Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins.
Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.
El Harchaoui
Karim
K
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands.
Akdim
Fatima
F
Stroes
Erik S G
ES
Trip
Mieke D
MD
Kastelein
John J P
JJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D002986:Clinical Trials as Topic; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011973:Receptors, LDL / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; D002784:Cholesterol