Review Article

Address correspondence to Dr Seemant Chaturvedi, Wayne State University, 4201 Saint Antoine Street, 8C University Health Center, Detroit, MI 48201, schaturv@med.wayne.edu. Relationship Disclosure: Dr Bhattacharya reports no disclosure. Dr Chaturvedi has received personal compensation for speaking or consulting activities from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, and Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; has received personal compensation for expert witness testimony; and has received research support from Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, and Merck/Schering-Plough. Unlabeled Use of Products/Investigational Use Disclosure: Drs Bhattacharya and Chaturvedi report no disclosure. Copyright * 2011, American Academy of Neurology. All rights reserved.

Dyslipidemia Management
Pratik Bhattacharya, MD, MPH; Seemant Chaturvedi, MD, FAHA, FAAN ABSTRACT
Purpose of Review: Numerous studies have been conducted in the past decade evaluating the use of statins and other lipid therapies for reducing vascular events. These studies have impacted the area of stroke prevention. Recent Findings: For patients with established coronary artery disease, statins reduce the rate of stroke. High-dose statin treatment has also been found to reduce the rate of stroke in patients with recent cerebrovascular events and no evidence of heart disease. As a result, initiation of statin therapy for patients with stroke or TIA is now recommended in clinical guidelines. Whether agents that modulate high-density lipoprotein cholesterol are effective in reducing stroke is still the subject of clinical study. Summary: Most patients with stroke or TIA should be treated with statins. The era of multimodal medical therapy for stroke prevention is now well established.
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INTRODUCTION There have been several advances in the understanding of dyslipidemia and its management in the last decade. The results of several epidemiologic studies and clinical trials have been reported, resulting in landmark changes in treatment paradigms. Treatment goals for lowdensity lipoprotein cholesterol (LDL-C) levels have changed. A new category of patients with very high cardiovascular risk has been identified. The role of several emerging cardiovascular risk factors, such as high-sensitivity C-reactive protein (hsCRP) and lipoprotein(a) [Lp(a)], has been elucidated, and studies regarding treatment of these factors are now available. This article revisits the Adult Treatment Panel III (ATP III) guidelines established in the earlier part of the decade. It outlines the results of studies that led to updated treatment goals for LDL-C and describes the results of two important clinical trials, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and Stroke Prevention by Ag-

gressive Reduction in Cholesterol Levels (SPARCL), which demonstrated the role of statins in primary and secondary stroke prevention, respectively. It describes the current understanding of the pleiotropic effects of statins. Finally, it addresses the role and treatments of secondary targets of dyslipidemia management, such as low high-density lipoprotein cholesterol (HDL-C) and elevated Lp(a). The developments in the treatment of lipid disorders expand the armamentarium of the neurologist aiming to reduce the burden of stroke. LOW-DENSITY LIPOPROTEIN CHOLESTEROL A large meta-analysis of randomized trials using statins for primary or secondary prevention demonstrated a significant correlation between the extent of LDL-C reduction and the degree of protection from stroke. The study estimated that each 10% reduction of LDL-C reduced the risk of stroke by about 15.6%.1 Because of the strong epidemiologic evidence supporting the benefit of LDL-C reduction, LDL-C
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remains the primary target for treatment of dyslipidemia. Low-Density Lipoprotein Cholesterol Treatment Guidelines The ATP III National Cholesterol Education Program recommendations have guided the management of dyslipidemia in the United States.2 Per these guidelines, all adults age 20 years or

older should get a fasting lipid profile once every 5 years. The 2001 guidelines stratify patients into three coronary heart disease (CHD) risk categories (Table 3-1). Patients in the high risk category have a greater than 20% risk of developing or having a recurrence of CHD in 10 years. Patients in the moderate risk category have a 10% to 20% risk of a CHD event in 10 years, based on the

TABLE 3-1 Adult Treatment Panel III Risk Stratification to Guide Treatment Goals for Low-Density Lipoprotein Cholesterol Low-Density Lipoprotein Cholesterol Goal
Optional goal of G 70 mg/dL

Risk Category
Very high risk (Adult Treatment Panel [ATP] III update) Established cardiovascular disease plus: Multiple major risk factors (especially diabetes) Severe and poorly controlled risk factors (especially continued cigarette smoking) Multiple risk factors of the metabolic syndrome (especially triglycerides Q 200 mg/dL plus nonYhigh-density lipoprotein cholesterol [HDL-C] Q 130 mg/dL and HDL-C G 40 mg/dL) Coronary artery syndromes High risk (original ATP III guidelines) Established coronary heart disease (CHD) CHD risk equivalents: Other forms of atherosclerosis, such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid disease Moderate risk Two or more of the following risk factors that modify low-density lipoprotein cholesterol goals: Cigarette smoking Hypertension (blood pressure Q 140/90 mm Hg or on antihypertensive medication) Low HDL-C (G 40 mg/dL) Family history of premature CHD (CHD in male first-degree relative G 55 years; CHD in female first-degree relative G 65 years) Age (men Q 45 years; women Q 55 years) Low risk None or one of the risk factors outlined above

G 100 mg/dL

G 130 mg/dL

G 160 mg/dL

Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486Y2497. Copyright B 2001, American Medical Association. All rights reserved.

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Dyslipidemia
KEY POINTS

h Low-density lipoprotein
cholesterol is the key treatment target for patients with atherosclerotic vascular disease.

h In the past decade,

more aggressive low-density lipoprotein cholesterol reduction has been emphasized by clinical guidelines.

h Some studies in the

primary prevention setting have shown a reduction in stroke with statin use, but the results have been somewhat inconsistent. The evidence is strongest for patients with diabetes or multiple risk factors.

Framingham Risk Score. Patients in the low risk category have a less than 10% risk of having a CHD event in 10 years. The LDL-C treatment target for the high risk group is less than 100 mg/dL, for the moderate risk group is less than 130 mg/dL, and for the low risk group is less than 160 mg/dL.2 Following the publication of the 2001 guidelines and LDL-C goals, the results of several seminal clinical trials evaluating statins in primary and secondary prevention were published, prompting an update to the ATP III guidelines in 2004.3 The updated guidelines defined a new risk class: very high risk (Table 3-1). Results of contemporary clinical trials showed that an LDL-C of 100 mg/dL was not sufficient to prevent cardiovascular events for these very high risk patients, and more aggressive lowering of LDL-C resulted in additional cardiovascular risk reduction. An optional LDL-C target of 70 mg/dL was recommended for patients at very high risk.3 These targets were also recommended by the secondary stroke prevention guidelines from the American Heart Association (AHA) in 2006. Low-Density Lipoprotein Cholesterol Targets for Stroke Risk Reduction The Treating to New Targets (TNT) Trial was designed to evaluate the effect of LDL-C target levels below 100 mg/dL on vascular event risk reduction for patients with CHD.4 The study randomized patients with CHD to receive either atorvastatin 10 mg/d or atorvastatin 80 mg/d. The mean LDL-C levels achieved were 77 mg/dL in the 80 mg/d group and 101 mg/dL in the 10 mg/d group. This translated to a significant 25% risk reduction for fatal and nonfatal strokes in the high-dose group compared with the low-dose group over the follow-up period of about 5 years. The study confirmed the accumulating body of

evidence that intensive statin therapy lowering LDL-C to levels below previously established targets is an effective stroke prevention strategy.4 In 2011, in view of the benefit noted from aggressive lowering of LDL-C in the SPARCL trial, the AHA presented recommendations for LDL-C reduction greater than 50%, with targets of less than 70 mg/dL for all patients with strokes or TIAs, even those without CHD.5 Therapeutic Lifestyle Changes Therapeutic lifestyle changes are advocated by the ATP III panel and must accompany any lipid-lowering regimen. Specifically, these include reduction of intake of saturated fats (less than 7% of total calories) and cholesterol (less than 200 mg/d); therapeutic options for enhancing LDL-C lowering, such as plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber (10 g to 25 g/d); weight reduction; and at least moderate physical activity.2 Primary Prevention Studies Low-density lipoprotein cholesterol in high-risk patients. Patients with hypertension, diabetes, or other vascular risk factors who have not experienced a major vascular event are at lower risk for stroke than patients who have already had a cardiac or cerebral ischemic event. Therefore, primary prevention studies in these populations are usually not designed to prove a reduction in stroke, as stroke is typically a secondary end point of interest. These studies have been reviewed elsewhere. To summarize, the primary prevention studies were conducted in patients with elevated cholesterol or in those with multiple other risk factors. Figure 3-1 provides an overview of the effects of LDL-C lowering on the risk of stroke. Although the effects of statins on overall cardiovascular outcomes were robust, statin use did not consistently reduce stroke risk.
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Primary prevention in patients with normal low-density lipoprotein cholesterol levels. About half of all myocardial infarctions and strokes occur among patients with levels of LDL-C below currently recommended treatment thresholds. HsCRP is an inflammatory biomarker established as an independent predictor of vascular events. The JUPITER trial was designed to evaluate statin use as a primary prevention strategy among patients with normal LDL-C but with elevated hsCRP.6 Men 50 years and older and women 60 years and older were recruited if they had an LDL-C less than 130 mg/dL and an hsCRP greater than or equal to 2 mg/dL. Participants were randomized in a double-blind manner to receive either rosuvastatin 20 mg/d or placebo. The study was terminated early after a median follow-up of 1.9 years because of a strong effect size for the primary and secondary outcomes overall, as well as within prespecified subgroups.6 LDL-C level in the treatment arm was reduced to a median of 55 mg/dL. The relative risk reduction was a robust 44% for the primary end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or death from cardiovascular causes).6 A 47% relative risk reduction resulted for the secondary end point of myocardial infarction, stroke, or death from cardiovascular causes.6 Similar results were found for participants with elevated hsCRP and no other ATP III risk factors.6 Specifically, a 48% relative risk reduction for both fatal and nonfatal stroke6 and a 51% reduction in the risk of ischemic strokes occurred over the observation period.7 The absolute risk reduction of both the primary outcome and the secondary outcome of stroke was greater in participants older than 70 years.8 The study results were further analyzed to determine the projected 5-year
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number needed to treat (NNT). The 5year NNT for the primary outcome was 25; for myocardial infarction, stroke, or any death was 299; and for any stroke was 123.7 To put this in perspective, previously reported NNTs for antihypertensive therapy in primary stroke prevention were between 80 and 160, and the 5-year NNT for aspirin in primary prevention is more than 300.9 One concern about the JUPITER results was whether the cardiovascular benefit seen was truly due to hsCRP lowering and not simply a result of aggressive LDL-C lowering. In a

FIGURE 3-1

Relationship between odds ratios for stroke events and corresponding low-density lipoprotein cholesterol reduction. The regression line has been plotted and weighted for the inverse of the variance of odds ratios. *Size-weighted combined estimates for the small trials. Post-CABG = Post Coronary Artery Bypass Graft trial; GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nellInsufficienza Cardiaca trial; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial; ALLHAT-LLT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid Lowering Trial; WOSCOPS = West of Scotland Coronary Prevention Study; LIPID = Long-Term Intervention With Pravastatin in Ischaemic Disease trial; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS = Heart Protection Study; ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm trial; SSSS = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events trial; GREACE = Greek Atorvastatin and Coronary Heart Disease Evaluation study; MIRACL = Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering trial; LDL = low-density lipoprotein.

e P, Touboul PJ. Reprinted with permission from Amarenco P, Labreuche J, Lavalle Statins in stroke prevention and carotic atherosclerosis: systematic review of up-to-date meta-analysis. Stroke 2004;35(12):2902Y2909.

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Dyslipidemia
KEY POINT

h A large study has shown

a reduced rate of stroke in patients with average low-density lipoprotein cholesterol levels but increased C-reactive protein levels who are treated with statins.

subsequent analysis of the study results, the authors showed that hsCRP lowering did provide an additional cardiovascular benefit (reduction in event rates) in participants who achieved LDL-C goals of less than 70 mg/dL.10 Implications of the JUPITER study for primary prevention. An estimate using National Health and Nutrition Examination Survey data and JUPITER criteria suggests that an additional 6.5 million US adults should be on statins.11 Two studies have evaluated the costeffectiveness of treating patients with low LDL-C and elevated hsCRP with statins for primary prevention.12,13 Both analyses concluded this strategy to be cost-effective in the long run. The 2009 Canadian guidelines for diagnosis and treatment of dyslipidemia recommend measurement of hsCRP in men older than 50 years and women older than 60 years who are at moderate risk for cardiovascular disease (based on the Framingham score) and whose LDL-C levels are less than 130 mg/dL.14 Following the initiation of health behavior interventions, the guidelines recommend statins for the above patients if their hsCRP is higher than 2 mg/dL.14 The ATP III recognized hsCRP as an emerging risk factor. The panel did not recommend modification of LDL-C goals based on the presence of an elevated hsCRP but acknowledged its utility to guide the intensity of risk reduction therapy.2 The ATP IV panel guidelines for lipid management are expected in late 2011. A greater influence of hsCRP in risk stratification and treatment is anticipated. Secondary Prevention Studies Low-density lipoprotein cholesterol and stroke prevention in patients with coronary heart disease. Most studies evaluating the use of statins for secondary prevention have been conducted in patients with established

CHD. The studies have evaluated different agents in varying doses. In the Scandinavian Simvastatin Survival Study, which enrolled patients with established CHD, simvastatin 20 mg to 40 mg/d reduced LDL-C by about 35% throughout the study duration. The simvastatin group had a 30% relative risk reduction of fatal and nonfatal cerebrovascular events compared with placebo.15 In the Cholesterol and Recurrent Events (CARE) trial, patients with myocardial infarction and average levels of LDL-C (mean=139 mg/dL) were randomized to receive either pravastatin 40 mg/d or placebo. Pravastatin lowered LDL-C by about 28% through the follow-up period and showed a 31% relative risk reduction (1.2% absolute risk reduction) in all strokes.16 The Greek Atorvastatin and Coronary heart disease Evaluation (GREACE) study randomized patients with established CHD to receive either atorvastatin (doses titrated from 10 mg to 80 mg/d to reach LDL-C less than 100 mg/dL) or usual medical care. Atorvastatin resulted in a 43% mean lowering of the LDL-C and a 47% relative risk reduction in all strokes.17 In the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, patients with established CHD and a moderately high LDL-C (mean= 150 mg/dL) were randomized to receive either pravastatin 40 mg/d or placebo. Pravastatin resulted in a 25% mean decrease in LDL-C compared with placebo. A 19% relative risk reduction (0.8% absolute risk reduction) for any stroke was achieved with pravastatin.18 In a subsequent analysis of the results of this study, the relative stroke risk reduction was even more impressive among patients with diabetes and those with impaired fasting glucose.19 Patients with recent acute coronary events were randomized to receive either high-dose atorvastatin (80 mg/d) or
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placebo in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study.20 Over a short duration of follow-up of 16 weeks, high-dose atorvastatin resulted in a 40% reduction in LDL-C and a significant 50% relative risk reduction in fatal and nonfatal strokes. The study established that the benefit of stroke risk reduction can be achieved soon after a coronary event by vigorous cholesterol lowering with atorvastatin.20 In summary, patients with acute and chronic CHD appear to benefit in terms of stroke risk reduction with the use of statin therapy. Low-density lipoprotein cholesterol and stroke prevention for patients without coronary heart disease. Another question is whether patients with a previous stroke but no definite coronary event benefit from cholesterol lowering. The Heart Protection Study (HPS) was the first study to present data on a subgroup of patients with prior stroke. Participants in the HPS were randomized to receive either simvastatin 40 mg/d or placebo.21 The study found a marked benefit from simvastatin use in terms of a reduction of major coronary events and revascularizations. However, there was no reduction in the risk of strokes among par-

ticipants who had had prior strokes.21 There are two possible explanations for this negative result. First, on average, patients in the HPS were recruited 4.3 years after the initial event, and the risk of recurrent stroke is highest in the first years after stroke. Second, the study was not powered to evaluate secondary stroke prevention as an end point. The patient in Case 3-1 is illustrative of prevention in a symptomatic patient. The SPARCL study was the first study to evaluate the efficacy of statins to reduce the risk of recurrent stroke in patients who had had a recent TIA or stroke.22 Patients with LDL-C between 100 mg/dL and 190 mg/dL without CHD who had had a stroke or TIA within 6 months of the study were randomized to receive either atorvastatin 80 mg/d or placebo. On this regimen, the mean LDL-C achieved over the study duration in the atorvastatin group was 73 mg/dL.22 Results showed a 16% relative risk reduction in the primary outcome of fatal or nonfatal stroke with high-dose atorvastatin.22 The absolute risk difference at 5 years was 2.2% (the 5-year NNT with atorvastatin 80 mg/d to prevent one fatal or nonfatal stroke was 46). If patients who discontinued treatments were excluded, the relative risk reduction

Case 3-1
A 52-year-old African American man with a history of hypertension and smoking presented with an episode of transient visual loss in the left eye. The next day, he had expressive aphasia for 30 minutes. He had no history of coronary artery disease. A cerebral angiogram revealed 80% stenosis in the cavernous segment of the internal carotid artery. His lipid profile was as follows: total cholesterol 270 mg/dL, low-density lipoprotein cholesterol (LDL-C) 168 mg/dL, high-density lipoprotein cholesterol 52 mg/dL, and triglycerides 220 mg/dL. Comment. The patient in this case has documented atherosclerosis in the internal carotid artery. On the basis of the results of the SPARCL study, the patient should be started on statin treatment. With a starting LDL of 168 mg/dL, the patient will require a potent agent to reduce the LDL-C to less than 100 mg/dL. An LDL-C of less than 70 mg/dL would be desirable. Statin use in such patients reduces stroke risk by at least 16%.

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Dyslipidemia
KEY POINT

h The SPARCL study

established the value of statin treatment in patients with a recent TIA or stroke but no definite heart disease.

increased to 18%. There was also a 26% reduction in the risk of subsequent TIAs. Patients whose LDL-C decreased to less than 70 mg/dL had a 28% greater relative stroke risk reduction. Consistent with the HPS, a significant risk reduction occurred for coronary events.22 In a subgroup analysis of the SPARCL results, no significant difference in results was observed for patients younger than 65 years compared with older participants.23 There was no difference in all-cause mortality between the two groups, but the atorvastatin group had a significant reduction in fatal strokes.22 When the outcomes were evaluated by stroke subtypes, the atorvastatin group had a 22% relative risk reduction in ischemic stroke when compared with placebo.22 In a further exploratory analysis, patients on atorvastatin had significantly milder recurrent strokes and TIAs (assessed as modified Rankin Scale scores 3 months after the outcome) than those on placebo.24 Statins Risk of hemorrhagic stroke with statin use. Several epidemiologic studies have found that lower cholesterol levels increase the risk of hemorrhagic stroke. For instance, in the Multiple Risk Factor Intervention Trial (MRFIT), patients with cholesterol less than 160 mg/dL had a

threefold greater risk of death from intracranial hemorrhage.25 Similarly, in a pooled cohort analysis of Atherosclerotic Risk In Communities (ARIC) and Cardiovascular Health Study (CHS) data, low LDL-C was inversely associated with incident intracranial hemorrhage.26 Should the results of these observational studies affect a clinicians decision to treat with statins? An important finding in the SPARCL study was that subjects in the atorvastatin arm had a higher risk of hemorrhagic stroke (2.3% versus 1.4% in the placebo group). However, the incidence of fatal hemorrhages was not significantly different in the two groups.22 Further, the level of LDL-C did not predict the occurrence of a hemorrhagic stroke (ie, aggressive LDL-C lowering [mean 61 mg/dL within 1 month of initiating atorvastatin] did not result in increased hemorrhages). A post hoc analysis of the study results determined that hemorrhages tend to occur more in patients whose index events were hemorrhagic strokes. Male sex, advanced age, hypertension (especially poorly controlled), and small vessel diseaseY related strokes also conveyed higher risk for developing hemorrhages, as illustrated in Case 3-2.27 Patients with hemorrhagic strokes are often at high risk of ischemic strokes and coronary

Case 3-2
A 65-year-old woman with a history of hypertension and a myocardial infarction 5 years ago presented with left hemiparesis. Her blood pressure was inconsistently controlled, and she had left ventricular hypertrophy. A head CT revealed a 28-mL right putaminal hemorrhage. The patient was previously on a statin. The neurologist was called to advise regarding whether the statin should be discontinued. Comment. There is no definite proof that continued statin use will increase the risk of a second hemorrhagic stroke. The patient has advanced hypertension, which is the major risk factor for cerebral hemorrhage. The patients coronary artery disease is a proven indication for statin treatment. The cerebral hemorrhage emphasizes the importance of blood pressure control in the future.

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disease because of common risk factors. Therefore, the benefits of initiating statins to prevent ischemic stroke in patients with intracerebral hemorrhage should be carefully balanced with the risks of recurrent hemorrhage. The efficacy of different statins in lowering low-density lipoprotein cholesterol. In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) study, a large group of patients was randomized to receive different doses of rosuvastatin, atorvastatin, simvastatin, and pravastatin.28 Over an average of 6 weeks, patients taking rosuvastatin achieved an 8.2% greater LDL-C reduction than those taking atorvastatin and a greater LDL-C reduction and HDL-C elevation than those taking atorvastatin, simvastatin, and pravastatin. A significantly higher proportion of patients on rosuvastatin reached their target LDL-C. Most of the lipid-lowering benefits of rosuvastatin were seen at the lowest dose of 10 mg/d.28 The ATP III update recommended using a statin dose that reduces plasma LDL-C by at least 30% to 40%. Across several studies outlined in this review, the best results were obtained with that degree of LDL-C reduction. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid Lowering Trial (ALLHAT-LLT), only 18% LDL-C reduction was noted, and no benefit was seen. The equivalent doses suggested to achieve 30% to 40% LDL-C reduction are atorvastatin 10 mg/d, pravastatin 40 mg/d, simvastatin 20 mg to 40 mg/d, fluvastatin 40 mg to 80 mg/d, and rosuvastatin 5 mg to 10 mg/d. Recently, the US Food and Drug Administration issued a warning regarding an increased risk of muscle toxicity with the highest approved dose of simvastatin (80 mg). To reiterate, the recent secondary prevention of stroke guidelines recommend a 50% LDL-C lowering among patients with a prior stroke or TIA.5
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Multimodal lipid therapies. While statins are excellent agents to lower LDL-C, a large number of ischemic strokes occur among patients with type 2 diabetes and metabolic syndrome. These patients have a pattern of combined atherogenic dyslipidemia characterized by hypertriglyceridemia, low HDL-C, a preponderance of small dense LDL-C particles, and an accumulation of cholesterol-rich remnants (such as apolipoprotein B). Statins have modest efficacy in the treatment of increased triglycerides or low HDL-C. In such cases, combination therapies using niacin, fibrates, ezetimibe, and statins (based on their safety and effectiveness) may be reasonable. Pleiotropic effects of statins. A metaanalysis of randomized trials for statin use in stroke prevention estimated that LDL-C reduction explained about 35% to 80% of stroke risk reduction.1 This suggests that LDL-C reduction is the most important effect of statin therapy, but other nonYlipid-lowering effects of statins also contribute to stroke risk reduction. In vivo and in vitro studies have elucidated various nonlipid mechanisms of statin action29: & Statins improve endothelial function, partly by LDL-C reduction and also by increase of endothelial nitric oxide. Statins increase nitric oxide by upregulation of nitric oxide synthase. & Statins inhibit inflammatory responses by reducing various markers of inflammation, including hsCRP, phospholipase A2, nuclear factor-0B, interleukins, and cytokines. & Statins demonstrate antioxidant activity by downregulating the production of reactive oxygen species while upregulating nitric oxide synthase. & Statins modulate the immune response by downregulating major histocompatibility complex II expression on blood immune cells. Major histocompatibility complex II
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Dyslipidemia
KEY POINT

h Statins have a variety of

biologic effects in addition to low-density lipoprotein cholesterol lowering.

&

&

&

is normally responsible for recognizing and processing antigens to initiate an immune response. Statins stabilize atherosclerotic plaque by causing plaque regression in the long run. In the short term, statins decrease macrophage proliferation and matrix metalloproteinase production from activated macrophages within the plaque. Matrix metalloproteinases weaken fibrous plaque, making it vulnerable to rupture. Statins modulate platelet function. The precise mechanisms are unknown, but statins probably modify cholesterol content in platelet walls, reduce the production of thromboxane A2, and decrease platelet activation by upregulating nitric oxide. Accumulating experimental evidence indicates that statins may provide neuroprotection through neurogenesis and synaptogenesis after ischemic strokes.

LOW HIGH-DENSITY LIPOPROTEIN CHOLESTEROL Epidemiologic data from the Northern Manhattan Study suggested that HDL-C greater than 35 mg/dL was protective against ischemic stroke.30 The study also found a dose-response relationship; HDL-C greater than or equal to

50 mg/dL offered significantly greater protection against ischemic stroke than HDL-C 35 mg/dL to 49 mg/dL.30 This relationship held true across all races/ethnicities. Later, a case-control study showed that subjects in the higher quintiles of HDL-C values had better protection against ischemic stroke than those in the lowest quintile.31 In both studies, the benefit was the greatest against large vessel atherosclerotic strokes.30,31 The treatment of low HDL-C can be quite challenging. Therapeutic lifestyle changes, such as vigorous exercise, adjustment of alcohol intake, and weight loss, are known to increase HDL-C. However, these measures appear to be more effective in patients with preexisting normal-high HDL-C and not as effective in those with low HDL-C.32 Target goals for HDL-C are not defined, but drug treatment is recommended if HDL-C is less than 40 mg/dL, as illustrated in Case 3-3. No studies have demonstrated a protective role against stroke using either niacin or fibrates as monotherapy. Niacin has primarily been studied in cardiovascular disease. When niacin combined with simvastatin was compared with placebo in patients with CHD and low HDL-C, the combination treatment decreased LDL-C by 42% and increased HDL-C by 26%. The simvastatin-niacin

Case 3-3
A 58-year-old Asian woman with a history of diabetes and hypertension experienced the sudden onset of gait difficulty and right arm clumsiness. A brain MRI revealed a right cerebellar infarct with right vertebral artery occlusion. Her lipid profile was as follows: total cholesterol 180 mg/dL, low-density lipoprotein cholesterol (LDL-C) 98 mg/dL, high-density lipoprotein cholesterol (HDL-C) 32 mg/dL, and triglycerides 160 mg/dL. After being started on simvastatin 40 mg, her LDL-C improved to 74 mg/dL, but her HDL-C was 30 mg/dL. She was started on niacin 1500 mg per day and her HDL-C improved from 30 mg/dL to 46 mg/dL. Comment. The patient has a low HDL-C level despite statin treatment. Therapy with niacin would be reasonable. Clinical trials to assess whether niacin as an adjunct to statin treatment reduces cardiovascular events are in progress.

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group had a 90% reduction in clinical events, including stroke.33 The second and third Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER-2 and ARBITER-3) studies randomized patients taking statins at baseline (as most stroke patients would) to receive either extended-release niacin or placebo. At the end of 2 years, subjects taking niacin had a 23% increase in HDL-C and a significant atherosclerosis regression of carotid intimal medial thickness.34 A recent clinical trial studied the effect of adding extended-release niacin in patients with established vascular disease who were already being treated with statins but had low HDL-C levels. The trial, the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, was halted because of the lack of benefit seen with adding niacin to the lipid regimen. Further details of the study have not been published at the time of this writing. Fibrates are also effective in raising HDL-C. However, in a head-to-head comparison study, niacin 2000 mg/d increased HDL-C more than gemfibrozil 1200 mg/d, in addition to decreasing the total cholesterol to HDL-C ratio and Lp(a) levels.35 A newer class of agents is based on the cholesteryl ester transfer protein (CETP), which promotes the transfer of cholesteryl esters from HDL-C to other lipoproteins; the inhibition of CETP raises HDL-C and decreases LDL-C. The first of the CETP inhibitors, torcetrapib, was tested in a randomized double-blind study of patients at high cardiovascular risk.36 At 12 months, there was a 72.1% increase in HDL-C and a 24.9% decrease in LDL-C compared with baseline; however, the drug also caused an increase in aldosterone production, hypokalemia, significant blood pressure elevations, and a
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25% increase in cardiovascular events.36 Two other CETP inhibitors, anacetrapib and dalcetrapib, do not appear to have such toxicities and are currently undergoing safety and efficacy trials. LIPOPROTEIN(a) The ATP III regarded Lp(a) as an emerging cardiovascular risk factor. A recent collaborative evaluation of 24 cohort studies has shown that Lp(a) is an independent risk factor for ischemic stroke.37 Structurally, Lp(a) comprises an LDL-C moiety with two attached proteins, apolipoprotein (a) and apolipoprotein B-100.38 Lp(a), with its LDL-C moiety, is retained more avidly in the vessel wall than LDL-C, leading to its proatherogenic tendency. Secondly, it interferes with LDL-CYclearing pathways from the vessel wall. Third, apolipoprotein (a) is similar to plasminogen, and Lp(a) interferes with the physiologic role of plasminogen, leading to a prothrombotic state. Finally, Lp(a) acts as a proinflammatory agent by binding and accumulation of oxidized phospholipid molecules.38 Target goals for Lp(a) have not been defined. There appears to be a continuous increase in risk as levels of Lp(a) rise.37 Levels higher than 30 mg/dL seem to correlate with poor prognosis in patients with established coronary artery disease, suggesting a role in prognostication for secondary prevention cases.39 Lp(a) is believed to be genetically determined and the influence of age, diet, or environment is uncertain. Two therapies have been shown to be effective in reducing Lp(a) levels: niacin and estrogen. The mechanism by which niacin reduces Lp(a) levels is not understood, but it has been shown to reduce Lp(a) levels by 36% to 38%.40,41 Estrogen is believed to upregulate LDL-C receptor activity, leading to increased Lp(a) clearance. This is consistent with the fact that postmenopausal women

KEY POINT

h Studies are in progress

to determine whether medications that raise high-density lipoprotein cholesterol can reduce major vascular events, including stroke.

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Dyslipidemia

tend to have higher Lp(a) levels. Estrogen therapy in these women tends to reduce Lp(a) levels.42 EZETIMIBE Trials evaluating ezetimibe therapy have not assessed hard clinical end points. A systematic review of 12 studies using ezetimibe as monotherapy found a modest 18.5% reduction in LDL-C, a 3% elevation in HDL-C, and an 8% reduction in triglyceride levels. Most studies evaluated ezetimibe as combination therapy with other lipid-lowering agents.43 In the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study, the combination of simvastatin 80 mg/d and ezetimibe 10 mg/d was compared with simvastatin 80 mg/d. Combination therapy reduced LDL-C by 17% and hsCRP by 26%; however, carotid intimal medial thickness was the same in both groups.44 In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, clinical end points were actually measured. The rates of ischemic cardiovascular events (a secondary end point) were lower in the combination therapy group.45 However, when participants without coronary artery disease were analyzed, the modest 22% relative risk reduction in ischemic events seen with the combination therapy was similar to the 24% risk reduction found in the simvastatin monotherapy arm of the HPS. Until further data from largescale randomized trials are available, it appears that adding ezetimibe does not offer additional cardiovascular benefit over high-dose statin monotherapy. However, ezetimibe alone or in combination may have a role in patients who are unable to tolerate statins because of adverse effects. REFERENCES
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