Lipid-Lowering Drugs in the Treatment of Atherosclerosis
The bile-acid-sequestering agents (resins) colestipol and cholestyramine are generally considered to be the most effective of the currently marketed drugs for lowering plasma LDL-C levels. The resins either have no effect on or produce a slight increase in HDL-C and TG levels. They are contraindicated as single-drug therapy of type III and IV hyperlipoproteinemia. The resins interrupt the enterohepatic circulation of bile acids and increase the number of LDL receptors and LDL catabolism. Because of this mechanism of action, the resins act synergistically with other available drugs. They are nonabsorbable drugs, and their long-term safety and ability to reduce CHD risk were demonstrated in the Lipid Research Clinics’ Coronary Primary Prevention Trial (1984). They are the only drugs recommended for use in children and young adults. If the cost is calculated per amount of LDL-C lowering, resin therapy compares favorably with other drugs except nicotinic acid. The disadvantages include the method of administration, gastrointestinal side effects, and altered absorption of many drugs, including the thiazides, ß blockers, coumarin anticoagulants, digitoxin, and thyroxine.
Nicotinic acid, an inhibitor of lipoprotein synthesis, reduced the incidence of CHD in the Coronary Drug Project (1975), and total mortality was reduced in the long-term follow-up evaluation. The advantages of nicotinic acid are cost, tablet form, and favorable lipid effects (reduced cholesterol, LDL-C., and TG and increased HDL-C). The disadvantages include flushing, which can be attenuated by pretreatment with inhibitors of prostaglandin synthesis, hyperuricemia, and hepatic function abnormalities. Gemfibrozil primarily reduces TG and increases HDL-C with variable effects on LDL-C. The heterozygous type II patient is unlikely to respond. The long-term safety and efficacy of gemfibrozil are currently being evaluated in the Helsinki Heart Study (1982). The effects and action of clofibrate are similar, decreased lipoprotein synthesis and increased lipolytic effect, but clofibrate is not routinely recommended because of long-term toxicity, as noted in the WHO study (Committee of Principle Investigators, 1978). Dextrothyroxine modestly lowers LDL-C., but its use is very limited because of cardiovascular problems (Coronary Drug Project Research Group, 1972). Probucol primarily lowers LDL-C but also lowers HDL-C. It accumulates in LDL, and the rate of LDL catabolism is increased. Studies currently under way suggest that probucol has an antioxidant effect and prevents cholesterol deposition in tissues.
A new class of drugs, the HMG-CoA reductase inhibitors, exemplified by compactin and mevinolin, offer great promise for the future for lowering LDL-C. They inhibit cholesterol synthesis, increase the number of LDL receptors and LDL uptake, and are very effective in the heterozygous type II patient. They also act synergistically with the resins.
KeywordsFamilial Hypercholesterolemia Lipid Research Clinic Helsinki Heart Study Coronary Drug Project Hypolipidemic Agent
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