Ezetimibe: A First-in-Class, Novel Cholesterol Absorption Inhibitor

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1 Cardiovascular Drug Reviews Vol. 21, No. 4, pp Neva Press, Branford, Connecticut Ezetimibe: A First-in-Class, Novel Cholesterol Absorption Inhibitor Leslie J. Lipka Schering-Plough Research Institute, Kenilworth, NJ, USA Keywords: Cholesterol absorption Ezetimibe Hypercholesterolemia Lipid-lowering combination therapy. ABSTRACT Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)-designated low density lipoprotein cholesterol (LDL-C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid-lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid-lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL-C, as well as incremental increases in high-density lipoprotein cholesterol (HDL-C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL-C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2- to 3-fold upward titration of the corresponding statin dose. Ezetimibe-statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid-lowering mechanisms, ezetimibe coadministered with a statin offers an Address correspondence and reprint requests to: Leslie J. Lipka, MD, PhD, Schering-Plough Research Institute, 2015 Galloping Hill Road, MS 3005, Kenilworth, NJ 07033, USA. Tel.: +1 (908) ; Fax: +1 (908) ; leslie.lipka@spcorp.com 293

2 294 L. J. LIPKA effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease. INTRODUCTION The role of hypercholesterolemia in coronary heart disease (CHD) is well established as demonstrated by extensive multicenter, randomized, placebo-controlled clinical studies showing that reductions in low-density lipoprotein cholesterol (LDL-C) decrease the incidence of CHD events (9,14,31,32,38,40,48,51). As a result, LDL-C has been identified by the National Cholesterol Education Program s (NCEP) Third Report of the Adult Treat Panel (ATP III) as an important cause of CHD and is currently the main focus of lipid-lowering therapy (11). Various lipid-lowering agents act by targeting different sites of lipid metabolism. Statins decrease plasma cholesterol through inhibition of hepatic hydroxymethyl glutaryl (HMG) coenzyme A-reductase, a key enzyme required for cholesterol biosynthesis (33). Bile acid sequestrants, such as cholestipol and cholestyramine, reduce the recirculation of bile acids to the liver, causing a compensatory increase in cholesterol catabolism. Subsequent decreases in hepatocyte cholesterol concentration lead to increased LDL receptor upregulation and removal of circulating LDL-C (33,39). Nicotinic acid (niacin) reduces the mobilization of free fatty acids from adipose tissue, which in turn decreases triglyceride synthesis and secretion of very low-density lipoprotein (VLDL). Since VLDL particles may be converted to LDL-C, the net result is an overall reduction in LDL-C levels. Through induction of hepatic and muscle free fatty acid oxidation, fibrates lower blood triglyceride levels by decreasing hepatic lipogenesis and the secretion of triglyceride-rich lipoproteins (23). In spite of the availability of diverse lipid-lowering agents, significant numbers of patients are not receiving adequate treatment (55). According to a Managed Care Organization database study of more than 124,000 subjects, between 54 and 79% of those at risk for CHD (i.e., with a history of CHD, diabetes, or two or more risk factors) and who missed their LDL-C goal by more than 30 mg dl, remained untreated. Similar findings were reported in a demographic study consisting of more than 138,000 patients discharged from the hospital following acute myocardial infarction (MI) (13). Less than half of all patients including those with a previous history of CHD, diabetes, and hypercholesterolemia received follow-up lipid-lowering therapy. Many patients fail to attain LDL-C goals even when taking lipid-lowering therapy (38). An evaluation of 4,888 patients in the Lipid Treatment Assessment Program (L-TAP), including those with established CHD (30%) or at high risk for CHD (47%), showed that only 38% achieved NCEP-designated LDL-C goals. Patients with CHD (37%) and those at high risk for CHD (18%) were less likely to reach LDL-C goals than low-risk patients (68%). Moreover, a recent study of 367 hyperlipidemic patients in a preventive cardiology practice showed that the lipid-lowering effects of statins were less evident in clinical practice than randomized, placebo-controlled clinical studies, an effect attributed to decreased patient compliance (15). These observations underscore the need for more aggressive lipid-lowering therapy, a goal that is more likely to be achieved with the combined use of agents that lower LDL-C

3 EZETIMIBE 295 by different mechanisms of action than by monotherapy (33). Statins plus a bile acid sequestrant or niacin are the most common form of combination therapy currently recommended by the NCEP (11,30). However, the inconvenient dose regimens required for bile acid sequestrants and statin titration, as well as the side effects of nicotinic acid, are major limitations to combination therapy. These impediments create a significant unmet need for improved combination treatment strategies (22,30,39). This article reviews preclinical and clinical data on the efficacy and safety of ezetimibe, the first in a novel class of cholesterol absorption inhibitors for the treatment of hypercholesterolemia (61,62). Observations from these studies suggest that ezetimibe effectively reduces hypercholesterolemia and has potential for treating various disorders of lipid metabolism. Ezetimibe may be effectively used as monotherapy or in combination with statins due to the complementary mechanism of action of these two agents, which results in incremental reductions in plasma LDL-C (8). METABOLISM Human Pharmacokinetics The absorption, metabolism, and excretion of ezetimibe were determined in an openlabel study of 8 healthy male volunteers (37). Following a single administration of 20 mg [ 14 C]ezetimibe to fasted subjects, ezetimibe was rapidly absorbed and extensively metabolized by glucuronidation of the 4-hydroxy phenyl group; within 30 min of administration, approximately 90% of the total plasma radioactivity was attributed to the pharmacologically active ezetimibe-glucuronide metabolite. Maximal concentrations of ezetimibe and its glucuronide appeared in the plasma within 2 to 3 h. Thereafter, concentrations of ezetimibe and its glucuronide rapidly declined, although both showed multiple peaks suggestive of enterohepatic recirculation. Ezetimibe was excreted mostly in the feces, with a minor fraction appearing in the urine (78 vs. 11% of radiolabeled drug, respectively). The relatively high proportion of fecal ezetimibe (69% of administered dose) suggests limited absorption and possible hydrolysis of the glucuronide metabolite. The half-life for singledose, oral ezetimibe could not be reliably estimated by regression analysis; however, the half-life of drug-derived urinary radioactivity was ~24 h. The absolute bioavailability of ezetimibe could not be determined since the drug is virtually insoluble in aqueous media suitable for intravenous administration. The pharmacokinetics of ezetimibe was genderindependent (68). Once-daily dosing Pharmacokinetics of ezetimibe administered once daily to rats (2000 mg kg), dogs (100 mg kg), and humans (10 or 20 mg tablet) showed several common findings that led to the recommended once-daily dosing of ezetimibe. These included: multiple plasma drug peaks indicative of enterohepatic recycling; extensive conjugation of ezetimibe to glucuronide (90 99%); effective half-lives, indicating accumulation potential, were ~8 and 22 h in dogs and humans, respectively (69).

4 296 L. J. LIPKA FIG. 1. Localization of radiolabeled ezetimibe in the intestinal villi 3 h after intravenous administration of tritiated ezetimibe in the bile duct-cannulated rat. White grains delineate radiolabeled ezetimibe concentrated at the surface of enterocytes within intestinal villi. Reprinted from ref. 61 with permission from Macmillan Publishers Ltd. Animal Pharmacokinetics Ezetimibe metabolism was similar across different species (rat, dog, and human). Following oral administration, ezetimibe was rapidly absorbed, extensively conjugated to its glucuronide, and exhibited multiple plasma peaks suggestive of enterohepatic recycling (12,19,47,69). Ezetimibe was excreted primarily in the feces (19). The plasma half-life for ezetimibe was 22 h following 10 days daily treatment in humans (10 or 20 mg tablet) (69). The maximum tolerated doses of ezetimibe in a chronic study (104 weeks) in rats have been reported to be 1500 mg kg day (males) and 500 mg kg day (females). Mice tolerated ezetimibe at doses up to 500 mg kg day (35). As in humans, rodent drug disposition studies demonstrated that ezetimibe is primarily metabolized to its glucuronide, a more potent inhibitor of cholesterol absorption than the parent compound (37,61). In bile duct-cannulated rats, intravenous [ 3 H]ezetimibe localized within enterocytes at the villus tips in the intestinal wall, a site predominantly associated with cholesterol uptake and transepithelial transport (52,61) (Fig. 1). These studies indicate that ezetimibe blocks cholesterol uptake and absorption by intestinal enterocytes. Such an effect may be amplified by glucuronidation and enterohepatic recycling, which result in repeated delivery of ezetimibe and its glucuronide to the intestinal lumen. Ezetimibe differs from other intestinally acting cholesterol-lowering agents in that it is an inhibitor of cholesterol absorption, does not affect lipid metabolism, and has minimal effect on acyl coenzyme A:cholesterol O-acyltransferase (ACAT) molecular activity (18). Although its precise molecular mechanism of action is unknown, studies suggest that ezetimibe has no effect on the expression of known ATP-binding cassette (ABC) cholesterol transporter genes (41).

5 EZETIMIBE 297 There is evidence that suggests ezetimibe decreases cholesterol absorption. In one study, fecal cholesterol levels increased in ApoE knockout mice treated with ezetimibe mg kg day for 3 days (6). In another study, ezetimibe significantly increased the accumulation of cholesterol within the lumen of the small intestine in rats receiving radiolabeled cholesteryl oleate and free-cholesterol (P < 0.01, compared with untreated controls) (62). In the same study, ezetimibe significantly decreased the intestinal wall cholesterol levels in bile-duct cannulated rats receiving radiolabeled cholesteryl oleate and free-cholesterol (P < 0.01, compared with untreated controls) (62). Further studies are ongoing to determine the molecular mechanism whereby ezetimibe blocks cholesterol uptake from the intestinal lumen. PRECLINICAL PHARMACOLOGY Discovery The full chemical name of ezetimibe is: {1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone}. Ezetimibe was derived from an active metabolite of SCH {[3R,4S]-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone)}, a potent cholesterol absorption inhibitor in animal and human models of hypercholesterolemia (46,50,63). As demonstrated in the bile duct-cannulated rat, ezetimibe was a more potent inhibitor of cholesterol absorption than SCH (>95 vs. 70%) and showed a higher degree of retention in the intestinal wall (63). In Rhesus monkeys fed a high cholesterol diet, ezetimibe was 400 times more potent than SCH at reducing cholesterol absorption (63). These observations prompted more extensive exploration of ezetimibe s lipid-lowering potential in animal models of hypercholesterolemia and clinical studies in patients with hypercholesterolemia. Effects of Ezetimibe in Experimental Hypercholesterolemia The lipid-lowering and anti-atherosclerotic efficacy of ezetimibe in diverse animal models of hypercholesterolemia and dyslipidemia are summarized in Table 1. Primate hypercholesterolemia In Rhesus monkeys fed a high cholesterol diet, orally administered ezetimibe caused dose-related reductions in plasma total cholesterol. Daily doses as low as mg kg ezetimibe abolished the increase in plasma total cholesterol observed in cholesterol fed animals (60). Ezetimibe normalized plasma total cholesterol within 10 days of treatment, an effect that was sustained for at least 3 days after withdrawal of drug treatment. Dose related decreases in plasma LDL-C, but not changes in plasma high-density lipoprotein cholesterol (HDL-C) or triglycerides, were also observed 3 weeks after treatment with ezetimibe. However, ezetimibe had a favorable effect on plasma LDL-C:HDL-C ratios, which were reduced from 1.75 in untreated animals to 0.69 in monkeys receiving 0.01 mg kg ezetimibe.

6 298 L. J. LIPKA TABLE 1. Effects of ezetimibe on experimental dyslipidemia and atherosclerosis (6,8,59,60) Experimental model Main effects Clinical disease application Primate hypercholesterolemia TC Primary hypercholesterolemia LDL-C LDL-C:HDL-C ratio Canine TC (ezetimibe alone) hypercholesterolemia Synergistic TC (ezetimibe + statin) Obese hyperinsulinemic hamster dyslipidemia ApoE deficient mice Normalized VLDL-C, IDL-C, triglycerides LDL-C LDL-C:HDL-C ratio Hepatic cholesterol Cholesterol absorption TC LDL-C VLDL IDL cholesterol HDL-C Hepatic cholesterol Atherosclerosis lesions Primary hypercholesterolemia (monotherapy and combination therapy) Combined dyslipidemia Atherosclerosis Primary hypercholesterolemia TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; VLDL-C, very-low-density lipoprotein cholesterol; IDL-C, intermediate-density lipoprotein cholesterol. Ezetimibe also dose-dependently reduced intestinal cholesterol absorption in hypercholesterolemic Rhesus monkeys with an ED 50 of mg kg (63). Dose-related reductions in LDL-C levels were also observed with an approximate ED 50 of mg kg day. Apolipoprotein E-deficient mice The lipid-lowering and anti-atherosclerotic effects of ezetimibe were also explored in apolipoprotein E (ApoE) deficient (ApoE ) mice (6). After oral administration for 3 days, ezetimibe significantly inhibited cholesterol absorption in ApoE knockout mice; approximately 50% inhibition was achieved at 0.3 mg kg day ezetimibe with >90% inhibition at 10 mg kg day (P < 0.05 compared with untreated controls). In addition, 0.005% ezetimibe in mouse chow for 6 months significantly decreased plasma total cholesterol, LDL-C, and VLDL-chylomicron cholesterol levels by 61 to 68%, 53 to 67%, and 80 to 89%, respectively (P < 0.05, compared with untreated mice). Plasma HDL-C levels were significantly increased (P < 0.001, compared with untreated mice). Accumulation of hepatic free cholesterol and esterified cholesterol was significantly lower after 6 months daily treatment with 4.5 to 5.9 mg kg ezetimibe (P < 0.05, compared with untreated mice). All lipid-lowering effects were independent of dietary cholesterol intake. Ezetimibe significantly reduced the development and progression of aortic and carotid artery atherosclerotic lesions following 6 months treatment in ApoE mice fed highand low-cholesterol diets (7) (Fig. 2). Atherosclerotic lesions were diminished in the

7 EZETIMIBE 299 Control Ezetimibe 5 mg kg d FIG. 2. Ezetimibe reduces carotid artery atherosclerosis in ApoE knockout mice. Mice were fed a 0.15% cholesterol diet for 6 months. Image courtesy of Harry R. Davis, PhD (7). aortic arch (81 87%), thoracic aorta (68 74%), and abdominal aorta (47 71%) (P < 0.05, compared with untreated mice). Obese hyperinsulinemic hamster dyslipidemia In the obese hyperinsulinemic hamster model of hypercholesterolemia, daily oral administration of 1 mg kg ezetimibe for up to 84 days normalized VLDL cholesterol, intermediate-density lipoprotein (IDL) cholesterol, and triglyceride levels, and lowered LDL-C below chow-fed levels (59). The HDL-C:LDL-C ratio was significantly elevated following ezetimibe treatment. Accumulation of free cholesterol and cholesteryl ester in the liver was completely suppressed by ezetimibe. These findings support the potential efficacy of ezetimibe for treating combined dyslipidemia associated with type 2 diabetes in humans. Ezetimibe dose-dependently inhibited diet-induced hypercholesterolemia in hamsters with an ED 50 of 0.04 mg kg (62). LDL-C levels were significantly lower in animals receiving 3 of 4 high cholesterol diets or normal chow diet following daily administration of ezetimibe 1 mg kg, compared with untreated animals (P < 0.05). Canine hypercholesterolemia The lipid-lowering effects of orally administered ezetimibe (alone or in combination with a statin) were determined in beagles fed a high cholesterol diet (8). After 7 days of treatment, ezetimibe 0.01 and 0.03 mg kg elicited a dose-related decrease in plasma total cholesterol (P < 0.05). The calculated ED 50 of ezetimibe was mg kg day, with maximal inhibition of ~80% at 0.03 mg kg day. Furthermore, a synergistic lowering of

8 300 L. J. LIPKA plasma cholesterol levels was achieved following 2 weeks of daily combination therapy with mg kg ezetimibe and either lovastatin (5 mg kg), pravastatin (2.5 mg kg), fluvastatin (5 mg kg), simvastatin (1 mg kg), or atorvastatin (1 mg kg) (P < 0.05). In contrast, 2 weeks of treatment with lovastatin 5 mg kg monotherapy or ezetimibe mg kg monotherapy did not significantly affect plasma cholesterol levels. Pharmacokinetic studies showed ezetimibe did not interact with any of the statins tested. These findings support the use of lipid-lowering agents with complementary mechanisms of action (i.e., a cholesterol absorption inhibitor coadministered with a cholesterol synthesis inhibitor). Pharmacology in rats In an acute model of intestinal absorption using radiolabeled cholesterol in rats, ezetimibe inhibited the appearance of radiolabeled cholesterol in plasma with an ED 50 of mg kg, at 90 min after treatment, indicating that the onset of activity is rapid (63). The highest dose of ezetimibe (3 mg kg) significantly reduced cholesterol by 94% (P < compared with vehicle control) (62). This suggests the maximal effective dose is about 3 mg kg. CLINICAL STUDIES Inhibition of Cholesterol Absorption Preclinical studies suggest ezetimibe selectively prevents dietary and biliary cholesterol uptake and transport across the intestinal wall (6,61). Clinical studies have since confirmed cholesterol absorption inhibition in humans (57). These inhibitory effects of ezetimibe on cholesterol absorption in humans were established in a double-blind, placebocontrolled, crossover study of 18 patients with mild hypercholesterolemia. After 2 weeks of daily treatment with 10 mg ezetimibe, fractional cholesterol absorption rates were significantly decreased by 54%, compared to placebo (P < 0.001). This was accompanied by significant decreases in plasma LDL-C (24%) and total cholesterol (15%) from baseline (P < 0.001). Moreover, significant reductions in plasma campesterol (48%) and sitosterol (41%) suggested ezetimibe s potential for treating rare disorders of lipid metabolism, such as homozygous sitosterolemia. Efficacy in Primary Hypercholesterolemia Monotherapy The efficacy and safety of ezetimibe were evaluated in two, Phase III, 12-week randomized, double-blind, placebo-controlled studies of 1719 patients with primary hypercholesterolemia (10,24). Patients had baseline LDL-C levels of mg dl and triglyceride levels 350 mg dl. One third had two or more risk factors for CHD and one third had hypertension. Patients were randomized to receive 10 mg ezetimibe or placebo once daily for 12 weeks.

9 EZETIMIBE 301 Ezetimibe significantly reduced LDL-C levels from baseline by 18%, compared with increases of 1.1 to 1.4% in the placebo group (P < 0.01). These effects were observed at 2 weeks and sustained throughout the treatment period. In both studies, 60% of ezetimibetreated patients achieved reductions in LDL-C 15%, a rate approximately 6-fold higher than for placebo (10,24). Ezetimibe significantly improved plasma total cholesterol, HDL-C, and Apo B in both studies, and in one study improved plasma triglyceride levels (P < 0.01, compared with placebo) (10). Ezetimibe was well tolerated, with an incidence of adverse events (AEs) similar to that with placebo group (10,24). Discontinuation due to AEs was also similar between ezetimibe and placebo. Serum lipid-soluble vitamins, prothrombin time, and baseline or stimulated cortisol levels were unaltered by ezetimibe treatment (24). The optimal lipid-lowering dose of ezetimibe was determined in a pooled analysis of 432 patients administered over a 12-week period (3). Patients in the ezetimibe 10 mg group had a significantly greater decrease in LDL-C levels compared with the ezetimibe 5 mg group (P < 0.05). More patients receiving ezetimibe 10 mg had LDL-C reductions >15% and >25% relative to ezetimibe 5 mg. The safety profile of both doses was similar, so 10 mg was the optimal clinical dose. However, doses up to 40 mg day over a period of 8 weeks have been studied in patients with primary hypercholesterolemia (54). Doses of 50 mg day have been studied for up to 2 weeks (35). Monotherapy is appropriate in patients who require modest LDL-C reduction or for patients who do not tolerate other lipid-lowering agents. In addition, ezetimibe is indicated as monotherapy in patients with homozygous sitosterolemia. Current monotherapy with lipid-lowering agents, including statins, has several limitations. Because ezetimibe and statins control cholesterol levels through different pathways, their complementary mechanisms of action are expected to produce incremental decreases in blood cholesterol levels. Combination therapy: Ezetimibe combined with ongoing statin Ezetimibe was assessed for its additive lipid-lowering effects in an 8-week, doubleblind, placebo-controlled trial of 769 patients with primary hypercholesterolemia already receiving statin therapy (16). All patients were taking a stable dose of statin for more than 6 weeks. The majority of patients were taking simvastatin or atorvastatin, with one third taking other statins (lovastatin, pravastatin, cerivastatin, and fluvastatin); in most cases the dose of each statin was submaximal. Statin doses were not titrated during the trial. Patients were stratified according to the following risk categories and were at or above the respective NCEP ATP II- recommended LDL-C target levels: Category 1 (LDL-C < 160 mg dl for patients without CHD and 1 risk factor); Category II (LDL-C < 130 mg dl for patients without CHD and 2 risk factors); and Category III (LDL-C 100 mg dl for patients with established but stable CHD, or CHD equivalent). Approximately 68% of patients were in Category III. Baseline serum triglyceride levels were 350 mg dl. Patients were randomized to receive daily treatment with either placebo (n = 390) or 10 mg ezetimibe (n = 379) plus continued statin therapy. The statin plus placebo groups were as follows: simvastatin (n = 112); atorvastatin (n = 152); other statins (n = 105). Note that 21 patients were enrolled while taking non-marketed statins, bringing the total to 390 in this

10 302 L. J. LIPKA Week 2 Endpoint 0 Simvastatin Atorvastatin Other statin Simvastatin Atorvastatin Other statin Mean % change in LDL-C Statin plus placebo ( n =390) Statin plus ezetimibe ( n = 379) FIG. 3. Mean percentage decreases from baseline in LDL-C following the addition of ezetimibe in patients with primary hypercholesterolemia already taking simvastatin, atorvastatin, or another statin during 8 weeks of therapy. Ezetimibe 10 mg day was administered to patients already receiving statin therapy (simvastatin or atorvastatin mg; lovastatin or pravastatin mg; fluvastatin mg; or cerivastatin mg) (16). group. The statin plus ezetimibe groups were as follows: simvastatin (n = 114); atorvastatin (n = 136); other statins (n = 106). Note that 23 patients were enrolled while taking nonmarketed statins, bringing the total to 379 in this group. Addition of ezetimibe to ongoing statin monotherapy caused an additional lowering of LDL-C by 25.1%, compared with 3.7% in the statin monotherapy group (P < 0.001) (16). These effects, which peaked around 2 weeks and were sustained throughout the 8-week treatment, were similar regardless of the type of statin used (Fig. 3). Of those patients whose LDL-C was above NCEP ATP II specified LDL-C goals on statin monotherapy, the proportion attaining their respective goals was significantly greater in the ezetimibe plus statin group (71.5%) than in the statin monotherapy group (18.9%) (odds ratio 23.7; P < 0.001). Ezetimibe plus statin therapy also increased HDL-C (P < 0.05) and reduced triglycerides (P < 0.001) compared with statin plus placebo (16). Compared to statin plus placebo, ezetimibe plus statin also significantly improved indicators of CHD risk, such as C- reactive protein (P < 0.05), total cholesterol, non-hdl-c, Apo B, LDL-C: HDL -C, and total cholesterol: HDL-C (P < 0.001). The efficacy of ezetimibe was unaffected by age, gender, race, NCEP ATP II category, body mass index, and waist circumference. In both treatment groups the overall incidence of AEs was similar and there were no significant differences in the incidence of hepatic- or muscle-related AEs (16). No clinically relevant differences in laboratory or safety analyses were observed in either treatment group.

11 EZETIMIBE 303 Combination therapy: Ezetimibe given at onset of statin therapy Ezetimibe was assessed for its incremental lipid-lowering effects when given at the beginning of statin treatment in four 12-week, randomized, double-blind, placebo-controlled studies of patients with hypercholesterolemia (1,5,20,34). Each study assessed the efficacy and safety of ezetimibe coadministered with either simvastatin (n = 668), atorvastatin (n = 628), pravastatin (n = 538), or lovastatin (n = 548). Patients at baseline had LDL-C levels between 145 and 250 mg dl, and plasma triglycerides 350 mg dl; 38 to 49% had a family history of CHD (41 44). After a 2- to 12-week washout period, patients were randomized to receive ezetimibe 10 mg alone; statin monotherapy (simvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; pravastatin 10, 20, or 40 mg; or lovastatin 10, 20, or 40 mg); ezetimibe 10 mg combined with corresponding doses of simvastatin, atorvastatin, pravastatin, or lovastatin; or placebo. The effects of ezetimibe plus each statin were compared with the effects of each statin alone and ezetimibe alone with respect to numerous endpoints, including percent changes from baseline in LDL-C, HDL-C, and triglycerides. In each study the coadministration of ezetimibe plus a statin caused significant decreases in LDL-C, compared with the respective statin monotherapy. Reductions in LDL-C from baseline following ezetimibe plus statin combination therapy varied according to the dose of statin, and ranged from 46 to 58% for simvastatin (10 to 80 mg), 53 to 61% for atorvastatin (10 to 80 mg), 34 to 42% for pravastatin (10 to 40 mg), and 34 to 46% for lovastatin (10 to 40 mg) (Fig. 4a) (1,5,20,34) In each study, ezetimibe plus statin (10 mg) combination therapy was as effective at reducing LDL-C as a 2- to 3-fold upward titration of the corresponding statin monotherapy dose. In general, the beneficial effects of ezetimibe plus statin combination therapy were apparent at 2 weeks and were sustained throughout the 12-week treatment period. The additional LDL-C reduction provided by ezetimibe when coadministered with atorvastatin 80 mg was significantly greater than that of atorvastatin 80 mg, indicating that ezetimibe does have an incremental effect even with a high dose of statin (Fig. 4b). Significant decreases in triglyceride levels from baseline were also observed for ezetimibe combined with statins in all 4 studies (P < 0.01, compared with statin monotherapy) (1,5,20,34). Additionally, significant increases in HDL-C from baseline (range 2.4 5%) were detected for each combination treatment group with the exception of ezetimibe plus pravastatin. Ezetimibe plus statin combination therapy was well tolerated and no clinically relevant differences were observed with respect to AEs, or discontinuations due to AEs between the ezetimibe plus statin and statin monotherapy groups in each of the 4 studies (1,5,20, 34). The safety profile of ezetimibe plus statin was similar to that of statin monotherapy; there were low incidences of elevated hepatic enzymes and creatinine phosphokinase in both treatment groups. The lipid-lowering effects of ezetimibe combined with statins were incremental rather than additive ; addition of ezetimibe 10 mg to any of the statin doses tested provides beneficial increases in lipid-lowering without compromising tolerability. Combination treatment with ezetimibe 10 mg plus low dose statin is at least as effective as high dose statin monotherapy; thus, low dose combination therapy retains efficacy and minimizes the need for statin titration and associated increased risk for side effects (Fig. 4).

12 304 L. J. LIPKA a 0 Simva Simva 10 mg 10 mg Simva Simva 20 mg 20 mg Simva Simva 40 mg 40 mg Simva Simva 80 mg 80 mg b 0 Atorva Atorva 10 mg 10 mg Atorva Atorva 20 mg 20 mg Atorva Atorva 40 mg 40 mg Atorva Atorva 80 mg 80 mg Mean%changeinLDL-C Simvastatin ( n = 263) Ezetimibe10mg+simvastatin( n =274) Mean%changeinLDL-C Atorvastatin ( n = 248) Ezetimibe 10 mg + atorvastatin ( n = 255) c Mean%changeinLDL-C Prava 10 mg Prava 10 mg Prava 20 mg Prava 20 mg Prava 40 mg Prava 40 mg Pravastatin ( n =205) Ezetimibe10mg +pravastatin( n =204) d Mean%changeinLDL-C Lova 10 mg Lova 10 mg Lova 20 mg Lova 20 mg Lova 40 mg Lova 40 mg Lovastatin ( n = 220) Ezetimibe10mg +lovastatin( n = 192) FIG. 4. Mean percentage decreases from baseline in LDL-C 12 weeks after initiation of ezetimibe plus a statin in patients with primary hypercholesterolemia: a, simvastatin; b, atorvastatin; c, pravastatin; d, lovastatin. Patients received different daily doses of simvastatin, atorvastatin, pravastatin, or lovastatin either alone or in combination with ezetimibe 10 mg. Patients were not on statin therapy at baseline. Adapted with permission from refs. 1,5,20,34. LDL-C, low-density lipoprotein cholesterol; Simva, simvastatin; Atorva, atorvastatin; Prava, pravastatin; Lova, lovastatin; EZE, ezetimibe. *P < 0.01 vs. statin alone. Efficacy in Special Populations Heterozygous familial hypercholesterolemia Heterozygous familial hypercholesterolemia (HeFH) is associated with expression of defective LDL receptors, elevated total cholesterol and LDL-C levels, and an increased risk for premature CHD (58). The efficacy of ezetimibe added to ongoing atorvastatin monotherapy was determined in a randomized, double-blind, 14-week study of 621 patients with either HeFH, documented CHD, or 2 risk factors, and LDL-C 130 mg dl (54). Patients taking open-label atorvastatin 10 mg day with uncontrolled LDL-C ( 130 mg dl) were randomized into 2 groups: those receiving 10 mg ezetimibe or an additional 10 mg atorvastatin daily. The atorvastatin dose in each treatment group was doubled if LDL-C levels remained above 100 mg dl at 4 and or 9 weeks; a maximum of 40 mg day atorvastatin was given in combination therapy, and a maximum of 80 mg day was given as monotherapy. The primary endpoint was the percentage of patients reaching a target LDL-C goal of 100 mg dl at 14 weeks. The secondary endpoint was the percentage LDL-C reduction at 4 weeks; this allowed a direct comparison between ezetimibe added to atorvastatin 10 mg vs. atorva-

13 EZETIMIBE 305 FIG. 5. Percentage of patients with heterozygous familial hypercholesterolemia (HeFH) reaching LDL-C goal 14 weeks after adding ezetimibe to atorvastatin therapy. Group 1 consisted of patients with HeFH, CHD, or 2 risk factors and LDL-C 130 mg dl (n = 621) (54). Group 2 is a subgroup of Group 1 and consisted of patients with HeFH only (n = 362) (64). Atorvastatin dose was doubled up to a maximum of 40 mg or 80 mg daily for ezetimibe combination therapy and atorvastatin therapy, respectively. LDL-C, low-density lipoprotein cholesterol. *P < 0.01 vs. statin alone. % Patients at goal LDL-C All subjects ( n = 621) Atorvastatin HeFH subjects ( n = 362) Ezetimibe 10 mg plus atorvastatin statin 20 mg. The mean baseline LDL-C during daily atorvastatin therapy was approximately 187 mg dl. After 14 weeks of treatment, a significantly greater proportion of patients reached LDL-C goal in the ezetimibe plus atorvastatin group (22%), compared to atorvastatin monotherapy (7%; P < 0.01) (54). After 4 weeks of treatment LDL-C levels were significantly reduced from baseline on atorvastatin 10 mg in patients receiving ezetimibe 10 mg plus atorvastatin 10 mg, compared to patients receiving atorvastatin 20 mg (22.8 vs. 8.6%; P < 0.01) (Fig. 5). Similar effects were observed in the subgroup of 362 patients with HeFH-ezetimibe plus atorvastatin combination treatment resulted in a 4-fold increase in the number of patients reaching LDL-C goal compared with atorvastatin monotherapy at 14 weeks (17 vs. 4%; P < 0.01) (64). Ezetimibe plus atorvastatin coadministration was well tolerated, with a safety profile similar to that of atorvastatin alone (54,64). These data show that ezetimibe combined with a statin substantially increases the chances of achieving LDL-C goal even in high risk patients. This combination treatment strategy offers a viable approach for patients with HeFH for whom effective treatment options are limited. Homozygous familial hypercholesterolemia Homozygous familial hypercholesterolemia (HoFH) is a heritable condition involving 2 LDL-C receptor gene mutations that lead to diminished LDL-C catabolism and to hypercholesterolemia (58). Disease is characterized by early development of xanthomas and atherosclerosis before the onset of puberty. LDL apheresis is a promising but inconvenient treatment procedure, and HoFH is resistant to current therapies. Therefore, there is a significant unmet need for treating this disease. Since ezetimibe plus a statin produced incremental lipid-lowering effects over statin monotherapy in primary hypercholesterolemia, the utility of this combination therapy was evaluated in a 12-week study of 50 patients diagnosed with HoFH (17). Patients were on an NCEP Step I (or stricter) diet taking open-label daily atorvastatin 40 mg or simvastatin 40 mg (statin 40); half were on LDL-apheresis, and 41 45% had premature CHD. Patients were randomized to receive double-blind daily treatments consisting of atorvastatin or

14 306 L. J. LIPKA 0 Mean % change in LDL-C Statin 80 mg ( n = 17) statin 40 mg/80 mg ( n = 33) statin 80 mg ( n =17) FIG. 6. Mean percentage decreases in LDL-C after 12 weeks treatment with ezetimibe plus 40 or 80 mg atorvastatin simvastatin, compared to 80 mg atorvastatin simvastatin monotherapy in patients with homozygous familial hypercholesterolemia (HoFH). Adapted with permission from ref. 17. LDL-C, lowdensity lipoprotein cholesterol; EZE, ezetimibe 10 mg. *P = vs. statin alone; P = vs. statin alone. simvastatin 80 mg (statin 80); ezetimibe 10 mg plus statin 40; or ezetimibe 10 mg plus statin 80 for 12 weeks. Direct LDL-C levels were significantly decreased over the 12-week treatment period following addition of ezetimibe to statin 40 mg statin 80 mg (20.7%), compared with the statin 80 mg group (6.7%; P = 0.007) (17). These effects were most pronounced in patients receiving high dose statin ezetimibe plus statin 80 mg decreased LDL-C levels from baseline on 40 mg statin by 27.5 vs. 7.0% in the statin 80 mg treatment group (P = ) (Fig. 6). A significantly greater proportion of patients achieved decreases in LDL-C of 15% following addition of ezetimibe to statin 40 mg statin 80 mg (58%), compared to the statin 80 mg group (18%; P = 0.001) (17). Again, this effect was most evident in patients receiving high dose statin (76% for ezetimibe plus statin 80 mg vs. 18% for statin 80 mg; P 0.001). Reduced LDL-C levels peaked around 2 weeks and the response was sustained throughout the 12-week treatment period. Although there was a trend towards a favorable effect on other lipid parameters (e.g., triglycerides, and apolipoprotein A-1 and B) following ezetimibe combination therapy, only decreases in total cholesterol levels from baseline in patients receiving ezetimibe plus statin 40 mg 80 mg achieved significance, compared with statin 80 mg alone, (18.7 vs. 5.3%; P < 0.01) (17). Ezetimibe combination therapy was well tolerated, and the incidence of AEs and results of a range of safety tests (laboratory results, ECG, cardiopulmonary examinations) were similar between ezetimibe statin combination therapy and statin monotherapy (17). The efficacy of ezetimibe in this patient population indicates that ezetimibe acts through mechanisms independent of LDL-C receptors. Moreover, ezetimibe s complementary mode of action offers an effective therapeutic approach to patients with HoFH. Efficacy in homozygous sitosterolemia Homozygous sitosterolemia is an autosomal recessive disorder resulting from mutation of genes encoding ABCG5 and ABCG8 lipid transporter proteins (4). The disease is characterized by hyperabsorption and decreased biliary excretion of dietary sterols, hypercho-

15 EZETIMIBE 307 lesterolemia, premature development of atherosclerosis, and abnormal hematological and liver function tests (4,36). Homozygous sitosterolemia is poorly controlled with currently available therapies patients frequently experience elevated plant sterol concentrations and progressive complications stressing the need for more effective treatment (49). Moreover, recent studies suggest that elevated sterols are associated with an increased risk for CHD (56). Since ezetimibe blocks the intestinal absorption of campesterol and sitosterol in addition to cholesterol in humans, it was studied for its potential efficacy in an 8-week randomized, double-blind, placebo-controlled trial of 37 patients with homozygous sitosterolemia (49). Ezetimibe 10 mg day caused a significantly greater reduction in plasma sitosterol concentrations from baseline ( 21%), compared with placebo (+4%; P < 0.001) (49). Plasma campesterol concentrations were lowered by 24.3% following ezetimibe therapy, compared with an increase of 3.2% in the placebo group. These effects were independent of concomitant treatment with bile acid sequestrants or statins. Total plasma sterol and apolipoprotein B levels were lower in the ezetimibe group than in the placebo group at the end of the 8-week treatment period. LDL-C levels were reduced to a numerically greater extent by ezetimibe than by placebo, although this difference was not significant (49). Ezetimibe was well tolerated in this patient group. SAFETY Ezetimibe, as monotherapy, has a safety profile similar to that of placebo. The drug blocks cholesterol absorption without affecting the absorption of other lipids or lipid soluble molecules, such as triglycerides, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rodents. In humans, ezetimibe had no effect on plasma concentration of fat-soluble vitamins A, D, and E, and no effect on prothrombin time (surrogate for vitamin K) (24,62). In addition, unlike many lipid-lowering agents, ezetimibe monotherapy in humans is not associated with elevated liver enzymes or muscle enzymes (10,24). When coadministered with statins, a slightly greater incidence of elevated liver transaminases (ALT and or AST) 3 ULN have been observed, but these are generally asymptomatic, not associated with cholestasis, and reversible upon discontinuation or continuation of treatment. There is no potentiation of muscle toxicity or increase in creatine phosphokinase when ezetimibe is used with statins (1,5,20,34). In contrast to statins, ezetimibe is not metabolized through cytochrome P450 isoenzymes and, consequently, has a lower propensity for drug-drug interactions (65,67). Pharmacokinetic and pharmacodynamic studies have shown that ezetimibe does not interact with any of the following drugs: warfarin, oral contraceptives, digoxin, or cimetidine (2,21,28,29). Clinical studies have demonstrated the lack of interaction between ezetimibe and various lipid-lowering agents, such as statins and fenofibrate (25 27,42,44,45,53,67). In certain pharmacokinetic studies, coadministration of ezetimibe with fenofibrate (42) or gemfibrozil (43) increased the maximum plasma concentration and the area under the time-versus-plasma concentration curve for total ezetimibe, but this increase in ezetimibe bioavailability was not clinically significant. However, until ezetimibe coadministration

16 308 L. J. LIPKA with fenofibrate or gemfibrozil has been evaluated in clinical studies, the concurrent use of these agents with ezetimibe is not recommended. SUMMARY AND CONCLUSIONS In spite of the availability of a diverse range of lipid-lowering agents, significant numbers of patients at risk for CHD fail to reach their LDL-C goal, and many remain untreated. Recently published NCEP guidelines advocate a more aggressive approach to lipid-lowering therapy, including the combined use of agents that act through different mechanisms of action. Because combination therapies for hypercholesterolemia are generally limited by poor compliance and reduced tolerance, there is a growing unmet need for safer and more effective treatment strategies. Ezetimibe is the first in a class of orally active cholesterol absorption inhibitors that has potent lipid-lowering and anti-atherosclerotic effects in animal models of hypercholesterolemia and dyslipidemia. Ezetimibe s mechanism of action complements that of cholesterol synthesis inhibitors. Clinical studies in patients with primary hypercholesterolemia, many of whom are at high risk for CHD, demonstrated incremental lowering of LDL-C after initiating treatment with ezetimibe plus a statin, or adding ezetimibe to ongoing statin therapy. Moreover, ezetimibe plus statin therapy significantly improved the proportion of patients achieving LDL-C goal. The advantage of this approach is underscored by the fact that ezetimibe administered with low-dose statin was as effective as a 2- to 3-fold dose titration of statin alone. Favorable effects on HDL-C and triglycerides were also generally noted. Similar effects on LDL-C were also observed in patients with HoFH and HeFH, and further studies are eagerly awaited to determine whether the addition of ezetimibe to a statin prevents the development or progression of CHD. In contrast to certain lipid-lowering agents, ezetimibe has exhibited a low propensity for drug-drug interactions and has demonstrated an excellent safety and tolerability profile. The convenient once-daily administration of ezetimibe and decreased need for statin titration may contribute to patient compliance. Ezetimibe shows promise for the management of patients with homozygous sitosterolemia, as demonstrated by its ability to decrease plasma campesterol and sitosterol levels. Since elevated sitosterol levels are associated with increased CHD, it is important to establish the long-term effects of ezetimibe on cardiovascular outcomes in this disease. In conclusion, ezetimibe plus statin combination therapy fulfills a critical unmet need for safer and more effective treatment of patients with hypercholesterolemia. REFERENCES 1. Ballantyne C, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: A prospective, randomized, double-blind trial. Circulation 2003;107:

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