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PubMed2003

Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor.

BACKGROUND: Ezetimibe is the first of a new class of antihyperlipidemic agents, the cholesterol-absorption inhibitors. It is indicated for monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) in patients with primary hypercholesterolemia, in combination with simvastatin or atorvastatin in patients with homozygous familial hypercholesterolemia, and as monotherapy in patients with homozygous familial sitosterolemia. OBJECTIVE: This article reviews available data on the clinical pharmacology, clinical efficacy, and tolerability of ezetimibe. METHODS: A literature review was conducted using the search terms ezetimibe and SCH 58235 to identify articles and abstracts indexed in MEDLINE and the Iowa Drug Information Service from 1966 to February 2003. The reference lists of the identified articles were reviewed for additional publications. RESULTS: In adults, ezetimibe 10 mg PO given once daily has been reported to reduce intestinal cholesterol absorption by 54% from baseline in association with a compensatory increase in endogenous cholesterol synthesis. Within 2 weeks of its initiation, ezetimibe monotherapy produced a 17% to 20% reduction from baseline in low-density lipoprotein cholesterol (LDL-C); in combination with statins, ezetimibe produced a reduction in LDL-C of up to 40% over the same period. Based on studies performed to date, ezetimibe appears to be well tolerated, with a safety profile similar to that of placebo. Because ezetimibe is eliminated primarily by glucuronidation and not by cytochrome P450 (CYP) oxidation, it is subject to minimal drug interactions involving the CYP enzyme system. CONCLUSIONS: Ezetimibe is an option for monotherapy in patients with mild hypercholesterolemia or in those requiring adjunctive drug therapy for reduction of LDL-C levels. It may be useful in patients at risk for adverse events (eg, liver toxicity, myopathy) from other hypocholesterolemic agents. Additive LDL-C-lowering effects of ezetimibe may allow use of lower doses of conventional agents (eg, statins, fibric acid derivatives, niacin) to achieve an equivalent effect, thereby reducing the potential for adverse events and drug interactions. However, because trials have lasted no longer than 12 weeks, the long-term effect of ezetimibe on cardiovascular morbidity and mortality remains to be determined.

Animals↗

PubMed2002

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.

OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia. BACKGROUND: Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals. METHODS: After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =145 mg/dl to < or =250 mg/dl and triglycerides (TG) < or =350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups. RESULTS: Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo. CONCLUSIONS: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.

Adult↗

PubMed2001

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function.

1. Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies. 2. Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat. 3. Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED(50) of 0.04 mg kg(-1). Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 - 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (-94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats. 4. Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would.

Animals↗

PubMed2001

Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice.

Ezetimibe (SCH58235) is a potent, selective, cholesterol absorption inhibitor. The objective of this study was to determine whether ezetimibe reduces plasma cholesterol and inhibits atherogenesis in apolipoprotein E knockout (apoE-/-) mice. Cholesterol absorption was inhibited by >90% at doses of ezetimibe >3 mg/kg in apoE-/- mice. Atherosclerosis and lipoprotein changes were determined in apoE-/- mice fed a high-fat (0.15% cholesterol) "western" diet, a low-fat (0.15% cholesterol) diet, or a semisynthetic cholesterol-free diet with or without ezetimibe (5 mg/kg per day) for 6 months. Ezetimibe reduced plasma cholesterol levels from 964 to 374 mg/dL, from 726 to 231 mg/dL, and from 516 to 178 mg/dL in the western, low-fat, and cholesterol-free diet groups, respectively. The reductions occurred in the very low density and low density lipoprotein fractions, whereas high density lipoprotein cholesterol levels were increased by ezetimibe treatment. Ezetimibe reduced aortic atherosclerotic lesion surface area from 20.2% to 4.1% in the western diet group and from 24.1% to 7.0% in the low-fat cholesterol diet group. Ezetimibe reduced carotid artery atherosclerotic lesion cross-sectional area by 97% in the western and low-fat cholesterol groups and by 91% in the cholesterol-free group. Ezetimibe inhibits cholesterol absorption, reduces plasma cholesterol, increases high density lipoprotein levels, and inhibits the progression of atherosclerosis under western, low-fat, and cholesterol-free dietary conditions in apoE-/- mice. Although apoE-/- mice are more hypercholesterolemic than are humans and low density lipoprotein reductions with ezetimibe are not as pronounced clinically, ezetimibe may inhibit atherogenesis in individuals consuming restricted-fat or western diets.

Administration, Oral↗

PubMed2006

Lipid-lowering effects of colesevelam HCl in combination with ezetimibe.

OBJECTIVE: The primary aim of this study was to compare the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein cholesterol (LDL-C) levels in subjects with primary hypercholesterolemia. METHODS: Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8-week washout period, subjects received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or colesevelam HCl placebo plus ezetimibe 10 mg/day for 6 weeks. The primary efficacy endpoint was the mean percent change in LDL-C during randomized treatment. Secondary endpoints included mean absolute change in LDL-C, mean absolute and mean percent change in levels of high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent changes in triglycerides (TG) and high-sensitivity C-reactive protein from baseline to end of treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-to-treat analysis. RESULTS: After 6 weeks of treatment, colesevelam HCl plus ezetimibe produced a mean percent change in LDL-C of -32.3% versus -21.4% with ezetimibe monotherapy (p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more effective than ezetimibe alone at producing mean percent reductions in TC, non-HDL-C, and apo B and increases in apo A-I (p < 0.005 for all). Neither treatment regimen resulted in significant changes in median TG levels compared with baseline (p = NS). Both treatments were safe and generally well tolerated. CONCLUSIONS: Colesevelam HCl plus ezetimibe combination therapy significantly reduced mean LDL-C, TC, non-HDL-C, and apo B levels and increased apo A-I levels (p < 0.005 for all) without significantly increasing median TG levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in that atherosclerotic coronary heart disease outcomes were not evaluated, this study demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who may have intolerances to statin therapy.

Adult↗

PubMed2006

Type of preexisting lipid therapy predicts LDL-C response to ezetimibe.

BACKGROUND: Ezetimibe as monotherapy or in combination with statins effectively lowers low-density lipoprotein cholesterol (LDL-C). However, there are few reports of ezetimibe's effect when added to ongoing non-statin lipid-lowering drugs or combination lipid-lowering therapy. OBJECTIVE: To evaluate the impact of preexisting lipid therapy on LDL-C response to ezetimibe. METHODS: We performed a retrospective review of all patients started on ezetimibe therapy at the Veterans Affairs Long Beach Healthcare System between March 1, 2003, and March 1, 2005. We calculated the ezetimibe-induced percent change in LDL-C in patients without concomitant changes in other lipid-lowering medications. We then stratified the population according to the type and number of preexisting lipid therapies and compared the LDL-C-lowering efficacy of ezetimibe among these groups. RESULTS: Overall, ezetimibe was associated with a 23.0% reduction in LDL-C. Patients with preexisting statin monotherapy had significantly greater LDL-C reduction with ezetimibe than did those with preexisting non-statin drugs (-26.1% vs -9.3%; p = 0.0138). In patients with no preexisting lipid therapy (n = 58), monotherapy (n = 115), double therapy (n = 36), or triple therapy (n = 9), ezetimibe decreased LDL-C by 17.3%, 21.4%, 33.5%, and 38.1%, respectively. This stepwise trend in increased ezetimibe efficacy was statistically significant, even with adjustments for baseline LDL-C. CONCLUSIONS: Ezetimibe's LDL-C-lowering effects are most pronounced when added to preexisting combination lipid therapy. It appears to be more effective when added to statin therapy compared with other lipid-lowering therapies.

Anticholesteremic Agents↗

PubMed2003

Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia.

This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol > or =145 mg/dl (3.75 mmol/L) and < or =250 mg/dl (6.47 mmol/L) and triglycerides < or =350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia.

Aged↗

PubMed2001

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Adolescent↗

PubMed2004

Consistency in efficacy and safety of ezetimibe coadministered with statins for treatment of hypercholesterolemia in women and men.

BACKGROUND: Women are often not treated as aggressively as men to control levels of low-density lipoprotein cholesterol (LDL-C), despite evidence that women and men realize comparable cardiovascular benefit from lipid-lowering therapy. Statins are the most effective drugs currently available for treating hypercholesterolemia. Despite the impressive cholesterol-lowering capacity of statins, however, many patients on statin therapy fail to reach established target levels of LDL-C. The cholesterol absorption inhibitor, ezetimibe, blocks the intestinal absorption of dietary and biliary cholesterol, a mechanism of action complementary to that of statins, which inhibit hepatic cholesterol synthesis. Ezetimibe coadministered with statins produces significant incremental reductions in LDL-C compared with statin monotherapy. METHODS: Four randomized, double-blind, placebo-controlled, balanced-parallel group trials compared the efficacy and safety of statin monotherapy (lovastatin or pravastatin 10, 20, or 40 mg; simvastatin or atorvastatin 10, 20, 40, or 80 mg) vs. ezetimibe 10 mg plus statin (as above). A gender subset analysis (women, n = 1065; men, n = 796) on data pooled across these four trials was carried out to determine whether ezetimibe plus statin for the treatment of hypercholesterolemia is equally efficacious in women and men. RESULTS: Compared with statin monotherapy, ezetimibe plus statin demonstrated greater efficacy in reducing blood levels of LDL-C, apolipoprotein B, and triglycerides and raising high-density lipoprotein cholesterol. The beneficial effects of ezetimibe were comparable in women and men. The safety profile of subjects receiving ezetimibe plus statin was similar to that of patients receiving statin monotherapy and similar between the two sexes. CONCLUSIONS: Ezetimibe plus statin was more effective than statin alone in improving the lipid profile of patients with hypercholesterolemia and was equally efficacious in women and men. Ezetimibe plus statin was well tolerated and had a favorable safety profile in both patient subgroups. Ezetimibe coadministered with statins, a dual inhibition treatment strategy that targets both cholesterol absorption and synthesis, is an effective therapeutic option for women with hypercholesterolemia.

Adult↗

PubMed2002

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.

Adolescent↗

PubMed2003

Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.

BACKGROUND: Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. METHODS AND RESULTS: In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides < or =350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. CONCLUSIONS: Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.

Anticholesteremic Agents↗

PubMed2004

Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.

This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia. Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treatment period 1, the mean decrease of LDL cholesterol was significantly (p </=0.001) greater for co-administration of 10/10 mg and 10/20 mg of ezetimibe + simvastatin than for 10 mg of atorvastatin. At the end of treatment period 4 and after comparing maximum doses, co-administration of 10/80 mg of ezetimibe + simvastatin was superior to 80 mg of atorvastatin in the percent LDL cholesterol decrease (-59.4% vs -52.5%, p <0.001) and HDL cholesterol increase (12.3% vs 6.5%; p <0.001). All treatments were well tolerated. Thus, a greater LDL cholesterol decrease and HDL cholesterol increase were attained by treating patients with co-administration of ezetimibe and simvastatin than with atorvastatin.

Anticholesteremic Agents↗

PubMed2005

Inhibition of intestinal cholesterol absorption by ezetimibe is a novel therapeutic target for fatty liver.

Ezetimibe is a novel lipid-lowering agent that inhibits intestinal absorption of dietary and biliary cholesterol. The effects of ezetimibe on low-density lipoprotein (LDL)-cholesterol were found to generally consistent across all subgroups analyzed, including baseline lipid profile, hypertension, diabetes mellitus, and body mass index. Furthermore, recent clinical studies also revealed that co-administration of ezetimibe with on-going statins offered a well-tolerated and efficacious treatment to lower LDL-cholesterol levels in hypercholesterolemic patients with diabetes mellitus or the metabolic syndrome. Niemann-Pick C1 like 1 (NPC1L1) protein is recently found to be critical for intestinal cholesterol absorption, and is a target protein for ezetimibe. Human NPC1L1 protein is predominantly expressed in liver, whereas small intestine expression is only about 2-4% of that found in the liver. Thus, NPC1L1 does not function solely in the intestinal cholesterol absorption. Furthermore, loss of NPC1L1 expression has been shown to protect against diet-induced fatty liver. These observations let us to speculate that ezetimibe will become a new therapeutic approach for the treatment of non-alcoholic fatty liver, the hepatic manifestation of insulin resistant patients with the metabolic syndrome. In this paper, we would like to propose the possible ways of testing our hypothesis as follows. (1) Does ezetimibe treatment improve fatty liver in patients with hypercholesterolemia or the metabolic syndrome? If the answers are yes, are these beneficial effects of ezetimibe superior to those of other anti-hyperlipidemic resins with equihypolipidemic properties? (2) Does ezetimibe treatment improve insulin sensitivity in fatty liver patients with the metabolic syndrome? (3) How about the effects of ezetimibe treatment on serum levels of adiponectin, a key adipokine with insulin-sensitizing property? Large clinical trials will provide us with more definite information whether ezetimibe treatment can improve fatty liver and resultantly reduce the risk of progression of liver diseases in patients with the metabolic syndrome.

Adiponectin↗

PubMed2006

Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

Two cases of myopathy associated with ezetimibe are reported. In the first case, a woman on ezetimibe monotherapy presented with muscle pain and an elevated concentration of creatine kinase (CK) on two occasions, with ezetimibe 10 mg and with ezetimibe 5 mg after a washout period. The recurrence of muscle pain after washout and the CK increase both supported the hypothesis that ezetimibe alone can be linked to myalgia. In the second case, a man had been treated with atorvastatin, and ezetimibe 10 mg was added to improve his lipid profile. Two months later, the patient complained of muscle pain and a CK increase was noted. The appearance of symptoms when adding ezetimibe to atorvastatin supports a potential pharmacokinetic and/or a pharmacodynamic interaction between these two drugs. These cases suggest that ezetimibe monotherapy as well as ezetimibe associated with the use of a statin may induce myalgia. The mechanism by which ezetimibe could cause muscle pain is not known.

Adult↗

PubMed2002

Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin.

AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.

Administration, Oral↗

PubMed2004

Aminopeptidase N (CD13) is a molecular target of the cholesterol absorption inhibitor ezetimibe in the enterocyte brush border membrane.

Intestinal cholesterol absorption is an important regulator of serum cholesterol levels. Ezetimibe is a specific inhibitor of intestinal cholesterol absorption recently introduced into medical practice; its mechanism of action, however, is still unknown. Ezetimibe neither influences the release of cholesterol from mixed micelles in the gut lumen nor the transfer of cholesterol to the enterocyte brush border membrane. With membrane-impermeable Ezetimibe analogues we could demonstrate that binding of cholesterol absorption inhibitors to the brush border membrane of small intestinal enterocytes from the gut lumen is sufficient for inhibition of cholesterol absorption. A 145-kDa integral membrane protein was identified as the molecular target for cholesterol absorption inhibitors in the enterocyte brush border membrane by photoaffinity labeling with photoreactive Ezetimibe analogues (Kramer, W., Glombik, H., Petry, S., Heuer, H., Schafer, H. L., Wendler, W., Corsiero, D., Girbig, F., and Weyland, C. (2000) FEBS Lett. 487, 293-297). The 145-kDa Ezetimibe-binding protein was purified by three different methods and sequencing revealed its identity with the membrane-bound ectoenzyme aminopeptidase N ((alanyl)aminopeptidase; EC 3.4.11.2; APN; leukemia antigen CD13). The enzymatic activity of APN was not influenced by Ezetimibe (analogues). The uptake of cholesterol delivered by mixed micelles by confluent CaCo-2 cells was partially inhibited by Ezetimibe and nonabsorbable Ezetimibe analogues. Preincubation of confluent CaCo-2 cells with Ezetimibe led to a strong decrease of fluorescent APN staining with a monoclonal antibody in the plasma membrane. Independent on its enzymatic activity, aminopeptidase N is involved in endocytotic processes like the uptake of viruses. Our findings suggest that binding of Ezetimibe to APN from the lumen of the small intestine blocks endocytosis of cholesterol-rich membrane microdomains, thereby limiting intestinal cholesterol absorption.

Absorption↗

PubMed2006

In vivo responsiveness to ezetimibe correlates with niemann-pick C1 like-1 (NPC1L1) binding affinity: Comparison of multiple species NPC1L1 orthologs.

Ezetimibe is the first in class 2-azetidinone that decreases plasma cholesterol by blocking intestinal cholesterol absorption. Ezetimibe effectively reduces plasma cholesterol in several species including human, monkey, dog, hamster, rat, and mouse, but the potency ranges widely. One potential factor responsible for this variation in responsiveness is diversity in ezetimibe metabolism. After oral administration, ezetimibe is glucuronidated. Both ezetimibe and the glucuronide lower plasma cholesterol; however, the glucuronide exhibits greater potency. Recent identification of Niemann-Pick C1 Like-1 (NPC1L1) as the molecular target of ezetimibe enables direct binding studies to be performed. Here, we report the cloning of NPC1L1 derived from multiple species and assess amino acid sequence homology among human, monkey, dog, hamster, rat, and mouse. The rank order of affinity of glucuronidated ezetimibe for NPC1L1 in each species correlates with the rank order of in vivo activity with monkey > dog > hamster and rat >> mouse. Ezetimibe analogs that bind to NPC1L1 exhibit in vivo cholesterol-lowering activity, whereas compounds that do not bind NPC1L1 are inactive. Specific structural components of ezetimibe are identified as critical for binding to NPC1L1. The results demonstrate that small variations in ezetimibe structure or in NPC1L1 amino acid sequence can profoundly influence ezetimibe/NPC1L1 interaction and consequently in vivo activity. The results demonstrate that the ability of compounds to bind to NPC1L1 is the major determinant of in vivo responsiveness.

Amino Acid Sequence↗

PubMed2005

Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels.

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment. Forty mildly hypercholesterolemic subjects were randomized to the following treatments for 4 weeks each: 10 mg/day ezetimibe combined with 25 g/day control spread; 10 mg/day ezetimibe combined with 25 g/day spread containing 2.0 g of plant sterols; 25 g/day spread containing 2.0 g of plant sterols; and placebo treatment consisting of 25 g/day control spread. Combination treatment of plant sterols and ezetimibe reduced low density lipoprotein cholesterol (LDL-C) by 1.06 mmol/l (25.2%; P < 0.001) compared with 0.23 mmol/l (4.7%; P = 0.006) with plant sterols and 0.94 mmol/l (22.2%; P < 0.001) with ezetimibe monotherapy. LDL-C reduction conferred by the combination treatment did not differ significantly from ezetimibe monotherapy (-0.12 mmol/l or -3.5%; P = 0.13). Additionally, the plasma lathosterol-to-cholesterol ratio increased with all treatments. Sitosterol and campesterol ratios increased after plant sterol treatment and decreased upon ezetimibe and combination therapy. Our results indicate that the combination of plant sterols and ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with mild hypercholesterolemia.

Absorption↗