Hypertriglyceridemia: a review of clinical relevance and treatment options: focus on cerivastatin

The triglyceride (TG) level is one of several lipid parameters that can aid prediction of coronary heart disease (CHD) risk. An elevated plasma TG level is strongly associated with an increased risk of CHD. Hypertriglyceridemia, the second most common dyslipidemic abnormality in hypertensive subjects after increased low-density lipoprotein cholesterol (LDL-C), is defined by the National Cholesterol Education Programme (NCEP) as a fasting TG level of > 2.26 mmol/l (> 200 mg/dl) and is recognised as a primary indicator for treatment in type IIb dyslipidemia. Raised TG levels can be present in individuals at risk for CHD when the total cholesterol is normal. However, not all individuals with raised TG levels have increased risk of CHD. Factors such as: diet, age, lifestyle, and a range of medical conditions, drug therapy and metabolic disorders, can all affect the TG level. In some of these circumstances, other factors protect against the risk of CHD, and can minimise or negate the effect of the risk factors present. Although TG reducing therapy has been shown to be associated with an improved clinical outcome, more research is needed to determine whether this is an independent effect of TG reduction or an effect of normalising the overall lipid profile in hypertriglyceridemic patients. Further trials are required to quantify the clinical benefits of lowering TG to 'target' levels and to confirm targets defined by NCEP-II (shown in Table 1). The role of TG in CHD pathogenesis is thought to involve several direct and indirect mechanisms, such as effects on the metabolism of other lipoproteins, transport proteins, enzymes, and on coagulation and endothelial dysfunction. More research is required to fully elucidate the role of TG, the ways in which it can influence other risk factors and the mechanism of its own more direct role in the atherogenic process. Patients with hypertriglyceridemia have been shown to respond well to dietary control and to the use of lipid lowering drugs such as 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors (known as statins), fibrates and nicotinic acids. However, recent retrospective real-life clinical studies show that only 38% of patients receiving some form of lipid-lowering therapy achieved NCEP-defined LDL-C target levels, demonstrating the need for the use of more aggressive treatment. In hypertriglyceridemic patients, the newer statins, cerivastatin and atorvastatin, have shown comparable efficacy in reducing TG compared with the older statins. Achieving NCEP target lipid levels has been shown to reduce the risk of cardiovascular disease in dyslipidemic individuals, including high-risk patient groups such as those with additional risk factors, existing heart disease, diabetes mellitus and metabolic syndrome. Although the latest clinical studies investigating combination therapies, i.e. dual therapy with both a statin and a fibrate, have demonstrated them to be effective for overall control of lipid parameters and reducing coronary events, it is not yet clear whether this offers any significant advantage over monotherapy. Results from ongoing longer-term end-point clinical studies may provide further information in this area and consequent reviews of primary care management policies for dyslipidemia. Statin monotherapy may be a reliable option for primary care treatment of dyslipidemia (including hypertriglyceridemia).     

Achieving LDL-C Target Levels: The Role of Statins

Summary

Epidemiological and clinical studies have clearly established the link between elevated low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD). Consequently, treatment guidelines have been developed that identify LDL-C as a causative factor for CHD and as a target for lipid-lowering therapy. The 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are considered the drugs of choice for lowering LDL-C in patients with hypercholesterolaemia. However, despite the proven efficacy of statins in reducing LDL-C, many patients do not achieve recommended LDL-C target levels. Surveys suggest that patients do not receive the appropriate drugs in adequate dosage to reach LDL-C target values. Success in achieving targets is lowest in patients at the highest risk, i.e. those with established CHD. The introduction of more potent HMG-CoA reductase inhibitors, or the use of higher doses of older statins, should allow more patients to achieve LDL-C target levels.     

Obesity as the core of the metabolic syndrome and the management of coronary heart disease

SUMMARY

The global burden of coronary heart disease (CHD) has led to the introduction of international guidelines to minimize the morbidity and mortality that result from this condition. These guidelines recognize the contribution of multiple risk factors to the development of CHD and advocate a multifaceted approach to treatment.

Obesity, particularly visceral adiposity, contributes to the clustering of many other risk factors, such as hypertension, insulin resistance/type 2 diabetes and dyslipidemia, within individual patients. The molecular mechanisms underlying the metabolic abnormalities induced by visceral adiposity have yet to be fully elucidated; however, adipocytokines such as adiponectin, tumor necrosis factor-α and resistin seem to play an important role in this process. Obesity is a major modifiable CHD risk factor, and the benefits of weight loss are numerous, leading to improvements in several co-morbidities.

Guidelines advocate lifestyle changes to correct excess bodyweight and improve the CHD risk factor profile. In addition, pharmacologic therapy is recommended for the management of other risk factors, such as hypertension and dyslipidemia, which may not be adequately controlled by lifestyle changes alone. Lowering low-density lipoprotein cholesterol (LDL-C) levels is the primary target for drug therapy for CHD prevention, and statins are first-line lipid-modifying therapy. The introduction of more efficacious statins with favorable effects on the lipid profile will optimize the control of dyslipidemia. Combining these new treatments with lifestyle changes and drug therapies for managing other CHD risk factors, as part of a multifaceted approach to treatment, will have benefits for CHD prevention.     

Beyond LDL-C – The Importance of Raising HDL-C

Summary

Epidemiological studies have established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk of coronary heart disease (CHD). Recent studies have demonstrated that low HDL-C levels, and high triglycerides and total cholesterol levels are independent predictors of CHD, and that the combination of these lipid abnormalities increases the risk of coronary events. In lipid-modifying intervention studies, agents that raise HDL-C levels have been shown to reduce the incidence of major coronary events. The VA-HIT study consisted of patients with low-density lipoprotein cholesterol (LDL-C) levels similar to those recommended by several guidelines but with low levels of HDL-C. This trial demonstrated that raising HDL-C levels with gemfibrozil reduced the risk of CHD-related events. While the mechanisms by which HDL-C exerts its anti-atherogenic effects have yet to be fully elucidated, its role in the reverse transport of cholesterol and the beneficial effects on endothelial function are plausible explanations for these actions.

Although LDL-C reduction is the primary goal in the treatment of dyslipidaemia, current guidelines recognise low HDL-C levels as a major risk factor for CHD. Indeed, the NCEP ATP III guidelines suggest that the treatment of isolated low HDL-C levels in CHD patients or individuals with CHD risk equivalents should be considered. The differing abilities of statins to raise HDL-C levels may be an important factor when making treatment decisions. New lipid-modifying drugs with beneficial effects on both HDL-C and LDL-C levels would be desirable additions to the currently available therapeutic options.     

Treatment of dyslipidemia in HIV-infected patients

Importance of the field: Patients infected with HIV are at high risk for dyslipidemia, insulin resistance and cardiovascular disease. Therapies to reverse these risks are complex, sometimes controversial, and not uniformly effective.

Areas covered in this review: Pathophysiology of the lipid abnormalities in HIV is discussed, including the causes of alterations in triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and insulin resistance. We discuss the therapy of dyslipidemia in HIV using a combination of available clinical evidence and expert opinion based on extensive clinical experience, with discussions of lifestyle intervention and diet, conventional pharmacotherapy with lipid-lowering medications including statins, fibrates, niacin and thiazolidinediones for dyslipidemia, and newer therapeutic approaches including omega fatty acids, acipimox, growth hormone and leptin.

What the reader will gain: A detailed understanding of the pathophysiology and rational or evidence-based approach to therapy of lipid abnormalities in patients infected with HIV.

Take home message: Treatment of dyslipidemia in patients with HIV is challenging and complicated by the risk of drug interactions. Appropriate therapy requires a sound understanding of pathophysiology and the principles of pharmacological and nonpharmacological therapeutic interventions. An evidence-based approach that combines lifestyle changes and drugs that are both safe and effective, singly and in combination, is described.     

Efficacy and safety of extended-release fluvastatin in Turkish patients with hypercholesterol­aemia: TULiPS (Turkish Lipid Study)

ABSTRACT

Objective: The efficacy and safety of extended-release fluvastatin (fluvastatin XL), 80?mg once daily, was assessed in Turkish patients with primary hypercholesterolaemia (low-density lipoprotein cholesterol (LDL?C) 3.37–5.70?mmol/l and triglyceride (TG) <?4.52?mmol/l).

Research design: in this open-label, prospective, multi-centre study, 154 patients were given fluvastatin XL 80?mg once daily and lipid levels were assessed after 2 and 12 weeks.

Results: Fluvastatin XL 80?mg once daily significantly reduced LDL?C levels by 38.8 and 38.1% at weeks 2 (n = 140) and 12 (n = 116), respectively (?p < 0.001 vs. baseline). Treatment with fluvastatin XL for 2 and 12 weeks significantly reduced total cholesterol levels by 30.2 and 27.4%, respectively (?p < 0.001 vs. baseline) and reduced TG levels by 14.9 and 7.5%, respectively (?p < 0.001 vs. baseline). Following stratification by risk factors for coronary heart disease (CHD) according to the National Cholesterol Education Program Adult Treatment Panel iii guidelines, 87.3% of patients with ≥?2 risk factors, and 67.4% of patients with existing CHD or CHD risk equivalents achieved target LDL?C levels (<?3.37?mmol/l and <?2.59?mmol/l, respectively) with fluvastatin XL. Fluvastatin XL reduced high-density lipoprotein cholesterol by 8.9 and 4.7% at weeks 2 and 12 weeks, respectively. fluvastatin XL 80?mg once daily was generally well-tolerated.

Conclusions: This open-label study indicates fluvastatin XL 80?mg once daily is an effective and well-tolerated lipid-lowering therapy for the reduction of CHD risk in Turkish patients.     

调血脂和抗动脉粥样硬化药物的应用现状和进展趋势

血脂异常主要表现为低密度脂蛋白胆固醇(LDL-C)、三酰甘油(TG)及载脂蛋白B(apoB)升高,高密度脂蛋白胆固醇(HDL-C)及apoA1降低,是导致冠心病,脑卒中和外周血管疾病的最主要危险因子之一.血脂异常也可导致冠状动脉粥样硬化症.虽然目前治疗目标集中在降低LDL-C上,但未来若干年内其他脂肪/脂蛋白和非脂肪因素有可能成为特殊治疗靶向.现对调血脂和抗动脉粥样硬化药物的应用状况和进展趋势作一介绍.     

Perspectives on low-density lipoprotein cholesterol goal achievement

ABSTRACT

Background: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD). European and US guidelines now recommend lower LDL-C levels, particularly in high-risk patients. Although LDL-C treatment goals to reduce the risk of CHD are clear, many patients do not reach their LDL-C goals.

Objectives: Examine consensus guideline targets for LDL-C lowering in patients at high or very high cardiovascular risk; examine cholesterol goal achievement in clinical practice; evaluate the effectiveness of ezetimibe/statin and other adjunctive lipid-lowering treatments in achieving LDL-C goals; and consider ongoing controversies and the randomized controlled trials that may help to resolve or better illuminate them.

Methods: An English-language PubMed search was conducted to identify prospective randomized controlled trials, open-label studies, and retrospective and observational studies from 2001 (same year that the executive summary of the National Cholesterol Education Program's Adult Treatment Panel III was published) to present for an analysis of the effects of adjunctive therapies on LDL-C lowering and goal attainment in patients at elevated cardiovascular risk.

Results: Elevated LDL-C is the primary target of lipid-lowering therapy; aggressive lowering is of great benefit to those at high risk. Statins are recommended first-line lipid-lowering agents, with a long, well-regarded history of efficacy and safety. Not all patients, however, can achieve recommended LDL-C goals simply using starting doses of statins. For such patients, more intensive therapy utilizing high-dose statins or combination therapy, including statins combined with other lipid-lowering agents, such as ezetimibe, bile acid resins (BARs), or niacin, is warranted. Potential limitations of the present review include possible publication bias and the focus on pharmacotherapy rather than lifestyle modification and the important objective of multiple risk-factor modification to reduce absolute global cardiovascular risk.

Conclusions: With a well-established link between elevated LDL-C and cardiovascular risk, aggressive LDL-C lowering becomes particularly important. Patients needing intensive LDL-C lowering to achieve goals will often require adjunctive treatments, including ezetimibe, BARs, or niacin along with statins. Given both their high mg: mg potency in lowering LDL-C and favorable tolerability and patient acceptance/adherence profile, ezetimibe/statin combination regimens arguably provide the greatest likelihood for patients to reach new, lower LDL-C targets; however, efficacy and safety data of any adjunctive treatment, along with drug costs and patient adherence to treatment (partly related to complexity of the regimen) all need to be considered when determining the optimal regimen to achieve LDL-C goals in individual patients according to their baseline absolute cardiovascular risk, LDL-C level, and consensus LDL-C targets.     

Physicians' perceptions and beliefs on the current dyslipidemia management practices within Saudi Arabia

BackgroundLimited reports addressing physicians’ understanding of the various low-density lipoprotein cholesterol (LDL-C) targets/statin intensity required for treating the various dyslipidemia patient populations in Saudi Arabia are available. Therefore, the current study assessed the perceptions and beliefs of practicing clinicians in Saudi Arabia regarding the current practice for management of dyslipidemia and potential perceived barriers to adherence to lipid guidelines encountered in their regular clinical practice. Knowledge of different clinical practices and beliefs could have a positive impact on improving the quality of future care provided by physicians.MethodsA survey questionnaire was designed to assess physicians’ familiarity, usage, and adherence to seven different international guidelines and used to evaluate the management of dyslipidemia, practice of patient treatment, and perceived obstacles to adhering to lipid guidelines related to specific patients, doctors, and practice issues.ResultsA total of 467 physicians were recruited for the study: (1) 57.2% were primary care physicians (PCPs) and (2) 42.8% were specialists. About 90.8% of them followed lipid guidelines of which the most common set were based on those by the American College of Cardiology/American Heart Association. The most utilized risk assessment tool was the atherosclerotic cardiovascular disease (ASCVD) risk calculator. About 60% of the physicians set an LDL-C target for their patients based on a combination of patients’ risk factors and lipid profiles. In all, 42.1% of the physicians chose not to change existing therapy among patients with dyslipidemia to attain a non-high-density lipoprotein goal with controlled LDL-C level. Atorvastatin accounted for the greatest percentage of primary and secondary prevention choices (71.9% and 69.6%, respectively). Rosuvastatin was mostly preferred by physicians for patients with familial hypercholesterolemia. About two-thirds of the physicians (77.9%) prescribed statins to diabetic patients aged 40–75 years. Statin intolerance was encountered by 62.9% of the physicians in ≤ 10% of patients by 62.9%. Therapeutic strategies included switching to an alternative statin (40.1%) followed by reducing the statin dose (35.3%). Ezetimibe was prescribed by most physicians (77.9%) as an add-on to statin if the LDL-C target was not achieved. Fibrate was most preferred by physicians (62.7%) for hypertriglyceremia treatment followed by statins (28.7% of the physicians). Sixty-six percent reported not using proprotein convertase subtilisin/kexin type 9 serine protease inhibitors in their clinical practice due to unavailability at their institute (51.8%), high costs (26.3%), and/or lack of knowledge (20.6%). Perceived barriers to guideline adherence identified by physicians were lack of familiarity and knowledge of the guidelines, patient non-adherence, medication costs, and lack of timely follow-up appointments and educational tools. Multiple similarities and differences were observed after comparisons were made between specialists and PCPs in terms of guideline preference, clinical practice, and perceived barriers.ConclusionDifferent perceptions and attitudes among physicians in Saudi Arabia were found due to variable recommendations by international lipid guidelines. Perceived barriers that included the patient, physician, and practice were identified by physicians at multiple levels. Multiple challenges and different action gaps were observed when comparing specialists to PCPs. It is recommended that standardized practices be followed by clinicians in Saudi Arabia, and actions to address the outlined barriers are essential for optimizing health outcomes and ASCVD prevention.     

Effect of atorvastatin on highdensity lipoprotein cholesteroland its relationship withcoronary events: a subgroupanalysis of the GREekAtorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

SUMMARY

Objective: To investigate the relationship between changes in high density lipoprotein cholesterol (HDL-C) levels after statin treatment and the risk for coronary heart disease (CHD)-related events in the secondary CHD prevention GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. These findings suggested that dose titration

with atorvastatin (10-80mg/day, mean 24mg/day) achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality, in comparison to usual care.

Methods: Analysis of variance was used to assess the effect of atorvastatin on HDL-C over

time (up to 48 months) in 1600 CHD patients. The time-dependent multivariate Cox predictive model, involving backward stepwise logistic regression, was used to evaluate the relation between coronary events and HDL-C changes.

Results: The mean increase in HDL-C levels during the study was 7%. All doses of atorvastatin significantly increased HDL-C levels. Increases were greater in men (7.8 vs 6.1%; p?=?0.02), in combined hyperlipidaemia (7.9 vs 6.4% for hypercholesterol-aemia; p?=?0.04), and in the lower baseline HDL-C quartile (9.2 vs 5.3%, 1st vs 4th quartile; p?=?0.001). After adjustment for 24 predictors of coronary events, multivariate analysis revealed a Hazards Ratio of 0.85 (95% confidence

interval 0.76-0.94; p?=?0.002) for every 4?mg/dL (0.1?mmol/L) increase in HDL-C.

Conclusions: There was a significant beneficial effect on HDL-C levels across the dose range of atorvastatin. Clinical outcomes in the structured care arm of GREACE were determined in part by the extent of atorvastatin-induced HDL-C increase. This effect was independent from benefit induced by low density lipoprotein cholesterol (LDL-C) reduction, suggesting that the CHD risk reduction associated with a rise in a low HDL-C at baseline remains significant under aggressive (-46%) LDL-C lowering conditions. However, the relationship between HDL-C and vascular risk may be weaker when LDL-C levels are aggressively lowered.     

Combination lipid therapy in type 2 diabetes mellitus

Introduction: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia – hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) – that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes.

Areas covered: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes.

Expert opinion: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

Rationale and design of a prospective clinical trial program to evaluate the glucose-lowering effects of colesevelam HCl in patients with type 2 diabetes mellitus

ABSTRACT

Background: Dyslipidemia and type 2 diabetes mellitus (T2DM) increase atherosclerotic coronary heart disease (CHD) risk. In patients with T2DM, improving lipid parameters reduces CHD risk, while optimizing glucose levels reduces microvascular complications and, possibly, macrovascular disease such as CHD. Unfortunately, many patients with T2DM do not achieve either lipid or glucose treatment targets.

Objective: Colesevelam HCl is a specifically engineered bile-acid sequestrant (BAS) indicated to reduce elevated low-density lipoprotein cholesterol concentrations. Earlier studies have demonstrated that BAS not only reduce cholesterol levels, but also lower glucose levels in patients with T2DM. These findings have prompted a robust, prospective phase 3 clinical trial program to further evaluate the safety and tolerability of colesevelam HCl when added to T2DM patients previously treated with metformin, insulin or a sulfonylurea. A limitation of these clinical trials is that none of them assessed colesevelam HCI monotherapy, nor directly compared the glucose-lowering effects of colesevelam HCI to established oral antidiabetes drugs. Nonetheless, this clinical trial program will better determine whether a single agent added to existing diabetes therapy can improve both lipid and glucose parameters in T2DM, which may allow more patients to achieve lipid and glucose treatment targets.

Conclusions: This phase 3 clinical trial program will evaluate colesevelam's glucose-lowering effects in patients with T2DM. In addition, based upon a review of the relevant medical literature through an online electronic PubMed search (without restriction to date other than otherwise occurs through PubMed), potential mechanisms as to how BAS may lower glucose levels are discussed.     

Relationship between LDL-C and non-HDL-C levels and clinical outcome in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study

SUMMARY

Background: Although available guidelines suggest reducing low-density lipoprotein cholesterol (LDL-C) to below 100?mg/dL (2.6?mmol/L), the importance of target-oriented therapy remains controversial. To assess whether achieving guideline-based targets is of benefit, the relationship between clinical outcomes and lipid levels (baseline and on-study) was evaluated in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. This study demonstrated significant reductions in morbidity and mortality associated with active dose titration of atorvastatin and structured management of dyslipidaemia.

Methods and results: Intention-to-treat analysis (Cox proportional hazards model)?was used to assess the relationship between lipid values and coronary events. Higher levels of LDL-C at baseline were associated with a greater risk of subsequent events among patients randomized to usual care. Reducing the LDL-C and the non-high density lipoprotein cholesterol (non-HDL-C) level to the National Cholesterol Educational Program (NCEP) Adult Treatment Panel (ATP) III goals required greater doses of atorvastatin for the higher baseline quartile of LDL-C. During the study there was a greater reduction in the risk of coronary heart disease (CHD) events in atorvastatin-treated patients who were in the highest quartile of LDL-C at baseline, after achieving the LDL-C treatment goal, in comparison to the usual care patients in the highest baseline LDL-C quartile.

Conclusions: Achieving the NCEP ATP III LDL-C and non-HDL-C goals by titrating up the dose of atorvastatin was associated with a significant reduction in vascular events in patients with CHD. The greatest benefit was seen in those patients with the highest baseline LDL-C levels.     

Statins: balancing benefits,efficacy and safety

Coronary heart disease (CHD) is the leading cause of death in the US. The risk of CHD is substantially increased in people with elevated levels of low-density lipoprotein cholesterol (LDL-C). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective drug class for lowering LDL-C. Long-term prospective studies have shown that statin therapy significantly reduces the risk of CHD morbidity and mortality in patients without or with evidence of established CHD (primary and secondary prevention, respectively). In 1988, treatment guidelines were first issued by the National Cholesterol Education Program Adult Treatment Panel I (NCEP-ATP I), then revised in 1993 (ATP II), to provide recommendations for the prevention and management of high cholesterol in adults. Despite these guidelines, recent national surveys have shown that effective therapies are being under-utilised and they often fail to achieve LDL-C goals established by NCEP-ATP II. The reasons appear to be multifactorial but include issues related to efficacy, safety, the potential for adverse drug reactions, failure to prescribe appropriate medication or dose and noncompliance with therapy. In the first major update of NCEP guidelines in almost a decade, the current ATP III recommendations have placed an increased number of Americans in the high-risk category, inviting even more aggressive therapy and escalating the challenge of reaching NCEP goals. New statins that may have even greater efficacy and less potential for drug interactions may help address some concerns associated with the failure to achieve treatment goals.     

Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid – a position paper developed by the European Consensus Panel on HDL-C*

SUMMARY

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines.     

Emerging drugs for hyperlipidemia

Importance of the field: Elevated concentrations of low-density lipoprotein (LDL) cholesterol are associated with increased risk of coronary atherosclerosis, and morbidity and mortality from coronary heart disease (CHD). Lowering of LDL cholesterol leads to a reduction in cardiovascular morbidity and all-cause mortality in individuals at risk for cardiovascular events and patients with established CHD. The mainstays of lipid lowering therapy today are the HMG-CoA reductase inhibitors (statins); however, the residual risk of cardiovascular events amongst individuals treated with statins remains a major healthcare concern.

Areas covered in this review: Emerging targets for lipid lowering therapy target pathways that regulate lipoprotein assembly, lipoprotein clearance and pro-atherogenic lipoprotein modification. These emerging drugs have novel mechanisms that include 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 pro-atherogenic lipoprotein remodeling (cholesterol ester transfer protein inhibitors (dalcetrapib, anacetrapib) and peroxisome proliferator activator agents (GFT-505, aleglitazar)) and inhibition of lipoprotein modification (heme oxygenase-1 inhibitor (succinobucol), phospholipase A₂ inhibitors (varespladib, darapladib)).

What the reader will gain: A review of the most recent data on emerging drugs in the treatment of hyperlipidemia.

Take home message: With these medications, we will achieve more effective reductions in cardiovascular morbidity and mortality than achieved with current lipid lowering therapies.     

Achieving 2003 European lipid goals with rosuvastatin and comparator statins in 6743 patients in real-life clinical practice: DISCOVERY meta-analysis

ABSTRACT

Background: There is an increasing body of evidence to support the benefits of reducing low-density lipoprotein cholesterol (LDL-C) levels and this has been reflected in a lowering of LDL-C goals recommended by international guidelines. Therefore, there is a growing need for effective lipid-modifying therapies to optimise the achievement of these more stringent LDL-C goals.

Objective: A meta-analysis of data pooled from five studies participating in the DISCOVERY (DIrect Statin COmparison of LDL‐C Values: an Evaluation of Rosuvastatin therapY) Programme was performed to compare the effect of rosuvastatin treatment with other statins in real-life clinical practice.

Results: These studies included 6743 patients with hypercholesterolaemia from different ethnicities, countries and cultural environments. The meta-analysis showed that significantly more patients receiving rosuvastatin 10?mg achieved the 2003 European LDL‐C goals compared with those who received atorvastatin 10?mg or simvastatin 20?mg (?p < 0.001 for both comparisons). A significantly greater proportion of patients receiving rosuvastatin 10?mg also achieved the 2003 European total cholesterol goal compared with those on atorvastatin 10?mg (?p < 0.001).

Conclusions: The meta-analysis showed that rosuvastatin was more effective than comparator statins at lowering LDL‐C levels and enabling patients to achieve lipid goals at recommended start doses. In addition, all statins studied were well tolerated and confirmed that rosuvastatin had a similar safety profile to other statins.     

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.