How Low to Go With Lipid-Lowering Therapies in a Cost-effective and Prudent Manner

The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol was a landmark document guiding health care professionals around the globe on how to administer lipid-lowering therapies. Those guidelines were primarily focused on statin therapy benefit groups. The writing committee found insufficient evidence for specific low-density lipoprotein cholesterol (LDL-C) treatment targets. There have been many important updates in the lipid literature since the publication of that document. Most importantly, clinical trials have provided definitive evidence for the pivotal role of LDL-C in atherogenesis and the improvement in clinical outcomes by means of aggressive LDL-C reduction. Ezetimibe, evolocumab, and alirocumab treatment resulted in substantial reductions in major adverse cardiovascular outcomes. These data encourage a discussion on whether LDL-C targets are warranted in primary and/or secondary prevention, and if so, how low should those targets be. In order to answer such questions, the costs and safety of such therapies, as well as the safety of very low levels of LDL-C need to be addressed. This review discusses the relationship between LDL-C lowering and cardiovascular risk reduction, the efficacy, safety, and cost-effectiveness of high-intensity lipid-lowering therapies, and the recommendations from the most recent lipid guidelines.     

High-Intensity Statins Benefit High-Risk Patients: Why and How to Do Better

Review of the US and European literature indicates that most patients at high risk for atherosclerotic cardiovascular disease (ASCVD are not treated with high-intensity statins, despite strong clinical-trial evidence of maximal statin benefit. High-intensity statins are recommended for 2 categories of patients: those with ASCVD (secondary prevention) and high-risk patients without clinical ASCVD. Most patients with ASCVD are candidates for high-intensity statins, with a goal for low-density lipoprotein cholesterol reduction of 50% or greater. A subgroup of patients with ASCVD are at very high risk and can benefit by the addition of nonstatin drugs (ezetimibe with or without bile acid sequestrant or bempedoic acid and/or a proprotein convertase subtilisin/kexin type 9 inhibitor). High-risk primary prevention patients are those with severe hypercholesterolemia, diabetes with associated risk factors, and patients aged 40 to 75 years with a 10-year risk for ASCVD of 20% or greater. In patients with a 10-year risk of 7.5% to less than 20%, coronary artery calcium scoring is an option; if the coronary artery calcium score is 300 or more Agatston units, the patient can be up-classified to high risk. If high-intensity statin treatment is not tolerated in high-risk patients, a reasonable approach is to combine a moderate-intensity statin with ezetimibe. In very high-risk patients, proprotein convertase subtilisin/kexin type 9 inhibitors lower low-density lipoprotein cholesterol levels substantially and hence reduce risk as well.     

The New Cholesterol Treatment Guidelines from the American College of Cardiology/American Heart Association, 2013: What Clinicians Need to Know

Abstract

The new American College of Cardiology/American Heart Association blood cholesterol guidelines of 2013 are the first major revision of cholesterol therapy guidance in over a decade. Commonly used low-density lipoprotein cholesterol (LDL-C) target goals have been abrogated in favor of intensity of statin therapy, more in line with data from randomized clinical trials. Four groups of adult patients have been identified from these studies who will most benefit from statins: patients with atherosclerotic cardiovascular disease (ASCVD); patients with primary elevations of LDL-C ≥ 190 mg/dL; diabetic patients between age 40 and 75 years without ASCVD whose LDL-C is between 70 and 189 mg/dL; and patients between age 40 and 75 years without ASCVD or diabetes with LDL-C between 70 and 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. This last primary prevention group has engendered the most controversy because the newly recommended risk calculator may overestimate risk or the 7.5% threshold may be too low, thereby subjecting too many patients to statins unnecessarily. This review summarizes the latest guidelines and pertinent evidence, and provides case examples to help clinicians familiarize themselves with the new recommendations.     

A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has recently released the new cholesterol treatment guideline. This update was based on a systematic review of the evidence and replaces the previous guidelines from 2002 that were widely accepted and implemented in clinical practice. The new cholesterol treatment guideline emphasizes matching the intensity of statin treatment to the level of atherosclerotic cardiovascular disease (ASCVD) risk and replaces the old paradigm of pursuing low-density lipoprotein cholesterol targets. The new guideline also emphasizes the primacy of the evidence base for statin therapy for ASCVD risk reduction and lists several patient groups that will not benefit from statin treatment despite their high cardiovascular risk, such as those with heart failure (New York Heart Association class II-IV) and patients undergoing hemodialysis. The guideline has been received with mixed reviews and significant controversy. Because of the evidence-based nature of the guideline, there is room for several questions and uncertainties on when and how to use lipid-lowering therapy in clinical practice. The goal of the Mayo Clinic Task Force in the assessment, interpretation, and expansion of the ACC/AHA cholesterol treatment guideline is to address gaps in information and some of the controversial aspects of the newly released cholesterol management guideline using additional sources of evidence and expert opinion as needed to guide clinicians on key aspects of ASCVD risk reduction.     

Lipid-lowering Therapy and Goal Achievement in High-risk Patients From French General Practice

Purpose

The goal of this study was to summarize patterns of lipid-lowering therapy (LLT) usage and achievement of guideline-identified lipid goals in a 2015 general practice cohort of French patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes mellitus (DM).

Associations between change in C-reactive protein and serum lipids during statin treatment

Hypolipidaemic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment reduces cardiovascular risk and is also associated with the reduction of C-reactive protein (CRP) concentrations. However, there is scant data concerning the relationship between CRP and lipid changes during statin treatment. We studied 60 hypercholesterolaemic coronary patients who participated in the Treat to Target (3T) study comparing atorvastatin and simvastatin. Serum lipids and CRP (with a sensitive method) were measured before treatment at baseline and after 12 months of statin treatment. Low-density lipoprotein (LDL) cholesterol was substantially decreased and high-density lipoprotein (HDL) cholesterol increased during statin treatment. CRP decreased significantly (sign test P = 0.03) during treatment, and the changes of CRP were significantly associated with changes in HDL cholesterol (r = ?0.45; P < 0.001) and apolipoprotein A1 (r = ?0.40; P < 0.001) but not with changes in LDL cholesterol or triglycerides. The change in HDL cholesterol explained 20% of the change in CRP during statin treatment. The results are in line with previous suggestions that HDL has anti-inflammatory properties.     

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.     

Improving lipid management--to titrate, combine or switch

Despite the benefits of statin therapy, cholesterol management remains suboptimal and many patients do not achieve their recommended low-density lipoprotein cholesterol (LDL-C) goals. The use of insufficient doses, limited drug effectiveness and poor patient compliance may contribute to the treatment gap. Options for improving lipid management include dose titration, combination therapy or prescribing a more efficacious statin. LDL-C reductions are generally modest when patients' current statin dose is titrated, and there may be an increased potential for adverse effects. Combining statin therapy with another lipid-modifying agent can provide additional LDL-C reductions, but cost, tolerability and compliance should be considered. In general, switching to a more efficacious statin is a cost-effective way of enabling more patients to achieve recommended targets without increasing dosages. When considering the options available, physicians should balance efficacy, cost and safety to enable more patients to attain LDL-C goals and achieve greater therapeutic gain from statin treatment.     

血脂特征对冠状动脉病变程度影响的研究

目的:探讨冠心病患者血脂特征对冠脉病变严重程度的影响。方法:住院患者322例行冠脉造影,冠脉造影正常者68例(21%),确诊冠心病患者254例(79%),其中单支病变组75例(30%),2支病变组83例(32%),3支病变组96例(38%);依据造影结果采用Gensini积分系统对冠脉病变程度进行评分。造影前常规测定总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、甘油三脂。对所得数据资料用SPSS10.0统计软件进行单因素方差分析和多元线性逐步回归法和logistic回归法分析。结果:冠心病组的高密度脂蛋白胆固醇水平明显低于正常组,低密度脂蛋白胆固醇水平高于正常组,差异有统计学意义。各组的总胆固醇、甘油三酯差异无统计学意义。多元线性回归和Logistic回归分析显示高密度脂蛋白胆固醇和低密度脂蛋白胆固醇进入回归方程,高密度脂蛋白胆固醇的OR值较大。结论:低密度脂蛋白胆固醇增高和高密度脂蛋白胆固醇降低是冠状动脉病变及病变程度加重的主要危险因素,其中高密度脂蛋白胆固醇对冠脉病变的影响程度可能强于低密度脂蛋白胆固醇。     

高密度脂蛋白胆固醇、低密度脂蛋白胆固醇及其比值检测在中老年冠心病患者诊断和临床治疗中的意义

目的 探讨血清高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、LDL-C/HDL-C检测在中老年冠心病(CHD)患者中的意义.方法 分析经冠状动脉造影确诊为冠状动脉粥样硬化(药物治疗组)83例、CHD(支架植入组)163例及冠状动脉造影阴性(对照组)44例中老年病例的血清HDL-C、LDL-C、LDL-C/HDL-C比值与冠状动脉病变程度之间的关系.并比较各组间男女血脂水平的差异.结果 药物治疗组、支架植入组与对照组总胆固醇(T()、LDL-C、LDL C/HDL-C比值水平差异有统计学意义(P＜0.05或＜0.01).支架植入组TC、LDL-C、TC/HDLC比值水平明显高于药物治疗组及对照组(P＜0.05或＜0.01).支架植入组HDL-C显著低于药物治疗组及对照组(P＜0.05).药物治疗组女性HDL-C水平高于男性(P＜0.05),但女性TC/H DL-C比值、LDL-C/HDL-C比值低于男性(P ＜0.05).支架植入组女性TC和HDL-C高于男性(P＜0.05).对照组女性TC、HDL-C高于男性(P＜0.05),但女性TG/HDL C、LDLC/HDL-C低于男性(P＜0.05).结论 血清HDL-C、LDL-C、LDL-C/HDL-C比值与冠状动脉病变相关,对中老年CHD患者的诊断及临床治疗有使用价值.     

Impact of the new National Cholesterol Education Program (NCEP) guidelines on patient management

PURPOSE: To update nurse practitioners (NPs) on the latest National Cholesterol Education Program (NCEP) guidelines for the management of high blood cholesterol in adults. DATA SOURCES: The 2001 NCEP Adult Treatment Panel (ATP) III guidelines and supporting scientific reviews and reports of clinical trials related to the evidence upon which the guidelines are based. CONCLUSIONS: The many new features of the ATP III guidelines include an increased emphasis on the patient with multiple risk factors in order to identify appropriate candidates for primary prevention and on more stringent classifications of elevated lipid/lipoprotein levels. However, elevated levels of low-density lipoprotein (LDL) cholesterol continue to be the focus for both primary and secondary prevention, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are clearly the drugs of choice for decreasing LDL cholesterol in most patients. IMPLICATIONS FOR PRACTICE: Because NPs play key roles in optimizing treatment management, it is important that they become familiar with, and be prepared to help implement, these latest guidelines. By embracing the global risk assessment approach of ATP III and aggressively treating all at-risk patients, NPs can take a proactive role in helping to halt the progression of coronary heart disease and its consequences.     

Future directions in lipid therapies

Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterolabsorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.     

The clinical significance of serum high density lipoproteins

Serum high density lipoproteins (HDL) are a protective factor against atherosclerosis. Many epidemiological studies show a strong inverse relationship between serum HDL-cholesterol (HDL-C) and the likelihood of developing coronary artery disease (CAD). HDL-C levels appear to be a stronger predictive factor for CAD than serum total or low density lipoprotein cholesterol (LDL-C) levels. In the presence of high HDL-C levels, the development of CAD is unlikely even in persons with increased total or LDL-C. Conversely, subjects with low serum levels of HDL-C are at increased risk even if their total and LDL-C is within the "desirable" range. A number of studies have also shown that increasing HDL-C levels is associated with both primary and secondary prevention of atherosclerosis. HDL-C levels should be estimated in individuals with family and/or personal history of premature atherosclerosis, even if they have normal total cholesterol. Only the current problems with the accuracy and precision of the serum HDL-C assay prevent it from being the single most important test for assessment of the lipid risk factors for CAD. The most frequent causes of low HDL-C are smoking, obesity, and hypertriglyceridemia. Treatment of low HDL-C includes removal of these factors, and if this is ineffective, use of drugs. Gemfibrozil and niacin are most effective in raising serum HDL-C, although a number of other medications can markedly improve the total:HDL-C ratio.     

A Perspective on the New American College of Cardiology/American Heart Association Guidelines for Cardiovascular Risk Assessment

The recently published American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for cardiovascular risk assessment provide equations to estimate the 10-year and lifetime atherosclerotic cardiovascular disease (ASCVD) risk in African Americans and non-Hispanic whites, include stroke as an adverse cardiovascular outcome, and emphasize shared decision making. The guidelines provide a valuable framework that can be adapted on the basis of clinical judgment and individual/institutional expertise. In this review, we provide a perspective on the new guidelines, highlighting what is new, what is controversial, and potential adaptations. We recommend obtaining family history of ASCVD at the time of estimating ASCVD risk and consideration of imaging to assess subclinical disease burden in patients at intermediate risk. In addition to the adjuncts for ASCVD risk estimation recommended in the guidelines, measures that may be useful in refining risk estimates include carotid ultrasonography, aortic pulse wave velocity, and serum lipoprotein(a) levels. Finally, we stress the need for research efforts to improve assessment of ASCVD risk given the suboptimal performance of available risk algorithms and suggest potential future directions in this regard.     

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.     

The nurse practitioner's role in helping patients achieve lipid goals with statin therapy

PURPOSE: To discuss the merits of statins in achieving lipid goals and the role of nurse practitioners (NPs) in improving adherence to medical regimens with the goals of improving patient outcomes, reducing cardiovascular disease (CVD) risk within the population at large, and enhancing patients' ability to reach their individual goals. DATA SOURCES: Original research articles, journal articles, professional association practice guidelines. CONCLUSIONS: Despite extensive research clearly documenting the relation between lowering low-density lipoprotein cholesterol (LDL-C) and decreasing rates of cardiovascular events and deaths, lipid-lowering therapy is not being aggressively managed to achieve optimal lipid levels and CVDs remain the leading cause of death among adults in the United States. Contributing factors include lack of patient adherence with prescribed therapy, absence of dose titration when needed, and suboptimal follow-up. Two pathways to improving compliance are the following: first, use of a starting dose of a more efficacious statin to allow more patients to reach their LDL-C goal and, second, more effective primary care programs with NPs as team leaders who can assess and diagnose patients, then develop individual treatment plans and follow-up with patients to ensure that their lipid goals are met. IMPLICATIONS FOR PRACTICE: NPs are well suited to manage patients with hypercholesterolemia. The NP can bridge all aspects of care for the patient by overseeing assessment and treatment of cardiovascular risk factors, including elevated levels of LDL-C, initiating pharmacotherapy when needed, and establishing for each patient an individualized program that features education, support, and follow-up.     

Calcium — a Neglected Key Factor in Arteriosclerosis. The Pathogenetic Role of Arterial Calcium Overload and Its Prevention by Calcium Antagonists

Using specific calcium antagonists as experimental tools, both the physiological messenger and current carrying functions of calcium ions as well as their pathogenetic potencies could be elucidated. Notably, excess intracellular calcium signalling and intra-and extracellular calcium overload turned out to be pathogenetic principles of general importance. In this context, progressive calcium overload of arteriosclerotic vascular walls and the antiarteriosclerotic effects of calcium antagonists, deserve particular interest. In fact, with the help of calcium antagonists, arterial calcium overload as decisive component of various types of experimental arteriosclerosis became accessible to a direct therapeutic intervention. According to their responsiveness to calcium antagonists, two pathophysiologically different types of experimental coronary plaques could be characterized: (1) The calcium type, i.e. coronary calcinosis of vitamin D₃-intoxicated rats highly sensitive to calcium antagonist treatment, (2) the cholesterol type, represented by coronary atheromata of cholesterol-intoxicated rabbits; this primary coronary cholesterol accumulation could not be inhibited by calcium antagonists. The formation of conventional human coronary artery plaques is characterized from the very early lesion onwards by a progressive local uptake of calcium, finally leading to lethal consequences. Conversely, the analysis of the mural cholesterol does not allow to discriminate arteriosclerotic from normal coronary artery segments. Thereby, conventional human coronary plaques typically represent a calcium-dominated type of human arteriosclerosis and differ widely from plaques produced in cholesterol-fed rabbits. The results indicate the decisive pathophysiological role of calcium and calcium overload in both calcium-dominated types of experimental arteriosclerosis and conventional human coronary artery plaques. Moreover, the antiarteriosclerotic effects of calcium antagonists are demonstrated to be based — in various types of experimental arteriosclerosis — on the inhibition of intra-and extracellular calcium overload of arterial walls evoked by various risk factors (vitamin D₃ intoxication, hypertension, nicotine, diabetes).     

冠心病危险生物学标志物的探索

目的对冠状动脉粥样硬化性心脏病(简称冠心病)的危险因素进行再评估,寻找更全面的冠心病预警指标。方法收集2018年8月至2019年12月四川大学华西医院经冠脉造影确诊为冠心病,且确认入院前未服用过他汀类等降脂药的298例患者作为冠心病组,收集无冠心病的健康人群290例作为对照组,分析两组患者病史和实验室指标的差异。结果冠心病组三酰甘油(TG)、非高密度脂蛋白胆固醇(Non-HDL-C)、残余胆固醇(RC)、单核细胞显著高于对照组,差异有统计学意义(P<0.05);冠心病组总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白A(apoA)和同型半胱氨酸(Hcy)显著低于对照组,差异有统计学意义(P<0.05),多因素logistic回归分析提示TG、RC和Non-HDL-C升高是冠心病的独立危险因素,而apoA是冠心病的保护因素。结论临床在关注传统血脂四项的基础上,也应注意监测RC、Non-HDL-C、apoA水平。     

CETP inhibition in cardiovascular risk management: a critical appraisal

In view of the cardioprotective effect of high-density lipoproteins (HDL) and the limited effects of statin and fibrate therapy on HDL cholesterol, it is clinically relevant to test whether pharmacological treatment aimed at raising HDL lowers cardiovascular risk. Cholesteryl ester transfer protein (CETP) is a new therapeutic target, because the cholesteryl ester transfer process lowers HDL cholesterol and contributes to an atherogenic lipoprotein profile, particularly when plasma triglycerides are high. Clinical evidence suggests that coronary artery calcification as well as intima media thickness is positively related to plasma cholesteryl ester transfer, and that high plasma CETP concentration is associated with increased cardiovascular risk in hypertriglyceridaemia. However, CETP could also have anti-atherogenic potential, since it provides a potentially beneficial route for delivery of HDL-derived cholesteryl esters to the liver. In addition, CETP could also favourably stimulate peripheral cell cholesterol removal and enhance hepatic cholesterol uptake. Recent evidence suggests that a high CETP level may confer lower cardiovascular risk in the context of low triglycerides. At maximal doses, the CETP inhibitors JTT-705 and torcetrapib elicit a marked rise in HDL cholesterol of up to 34% and 91-106%, respectively. The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large-scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin. When and how to use CETP inhibitors, e.g. in combination with a statin or a fibrate, is a major challenge. We propose that low HDL cholesterol in the context of high triglycerides, such as found in type 2 diabetes mellitus, could become an important indication area for this new class of drugs.