Aggressive Low-density Lipoprotein Cholesterol Lowering Research Articles

Does Adopting Western Low-density Lipoprotein Cholesterol Targets Expose Indians to a Higher Risk of Cardiovascular Events? Expert Opinion From the Lipid Association of India.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association.

The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.

The PACMAN-AMI trial: a revolution in the treatment of acute coronary syndromes.

After an acute coronary syndrome (ACS), the risk of major adverse cardiovascular events (MACE) persists despite the reperfusion of the culprit lesion. The addition of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to standard lipid-lowering therapies has been demonstrated to effectively reduce the levels of low-density lipoprotein cholesterol (LDL-C), with a consistent decrease of MACE in large, randomized clinical trials enrolling patients at high risk of cardiovascular events. There is a strong rationale for an immediate and aggressive LDL-C lowering with the use of PCSK9i in ACS patients. The PACMAN-AMI trial tested this hypothesis demonstrating that in ACS patients, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks, as assessed by novel intra-coronary imaging modalities. These findings might provide the mechanistic rationale in favour of early initiation of very intensive LDL-C-lowering therapy in the acute setting of ACS, potentially modifying the actual common pattern of treatment.

Medical treatment of dyslipidemia in the elderly

Worldwide, the proportion of the population aged 65 years or older is rapidly increasing, along with the prevalence of dyslipidemia and cardiovascular disease. Because of decreased physiological functions and comorbidities in the elderly, it is difficult to determine a treatment strategy for each individual. According to the guidelines for dyslipidemia in Europe and the United States, aggressive low-density lipoprotein cholesterol lowering is recommended for secondary prevention of cardiovascular disease as in the younger patient group. Also, newer cholesterol-lowering agents, ezetimibe and PCSK9 inhibitor can be added to achieve treatment goals in high risk groups. However, considering the conflicting study results in primary prevention, it is necessary to fully consider life expectancy and side effects of medications to determine whether to initiate treatment. Several on-going studies are expected to give answers to many complex clinical situations of dyslipidemia treatment in the elderly.

Evidence for intensive LDL-C lowering for acute coronary syndrome: Recommendations from the Lipid Association of India

Patients with acute coronary syndrome (ACS) have a high risk of subsequent adverse cardiovascular outcomes, particularly within the first 30 days. Although it is well documented that initiation of statin therapy in the setting of ACS improves short- and long-term cardiovascular outcomes, and achievement of lower levels of low density lipoprotein cholesterol (LDL-C) incrementally improves outcomes, many patients with ACS have persistent hypercholesterolemia after discharge from the hospital. This is a missed opportunity that prompted the Lipid Association of India to develop recommendations for earlier initiation of more aggressive LDL-C lowering treatment, particularly for patients of South Asian descent who are well-documented to have earlier onset of more aggressive atherosclerotic cardiovascular disease. The Lipid Association of India recommends individualized aggressive LDL-C goals after ACS, which can be rapidly achieved with high intensity statin therapy and subsequent goal-directed adjunctive treatment with ezetimibe and PCSK9 inhibitors. Improved treatment of hypercholesterolemia achieved within weeks after ACS has the potential to reduce the high rate of morbidity and mortality in these high risk patients.

Acute arterial events across all vascular territories in the FOURIER trial

Abstract Background In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial, adding the PCSK9 inhibitor evolocumab to statin therapy reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Although atherosclerotic coronary, cerebrovascular, and peripheral vascular events share a related pathobiology, the effect of aggressive LDL-C lowering with PCSK9 inhibition on the risk of acute arterial events across all three vascular beds is not well-described. Purpose To assess the efficacy of evolocumab on acute arterial events in all vascular territories including coronary, cerebral, and peripheral vascular beds. Methods In the FOURIER trial, patients (n=27,564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). Acute arterial events were defined as a composite of coronary (coronary heart disease [CHD] death, myocardial infarction [MI], or urgent coronary revascularization), cerebrovascular (ischemic stroke, transient ischemic attack [TIA], or urgent cerebral revascularization), or peripheral vascular (acute limb ischemia, major amputation, or urgent peripheral revascularization) events. Cox proportional-hazard models were used to assess the efficacy of evolocumab on these outcomes. Landmark and total event analyses were also done. Results Of the 2,210 first acute arterial events occurring during follow-up, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced the risk of a first acute arterial event by 19% (HR 0.81, 95% CI 0.74–0.88; P&amp;lt;0.001), with significant individual reductions in acute coronary (HR 0.83; 95% CI 0.75–0.91; P&amp;lt;0.001), acute cerebrovascular (HR 0.77; 95% CI 0.65–0.92; P=0.004), and acute peripheral vascular (HR 0.58; 95% CI 0.38–0.88; P=0.01) events (Figure, top). The magnitude of the risk reduction with evolocumab tended to increase over time, with a 16% reduction (HR 0.84; 95% CI 0.75–0.96) in the first year followed by a 24% reduction (HR 0.76; 95% CI 0.67–0.85) thereafter (Figure, bottom). There were 3,780 total acute arterial events (first plus recurrent), with a 22% reduction with evolocumab (incidence rate ratio [RR] 0.78; 95% CI 0.70–0.87). Evolocumab prevented 496 total acute arterial events as compared to 222 first events. Conclusions The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced the risk of acute arterial events across all vascular territories with a robust effect over time. These findings indicate a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The FOURIER trial was supported by Amgen.

Effectiveness and Safety of Lipid-Lowering Drug Treatments in Japanese Patients with Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up. Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients. Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events. Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation.

Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

Predicting, preventing, and managing cardiovascular and chronic kidney disease progression in people with type 2 diabetes: How to improve on traditional strategies.

Cholesterol-Lowering Agents.

Loss-of-function variants in PCSK9 (proprotein convertase subtilisin-kexin type 9) are associated with lower lifetime risk of atherosclerotic cardiovascular disease) events. Confirmation of these genetic observations in large, prospective clinical trials in participants with atherosclerotic cardiovascular disease has provided guidance on risk stratification and enhanced our knowledge on hitherto unresolved and contentious issues concerning the efficacy and safety of markedly lowering LDL-C (low-density lipoprotein cholesterol). PCSK9 has a broad repertoire of molecular effects. Furthermore, clinical trials with PCSK9 inhibitors demonstrate that reductions in atherosclerotic cardiovascular disease events are more effective in patients with recent myocardial infarction, multiple myocardial infarctions, multivessel coronary artery disease, and lower extremity arterial disease. The potent LDL-C lowering efficacy of PCSK9 inhibitors provides the opportunity for more aggressive LDL-lowering strategies in high-risk patients with atherosclerotic cardiovascular disease and supports the notion that there is no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been associated by a safety profile superior to that of other classes of LDL-lowering agents. These clinical trials provide evidence that LDL lowering with PCSK9 inhibitors is an effective therapy for lowering cardiovascular events in high-risk patients with LDL-C levels ≥70 mg/dL on maximally tolerated oral therapies, including statins and ezetimibe.

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in Japanese patients with stable coronary artery disease

Background: Recent clinical trials have demonstrated that intensive low-density lipoprotein-cholesterol (LDL-C) lowering therapy by strong statins could prevent recurrent cardiovascular event and have beneficial regressive effects on coronary plaques. Otherwise, the use of ezetimibe in combination with statin has been reported to provide greater reduction in LDL-C level than statin monotherapy. However, it is not established whether additional LDL-C lowering achieved with the addition of ezetimibe to statin monotherapy will lead to further reduction in coronary plaque volume. Methods: In this prospective, open-label, randomized study, 40 patients with stable coronary artery disease (CAD) requiring percutaneous coronary intervention (PCI), whose LDL-C levels were higher than 100 mg/dl, were divided into combination therapy group (n=21, rosuvastatin 5mg plus ezetimibe 10mg daily) or statin monotherapy group (n=19, rosuvastatin 5mg daily). Serial volumetric intravascular ultrasound (IVUS) analysis were performed at baseline and after 6 months of follow-up for a non-PCI site. Results: LDL-C level was significantly decreased by 54.1% in the combination group (from 132.7±31.7 mg/dl to 59.5±17.1 mg/dl, p<0.001) vs. 42.1% in the monotherapy group (from 122.0±15.7 mg/dl to 69.1±19.7 mg/dl, p<0.001). Plaque volume (PV) was significantly reduced in the combination group (14.2±12.9% decrease) compared with the monotherapy group (2.1±17.0% decrease; p=0.016). Moreover, percent change in PV showed a significantly positive correlation with percent change and nominal change of LDL-C (r=0.403, p=0.011, and r=0.418, p=0.008, respectively), and percent change of non high-density lipoprotein cholesterol (r=0.380, p=0.024). It also showed a significant positive correlation with follow-up small dense LDL level (r=0.455, p=0.006). Conclusions: Aggressive LDL-C lowering therapy by ezetimibe in addition to statin may exert significant regression of coronary plaque volume compared with usual-dose statin monotherapy in patients with stable CAD.

A Reappraisal of the Risks and Benefits of Treating to Target with Cholesterol Lowering Drugs

Atherosclerotic cardiovascular disease (CVD) is the number one cause of death globally, and lipid modification, particularly lowering of low density lipoprotein cholesterol (LDLc), is one of the cornerstones of prevention and treatment. However, even after lowering of LDLc to conventional goals, a sizeable number of patients continue to suffer cardiovascular events. More aggressive lowering of LDLc and optimization of other lipid parameters like triglycerides (TG) and high density lipoprotein cholesterol (HDLc) have been proposed as two potential strategies to address this residual risk. These strategies entail use of maximal doses of highly potent HMG CoA reductase inhibitors (statins) and combination therapy with other lipid modifying agents. Though statins in general are fairly well tolerated, adverse events like myopathy are dose related. There are further risks with combination therapy. In this article, we review the adverse effects of lipid modifying agents used alone and in combination and weigh these effects against the evidence demonstrating their efficacy in reducing cardiovascular events, cardiovascular mortality, and all cause mortality. For patients with established CVD, statins are the only group of drugs that have shown consistent reductions in hard outcomes. Though more aggressive lipid lowering with high dose potent statins can reduce rates of non fatal events and need for interventions, the incremental mortality benefits remain unclear, and their use is associated with a higher rate of drug related adverse effects. Myopathy and renal events have been a significant concern with the use of high potency statin drugs, in particular simvastatin and rosuvastatin. For patients who have not reached target LDL levels or have residual lipid abnormalities on maximal doses of statins, the addition of other agents has not been shown to improve clinical outcomes and carries an increased risk of adverse events. The clinical benefits of drugs to raise HDLc remain unproven. In patients without known cardiovascular disease, there is conflicting evidence as to the benefits of aggressive pursuit of numerical lipid targets, particularly with respect to all cause mortality. Certainly, in statin intolerant patients, alternative agents with a low side effect profile are desirable. Bile acid sequestrants are an effective and safe choice for decreasing LDLc, and omega-3 fatty acids are safe agents to decrease TG. There remains an obvious need to design and carry out large scale studies to help determine which agents, when combined with statins, have the greatest benefit on cardiovascular disease with the least added risk. These studies should be designed to assess the impact on clinical outcomes rather than surrogate endpoints, and require a comprehensive assessment and reporting of safety outcomes.

The case for more intensive use of statins.

The case for more intensive use of statins.

Statin Therapy for Healthy Men Identified as “Increased Risk”

ATHEROSCLEROTIC CORONARY HEART DISEASE (CHD) is the most common cause of morbidity and mortality in the world. The “lipid hypothesis” of CHD is clearly established: (1) circulating cholesterol plays a central role in atherogenesis and is an integral component of the requisite lesion, the coronary plaque; (2) cholesterol levels beginning in childhood predict lifetime risk of atherosclerotic CHD events in a dose-response relationship; and (3) statins lower cholesterol levels and reduce CHD and cerebrovascular events directly proportional to the degree of low-density lipoprotein cholesterol (LDL-C) lowering. As a result, guidelines from around the world support a combined lifestyle and pharmacologic approach to cholesterol lowering directed at patients with elevated CHD risk. Assuming a high-density lipoprotein cholesterol (HDL-C) level of about 40 mg/dL, the patient in this common clinical scenario would have an “intermediate” 10-year risk for developing CHD (approximately 10%) based on the Framingham Risk Score (FRS). As always, lifestyle change is the first-line therapy. However, if this patient’s cholesterol level remains abnormal, despite sustained attempts at lifestyle optimization, statin therapy should be considered with the goal of reducing CHD risk. Current guidelines suggest an LDL-C goal of less than 130 mg/dL with an optional target of less than 100 mg/dL. In the shared decision-making process, the clinician should explicitly inform this patient that a statin is likely to reduce the chance of a first CHD event and reduce the chance of stroke and may offer a survival benefit that is likely to become more evident over a lifetime. Evidence Supporting Primary Prevention The WOSCOPS enrolled 6595 men aged 45 to 64 years with no previous history of myocardial infarction and a mean (SD) plasma cholesterol level of 272 (23) mg/dL. Treatment with pravastatin, 40 mg, resulted in a 31% reduction in myocardial infarction and CHD-related death (248 vs 174 events and 135 vs 106 deaths for placebo vs pravastatin, respectively). Similarly, the AFCAPS/TexCAPS randomized 6605 asymptomatic adults with a mean (SD) LDL-C level of 150 (17) mg/dL and low HDL-C (36 [5] mg/dL in men and 40 [5] mg/dL in women) to lovastatin, 20 to 40 mg, vs placebo. Treatment with lovastatin reduced the incidence of first major coronary events by 37% and myocardial infarction by 40% (183 vs 116 events and 95 vs 57 myocardial infarctions for placebo vs lovastatin, respectively). The JUPITER trial enrolled 17 802 healthy men and women with so-called normal LDL-C less than 130 mg/dL and elevated high-sensitivity C-reactive protein greater than 2.0 mg/L. Aggressive lowering of LDL-C in those randomized to receive rosuvastatin, 20 mg, reduced the risk of myocardial infarction, stroke, and revascularization by about 44% (251 vs 142 events for placebo vs rosuvastatin) and total mortality by 20% (247 vs 198 events, respectively). The effect of aggressive LDL-C lowering in JUPITER was substantial considering that the baseline median LDL-C was just 108 mg/dL. Subanalysis demonstrated the largest absolute reduction in patients with a FRS of 11% to 20% (145 vs 74 events for placebo vs rosuvastatin; hazard ratio [HR], 0.51; 95% CI, 0.39-0.68) followed by those with FRS of 5% to 10% (59 vs 32 events; HR, 0.55; 95% CI, 0.36-0.84).

HDL-C: Role as a risk modifier

Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C). The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C.

Persistent dyslipidemia in statin-treated patients. focus on comprehensive lipid management survey in Swiss patients

Statin therapy reduces cardiovascular morbidity and mortality. However, a substantial residual cardiovascular risk can be observed in patients receiving this therapy due to persisting lipid abnormalities as well as to the lack of a systematic global risk-reduction strategy. The objective of the study was to assess the prevalence of dyslipidemia in a cohort of patients living in Switzerland and receiving statin therapy. This cross-sectional study was conducted by 61 primary care physicians, cardiologists, endocrinologists and internists in Switzerland. Patients were consecutive outpatients≥45 years-old, on statin therapy for at least 3 months with available lipid values. A clinical examination and a recording of the latest lipid values on statin therapy were performed in all patients. A total of 473 patients (age 66.3±9.41 years; 61.9% male) were included in the final analysis. Under statin therapy, 40% of the analysed patients had a normal lipid profile, 32.6% presented increased low-density lipoprotein cholesterol (LDL-C) (3.35±0.88 mmol/L), 28.8% low high-density lipoprotein-cholesterol (HDL-C) (0.95±0.18 mmol/L) and 31.1% elevated triglycerides (2.69±1.04 mmol/L). It is of note that the included population was characterised by a high prevalence of cardiovascular risk factors (86.5% patients had 10-year cardiovascular risk>20%). Nevertheless, the lipid lowering therapy was modified in only 15.4% of the patients. Persistent dyslipidemia is a reality in statin-treated patients and may contribute to their residual cardiovascular risk. Therefore, comprehensive lipid management should be preferred to aggressive LDL-C lowering alone. Moreover, strategies to assess and modify the global cardiovascular risk of patients should be taken into account as an important component of primary and secondary prevention.

Influence of simvastatin, fenofibrate and/or ezetimibe on correlation of low-density lipoprotein and nonhigh-density lipoprotein cholesterol with apolipoprotein B in mixed dyslipidemic patients

Correlations between low-density lipoprotein cholesterol (LDL-C), or nonhigh-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (Apo B) change after statin therapy has been initiated in hypercholesterolemic patients. This post-hoc analysis studied the correlation between these parameters in patients with mixed dyslipidemia before and after receiving lipid-lowering treatment. Data from two randomized, double-blind studies of 1112 patients with mixed dyslipidemia receiving treatment (ezetimibe 10 mg, ezetimibe/simvastatin 10/20 mg, fenofibrate 160 mg, ezetimibe + fenofibrate 10/160 mg, or ezetimibe/simvastatin + fenofibrate 10/20/160 mg) were pooled. Correlation analyses and simple linear regression analyses were performed at baseline in untreated patients and after 12 weeks of treatment in the whole pooled population, the treatment groups, and after stratification by baseline triglyceride levels (150-250, ≥ 250 mg/dL) within the treatment groups. Both LDL-C and non-HDL-C were closely correlated with levels of Apo B at baseline, and these correlations improved after treatment. When using the fitted simple linear regression equations, we found that the on-treatment LDL-C and non-HDL-C levels corresponding to an Apo B of 90, 80, and 70 mg/dL were lower than proposed LDL-C and non-HDL-C treatment targets. For TG ≥ 250 mg/dL, the corresponding LDL-C was generally lower than that for triglycerides 150-250 mg/dL, except in the cases with fenofibrate in the treatment. The results of these analyses suggest that achieving goal-specified levels of Apo B in statin-treated patients with mixed dyslipidemia would require more aggressive LDL-C lowering to achieve the greatest reduction in LDL particle number.

Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol?

Despite aggressive low-density lipoprotein cholesterol lowering, patients continue to be at significant risk of cardiovascular events. Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel guidelines, non-HDL-C was introduced as a secondary target of therapy. A combined post-hoc analysis of data from two prospective, randomized trials assessing the role of statins in patients with established coronary heart disease showed that on-treatment levels of non-HDL-C were more closely associated with cardiovascular outcomes than levels of low-density lipoprotein cholesterol. A recent meta-analysis of the relationship between non-HDL-C reduction and coronary heart disease risk showed that most lipid-modifying drugs used as monotherapy have a 1 : 1 relationship between percentage non-HDL-C lowering and percentage coronary heart disease reduction. In the European Prospective Investigation Into Cancer and Nutrition-Norfolk prospective population study (n = 21,448), participants with high non-HDL-C levels were at increased coronary heart disease risk independently of their low-density lipoprotein cholesterol levels. Because non-HDL-C appears to be superior for risk prediction beyond low-density lipoprotein cholesterol, future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies. There is an increased need to have non-HDL-C reported on routine lipid panels, especially because it would be at no added cost.