstrated a significant improvement in cardiovascular risk with treatment of hypercholesterolaemia. Furthermore the improvement in cardiovascular risk increased progressively year by year. These two well-designed trials provide the strongest evidence that cholesterol-lowering therapy is worthwhile. Both these studies were of insufficient size to examine mortality as an end-point, and this was appreciated when they were designed. Despite this limitation some critics erroneously state that ‘the trials showed that treating hypercholesterolaemia has no effect on mortality’! Unfortunately, although well-designed trials have been undertaken, many poorly constructed trials with inconclusiveresults litter the literature and some hint at an increase in mortality due to violent death and suicide in treated patients. Overall, however, the weight of evidence favouring the judicious treatment of lipid disorders is great.
OTHER LIPID DISORDERS
Low lipid levels can be found in severe protein-energy malnutrition. They are also seen occasionally with severe malabsorption and in intestinal lymphangiectasia.
Familial a-lipoprotein deficiency (Tangier disease)
One of the two HDL apoproteins, apoprotein A-I, is deficient in homozygotes with this very rare disease, so that there is little HDL in plasma. Tangier disease is inherited as an autosomal recessive. The serum cholesterol is low, but serum triglycerides are normal or high. Cholesterol accumulates in reticuloendothelial tissue, although the mechanism is uncertain, producing enlarged and orange-coloured tonsils and hepatosplenomegaly. There are also corneal opacities and a polyneuropathy.