NEW TARGETS FOR LIPID-LOWERING AND ATHEROSCLEROSIS PREVENTION

The effectiveness of plasma lipid lowering in the clinic is well suppo rted by a growing number of contributions, indicating the significant improvement in cardiovascular risk in primary and particularly in seco ndary prevention. While these studies have clearly indicated that the more potent agents for cholesterol reduction can provide a very effect ive help, other pathways of lipid metabolism have gained interest. The se should be evaluated, in the hope of providing a more complete answe r to the question of regulating lipid absorption, distribution, and ti ssue deposition. In addition to newer more potent systemic lipid-lower ing drugs (in particular hydroxymethylglutaryl coenzyme A reductase in hibitors), nonsystemic agents, including cholesterol sequestrants, are receiving attention. Some of these are effective at low concentration s, thus providing a potentially powerful tool for plasma cholesterol r egulation. Another area of development is that of acyl coenzyme A chol esterol acyltransferase inhibitors, i.e., drugs interfering with chole sterol esterification in tissues, particularly in the arterial wall; t he major problem with these seems to be that of poor tolerability and of lack of definitive proof of plasma cholesterol reduction in humans. At present, drugs for the treatment of elevated lipoprotein(a) levels are not available, with few exceptions; in this case, a better unders tanding of the regulation of lipoprotein(a) metabolism and of the pote ntial benefit of treatment seems necessary. Elevation of congenitally low high density lipoprotein cholesterol levels may also be an importa nt target: microsomal enzyme inducers have been tested, but have not p rovided a clinically significant response; drugs with a mixed endocrin e-hypolipidemic activity possibly may prove effective. Other targets, e.g., the correction of the lipoprotein pattern characterized by ''sma ll low density lipoprotein,'' and the development of drugs specificall y acting on the cholesteryl ester transfer protein and lipoprotein lip ase systems, are being explored. Finally, new areas of development are in recombinant apolipoproteins (apo's) and in gene therapy. One case, i.e., that of apo A-I/HDL, is entering the clinical field; the mutant apo A-I-Milano might provide help because of a combined cholesterol r emoving/fibrinolytic activity. In the case of gene therapy, at present , data on low density lipoprotein receptor replacement are encouraging . Further options, such as gene transfer in the arterial wail to induc e vascular protection/disobliteration of occlusions, are also being te sted.