New drugs for treating dyslipidemia: beyond statins

Abstract

Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment.

Keywords: Dyslipidemia; MTP inhibitor; PCSK9 inhibitor.

Fig. 1. Residual risk for developing cardiovascular disease still remains despite proper range of low density lipoprotein cholesterol reduction: Results from many different statin trials. 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events; WOSCOPS, West of Scotland Coronary Prevention Study; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; AFCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS, Heart Protection Study; PROSPER, Prospective Study of Pravastatin Elderly at Risk; CARDS, Collaborative Atorvastatin Diabetes Study; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-lowering Arm; TNT, Treating to New Targets; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; IDEAL, Incremental Decrease in End Points through Aggressive Lipid Lowering. Adapted from Lim et al., with permission from Elsevier [1].

Fig. 2. Therapeutic mechanism of pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Binding of PCSK9 to the low density lipoprotein (LDL) receptor leads to the degradation of LDL receptor at lysosome. PCKS9 inhibitor, a monoclonal antibody against PCKS9, inhibits the binding of PCSK9 and LDL receptor, which results in the recycling of LDL receptor and increased expression of LDL receptor at cell membrane. LDL-C, low density lipoprotein cholesterol.

Fig. 3. Therapeutic mechanism of lomitapide and mipomersen. The assembly of very low density lipoprotein (VLDL) requires the loading of triglyceride (TG) to the apolipoprotein B (ApoB) in the liver. The microsomal triglyceride transfer protein (MTP) works in this proccess and transfers TG to the ApoB. The secreted VLDL is converted to low density lipoprotein (LDL) in the bloodstream. The lomitapide inhibits the action of MTP and mipomersen inhibits the synthesis of ApoB. These two agents eventually inhibit the assembly of VLDL in the liver, which results in decreased LDL in the bloodstream. IDL, intermediate-density lipoprotein.