New targets for lipid lowering and atherosclerosis prevention

The effectiveness of plasma lipid lowering in the clinic is well supported by a growing number of contributions, indicating the significant improvement in cardiovascular risk in primary and particularly in secondary prevention. While these studies have clearly indicated that the more potent agents for cholesterol reduction can provide a very effective help, other pathways of lipid metabolism have gained interest. These should be evaluated, in the hope of providing a more complete answer to the question of regulating lipid absorption, distribution, and tissue deposition. In addition to newer more potent systemic lipid-lowering drugs (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors), nonsystemic agents, including cholesterol sequestrants, are receiving attention. Some of these are effective at low concentrations, thus providing a potentially powerful tool for plasma cholesterol regulation. Another area of development is that of acyl coenzyme A cholesterol acyltransferase inhibitors, i.e., drugs interfering with cholesterol esterification in tissues, particularly in the arterial wall; the 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 understanding of the regulation of lipoprotein(a) metabolism and of the potential benefit of treatment seems necessary. Elevation of congenitally low high density lipoprotein cholesterol levels may also be an important target: microsomal enzyme inducers have been tested, but have not provided a clinically significant response; drugs with a mixed endocrine-hypolipidemic activity possibly may prove effective. Other targets, e.g., the correction of the lipoprotein pattern characterized by "small low density lipoprotein," and the development of drugs specifically acting on the cholesteryl ester transfer protein and lipoprotein lipase 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-IMilano might provide help because of a combined cholesterol removing/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 wall to induce vascular protection/disobliteration of occlusions, are also being tested.