Cholesterol Absorption Inhibitors: Defining New Options in Lipid Management W

Cholesterol absorption inhibitors: Defining new options in lipid management W. Virgil Brown, Emory University

Journal Title: Clinical Cardiology Volume: Volume 26, Number 6 Publisher: Wiley Open Access: Various Creative Commons Licenses | 2003-06-01, Pages 259-264 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1002/clc.4950260604 Permanent URL: https://pid.emory.edu/ark:/25593/v75qr

Cholesterol Absorption Inhibitors: Defining New Options in Lipid Management

W. VIRGIL BROWN, M.D. Emory University School of Medicine, Atlanta; Medicine Service Line, Atlanta VA Medical Center, Decatur, Georgia, USA

Summary: Although many studies have documented that re- ing greater LDL-C and triglyceride reductions and greater im- duction of plasma cholesterol levels decreases the risk of coro- provements in HDL-C than statin monotherapy. This could of- nary artery disease, it remains the most common cause of fer another important option in clinical practice for manage- death in the Western world. Current therapeutic options are ef- ment of hypercholesterolemic patients. fective in lowering cholesterol, especially in clinical trials, but clinical application is not optimized for many reasons. Dietary restriction for long-term management of hypercholesterol- Key words: hypercholesterolemia, dyslipidemia, statins, com- emia is helpful but usually insufficient to reduce low-density bination therapy, ezetimibe, cholesterol absorption inhibitors lipoprotein cholesterol (LDL-C) to goal levels. Powerful drugs are available, but these are often insufficient to meet the clinical demands for cholesterol-lowering therapy. Phytosterols Introduction and phytostanols have been partially effective by providing some inhibition of absorption of cholesterol. Compounds that The risk of coronary artery disease (CAD) correlates di- specifically and more effectively block intestinal absorption of rectly with total serum cholesterol and its major component, dietary and biliary cholesterol should provide a significant low-density lipoprotein cholesterol (LDL-C).1, 2 An inverse new agent for altering lipoprotein concentrations favorably. relationship exists between high-density lipoprotein choles- Ezetimibe is the first of this class of compounds that act at the terol (HDL-C) and CAD.1 Several clinical trials have demon- gut epithelium to reduce cholesterol absorption in the mil- strated the benefit of lowering total cholesterol and LDL-C ligram dose range markedly. Clinical studies indicate that eze- and increasing HDL-C.3Ð9 However, CAD remains the most timibe effectively decreases LDL-C by 15 to 20% as mono- common cause of death in the Western world.10 Current ther- therapy, with a favorable safety profile. Moreover, results from apeutic options are effective in lowering cholesterol, especial- preliminary clinical trials indicate that ezetimibe given con- ly in clinical trials, but clinical application is not optimized for comitantly with a statin provides additive efficacy. The combi- many reasons.11, 12 In fact, recent studies have revealed that nation represents a new approach to lipid management, achiev- many high-risk patients receiving lipid-lowering therapy are still not at recommended National Cholesterol Education Program goals for LDL-C.11, 13, 14 Furthermore, numerous angiographic, epidemiologic, and clinical trials have demonstrated the beneficial effects of lowering serum cholesterol, including reducing the progression of atherosclerosis15 and The author was a consultant to Schering-Plough Corporation during reducing the incidence of coronary and cerebrovascular the development of the agent ezetimibe. events.16 Moreover, knowledge of the dynamics of atherosclerotic plaque formation, including the role of lipoprotein and Source of financial support: Schering-Plough Research Institute, Kenilworth, N.J. chylomicron composition, is evolving and leading to a better understanding of the mechanisms involved in preventing coro- Address for reprints: nary artery-related events.17Ð20 W. Virgil Brown, M.D. New options are needed to meet the clinical demands for Emory University cholesterol-lowering therapy. One of the most promising new Atlanta VA Medical Center classes of drugs is the selective cholesterol absorption in- Decatur, GA 30033, USA hibitors, the first of which is ezetimibe. Ezetimibe is a selective e-mail: [email protected] inhibitor of cholesterol absorption that significantly lowers Received: July 11, 2001 LDL-C and very low-density lipoprotein cholesterol (VLDL- Accepted with revision: October 16, 2002 C). An associated small rise in HDL-C and a fall in triglyc- 260 Clin. Cardiol. Vol. 26, June 2003 erides may accompany this effect.21Ð23 Moreover, preliminary A New Class of Drugs clinical trial results indicate that ezetimibe given concomitantly with low-dose 3-hydroxy-3-methylglutaryl coenzyme A Ezetimibe, 1-(4-flurophenyl)-(3R)-[3-(4-flurophenyl)-(3S)- (HMG-CoA) reductase inhibitors (statins) represents a new hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH approach to lipid management, achieving greater LDL-C re- 58235), is a 2-azetidinone (Fig. 1). It is the first of the selective ductions while offering a safety profile similar to that of statin cholesterol absorption inhibitors, compounds that effectively monotherapy.24Ð26 This could increase the number of patients block absorption of dietary and biliary cholesterol.29Ð31 Se- in clinical practice in whom optimal cholesterol concentra- lective cholesterol absorption inhibitors prevent the absorption tions are possible. Also, ongoing in vitro and animal study re- of cholesterol by inhibiting the passage of dietary and biliary sults with ezetimibe may help define the role of the cholesterol cholesterol across the intestinal wall.31 Ezetimibe selectively content of chylomicron and VLDL-C remnants in the athero- blocks dietary and biliary cholesterol before cholesterol reach- sclerotic process and provide an additional rationale for man- es acyl-CoA:cholesterol acyltransferase (ACAT) for esterifica- aging the concentration and composition of the triglyceride- tion.23 Ezetimibe does not affect the absorption of triglycerides, rich lipoproteins. as do pancreatic lipase inhibitors (e.g., orlistat), and does not decrease the absorption of fat-soluble vitamins, which may occur with bile acid sequestrants and plant sterols.31 Inhibiting Cholesterol Absorption Ezetimibe is rapidly and extensively conjugated by uridine diphosphate-glucuronosyltransferase in the intestine and is Plasma cholesterol is derived from biosynthesis and intes- then quickly circulated to the liver and returned to the in- tinal uptake.27, 28 In most patients, approximately 50% of testines via the bile, with only minimal urinary excretion.32Ð34 cholesterol available for intestinal uptake comes from biliary The estimated effective half-life of ezetimibe in humans is 24 secretion, 31% from diet, and 19% from intestinal cell degra- h.32 Accumulation within the epithelial cell of the small intes- dation. From the cholesterol in the intestine, 40 to 60% is ab- tine, high extraction from the portal venous blood, and rapid sorbed and the remainder is excreted in feces. In the average enterohepatic recycling appear to cause localization of ezetim- person, about 500 mg of cholesterol passes into the blood each ibe within the intestinal lumen, with a small associated sys- day as a component of chylomicrons. temic exposure.33, 34 This recycling provides for a long half- Absorption of cholesterol occurs in the proximal small in- life with predominant localization in the intestine and permits testine and requires emulsification, hydrolysis of ester bonds, once-daily administration without regard to meals. Studies micellar solubilization, absorption into the intestinal cells, in men and women, as well as in young and elderly adults, in- reesterification within the cells, incorporation into chylomi- dicate no clinically significant pharmacokinetic differences crons, and secretion into intestinal lymphatics.28 Chylomi- between these groups.32, 33 At doses of 20 mg daily (twice the crons enter the blood from the lymph, where lipoprotein expected recommended dose), ezetimibe has no effect on N- lipase hydrolyzes triglycerides, converting them into chylo- acetyltransferase or the cytochrome P450 enzymes CYP1A2, micron remnants. These remnants, which may be atherogenic 2D6, 3A4, or 2C8/9.35 No pharmacokinetic interactions be- when sufficiently small or when the endothelium is sufficient- tween ezetimibe and statins have been identified.36Ð38 Thus, ly damaged, are transported in blood from the surface of pe- combination therapy should be safe and predictable. ripheral endothelial cells to the liver for further processing. Within the liver, the cholesterol delivered by chylomicrons Other Intestinally Acting Agents enters the cholesterol pool that controls the synthesis of several key proteins in the regulation of cholesterol metabolism, in- The intestine is also the main site of action of other drug cluding the LDL-C receptor and HMG-CoA reductase. Some classes sometimes used to decrease blood cholesterol levels. of this cholesterol is directly excreted into bile, some is me- However, these drugs may be poorly tolerated, and their mech- tabolized into bile acids, and the remainder is packaged into anism of action is different from that of selective cholesterol VLDL-C to be secreted back into plasma. The loss of cholesterol through the feces depends on the efficiency of intestinal absorption of cholesterol, which correlates with blood choles- 28 terol concentrations. OH The multiple steps in intestinal absorption of cholesterol OH provide an opportunity for interfering with the metabolic process, as well as therapeutic targets for further reductions F N in cholesterol absorption, to alter cholesterol concentrations O and serum lipoproteins. The site of intestinal cholesterol absorption is an ideal target for selective drug action. Because F approximately 50% of cholesterol presented to the intestine FIG. 1 Chemical structure of ezetimibe, a potent and selective inhib- is from biliary secretion, the efficacy of blocking cholesterol itor of dietary and biliary cholesterol absorption: 1-(4-flurophenyl)- absorption does not solely depend on the level of dietary (3R)-[3-(4-flurophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydrox- cholesterol.28 yphenyl)-2-azetidinone (SCH 58235), a 2-azetidinone. W. V. Brown: Selective cholesterol absorption inhibitors 261 absorption inhibitors. The cholesterol-lowering effect of bile creasing dietary fats and cholesterol in individuals with ele- acid sequestrants (e.g., cholestyramine and colestipol) is at- vated serum cholesterol concentrations.43 Recommendations tributable to reversible binding of the drug to bile acids in the for dietary changes are similar to those of the Second Joint intestinal lumen. This binding promotes fecal elimination of Task Force of European and other Societies for Coronary bile acids, thus reducing their return to the liver and inducing Prevention.44 The role of restricting dietary fats and choles- conversion of hepatic cholesterol to additional bile acids. The terol to reduce serum cholesterol concentrations was first es- fall in the amount of cholesterol in the liver upregulates hepat- tablished by metabolic ward studies and later in observational ic LDL-C receptors.28 These bile acid sequestrants do not in- studies of communities.45Ð47 Customary low-cholesterol diets hibit cholesterol absorption. Moreover, they require mealtime reduce the plasma cholesterol by approximately 5 to 15%, and administration and high doses for optimal efficacy.39 The pri- this is often very helpful but insufficient for many patients.45Ð49 mary limiting factor with these agents is poor patient accep- Individual counseling and behavior modification are needed to tance. Although some improvements in dosage form have achieve maximum efficacy with dietary restrictions.48 Diet, been made, compliance remains low. In addition to poor particularly emphasizing saturated fat restriction, should be a palatability, these agents often cause gastrointestinal side ef- part of every patient’s complete management for risk reduc- fects that limit patient acceptance. For all these reasons, clini- tion. Dietary cholesterol restriction only partially addresses the cal use remains very limited. problem, since only half or less of absorbed cholesterol comes Plant sterols or stanols physically alter the presentation of from dietary sources.46, 50 As a result, drug therapy is almost the micelles to the gut epithelium and are not totally specific in always required to obtain the currently recommended target inhibition of cholesterol absorption.28 Mealtime doses of ≥1g LDL-C concentrations. This is particularly true when LDL-C are required, and they may cause a small decrease in the plas- of < 100 mg/dl is the goal, as in patients with risk factors that ma concentrations of fat-soluble vitamins. Pancreatic lipase predict a more than 20% incidence of myocardial infarction or inhibitors are useful for reducing triglyceride absorption but coronary artery death, with diabetes, or with manifest vascular are not very effective for reducing serum cholesterol. Gastro- disease. The selective cholesterol absorption inhibitors, which intestinal adverse effects such as flatulence and oily stools are may block absorption of all cholesterol presented to the in- common. One area of drug development research has involved testinal cells for absorption and which offer ease of use, should inhibition of the enzyme ACAT, which facilitates esterification provide benefits additional to those achieved with adherence of free cholesterol once absorbed into the enterocytes. Ava- to dietary restrictions. simibe, an inhibitor of ACAT, has been demonstrated to reduce atherosclerosis in mice40 and to limit macrophage accumulation in atherosclerotic lesions in rabbits.41 It is currently Clinical Applications of Selective Cholesterol in early clinical studies.42 Absorption Inhibitors

Preliminary clinical studies indicate that ezetimibe is effec- Dietary Restriction versus Inhibition of tive in lowering cholesterol concentrations in monotherapy Cholesterol Absorption and in combination with statins.21, 22 Two multicenter, placebo-controlled, double-blind, parallel-group studies evaluated Dietary restriction for the long-term management of hy- the effect of ezetimibe (n = 243) compared with placebo (n = percholesterolemia is helpful but often insufficient to reduce 88) in subjects with primary hypercholesterolemia. Pooled LDL-C to goal levels. In the United States, the National Cho- data from the two studies show that ezetimibe monotherapy lesterol Education Program recommends, as initial therapy results in a 15 to 20% decrease in LDL-C, with effects occur- and in combination with drugs, a two-step approach to de- ring within 1 week of therapy initiation (Table I).22 In patients

TABLE I From two studies of subjects with hypercholesterolemia, the pooled mean percentage reductions in lipid parameters from baseline to endpoint (12 weeks) with ezetimibe 5 mg/day, 10 mg/day, and placebo.22 % Change from baseline at endpoint (Mean ± SE) Treatment group No. ofpatients LDL-C HDL-C Triglycerides Placebo 87 0.4 ± 1.1 0.2 ± 1.0 1.3 ± 2.9 Ezetimibe 5 mg 124 15.7 ± 0.9a 2.9 ± 0.9a 5.8 ± 2.4 Ezetimibe 10 mg 118 18.5 ± 0.9a, b 3.5 ± 0.9a 4.9 ± 2.5 a p < 0.05 vs. placebo. b p < 0.05 vs. 5 mg. Adapted from Ref. No. 22. Abbreviations: SE = standard error, LDL-C = low-density lipoprotein cholesterol, HDL-C = high-density lipoprotein cholesterol. 262 Clin. Cardiol. Vol. 26, June 2003 with primary hypercholesterolemia, ezetimibe 10 mg once um cholesterol concentrations. Although the selective choles- daily produced an average 18.5 ± 0.9% reduction from base- terol absorption inhibitors may achieve significant LDL-C line in LDL-C levels at 12 weeks. This was significantly (p < reduction with both monotherapy and combination therapy, 0.05) greater than the 0.4 ± 1.1% reduction with placebo treat- ongoing in vitro and animal studies with ezetimibe may help ment. The HDL-C concentrations increased 3.5 ± 0.9% in pa- us discover other mechanisms of cholesterol deposition in tients treated with ezetimibe 10 mg/day; this was significantly atherosclerosis. Chylomicrons and their remnants vary in (p < 0.05) superior to the change in HDL-C (0.2 ± 1.0%) in the size, composition, and metabolism, depending on the ab- placebo groups. Also, a trend toward decreased triglyceride sorbed intestinal fat and cholesterol.16, 57 Chylomicron rem- levels was noted with ezetimibe (Table I). nants may be a causative factor in arteriosclerosis by directly The inhibition of dietary and biliary cholesterol absorption delivering cholesterol to the diseased arterial wall. Because by ezetimibe complements the mechanism of action of statins, chylomicrons have a higher turnover rate and are continuous- which inhibit cholesterol synthesis. Combination therapy with ly produced, they may contribute more cholesterol to tissues ezetimibe and simvastatin, atorvastatin, or lovastatin showed over 24 h than do LDL-C particles. Large chylomicron parti- significant reductions in total cholesterol,24Ð26 and clinical tri- cles can be metabolized to remnants that are comparable with als are under way to further define the efficacy of combination atherogenic VLDL-C remnants from the liver. These small therapy with higher doses and with other statins. Increasing chylomicron remnants may enter arterial walls through trans- the dose of statins does not proportionally decrease cholesterol cytosis, delivering cholesterol to tissue macrophages located concentrations; for example, doubling of the statin dose usual- in arterial lesions.57 In theory, by blocking absorption, eze- ly produces only an additional 6% decrease in LDL-C.39 The timibe should reduce the cholesterol ester content of chylomi- risk of adverse events, however, does increase in proportion to crons and thereby reduce their atherogenic potential (Fig. the size of the daily dose.51, 52 Neither new adverse events nor 2).58Ð60 Additional animal studies will be needed to develop an increased incidence of adverse events was identified when this theory fully. ezetimibe was given concomitantly with simvastatin or lova- Changes in chylomicron size and composition resulting statin.24, 25 If these and other early studies in a few thousand from administration of ezetimibe may also affect the uptake patients hold true, it is possible that ezetimibe combined with of remnants by the endothelium. Other possible effects of statins may have the efficacy of high-dose statins with a simi- the selective cholesterol absorption inhibitors under investi- lar rate of adverse events seen with the particular dose of the gation are their effect on blood coagulation dynamics and statin alone. Significant concentrations of ezetimibe are not their role in cardiac events.61 If any of these hypotheses can found in the liver or systemic circulation, and this may be one be proved, it may be shown that selective cholesterol ab- reason for the apparent low incidence of adverse effects and sorption inhibitors have unique mechanisms that can add to drug interactions. The option of safely adding a new therapy the benefits offered by the statins and other cholesterol-low- for those with severe hypercholesterolemia, such as that seen ering drugs. in familial LDL-C receptor deficiency, is promised by these studies. The combination of ezetimibe with high-dose statins may provide the needed additional LDL-C reduction not achievable with current therapeutic options. Fibric acid derivatives (e.g., fenofibrate, gemfibrozil) are Biliary Intestinal tract commonly used to manage hypertriglyceridemia. High triglyc- lumen eride concentrations are common in individuals with diabetes Plaque Bile acids CE formation mellitus. The fibric acid derivatives are effective in lowering Synthesis Free cholesterol Remnants serum triglyceride concentrations and in increasing HDL-C (FC) 7, 53, 54 Diet Unstirred concentrations, but may increase LDL-C concentrations. water Combination therapy with statins and fibric acid derivatives layers may be limited by an increased risk of myositis.55 A prelimi- Blood ENTEROCYTE Brush border nary study in 32 healthy hypercholesterolemic subjects indicat- Cholesterol ed that combining ezetimibe with fenofibrate results in an addi- FC biosynthesis 56 tional 23% lowering of LDL-C over fenofibrate alone. Cholesteryl FC ester (CE) Further studies on a larger number of subjects are needed to Micelles ACAT CE confirm the efficacy and safety of this combination. Chylomicrons Lymph

Theoretical Benefits beyond Additive Low-Density FIG. 2 Dietary and biliary cholesterol absorbed across the intestinal Lipoprotein Cholesterol Reduction border is incorporated into chylomicrons, which are reduced to chylomicron remnants that can contribute to atherogenesis. Blocking cholesterol absorption may reduce the cholesterol ester content of chylo- Altering the size and composition of serum lipoproteins microns. ACAT = acyl-CoA:cholesterol acyltransferase. Reprinted may significantly affect clinical outcomes independent of ser- from Ref. No. 60 with permission of the publisher W. B. Saunders. W. V. Brown: Selective cholesterol absorption inhibitors 263

Conclusions 15. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The Post Coronary Artery Bypass Graft Trial One of the new classes of cholesterol-lowering drugs is the Investigators. N Engl J Med 1997;336:153Ð162 selective cholesterol absorption inhibitors, the first of which is 16. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr: Primary prevention of ezetimibe. Ezetimibe is a selective inhibitor of cholesterol ab- acute coronary events with lovastatin in men and women with average cho- sorption that to date has shown a favorable safety profile. lesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Selective cholesterol absorption inhibitors could complement Atherosclerosis Prevention Study. J Am Med Assoc 1998;279:1615Ð1622 17. 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