Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia^®, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Ezetimibe in hypercholesterolaemia

Ezetimibe 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 II/III 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 I/II 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.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann–Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann-Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

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.     

Optimizing LDL-C lowering with statins

Clinical studies have demonstrated the efficacy of statins in reducing low-density lipoprotein cholesterol (LDL-C) and lowering coronary heart disease risk. However, many patients receiving statin therapy in clinical practice are not achieving their LDL-C goals. Generally, statins are initiated at starting doses, and doses should be titrated as needed until the goal of therapy is achieved or a second lipid-lowering drug is required; titration is required in the majority of patients who receive less efficacious agents. Most patients receiving statin therapy in clinical practice are maintained on their starting dose, and this frequently results in inadequate control of elevated cholesterol levels. A number of factors may limit dose titration in clinical practice, including the cost of therapy, safety of prescribing statins at high doses and the additional office visits required for evaluations and monitoring. There may be several solutions to this problem. The choice of statin appears to be one of the important factors influencing the success of therapy. Selecting a statin that provides greater LDL-C lowering enables more patients to achieve LDL-C goals, and the majority of patients can be effectively treated with starting doses of the more efficacious statins. Another factor influencing the success of therapy is the willingness to add other drugs to a statin to enhance LDL-C lowering. Choices here include niacin, a bile acid sequestrant, and ezetimibe, a new cholesterol absorption inhibitor. Of these approaches, use of a more efficacious statin is preferred to combination therapy because of cost, safety, effectiveness, and simplicity issues.     

A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial

OBJECTIVE: To determine the extent of reduction in low-density lipoprotein cholesterol (LDL-C) level and improvement in National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients. PATIENTS AND METHODS: In this multicenter, double-blind, placebo-controlled trial (from January 2003 to August 2003), hypercholesterolemic patients (from 299 US primary care and specialty practices) with LDL-C levels exceeding NCEP ATP III goals were randomized (2:1) to receive ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: In a study of 3030 randomized patients, ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8% in the total population, compared with an additional 2.7% reduction with placebo plus statin (treatment difference, -23.1%; P<.001); the treatment difference ranged from -19.9% to -24.0% (P<.001) in each NCEP ATP III risk category subgroup. Significantly (P<.001) more patients (71.0%) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin (20.6%). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitivity C-reactive protein levels. These benefits were consistent across sex, race, age, statin brand, and dose subgroups. Ezetimibe plus statin therapy was well tolerated, with a safety profile similar to placebo plus statin. CONCLUSION: Across multiple subgroups, ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment, as well as in other lipoproteins, compared with addition of placebo. The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone.     

Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with established cardiovascular disease: results of a Markov model for UK costs using data registries

BACKGROUND: Ezetimibe has been reported to improve lipid control in patients with established cardiovascular disease (CVD). OBJECTIVE: The aim of this study was to estimate the potential long-term impact on health status of prescribing ezetimibe in combination with statin therapy in patients with established CVD and evaluate its cost-effectiveness in a health economic model. METHODS: A Markov model was used to compare ezetimibe and statin combination therapy with statin monotherapy. A published relationship linking changes in low-density lipoprotein cholesterol and cardiovascular events was used to estimate the cardiovascular events avoided through lipid-lowering therapies. The model was populated using results of extensive literature searches and a meta-analysis of clinical evidence. An adjustment was applied to model second-line lipid-lowering benefits. Conservative assumptions were used to extend the patient pathway beyond the clinical evidence. The analysis took the perspective of the UK Department of Health; therefore, only direct costs were included. Costs were calculated as year-2006 British pounds. RESULTS: For a cohort of 1,000 hypothetical male patients aged 55 years, ezetimibe coadministered with current statin therapy was estimated to prevent a mean of 43 nonfatal myocardial infarctions, 7 nonfatal strokes, and 26 cardiovascular deaths over a lifetime, compared with doubling the current statin dose. The events avoided would provide a mean of 134 additional quality-adjusted life-years (QALYs). With a mean incremental cost of pound 3,693,000, the lifetime discounted cost per QALY gained would be pound 27,475 (95% CI, pound 27,331- pound 27,620) and would rise to pound 32,000 for men aged 75 years. CONCLUSIONS: The results suggest that, in some instances, ezetimibe coadministration may be cost-effective compared with statin monotherapy, but there are several limitations with this model. The economic effects of ezetimibe must be revisited when long-term effectiveness and safety data become available.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

Lipid-lowering: can ezetimibe help close the treatment gap?

Most patients who should be on lipid-lowering therapy are not receiving it, and most patients who are receiving it are not reaching their appropriate low-density lipoprotein (LDL) goals. This is in part because physicians and patients fear side effects of statins and other lipid-lowering agents. Ezetimibe (Zetia), a new lipid-lowering drug, may help physicians close this "treatment gap" in more patients, especially in combination with a statin.     

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?     

Ezetimibe-associated adverse effects: what the clinician needs to know

OBJECTIVE: Ezetimibe is a relatively new lipid lowering agent, which is indicated for the treatment of primary hypercholesterolaemia, either as monotherapy or in combination with other hypolipidaemic drugs. The objective of the present article was to review the side effects attributed to ezetimibe administration and discuss their possible underlying mechanisms. Moreover, we aimed to comment on the possible drug interactions of ezetimibe and present current guidelines regarding its safe use. METHODS: Relevant articles were identified through a PubMed search (up to June 2007). RESULTS: Compelling evidence from the majority of the data reviewed here showed that adverse effects associated with ezetimibe use are few and mild without having been associated with serious clinical outcomes. In most studies ezetimibe has not been associated with increased rates of myopathy or rhabdomyolysis, whether used alone or in combination with statins, although there have been some case reports of myopathy attributed to this agent. Moreover, ezetimibe has been associated with mild elevations of liver transaminases, mainly in combination with a statin. Other side effects are extremely rare. It should be noted, however, there are no long-term safety data or outcome studies for ezetimibe yet. CONCLUSIONS: Ezetimibe is a safe alternative option for hyperlipidaemic patients intolerant to other lipid lowering drugs as well as a beneficial supplementary agent for patients who do not reach the recommended serum cholesterol level with their current hypolipidaemic treatment. However, as is the case with all new medications, physicians should be alert to recognise adverse effects associated with ezetimibe and report them to regulatory authorities.     

Cross-Sectional Survey to Assess the Status of Lipid Management in High-Risk Patients With Dyslipidemia: Clinical Impact of Combination Therapy With Ezetimibe

BackgroundPrevious retrospective surveys have shown that lipid management goals are well achieved in patients with dyslipidemia at relatively low risk for atherosclerotic diseases. However, more than half of patients in high-risk groups have not achieved the management goals. Since these surveys, newer medications, including rosuvastatin and ezetimibe, have emerged in clinical practice that may influence lipid management.ObjectiveTo assess the current status of lipid management in high-risk patients, we conducted a cross-sectional study between January and March 2010.MethodsEligible patients were those with dyslipidemia who were classified into the primary prevention high-risk or secondary prevention groups according to the Japan Atherosclerosis Society guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases. Patient data were collected from 300 randomly selected physicians at hospitals and clinics across Japan if patients had been receiving the same statin with or without other lipid-lowering agents for ≥3 months. The main outcome was the percentage of patients who achieved the serum LDL-C goal according to the guideline.ResultsData were collected from 1720 patients. The LDL-C goal was achieved in 56.5% of patients (447 of 791) in the primary prevention high-risk group and in 24.5% (103 of 420) in the secondary prevention group by statin monotherapy. For patients who had not reached the LDL-C goal with statin therapy alone, 53.8% (113 of 210) in the primary prevention high-risk group and 63.8% (111 of 174) in the secondary prevention group achieved their lipid management goal with the addition of ezetimibe. Ezetimibe significantly lowered mean serum LDL-C levels by 17.9% to 34.6% when added to various statins (P < 0.001).ConclusionsAlthough strong statins are available, lipid management in high-risk patients remains unsatisfactory. More aggressive treatment is needed for these patients.     

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.     

Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the Ezetimibe add-on to statin for effectiveness trial

OBJECTIVE: To examine whether the improvements in lipid profiles and low-density lipoprotein cholesterol (LDL-C) goal attainment found in the Ezetimibe Add-On to Statin for Effectiveness trial occurred equally in the black, Hispanic, and white patient populations enrolled in the study. PATIENTS AND METHODS: In this double-blind, placebo-controlled study, patients were recruited from 299 community-based practices across the United States (January to August 2003). Patients with, hypercholesterolemia and LDL-C levels exceeding National Cholesterol Education Program Adult Treatment Panel III goals were randomized (2:1) to receive either ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: A total of 5802 patients were screened at baseline for the Ezetimibe Add-On to Statin for Effectiveness study. Of these, 2772 were excluded, and the remaining 3030 eligible patients were randomized. Ezetimibe, compared with placebo, added to statin therapy significantly reduced LDL-C levels from statin-treated baseline by 23.0% (white patients), 23.0% (black patients), and 21.0% (Hispanic patients). This effect was consistent across race and ethnicity groups (P > .50 for treatment-by-race interactions). Ezetimibe added to statin therapy also statistically significantly (P < .001) increased the percentage of patients attaining their LDL-C goal for their National Cholesterol Education Program Adult Treatment Panel III risk category in black (63.0%), Hispanic (64.8%), and white (72.3%) patients compared with placebo plus statin (32.9% black patients, 19.0% Hispanic patients, and 19.7% white patients). Ezetimibe treatment improved other lipid parameters across groups, including triglyceride, high-density lipoprotein cholesterol, non-high-density ilpoprotein cholesterol, and total cholesterol levels. Finally, the addition of ezetimibe reduced high-sensitivity C-reactive protein levels overall, and no significant interaction of treatment by race occurred (P = .83), Indicating a consistent effect across races. Ezetimibe was generally well tolerated, and no detectable differences occurred in the adverse event profile by race or ethnicity. CONCLUSION: Ezetimibe added to statin therapy is effective and well tolerated for improving the lipid profile and LDL-C goal attainment of patients regardless of race or ethnicity.     

Keeping an eye on cardiovascular risk. A practical, case-study approach to assessment in office practice

Primary care physicians typically encounter patients who are not at obvious risk for CAD but who nonetheless need and can benefit from lipid-lowering therapy. Applying algorithms or scoring systems can be helpful in estimating an individual patient's risk, but the basic tools available in everyday clinical practice can be used to alert physicians to elevated CAD risk in their patients. Those patients whose LDL-C level is at or above 220 mg/dL (5.69 mmol/L) should routinely and deservedly get clinical attention, but they account for only 2.5% to 5% of the population. Those with an "average" LDL-C level number in the millions, and from this patient pool come the coronary events that fill clinics and hospitals. Aggressive treatment approaches are required to meet NCEP objectives, and every indication suggests that these goals are just the minimum. The third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) has broadened the indications for drug therapy, reclarifying diabetes and peripheral vascular or cardiovascular disease equivalents and using a global evaluation concept, which will identify 30 million Americans in need of drug treatment. The statins safely and effectively lower LDL-C levels, which is the basis for instituting drug therapy, according to NCEP guidelines. Using these drugs also raises HDL-C levels, which is somewhat protective, and decreases triglyceride levels. The efficacy of statin therapy in both primary and secondary prevention of CAD is now well established. If used more often when dietary therapy fails, which happens quite often, and in doses sufficient to work effectively, statins have the power to turn the corner on the prevention and treatment of atherosclerotic coronary disease in the United States.     

Colesevelam hydrochloride in the management of dyslipidemia

Dyslipidemia is a highly heterogeneous group of disorders strongly influenced by both genetic and environmental factors. Dyslipidemia significantly increases risk for atherosclerotic disease and all of its various clinical manifestations. Identifying patients with dyslipidemia and initiating therapies aimed at normalizing the lipid profile has been demonstrated to significantly reduce the risk for myocardial infarction, stroke and cardiovascular mortality in both the primary and secondary prevention settings. Guidelines in Europe, Canada and the USA emphasize the need to reduce the burden of atherogenic lipoproteins in serum and to raise levels of high-density lipoproteins in patients at risk for cardiovascular events. Statins have emerged as front-line therapy for managing dyslipidemia, especially in patients with elevated serum levels of low-density lipoprotein cholesterol. As guidelines emphasize the need to reduce serum low-density lipoprotein cholesterol to lower levels, goal attainment can be challenging. The use of combination therapy increases the likelihood of therapeutic success for many patients. Furthermore, a significant percentage of patients with dyslipidemia either cannot achieve goals on statin monotherapy, choose not to take a statin or do not tolerate these drugs due to adverse side effects, such as myalgias, weakness or hepatotoxicity. This article summarizes the pharmacology, clinical efficacy and safety of colesevelam hydrochloride, a bile acid-binding resin. Bile acid-binding resins are orally administered anion-exchange resins that are not absorbed systemically. These agents bind bile acids and reduce their reabsorption at the level of the terminal ileum and prevent their enterohepatic recirculation. Colesevelam has a favorable side effect and toxicity profile and significantly impacts serum levels of lipoproteins when used as monotherapy or when used in combination with either statins or ezetimibe.     

Colesevelam hydrochloride in the management of dyslipidemia

Dyslipidemia is a highly heterogeneous group of disorders strongly influenced by both genetic and environmental factors. Dyslipidemia significantly increases risk for atherosclerotic disease and all of its various clinical manifestations. Identifying patients with dyslipidemia and initiating therapies aimed at normalizing the lipid profile has been demonstrated to significantly reduce the risk for myocardial infarction, stroke and cardiovascular mortality in both the primary and secondary prevention settings. Guidelines in Europe, Canada and the USA emphasize the need to reduce the burden of atherogenic lipoproteins in serum and to raise levels of high-density lipoproteins in patients at risk for cardiovascular events. Statins have emerged as front-line therapy for managing dyslipidemia, especially in patients with elevated serum levels of low-density lipoprotein cholesterol. As guidelines emphasize the need to reduce serum low-density lipoprotein cholesterol to lower levels, goal attainment can be challenging. The use of combination therapy increases the likelihood of therapeutic success for many patients. Furthermore, a significant percentage of patients with dyslipidemia either cannot achieve goals on statin monotherapy, choose not to take a statin or do not tolerate these drugs due to adverse side effects, such as myalgias, weakness or hepatotoxicity. This article summarizes the pharmacology, clinical efficacy and safety of colesevelam hydrochloride, a bile acid-binding resin. Bile acid-binding resins are orally administered anion-exchange resins that are not absorbed systemically. These agents bind bile acids and reduce their reabsorption at the level of the terminal ileum and prevent their enterohepatic recirculation. Colesevelam has a favorable side effect and toxicity profile and significantly impacts serum levels of lipoproteins when used as monotherapy or when used in combination with either statins or ezetimibe.     

Supratherapeutic response to ezetimibe administered with cyclosporine

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level < or = 97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (> or = 5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.     

Lipid-lowering effects of ezetimibe and simvastatin in combination

Ezetimibe/simvastatin is a combination of a statin and a cholesterol absorption inhibitor. This article reviews current information on the pharmacology, clinical efficacy and safety of ezetimibe/simvastatin combination therapy as a lipid-lowering pharmacologic option. Focus is on the LDL cholesterol-lowering efficacy of ezetimibe/simvastatin. PubMed was searched for english-language articles from January 2005 to 14 April 2010 using the keywords 'ezetimibe and simvastatin' and 'hyperlipidemia'. Reviewers screened all records and only English language papers and human clinical studies were included in the review. References of these papers were reviewed for relevant articles, and retrospective studies were excluded. Limitations include the exclusion of non-English publications, the use of only one data source (PubMed), and the fact that most studies were of short duration and several studies were of low quality (nonrandomized trials or meta-analyses). Ezetimibe and simvastatin has proven to be a well-tolerated, effective lipid-lowering drug combination. It is effective in reducing LDL-cholesterol and triglycerides, and increasing HDL-cholesterol. It also decreases C-reactive protein and exhibits some pleiotropic effects in a variety of patient populations. More data are needed to evaluate its effect on cardiovascular events/outcomes.