New lipid-lowering agents acting on LDL receptors

Curr Top Med Chem. 2005;5(3):233-42. doi: 10.2174/1568026053544524.

Abstract

The treatment of dyslipoproteinemia has proven a successful strategy in the prevention of cardiovascular diseases. The major target of hypolipidemic drugs is the reduction of low density lipoprotein cholesterol (LDL-C). HMG-CoA reductase inhibitors (HMGRI) effectively lower LDL-C by inhibiting the mevalonate pathway and enhancing the activity of the LDL receptor (LDL-R). Numerous clinical studies demonstrated convincingly, that the reduction of LDL-C lowers the incidence of cardiovascular events in primary and secondary prevention. Two new HMGRI, rosuvastatin and pitavastatin, have been evaluated in clinical trials. Both drugs demonstrated efficacy in lowering atherogenic lipoproteins. In addition to the reduction of LDL-C, they may have a higher potency to lower triacylglycerides (TG) and to increase HDL cholesterol (HDL-C) compared to currently available HMGRI. Other therapeutic strategies examined in experimental animals are the inhibition of squalene synthase, the first enzyme of the mevalonate pathway, which is specifically committed to cholesterol biosynthesis, and the direct up-regulation of LDL receptor activity. The latter compounds, the SCAP ligands, are the first members of a new class of hypolipidemic agents affecting the transcriptional regulation of genes involved in lipid metabolism. Recent treatment guidelines emphasise the importance of modifying lipid metabolism beyond lowering LDL-C, mainly by lowering TG and raising HDL-C. Although these actions are not primary targets of the compounds discussed here, it is interesting that drugs inducing the LDL-R usually also lower TG and, in the case of HMGRI, increase HDL-C.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Arteriosclerosis / drug therapy*
  • Cholesterol, LDL / blood
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors
  • Farnesyl-Diphosphate Farnesyltransferase / chemistry
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / drug therapy*
  • Hypolipidemic Agents / pharmacology*
  • Hypolipidemic Agents / therapeutic use
  • Lipid Metabolism
  • Lipids / blood
  • Mevalonic Acid / metabolism
  • Receptors, LDL / blood
  • Receptors, LDL / drug effects
  • Receptors, LDL / metabolism*
  • Transcription, Genetic

Substances

  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • Lipids
  • Receptors, LDL
  • Farnesyl-Diphosphate Farnesyltransferase
  • Mevalonic Acid