Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor that significantly lowers low- density lipoprotein cholesterol (LDL-C), and favourably affects triglyceride and high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins. Hepatic and extrahepatic (peripheral) cholesterol synthesis are well-known sources of cholesterol found in LDL-C. However, the emergence of ezetimibe has highlighted intestinal cholesterol absorption as an additional, important source of cholesterol in LDL-C, and has better illuminated how genetic factors, dietary content, pharmaceutical agents, and nuclear receptor activation (such as liver X receptors) all influence the relative contribution of these important cholesterol sources to LDL-C. In fact, investigations into ezetimibe have sometimes challenged existing scientific dogma, has prompted reconsideration of older data, and has helped create 'new' paradigms in cholesterol metabolism. Thus, ezetimibe's efficacy, excellent tolerability, and safety has not only expanded potential treatment options for dyslipidaemic patients, but also has promoted exploration of new frontiers of lipid research towards a better understanding of cholesterol metabolism.     

Non-low-density lipoprotein cholesterol-associated actions of ezetimibe: an overview

Ezetimibe, an intestinal cholesterol absorption inhibitor, lowers circulating low-density lipoprotein cholesterol (LDL-C) levels both when administered as monotherapy and in combination with other hypolipidaemic drugs, mostly statins. This review focuses on the effects of ezetimibe on non-LDL-C-associated variables. In most studies, ezetimibe effectively reduced triglyceride and increased high density lipoprotein cholesterol levels. The authors also consider the effect of ezetimibe on other variables such as C-reactive protein levels, insulin sensitivity and endothelial function. Ezetimibe is useful in patients with sitosterolaemia (a rare inherited disorder) as it significantly reduces plasma phytosterol concentrations. Ezetimibe fulfils two of the three essential characteristics of any drug (efficacy and safety). However, clinical studies are required to provide evidence of its ability to reduce vascular events.     

Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options

Introduction: A residual risk of morbidity and mortality from cardiovascular (CV) disease remains despite statin therapy. This situation has generated an interest in finding novel approaches of combining statins with other lipid-lowering agents, or finding new lipid and non-lipid targets, such as triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, cholesterol ester transfer protein (CETP), lipoprotein (a), fibrinogen or C-reactive protein. Areas covered: The recent results from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental clinical benefit when ezetimibe, a non-statin agent, was added to simvastatin therapy. Expert opinion: The results from IMPROVE-IT revalidated the concept that low-density lipoprotein cholesterol (LDL-C) levels are a clinically relevant treatment goal. This trial also suggested that further decrease of LDL-C levels (53 vs. 70 mg/dl; 1.4 vs. 1.8 mmol/l) was more beneficial in lowering CV events. This “even lower is even better” evidence for LDL-C levels may influence future guidelines and the use of new drugs. Furthermore, these findings make ezetimibe a more realistic option to treat patients with statin intolerance or those who cannot achieve LDL-C targets with statin monotherapy.     

The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel

ABSTRACT

There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance.

Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fatsoluble vitamins. In clinical studies, ezetimibe 10?mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34–53% and 17–18%, respectively.

The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.     

Ezetimibe and vascular inflammation

Atherosclerosis is an inflammation-based complex vascular disorder which causes coronary artery disease, stroke and peripheral artery disease. Its pathophysiological process consists of endothelial dysfunction, monocyte adhesion to endothelial cells, lipid and inflammatory cell accumulation in the vascular wall, and migration and proliferation of smooth muscle cells. Both hyperlipidemia and inflammation are profoundly involved in each step. Cholesterol lowering by HMG-CoA reductase (statin) is beneficial for treating atherosclerotic coronary artery disease and stroke, together with reducing a surrogate-marker of inflammation, C-reactive protein (CRP). Another recently established cholesterol lowering tool using an intestinal cholesterol absorption inhibitor, ezetimibe, has been applied for clinical treatment of hypercholesterolemia for several reasons. First, hypercholesterolemia is associated with increased intestinal cholesterol absorption. Second, low cholesterol absorption prevents cardiovascular events. Third, cholesterol metabolism analysis provides evidence that the long-term use of statin increases cholesterol absorption. In terms of low-density lipoprotein cholesterol (LDL-C) and CRP reductions, the more powerful effect of ezetimibe has been seen when the agent is combined with statins. However, the effect of ezetimibe monotherapy on CRP reduction has not been well defined. This review provides information on recently described clinical trials of ezetimibe monotherapy, stain monotherapy, and combined therapy for LDL-C lowering and vascular inflammation.     

Discovery, synthesis and evaluation of novel cholesterol absorption inhibitors

Chemical-based common feature pharmacophore modelling of Niemann Pick C1 Like 1 inhibitors was performed to provide some insights on the important pharmacophore features essential for Niemann Pick C1 Like 1 inhibition using Discovery Studio V2.5. After in-house database screening, a new series of substituted oxazolidinones, selected from the top ranked hits, have been synthesized and evaluated as novel cholesterol absorption inhibitors. All compounds demonstrated effect of different degrees in lowering the total cholesterol in serum, especially compounds 1a, 2a and 2d, the potency of which was comparable to that of ezetimibe. It was also found that 1a, 1d and 2d could raise high-density lipoprotein cholesterol levels markedly. Interestingly, compounds 2a-2f appeared to have the moderate potential to lower triglyceride levels, which were superior to that of normal cholesterol absorption inhibitors including ezetimibe.     

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.     

Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy. National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL-C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL-C levels. Based on these findings, the NCEP ATP III revised the LDL-C target from < 100 mg/dL (2.6 mmol/L) to < 70 mg/dL (1.8 mmol/L) (optional target) for very high-risk patients and < 130 mg/dL (3.4 mmol/L) to < 100 mg/dL (2.6 mmol/L) for moderately high-risk patients. For patients who fail to achieve their LDL-C target, inhibiting the two main sources of cholesterol - synthesis and uptake - can produce more effective lipid lowering, allowing more patients to reach their LDL-C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL-C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10 mg significantly reduces LDL-C compared with statin monotherapy. Thus, this treatment option may help patients reach the new 'stricter' cholesterol goals. This review, based on a Medline database search from January 2000 to August 2005, considers the LDL-C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.     

Update on patented cholesterol absorption inhibitors

Background: Atherosclerosis is one of the most life-threatening diseases primarily associated with hypercholesterolemia and is characterized by increased serum cholesterol level. Cholesterol originates from both its de novo synthesis within the hepatic cells and its absorption into the intestine in the form of dietary or bile cholesterol. Interventions influencing both of these processes are promising therapeutic options to lower the cholesterol level. Hydroxymethyl glutaryl-CoA reductase inhibitors, commonly known as statins, effectively block the rate determining step in the biosynthesis of cholesterol. Ezetimibe is the first new class of drugs used to treat hypercholesterolemia by inhibition of cholesterol absorption through Niemann Pick C1 Like 1 membrane of enterocytes. Therefore, combination therapy of ezetimibe and statins offers an efficacious new approach for the prevention and treatment of hypercholesterolemia. Objectives: The present review focuses on updates on ezetimibe and patented profile of novel cholesterol absorption inhibitors followed by critical analysis of different targets such as cholesterol esterase inhibitors, bile acid transport inhibitors or phospholipase-A₂ inhibitors, etc.which play an important role in the lipid absorption. Conclusion: The discovery of ezetimibe has opened a new door for the management of hyper-cholesterolemia in combination with statins. There are newer analogues that are under clinical trials, among which darapladib, FM-VP4 and A-002 are promising compounds.     

Effects of ezetimibe,either alone or in combination with atorvastatin,on serum visfatin levels: a pilot study

Introduction: Ezetimibe inhibits intestinal absorption of cholesterol and lowers circulating low-density lipoprotein cholesterol levels. Visfatin is a novel adipokine, which may be implicated in the atherosclerotic process. Objective: The aim of this study was to explore the possible association between ezetimibe administration and serum visfatin concentrations. Methods: Patients (n = 30) with primary dyslipidemia and another 30 who failed to reach their assigned low-density lipoprotein cholesterol target on atorvastatin therapy (20 mg/day) were included in the study. All participants were given ezetimibe at 10 mg/day for 12 weeks. Results: At baseline the visfatin levels correlated significantly with the total cholesterol (r = 0.61 and p < 0.01) and low-density lipoprotein cholesterol (r = 0.51 and p < 0.01) levels in the statin pretreatment group. Furthermore, in the statin group the post-treatment levels of visfatin and low-density lipoprotein cholesterol were significantly correlated (r = 0.57 and p < 0.01). The serum visfatin concentrations did not change significantly in either the monotherapy or statin pretreatment groups or in subgroups divided according to the baseline lipid variables. In both the ezetimibe monotherapy and ezetimibe plus atorvastatin groups the effect of ezetimibe on the lipid variables depended on the baseline lipid values. The low-density lipoprotein cholesterol:high density lipoprotein cholesterol ratio was consistently improved by ezetimibe in all groups or subgroups. Conclusions: Ezetimibe did not alter serum visfatin concentrations, either when administered as monotherapy or combined with a statin. Future studies investigating the effect of ezetimibe on visfatin levels need to include groups of patients with distinct lipid characteristics.     

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.     

Ezetimibe/Simvastatin

Ezetimibe/simvastatin (Inegy, Vytorin) therapy combines two lipid-lowering compounds with complementary mechanisms of action, thereby blocking the two sources of plasma cholesterol and improving lipid profiles. Thus, intestinal absorption of dietary cholesterol and related phytosterols is blocked by ezetimibe, with the biosynthesis of cholesterol in the liver inhibited by simvastatin.Developing management trends for primary hypercholesterolemia include the aggressive reduction of low-density lipoprotein cholesterol (LDL-C) to goals lower than previously considered appropriate, the targeting of lipid subfractions and atherogenic indices other than LDL-C alone, and the broader use of combination lipid-lowering therapy. In line with these trends, ezetimibe/simvastatin is an effective and generally well tolerated adjunct to dietary therapy for markedly reducing LDL-C levels, providing a 52% reduction with the recommended starting dosage. Furthermore, ezetimibe/simvastatin is formulated with variable doses of simvastatin (i.e. 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg) and hence, the dosage may be adjusted to suit the individual patient's needs. As longer-term efficacy, tolerability, economic and outcome data accrue, ezetimibe/simvastatin will be positioned more definitively relative to existing and emerging lipid-lowering treatments. Currently, ezetimibe/simvastatin therapy represents a valuable novel option for the management of primary hypercholesterolemia across diverse patient populations and as an adjunct to other lipid-lowering treatments in those with homozygous familial hypercholesterolemia.     

Ezetimibe and vascular endothelial function

Hypercholesterolemia is a major risk factor for cardiovascular diseases that has been managed mostly with 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) that suppress de novo cholesterol synthesis in the liver. Statins also have beneficial pleiotropic effects on the atherosclerotic process that are independent of their ability to lower lipid values. However, the levels of low-density lipoprotein cholesterol (LDL-C) in most hypercholesterolemic patients at high risk for cardiovascular disease do not reach the goals proposed by guidelines even when prescribed with statins. Ezetimibe is a new lipid-lowering agent that blocks the intestinal absorption of dietary and biliary cholesterol and reduces LDL-C levels, especially when combined with statins. However, its effect on cardiovascular events remains unknown. We reviewed the effects of ezetimibe on cardiovascular diseases, in particular, vascular endothelial function, which is initially impaired during the atherogenetic process and is an important predictor of cardiovascular events. The simultaneous inhibition of cholesterol synthesis by statin and of cholesterol absorption by ezetimibe might retard the atherogenetic process. These effects are considered to be mainly mediated by lipid lowering. However, further studies should elucidate the mechanism of the anti-atherosclerotic effects induced by ezetimibe; for instance, whether or not it directly affects atherogenesis independently from its lipid-lowering effects.     

Non-low-density lipoprotein cholesterol-associated actions of ezetimibe: an overview

Ezetimibe, an intestinal cholesterol absorption inhibitor, lowers circulating low-density lipoprotein cholesterol (LDL-C) levels both when administered as monotherapy and in combination with other hypolipidaemic drugs, mostly statins. This review focuses on the effects of ezetimibe on non-LDL-C-associated variables. In most studies, ezetimibe effectively reduced triglyceride and increased high density lipoprotein cholesterol levels. The authors also consider the effect of ezetimibe on other variables such as C-reactive protein levels, insulin sensitivity and endothelial function. Ezetimibe is useful in patients with sitosterolaemia (a rare inherited disorder) as it significantly reduces plasma phytosterol concentrations. Ezetimibe fulfils two of the three essential characteristics of any drug (efficacy and safety). However, clinical studies are required to provide evidence of its ability to reduce vascular events.     

Advancing therapy for hypercholesterolemia

Importance of the field: Hypercholesterolemia holds a key role in the development and progression of atherosclerosis and is a causative factor of coronary artery disease. Current guidelines for cholesterol treatment target low-density cholesterol (LDL-C) as the primary goal of therapy. Despite advances in the pharmacotherapy of atherosclerosis, the most successful agents used to treat this disease – HMG CoA reductase inhibitors – remain ineffective for the primary or secondary prevention of myocardial infarction in 50 – 60% of patients. Advancing therapy for hypercholesterolemia with new-emerging drugs either as monotherapy or in combination will hopefully improve cardiovascular outcomes.

Areas covered in this review: The two major sources of cholesterol in the human body are: i) biosynthesis of cholesterol by the liver; and ii) absorption by the intestines. Both play a pivotal role in the overall balance of cholesterol. A recent and more effective therapeutic strategy is to treat both sources of cholesterol simultaneously with a complementary mechanism of action. The present article presents cholesterol metabolism and reviews new emerging lipid-lowering drugs and therapies that: i) lower LDL-C; ii) lower triglycerides; and iii) increase high-density lipoprotein cholesterol.

What the reader will gain: This review summarizes the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using new emerging lipid-lowering drugs either alone or co-administered with statins in controlling cholesterol levels.

Take-home message: An elevated concentration of LDL-C plays a causal role in the development of cardiovascular disease. The new aggressive cholesterol treatment goals call for a more advanced therapeutic approach to maximize the cardiovascular benefits associated with lower LDL-C levels.     

Pharmacological management of diabetic dyslipidemia

Introduction: Diabetes mellitus is associated with increased cardiovascular disease (CVD) risk.

Areas covered: Main goal of hypolipidemic treatment in diabetic patients is low-density lipoprotein cholesterol (LDL-C) lowering with the use of statins. Addition of ezetimibe is useful in diabetic patients who cannot achieve their LDL-C target. However, many diabetic patients have increased residual CVD risk, which is mainly attributed to high triglycerides and low high-density lipoprotein (HDL-C) values. The addition of fenofibrate targets these variables and possibly reduces residual CVD risk, but a possible beneficial effect has been shown only in a pre-specified subgroup analysis in patients with high triglycerides and low HDL-C values. The newer proprotein convertase subtilisin/kexin type 9 inhibitors lower substantially LDL-C levels, but data from specifically designed trials in diabetic patients are not currently available. Although the cholesterol ester transfer protein (CETP) inhibitors have shown harmful effects or lack of efficacy in completed clinical trials, the newer CETP inhibitors have promising effects on lipid profile and carbohydrate metabolism, but their effects on CVD risk and safety profile have not been assessed.

Expert commentary: Clinicians have a range of pharmacological options to reduce the CVD risk of diabetic patients.     

Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXRβ activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element.     

The plasma concentration and LDL-C relationship in patients receiving ezetimibe

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low-density lipoprotein cholesterol (LDL-C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL-C is determined using Emax and regression models. Data from two phase II double-blind placebo-controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL-C from baseline (%LDL-C). Reductions in %LDL-C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and > 15 ng/ml, respectively, as compared with placebo. To achieve > 15% reduction in LDL-C, patients need to maintain trough concentrations > 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.     

The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel

There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance. Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. In clinical studies, ezetimibe 10 mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34-53% and 17-18%, respectively. The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.     

Novel LDL-oriented pharmacotherapeutical strategies

Elevated levels of low-density cholesterol (LDL-C) are highly correlated with increased risk of cardiovascular diseases (CVD). Thus, current guidelines have recommended progressively lower LDL-C for cholesterol treatment and CVD prevention as the primary goal of therapy. Even so, some patients in the high risk category fail to achieve recommended LDL-C targets with currently available medications. Thereby, additional pharmaceutical strategies are urgently required. In the review, we aim to provide an overview of both current and emerging LDL-C lowering drugs. As for current available LDL-C lowering agents, attentions are mainly focused on statins, niacin, bile acid sequestrants, ezetimibe, fibrates and omega-3 fatty acids. On the other hand, the emerging drugs differ from mechanisms are including: intervention of cholesterol biosynthesis downstream enzyme (squalene synthase inhibitors), inhibition of lipoprotein assembly (antisense mRNA inhibitors of apolipoprotein B and microsomal transfer protein inhibitors), enhanced lipoprotein clearance (proprotein convertase subtilisin kexin type 9, thyroid hormone analogues), inhibition of intestinal cholesterol absorption (Niemann-Pick C1-like 1 protein and acyl coenzyme A:cholesterol acyltransferase inhibitors) and interrupting enterohepatic circulation (apical sodium-dependent bile acid transporter inhibitors). Several ongoing agents are in their different stages of clinical trials, in expectation of promising antihyperlipidemic drugs. Therefore, alternative drugs monotherapy or in combination with statins will be sufficient to reduce LDL-C concentrations to optimal levels, and a new era for better LDL-C managements is plausible.