Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs.

Patients with heterozygous familial hypercholesterolemia (FH) constitute a unique population at high risk for the premature development of coronary artery disease (CAD) and in whom long-term hypocholesterolemic therapy to reduce elevated levels of low density lipoprotein (LDL) cholesterol is most clearly indicated. Optimal therapy invariably requires diet regulation plus hypolipidemic drug therapy. When used as single agents, the bile-acid sequestrants, cholestyramine and colestipol, lower LDL cholesterol concentrations by 20% to 35% in compliant patients, whereas decreases of 20% to 30% can be achieved with nicotinic acid in doses of 3 to 6 g/day. Bezafibrate, fenofibrate, and ciprofibrate have also been shown to lower LDL cholesterol levels by 20% to 30%, and these drugs are more effective than gemfibrozil and clofibrate. Probucol, neomycin, and D-thyroxine reduce LDL cholesterol concentrations by 10% to 15% in single-drug use. Clinical trials with a new class of drugs that inhibit the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, and that includes lovastatin, simvastatin, and pravastatin indicate that these drugs lower LDL cholesterol concentrations by 30% to 50% in patients with heterozygous FH. Combined drug therapy with a bile-acid sequestrant and nicotinic acid lowers LDL cholesterol by 40% to 55%, whereas fenofibrate, bezafibrate, or probucol plus a bile-acid sequestrant results in reductions varying from 25% to 50%. The combinations of an HMG CoA reductase inhibitor with either a bile-acid sequestrant or nicotinic acid appears to be the most promising, and these regimens reduce LDL cholesterol levels by 45% to 60%. With appropriate use, the currently available hypocholesterolemic drugs have the potential to markedly change the natural history of premature atherosclerosis that occurs in untreated patients with FH.