Ezetimibe therapy: mechanism of action and clinical update

Abstract

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.

Keywords: Nieman pick C1 like 1 protein; bile; coronary artery disease; ezetimibe; low-density lipoprotein cholesterol; statin.

Figure 1

Lipid and lipoprotein metabolism. Notes: Cholesterol, phytosterols and other lipids enter biliary micelles and are internalized via the NPC1L1 protein and the AP2/clathrin complex. Cholesterol can also reenter hepatocytes from the bile via canalicular NPC1L1. Nearly all phytosterols and some cholesterol are returned to the gut lumen or to the bile from hepatocytes via ABCG5 and ABCG8. Cholesterol can be converted in hepatocytes to primary bile acids, which are effluxed to the bile via ABCB11. ApoA-I is secreted by the liver or enterocyte or enters plasma on a chylomicron. VLDLs and chylomicrons traffic TG to muscle and adipocyte tissues. During lipolysis, surface phospholipids as well as fatty acids from the TG are also released: the resultant chylomicron remnant is cleared by the liver and the VLDL is converted to IDL, most of which are cleared by LDL receptors in the liver but some undergo additional lipolysis and form LDLs. During their plasma residence time the ApoB particles utilizing CETP exchange TG for CE with HDL particles. Smaller HDLs are lipidated at ABCA1, and larger HDLs at ABCG1 or SR B1. Larger HDLs can be delipidated by SR B1 at the liver, on adipocytes, or in steroidogenic tissues. Abbreviations: ABCA1, ATP-binding cassette transporter A1 (cholesterol efflux); ABCG1, ATP-binding cassette transporter (cholesterol efflux); ABCG5, ABCG8, ATP-binding cassette transporters G5 and G8 (sterol efflux); ABCB11, ATP-binding cassette transporter B11 (bile export pump); AP2, adaptor protein 2; ApA, apolipoprotein A; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL₂, larger HDL species; HDL₃, smaller HDL species; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; NPC1L1, Niemann–Pick C1-like 1 protein; SR B1, scavenger receptor B1; TG, triglyceride; TICE, transintestinal cholesterol efflux (putative receptor); VLDL, very low-density lipoprotein.

Figure 2

Effect of ezetimibe on NPC1L1-mediated internalization of cholesterol. Notes: NPC1L1 protein recycles between the plasma cell membrane and endocytic recycling compartment. When the extracellular cholesterol concentration is high, cholesterol is incorporated into the cell membrane and is sensed by cell surface–localized NPC1L1. NPC1L1 and cholesterol are then internalized together through clathrin/ AP2-mediated endocytosis and transported along microfilaments to the ERC in vesicles. The ERC is where cholesterol and NPC1L1 are stored. When the intracellular cholesterol level is low, ERC-localized NPC1L1 moves back to the PM along microfilaments in order to absorb cholesterol. Ezetimibe hinders the interaction of the NPC1L1/ cholesterol complex with the AP2-clathrin complex. Copyright © 2008, Elsevier. Adapted with permission from Ge L, Wang J, Qi W, et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008;7:508–519. Abbreviations: AP2, adaptor protein 2; ERC, endocytic recycling compartment; NPC1L1, Niemann–Pick C1-like 1 protein; PM, plasma membrane.

Figure 3

Proportional reduction in major ischemic events by mean decrease in LDL-C (mmol/L) in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (tertiles 1, 2, and 3 for severity of aortic valve stenosis) compared to 14 randomized trials in the Cholesterol Treatment Trialists meta-analysis. Copyright © 2010, Elsevier. Adapted with permission from Holme I, Boman K, Brudi P, et al. Observed and predicted reduction of ischemic cardiovascular events in the Simvastatin and Ezetimibe in Aortic Stenosis Trial. Am J Cardiol. 2010;105:1802–1808. The Study of Heart and Renal Protection (SHARP) data point is based on Baigent et al. 1 mmol/L approximates to 39 mg/dL of LDL-C. Abbreviation: LDL-C, low-density lipoprotein cholesterol.