Ezetimibe and bile acid sequestrants are attractive add-on therapies to lower LDL-C

Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond

Literature - Couture P, Lamarche B - Curr Opin Lipidol. 2013 Apr 6

Couture P, Lamarche B
Curr Opin Lipidol. 2013 Apr 6


Next to statins, ezetimibe and bile acid sequestrants (BAS) are attractive therapeutic options for cardiovascular disease (CVD) prevention, specifically in patients with hyperlipidemia who are unable to reach defined lipid targets with statin alone, or in patients with poor tolerance to statins.
Evidence suggests an important role for the intestine in maintaining whole-body cholesterol homeostatis. We here summarise this review that outlines the current understanding of the effect of ezetimibe and BAS on lipoprotein metabolism.

Intestinal cholesterol absorption and transport: a brief overview

Cholesterol is an important component of cell membranes, the precursor of bile acids and steroid hormones and is involved in multiple, physiological cellular processes. When present in high quantities for a prolonged period, cholesterol accelerates atherosclerosis. The body has several mechanisms to maintain cholesterol homeostasis, including de novo cholesterol synthesis, intestinal cholesterol absorption, bile acid synthesis and biliary cholesterol excretion and clearance.
About 50% of cholesterol is absorbed and retained in humans. The exact molecular mechanisms that regulate the amount of intestinal cholesterol absorption are not well understood. Excess cholesterol is excreted by the liver into bile.
The small intestine is also an important site of cholesterol and lipoprotein synthesis. Animal studies have given insight in the transcriptional regulation of de novo cholesterol synthesis. Transcriptional activity of the key genes LDL-R (LDL-receptor), HMG-CoAR (3-hydroxy-3-methylglutaryl-Coenzyme A reductase), PCSK9 (proprotein convertase subtilisin kexin-9), NPC1L1 (Niemann-Pick C1-like 1) and ABCG5/G8 (ATP-binding cassette G5/G8) is altered depending on whether sterols are in excess or depleted, through action of sterol regulatory element binding protein-2 (SREBP-2).

Mechanism of action of ezetimibe

Ezetimibe is a selective inhibitor of cholesterol absorption. It has been demonstrated in experimental models that ezetimibe binds to NPC1L1 and blocks the vesicular internalisation of NPC1L1 and cholesterol. Blockage of cholesterol absorption was associated with upregulation of key intestinal genes and proteins involved in LDL-uptake and de novo sterol synthesis, to wit SREBP-2, LDL-R and HMG-CoAR.

Impact of ezetimibe on lipoprotein metabolism

Statins inhibit HMG-CoAR, the rate-limiting step in the cholesterol biosynthesis. Despite statins being the cornerstone of treatment of atherogenic dyslipidemia, many patients still have LDL-C levels above guideline recommendations. Next to the rate of cholesterol synthesis, efficiency of cholesterol absorption appears very important as well for regulation of plasma lipoprotein levels, and thereby for CVD development.
Clinical studies suggest that coadministration of ezetimibe with statins can provide an additional 12-19% reduction in LDL-C in patients with primary hypercholesterolemia. Functional studies in humans have revealed that the combination of ezetimibe and simvastatin enhanced the catabolism of VLDL and LDL apoB-100, without affecting their production rate. Evidence also suggests that ezetimibe improves postprandial lipidemia when co-administered with a statin, as opposed to statin monotherapy. A study in a mouse model of metabolic syndrome indicated that several key intestinal genes involved in intracellular lipid trafficking and metabolism were downregulated after ezetimibe treatment.

Bile acid sequestrants

Bile acids are synthesised from cholesterol in the liver, via one of two parallel pathways, and then secreted into bile along with cholesterol and phospholipids. Humans synthesise around 500 mg of bile salts each day in order to compensate for faecal losses.
BAS are positively charged non-absorbed resins that bind the negatively charged bile acids in the intestine. When in complex, it is excreted more readily in the faeces. This is accompanied with depletion of the bile acids pool and upregulation of conversion of cholesterol to bile acid and a relative intracellular cholesterol depletion. Intracellular cholesterol depletion induces upregulation of sterol-sensing SREBPs, which subsequently upregulate expression of HMG-CoAR and LDL-R. This results in enhanced de novo cholesterol synthesis and increased uptake of LDL particles by hepatocytes and subsequent reduction in plasma LDL-C concentrations. Thus, BAS achieve their cholesterol-lowering effects mainly by disruption of the bile salts enterohepatic cycle leading to increased cholesterol conversion into bile salts.
Three BAS exist: cholestyramine, colestipol and the newer and more potent colesevelam-HCL. Low doses are generally well tolerated, whereas high doses can give gastrointestinal side-effects such as decreased absorption of fat and fat-soluble vitamins, and reduced absorption of several drugs by nonspecific binding.
Clinical studies have shown a reduction in plasma LDL-C concentration of 10-28% when BAS was administered as monotherapy. Since there is a tight relation between bile salts and triglyceride-rich lipoprotein metabolism, treatment with BAS has been shown to result in increased plasma triglyceride levels.
In combination with statins, BAS can yield a 10-15% further reduction in plasma LDL-C levels. Furthermore, evidence exists that BAS improve glycemic control in insulin-resistant individuals with both reductions in fasting glycemia and HbA1C.


Both ezetimibe and BAS favourably contribute to whole-body cholesterol homeostasis, and are associated with a systemic lowering of plasma LDL-C levels. They act through modulation of gene expression of several genes involved in lipoprotein metabolism. Combination therapy of statins with either ezetimibe or BAS is therefore recommended in dyslipidemic patients who do not achieve target LDL-C levels on statin monotherapy, or in patients who do not tolerate statins very well.
Further studies should shed light on specific effects of ezetimibe and BAS on apolipoprotein kinetics and their impact on cardiovascular risk.

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