Selective Cholesterol Absorption Inhibitor Research Articles

Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolaemia

The development of cholesterol-lowering drugs (including a variety of statins, bile acid-binding resins and recently discovered inhibitors of cholesterol absorption) has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined targets for LDL cholesterol concentrations. Combination therapy with drugs that have different or complementary mechanisms of action is often needed to achieve lipid goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to conventional drug treatment and remain at high risk for the development and progression of atherosclerotic cardiovascular disease and alternative approaches are needed. The discovery and development of ezetimibe (a novel, selective and potent cholesterol absorption inhibitor) has advanced the treatment of hypercholesterolaemia. New agents including the phytostanol preparation FM-VP4 and inhibitors of acyl coenzyme A:cholesterol acyltransferase, the apical Na+-dependent bile acid transporter and microsomal triglyceride transfer protein may also play a future role in combination therapy. This review focuses on the recent progress in the molecular mechanisms of intestinal cholesterol absorption and transport, and novel therapeutic approaches to inhibit the cholesterol absorption process.

The clinical effect and tolerability of ezetimibe in high-risk patients managed in a specialty cardiovascular risk reduction clinic

Ezetimibe (EZ) is a selective cholesterol absorption inhibitor approved for use in Canada. The effect and tolerability of EZ among patients was evaluated in the clinical setting of a specialty cardiovascular risk reduction clinic at the University of Alberta Hospital, Edmonton, Alberta. patients and All patients 18 years of age or older who were prescribed EZ were included, unless they failed to take EZ for a minimum of two weeks, did not have baseline and on-EZ low-density lipoprotein cholesterol (LDL-C) levels, or had concomitant lipid-lowering drugs or dosages changed within one month of starting EZ. Eighty-four patients (mean age 57.9 years) were included. By Framingham risk calculation, 71.4% were found to be high-risk patients, 13.1% moderate-risk patients and 15.5% low-risk patients; 66.7% of patients had prior cardiovascular events. On EZ, the mean reductions were: total cholesterol level 1.11 mmol/L (16.5%); LDL-C level 1.01 mmol/L (22.3%); high-density lipoprotein cholesterol level 0.06 mmol/L (4.6%); and ratio of total cholesterol level to high-density lipoprotein cholesterol level 0.68 mmol/L (12.8%); all were statistically significant (P<0.001). Results were similar when stratified by primary (n=28) versus secondary (n=56) prevention. Patients on EZ monotherapy (n=34) had mean LDL-C reductions of 1.03 mmol/L (20.5%) compared with 1.19 mmol/L (30.1%) or 0.95 mmol/L (22.5%), where EZ was added to low-dose or high-dose statins (P<0.01 for all). On EZ, 30 patients (35.7%) achieved previously unattainable target LDL-C levels. Four patients discontinued the drug due to side effects. EZ is safe and effective in high-risk patients treated in the clinical setting of a cardiovascular risk reduction clinic. A mean LDL-C reduction of 1 mmol/L (20% to 30%) in all patient subgroups is consistent with previous clinical trial results. The significant reduction in LDL-C (mean 22.5%) observed in the EZ plus high-dose statin subgroup provides clinical evidence for use of this medication beyond published studies.

Medifile drug information bulletin

The first edition of Medifile for 2006 provides information on two new drug classes, Atomoxetine and Ezetimibe. Strattera® (Atomoxetine) is the first non-stimulant drug registered for the management of Attention Deficit Hyperactivity Disorder (ADHD). Ezetrol® (Ezetimibe) is an anti-hyperlipidaemic and selective cholesterol absorption inhibitor. The selective cholesterol absorption inhibitors are the first new class of cholesterol lowering drugs in 15 years. Both products were launched in South Africa in 2005.

Combination of a Sterol Absorption Inhibitor and Cardiovascular Agents for the Treatment of Dyslipidemia

Although statins are effective in reducing cardiovascular risk, combination therapy may be required to meet recommended target LDL-C levels. However, the utility of current combination therapies with niacin or bile acid sequestrants is limited by side effects and compliance. Ezetimibe, as a selective cholesterol absorption inhibitor, represent a new class of pharmaceutical agents. The combination of ezetimibe with statins has shown a 16-21% increase in the percentage of patients achieving their ATP III LDL-C goal. Randomized, double-blind studies have shown that coadministration of ezetimibe with simvastatin is well tolerated, causing dose-dependent reduction in LDL-C and total cholesterol levels, with no apparent effect on high-density lipoprotein cholesterol or triglycerides. Even in diabetes mellitus type 2 patients; the addition of ezetimibe 10 mg to simvastatin 20 mg is more efficacious than doubling the dose of simvastatin in lowering lipid parameters. Similarly the coadministration of ezetimibe and rosuvastatin, has shown a mean incremental reduction in LDL-C of -16%, compared with rosuvastatin alone, while there was no apparent effect on HDL-C or triglycerides. Ezetimibe and fenofibrate co-administration has shown also improvement in the lipid/lipoprotein profile. The combination therapy with ezetimibe and statin or fibrate may be an effective therapeutic option for patients with dyslipidemia.

Ezetimibe: first in a new class of cholesterol absorption inhibitors

Ezetimibe is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol, which keeps the cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug–drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals ( p<0.001). Ezetimibe alone reduced plasma total and LDL-C (18%) levels ( p<0.001) in patients with primary hypercholesterolemia. When ezetimibe was added to ongoing statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia ( p<0.001). Ezetimibe, in combination with a statin, produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.

Lipid-lowering therapy

PREVIEWLipid therapy has come a long way in the past 20 years. In the late 1980s, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”) were introduced, and they have continued to demonstrate benefits in multiple large-Scale primary and secondary prevention trials. A broader understanding of the effects of statin medications has led to new therapeutic goals for different patient populations. In this article, Dr Smith discusses recent developments in statin therapy as well as the introduction of a new class of drugs called selective cholesterol absorption inhibitors.

Medical lipid-regulating therapy: current evidence, ongoing trials and future developments.

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.

Management of hyperlipidaemia associated with heart transplantation.

The past 20 years have seen considerable advances in the field of organ transplantation that have together led to a notable increase in survival rates and a reduction in postoperative morbidity of transplant recipients. However, these advances have been accompanied by the appearance of other complications of transplantation, such as post-transplant hyperlipidaemia, hypertension and graft coronary vasculopathy (GCV). GCV is an accelerated form of atherosclerosis in transplanted hearts that has proven to be one of the most important late complications of heart transplantation and is the single most limiting factor for long-term survival. The most important factors favouring the development of hyperlipidaemia after heart transplantation are inappropriate diet in combination with reduced physical activity, adverse effects of immunosuppressive therapy (ciclosporin [cyclosporin], corticosteroids) and polygenic hypercholesterolaemia in combination with ischaemic cardiomyopathy. The treatment of hyperlipidaemia in heart transplant recipients results in a variety of complications and side effects. In particular, interactions between lipid-lowering drugs and immunosuppressive therapy have been observed. Early attempts at treatment with bile acid binding agents and nicotinic acid derivatives often proved insufficiently effective, and led to unacceptable adverse effects and significant disturbances of ciclosporin metabolism. Fibric acid derivatives provided moderate reductions in triglyceride and total cholesterol levels that were mostly--with the exception of gemfibrozil--accompanied by significant impairment of renal function. Probucol achieved only an unsatisfactory reduction in low-density lipoprotein (LDL) cholesterol. Omega-3 fatty acids lower cholesterol levels and improve endothelial function in heart transplant recipients; however, the significance of these effects is still under discussion. As in the general patient population, use of HMG-CoA reductase inhibitors (statins) achieved significant reductions in cholesterol levels. Use of these substances has resulted in significantly extended long-term survival times, significantly less GCV and fewer severe graft rejections. Selective cholesterol absorption inhibitors, administered with or without statins, could provide another treatment option for heart transplant patients with hypercholesterolaemia. In severe familial hypercholesterolaemia, which is rarely observed in heart transplant recipients, treatment with statins can be combined with extracorporeal cholesterol elimination procedures such as heparin induced extracorporeal LDL cholesterol precipitation (HELP). HELP enables total cholesterol levels to be kept within any desired target range, and has been used successfully and without adverse effects in heart transplant recipients.

The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal.Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication.

Ezetimibe: a selective cholesterol absorption inhibitor.

Ezetimibe is the first agent of a novel class of selective cholesterol absorption inhibitors recently approved by the Food and Drug Administration for treatment in the United States. Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids. Ezetimibe localizes at the brush border of the small intestine and decreases cholesterol uptake into the enterocytes. Preclinical studies demonstrated lipid-lowering properties of ezetimibe as monotherapy and showed a synergistic effect in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The efficacy and safety of ezetimibe 10 mg/day have been established in phase III clinical trials. In these trials, ezetimibe was investigated as monotherapy, as an add-on to ongoing statin therapy, and as combination therapy with statins in patients with primary hypercholesterolemia. In addition, ezetimibe has been evaluated in patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia. When given as monotherapy or in combination with statins or fenofibrate, ezetimibe reduces low-density lipoprotein cholesterol (LDL) by 15-20% while increasing high-density lipoprotein cholesterol by 2.5-5%. Unlike other intestinally acting lipid-lowering agents, ezetimibe does not adversely affect triglyceride levels and, due to its minimal systemic absorption, drug interactions are few. Ezetimibe's side-effect profile resembles that of placebo when given as monotherapy or in combination with statins. In clinical practice, ezetimibe has a role as monotherapy for patients who require modest LDL reductions or cannot tolerate other lipid-lowering agents. In combination therapy with a statin, ezetimibe is used in patients who cannot tolerate high statin doses or in those who need additional LDL reductions despite maximum statin doses.

The place of ezetimibe in clinical practice.

Ezetimibe is the first selective cholesterol absorption inhibitor to be licensed in the UK. It interferes both with dietary cholesterol absorption and the enterohepatic circulation of cholesterol synthesized by the liver. As monotherapy it leads to modest reductions in plasma low-density lipoprotein cholesterol levels, but has synergistic effects when used with statins.

Pharmacological management of hyperlipidaemia

Coronary heart disease (CHD) is a major cause of morbidity and mortality. Recent evidence supports the benefits of intensive low density lipoprotein-cholesterol (LDL-c) reduc-of intensive low density lipoprotein-cholesterol (LDL-c) reduction on CHD risk with various ongoing end point trials addressing the issue of optimal cholesterol reduction. Statins reduce LDL-c, and have been shown to reduce CHD event rates in both primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-c reduction alone and may relate to effects on other lipid parameters. Fibrates represent the best treatment for raising high density lipoprotein-cholesterol (HDL-c) and a variety of agents, which specifically target HDL-c, are under development. New therapies being developed to meet the challenge of intensive cholesterol lowering include rosuvastatin, a potent statin, producing reductions in LDL-c of up to 69% and ezetimibe, a selective cholesterol absorption inhibitor, producing reductions in LDL-c of up to 25%. This review summarises the evidence regarding dyslipidaemia and vascular risk and how advances in lipid-lowering therapy may be important in future management of hyperlipidaemia.

The intestinal absorption of biliary and dietary cholesterol as a drug target for lowering the plasma cholesterol level.

Elevated plasma low-density lipoprotein cholesterol levels constitute a major risk factor for coronary heart disease. The plasma low-density lipoprotein cholesterol concentration is dictated partly by the efficiency of intestinal cholesterol absorption. The efficacy of treatments designed to block cholesterol absorption is partially offset to the extent that the liver compensates for the interruption to the enterohepatic movement of cholesterol by increasing the rate at which it synthesizes cholesterol. Currently, the most widely-used treatment for hypercholesterolemia is based on a class of agents (statins) that partially inhibit cholesterol synthesis within the body. Recent clinical trials with a unique, potent, and selective cholesterol absorption inhibitor (ezetimibe) used in combination with lower doses of various statins showed an additive reduction in plasma low-density lipoprotein cholesterol levels which equaled the reduction achieved with maximal doses of statins given alone. Combination therapy using a statin and this novel cholesterol absorption inhibitor represents an efficacious new approach to the treatment of hypercholesterolemia in the general population.

A novel therapeutic approach.

Since 1988, the National Cholesterol Education Program has identified low-density lipoprotein cholesterol (LDL-C) as the target of therapy; the new Adult Treatment Panel III (ATP III) guidelines continue the tradition of matching the aggressiveness of LDL-lowering therapy according to the risk of coronary heart disease (CHD). A significant change in the new guidelines is the definition of.CHD risk equivalents. and the inclusion of a modified Framingham global risk score. These revisions significantly raise the number of patients who qualify for lipid-lowering therapy. ATP III recognizes statins as the drug of first choice for LDL-C lowering. Statins are proven to be safe and effective for LDL-C reduction and are proven to reduce CHD event rates and mortality. Some patients are not candidates for statin therapy, however, and must rely on nonstatin agents that are less effective in reducing LDL-C, less safe, or poorly tolerated. Consequently, new cholesterol-lowering therapies are needed. Ezetimibe, approved by the U.S. Food and Drug Administration (FDA) in October 2002, is the first in a new class of selective cholesterol absorption inhibitors and offers a novel approach to the treatment of dyslipidemia. Phase 2 data demonstrated that ezetimibe lowers LDL-C by 18% and has a tolerability and short-term safety profile similar to placebo. This paper reviews the cholesterol metabolic pathways and the mechanism of action of the currently available lipid-modifying agents and introduces ezetimibe, the first selective cholesterol absorption inhibitor.

Overview of pharmacologic therapy for the treatment of dyslipidemia.

Although the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines stress the importance of nonpharmacologic lipid modification interventions such as diet and exercise, the guidelines also recognize that many patients will require drug therapy to achieve low-density lipoprotein cholesterol (LDL-C) target goals. Currently available lipid-modifying drugs include bile acid sequestrants (or resins), fibrates, nicotinic acid, and statins, with each class exerting different effects on the lipid profile. In addition, nonprescription agents such as plant stanols and sterols have been shown to be effective in modifying plasma lipids. Of these agents, the statins are the most effective, most widely prescribed, and best-tolerated form of lipid-lowering drug therapy. New formulations of other drugs, such as niacin and bile acid sequestrants, can also improve treatment regimes and reduce side effects, thereby improving patient compliance with these therapies. In patients who have high levels of LDL-C and triglycerides together with low concentrations of high-density lipoprotein cholesterol (HDL-C), combination therapy may be required. Ezetimibe, a selective cholesterol absorption inhibitor, is the first of a new class of lipid-lowering agents and provides a new agent for the management of patients with dyslipidemia. Data from the ezetimibe clinical development program suggests that this agent can be used alone or in combination with statins to reduce LDL-C, improve compliance, and bring more patients to ATP III target goal.

New drugs for the treatment of hypercholesterolaemia

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome P450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.

The future direction of cholesterol-lowering therapy.

Observational studies suggest a continuous positive relationship between vascular risk and cholesterol without any lower threshold level. We review recent and future clinical trials addressing the question of optimal treatment goals for cholesterol reduction and how these relate to present guidelines. With increasing focus on greater cholesterol reduction, new approaches to lipid-lowering therapy are being developed; we discuss some of these agents including the new statin, rosuvastatin and novel cholesterol transport inhibitors such as ezetimibe. The Heart Protection Study demonstrated that LDL cholesterol reduction to levels as low as 1.7 mmol/l was associated with significant clinical benefit in a wide range of high-risk individuals, irrespective of baseline cholesterol levels, with no apparent threshold level for LDL cholesterol with respect to cardiovascular risk. The Heart Protection Study also demonstrated that the benefits of LDL cholesterol reduction extend into peripheral vascular disease and cerebrovascular disease prevention and suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL cholesterol targets of 2.6 mmol/l, may result in undertreatment of a large number of patients. Various large end-point trials, including Treating to New Targets and Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine will attempt to further address the issue of optimal LDL cholesterol reduction. New therapies are being developed to meet the challenge of more intensive cholesterol lowering. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL cholesterol of 40-69% over its dose range of 5-80 mg. Ezetimibe is a selective cholesterol absorption inhibitor, with a site of action at the intestinal epithelium. Optimum reductions in LDL cholesterol of up to 25 and 60% reduction in chylomicron cholesterol content are seen with a 10-mg dose. Evidence is accumulating supporting the safety and benefits of aggressive cholesterol reduction, with no apparent threshold for LDL cholesterol. New therapies will aid in achieving lower cholesterol levels and the use of combination therapies targeting different aspects of cholesterol metabolism may produce additional benefits. Outcome studies are awaited to further address these issues.

Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After ≥2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides ≤350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL 3 cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters.

Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors.

Zetia (ezetimibe) is the first medication in the novel class of selective cholesterol-absorption inhibitors to be released in the United States. Ezetimibe selectively inhibits the uptake of cholesterol from the intestinal lumen at the level of the enterocyte in the intestinal brush border while having no effect on other sterols or lipid-soluble vitamins. Ezetimibe 10 mg daily produces a consistent reduction in low-density lipoprotein cholesterol (LDL-C) by approximately 15 to 20% when used as monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) or fenofibrate and a 4 to 9% increase in high-density lipoprotein cholesterol. Unlike other lipid-lowering medications that act in the gastrointestinal tract, ezetimibe does not appear to worsen hypertriglyceridemia. Ezetimibe also has an adverse-event profile that is similar to placebo when used as monotherapy or in combination with statins and fenofibrate. Studies of longer duration and with niacin, bile acid sequestrants, and gemfibrozil are warranted to more completely assess the safety of ezetimibe in combination therapy. To date, no clinically significant drug-drug interactions have been noted with the use of ezetimibe; however, further studies are warranted. Ezetimibe will be useful as monotherapy in patients who need modest reductions in LDL-C or are intolerant to other lipid-lowering medication, and in combination with a statin in patients who are unable to tolerate large doses of statins or need further reductions in LDL-C despite maximum doses of a statin. The long-term safety and the effect on cardiovascular morbidity and mortality of ezetimibe are unknown.

EZETIMIBE IN HYPERCHOLESTEROLAEMIA

SUMMARYEzetimibe is the first member of a new class of selective cholesterol absorption inhibitors, compounds that effectively block intestinal absorption of dietary and biliary cholesterol, without affecting absorption of fat soluble vitamins or triglycerides. Ezetimibe underwent glucuronidation to a single metabolite and localised at the intestinal wall, where it prevented luminal cholesterol absorption. Pre‐clinical studies demonstrated the lipid‐lowering and antiatherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe monotherapy have been determined in phase ll/lll studies: in phase II studies, the optimal efficacy was reached with ezetimibe 10 mg per day and the pooled efficacy data have shown that ezetimibe 10 mg has a positive effect on the lipoprotein profile with a significant reduction in LDL‐cholesterol of 18.5%, an increase in HDL‐cholesterol of 3.5% and a trend towards lowering in triglyceride concentrations (‐4.9%). The monotherapy phase III studies have confirmed the efficacy with a decrease in LDL‐C of 17.4% and have demonstrated an excellent safety and tolerability profile. The potential for a pharmacokinetic and/or pharmacodynamic interaction between ezetimibe and various statins and the efficacy and safety or the co‐administration of ezetimibe and statins have been evaluated in different phase l/ll studies: ezetimibe had no significant effect on the pharmacokinetics of simvastatin or atorvastatin. Ezetimibe 10 mg co‐administrated with the starting dose of any statin induced a mean 18% additive LDL‐C lowering effect. This additive 18% reduction in LDL‐C is achieved in one step compared with the three steps necessary with statin monotherapy.