CHAPTER 4

Hypercholesterolemia and Cardiovascular Risk

Recent Developments

Therapeutic lifestyle changes remain an essential modality in the management of hypercholesterolemia.

More aggressive management of cholesterol and risk factors has been emphasized by the US National Cholesterol Education Program (NCEP) and the European Society of Cardiology (ESC).

Numerous clinical trials have shown that effective reduction of low-density-lipoprotein cholesterol (LDL-C) levels substantially reduces the risk of coronary heart disease.

A number of tools (eg, Framingham, HeartSCORE, Pooled Cohort Equations) are available to assess the cardiovascular risk for an individual patient.

Statin therapy is recommended for the vast majority of dyslipoproteinemic adult patients with cardiometabolic risk.

Use of statins in acute coronary syndromes reduces the risk of recurrent coronary events.

Introduction

Coronary heart disease (CHD) is the leading cause of death in the United States and most of the developed world, accounting for more deaths than all forms of cancer combined. Several major studies have confirmed earlier reports that lowering elevated LDL-C levels reduces the risk of CHD. The NCEP provided 3 updates for treating elevated blood cholesterol levels in adults: Adult Treatment Panel (ATP) I, II, and III. ATP I proposed a strategy for primary prevention of CHD in persons with high levels of LDL-C (≥160 mg/dL) or borderline high levels of LDL-C (130– 159 mg/dL) and multiple (at least 2) risk factors (discussed later in the chapter). ATP II added intensive management of LDL-C in persons with established CHD (target cholesterol level <100 mg/dL). ATP III guidelines, which are very similar to those currently used in Europe and the rest of the developed world, recommend the following target levels for adults:

total cholesterol <200 mg/dL LDL cholesterol <100 mg/dL

HDL cholesterol ≥60 mg/dL (more is better) triglycerides <150 mg/dL

In 2013, a series of reports in the United States questioned the value of specific targets for LDL-C levels. These reports instead recommend the assessment of cardiovascular risk, followed by aggressive treatment with statin drugs in those most likely to benefit. These recommendations are discussed later in this chapter.

Lipoproteins, Cholesterol, and Cardiovascular Disease

Cholesterol and triglycerides are transported in the body by lipoproteins. The various classes of lipoprotein differ in the relative concentrations of their components: cholesterol, triglycerides, phospholipids, and proteins (apolipoproteins). Chylomicrons carry triglycerides following dietary lipid absorption, whereas very-low-density lipoproteins (VLDLs) produced by the liver carry most circulating triglycerides. LDL, or “bad cholesterol,” is a product of VLDL and intermediate-density- lipoprotein metabolism and is the primary carrier of cholesterol. High-density lipoprotein (HDL), or “good cholesterol,” is the smallest and densest lipoprotein particle. The result of the inflammatory interaction among these lipoproteins, macrophages, and the cellular components of the arterial wall is atherosclerosis. Although cholesterol levels are what is typically measured, it is the lipoproteins that interact with the arterial wall, producing plaques. The narrowing of the arterial lumen that occurs as a result of plaque growth or the rupture of a plaque with subsequent thrombosis leads to stroke and cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral arterial disease.

Risk Assessment

The cholesterol level of approximately half the US population puts these persons at significant risk. A fasting lipoprotein profile (total cholesterol, LDL-C, HDL-C, and triglyceride levels) helps determine an individual’s risk status. The US Preventive Services Task Force recommends screening for lipid disorders in men 20–35 years of age and women aged 45 years and older when other risk factors exist, and all men aged 35 years and older regardless of other risk factors. Experimental studies directly support the central role of LDL in atherogenesis, and lowering LDL-C levels is associated with a reduction in CVD risk. Conversely, HDL-C appears protective against atherosclerosis because of its anti-inflammatory properties and ability to transport cholesterol from vessel walls to the liver for disposal. In general, current guidelines recommend a high-HDL and lowLDL concentration to decrease CVD risk. Other CHD risk factors, such as hypertension, smoking, diabetes mellitus, obesity, and limited physical activity should be assessed and managed appropriately in all adults (Table 4-1). The INTERHEART study, which involved 15,000 patients with acute MI versus 15,000 controls in 52 countries, found that current smoking, hypertension, diabetes mellitus, abdominal obesity, psychosocial factors, and a raised apo B/apo AI ratio increased the risk of acute MI, while moderate or strenuous exercise, daily consumption of fruits and vegetables, and moderate alcohol consumption were protective.

Table 4-1

A number of risk assessment tools are available to estimate the 10-year risk of a cardiovascular event, including the Framingham Global Risk and Pooled Cohort Equations (United States); QRISK (United Kingdom); and HeartSCORE (Europe). Physicians are encouraged to use the risk tool best suited to the individual patient, since relative cardiac risk varies among national, ethnic, and racial groups. Use of these tools guides the clinician in identifying patients requiring aggressive treatment and those most likely to benefit.

2013 prevention guidelines tools: CV risk calculator (pooled cohort equations). American Heart Association website. http://my.americanheart.org/professional/StatementsGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp. Accessed June 23, 2014.

Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24(11):987–1003.

Goff DC Jr, Lloyd-Jones DM, Bennet G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2935–2959. Epub 2013 Nov 12.

HeartScore. European Society of Cardiology website. www.heartscore.org. Accessed June 23, 2014. QRISK2-2014 risk calculator. ClinRisk website. qrisk.org. Accessed June 23, 2014.

Risk assessment tool for estimating your 10-year risk of having a heart attack (Framingham Heart Study). National Heart, Lung and Blood Institute website. cvdrisk.nhlbi.nih.gov/calculator.asp. Accessed June 23, 2014.

Management

In its simplest terms, the management of hypercholesterolemia consists of matching the intensity of LDL-lowering therapy with absolute risk: the higher the risk, the lower the target level. This approach is based primarily on data from clinical trials and epidemiological studies, which have suggested that a direct relationship exists between the level of LDL-C and the risk of CHD. The ATP III guidelines suggest measuring fasting lipoprotein levels in patients with hypercholesterolemia, hyperlipidemia, and/or hyperlipoproteinemia. The clinician should also assess the presence of other risk factors (see Table 4-1) and the presence of clinical atherosclerotic disease, including clinical cardiovascular disease, carotid or peripheral arterial disease, or abdominal aortic aneurysm. The patient’s 10-year risk for CVD is determined based on these factors on a scale from lower risk to high risk. LDL treatment goals from the ATP III and similar guidelines are determined based on this risk level (Table 4-2). In contrast, the 2013 guidelines from the American College of Cardiology and the American Heart Association (ACC/AHA) recommend that patients be given the maximum tolerated intensity of a statin drug when a statin is indicated. These groups no longer advocate treatment to a

Once the LDL treatment goals have been reached, other lipid and nonlipid risk factors can be modified. Elevated triglyceride levels may respond to increased physical activity or weight management, but if the triglyceride levels are ≥200 mg/dL after the LDL goal is reached, a secondary goal of treatment would be a non–HDL-C (total – HDL) level of 30 mg/dL higher than the LDL goal.

Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51(15):1512–1524.

Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk. J Am Coll Cardiol. 2014;63(25 Pt B):2960–2984. Epub 2013 Nov 12.

Perk J, De Backer G, Gohlke H, et al; European Association for Cardiovascular Prevention & Rehabilitation; ESC Committee for Practice Guidelines. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33(13):1635–1701.

Rosenson RS. Screening guidelines for dyslipidemia. In: UpToDate, Freeman MW (ed), Waltham, MA. Available at www.uptodate.com. Accessed June 23, 2014.

The Role of Statins

For virtually all patients whose LDL-C goals cannot be achieved by therapeutic lifestyle changes alone, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, more popularly known as statins, are the first choice for medical therapy. Multiple trials involving the use of statins have reinforced the value of LDL-lowering therapy in reducing cardiometabolic disease. Moreover, the statins are the only class of drugs whose use has been shown to improve overall mortality in primary and secondary prevention. The Heart Protection Study, Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) study, and the PROVE IT study, among others, each demonstrated a decreased risk of major cardiovascular events in patients lowering their LDL-C levels with statins. Findings from the JUPITER trial suggest that statins—which are known to lower C-reactive protein levels in addition to having positive effects on hyperlipidemia—may decrease the risk of stroke, coronary artery disease, and death in apparently healthy persons without hyperlipidemia but with a C-reactive protein level of >2.0 mg/L. The beneficial effects of statins arise from the reduction of LDL-C levels, stabilization of atherosclerotic plaques, and decreased atherogenic inflammation.

The 2013 ACC/AHA guidelines identify 4 patient groups likely to benefit from statin use:

individuals with clinical atherosclerotic cardiovascular disease (ASCVD) individuals with LDL-C ≥190 mg/dL

individuals aged 40–75 years with diabetes (but without ASCVD) and LDL-C 70–189 mg/dL

individuals aged 40–75 years without diabetes or ASCVD with LDL-C 70–189 mg/dL and estimated 10-year ASCVD risk >7.5%.

In these patients, the ACC/AHA recommendation is the maximum tolerated statin therapy (see Table 4-4), while those intolerant of high-intensity therapy or at lower estimated cardiovascular risk may be treated with a moderate intensity. Current ESC and other international guidelines continue to recommend specific goals similar to those outlined in the NCEP/ATP III studies.

Other drugs used to lower LDL-C levels (see Table 4-3) include nicotinic acid, bile acid sequestrants, fibric acids, and cholesterol absorption inhibitors. While many of these drugs have been shown to lower LDL-C levels, they generally lack large randomized controlled trials demonstrating an effect on ASCVD or mortality. These drugs are often used worldwide; however, the most recent ACC/AHA guidelines do not support the use of these drugs in place of statins when statin therapy is effective and well tolerated. The role of these drugs when added to high-intensity statin use is still to be elucidated.

Adverse effects of statin use are rare but can include elevated hepatic transaminases, diarrhea, liver failure, polyneuropathy, and myopathy. Simvastatin should not be started at or increased to a dose of 80 mg per day because of the high risk of muscle injury. The risk of myopathy is also increased when simvastatin is used in conjunction with other medications, including amiodarone, some fibrates (gemfibrozil), and some calcium channel blockers. Cerivastatin was voluntarily withdrawn from the market after more than 52 reports of rhabdomyolysis and death related to this statin. Although these drugs are largely safe and effective, serious adverse effects must be carefully monitored for, especially in the first few months of treatment. Pregnant women should not take statin drugs due to possible teratogenic effects.

ESC Clinical Practice Guidelines. European Society of Cardiology website. www.escardio.org/Guidelines-&-Education/Clinical- Practice-Guidelines/listing. Accessed June 2, 2015.

Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207.

Rouleau J. Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE ITTIMI 22) trial. Am J Med. 2005;118(Suppl 12A):28–35.

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934. Epub 2013 Nov 12.

Waters D, Schwartz GG, Olsson AG. The Myocardial Ischemia Reduction With Acute Cholesterol Lowering (MIRACL) trial: a new frontier for statins? Curr Control Trials Cardiovasc Med. 2001;2(3):111–114.

Metabolic Syndrome

Metabolic syndrome comprises a constellation of lipid and nonlipid risk factors of metabolic origin. The International Diabetes Federation has developed a consensus definition for metabolic syndrome, which includes

central obesity (waist circumference):

United States: ≥102 cm (male); ≥88 cm (female)

Europe: ≥94 cm (male); ≥80 cm (female)

Asia; Central and South America: ≥90 cm (male); ≥80 cm (female)

plus any 2 of the following, or treatment for the condition listed:

raised triglyceride level ≥150 mg/dL

reduced HDL cholesterol <40 mg/dL (male), <50 mg/dL (female)

elevated blood pressure: systolic >130 mm Hg and/or diastolic >85 mm Hg elevated fasting blood glucose level ≥100 mg/dL

Metabolic syndrome is closely linked to insulin resistance. Excess body fat (particularly abdominal fat) and physical inactivity promote impaired responses to insulin, which may also occur as a genetic predisposition. The risk factors for metabolic syndrome are highly concordant; in aggregate, they increase the risk of CHD at any given LDL level. Management of the metabolic syndrome includes measures previously discussed for elevated LDL and triglyceride levels, as well as treatment of hypertension and the use of aspirin for CHD patients to reduce the prothrombotic state.

Grundy SM, Cleeman JI, Daniels SR, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112(17):2735–2752.

IDF worldwide definition of the metabolic syndrome. International Diabetes Federation website. www.idf.org/metabolic-syndrome Accessed January 8, 2014.

Ophthalmic considerations Hypercholesterolemia is a significant risk factor for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. The ophthalmologist may be the first physician to detect or recognize manifestations of atherosclerosis, particularly amaurosis fugax, retinal vascular emboli or occlusions, ischemic optic neuropathy, or cortical visual field deficits from a previous cerebral infarction. Detection of atherosclerosis may initiate a diagnostic evaluation that reveals significant carotid artery stenosis or coronary artery disease.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed to assess the effect of tight glycemic, dyslipidemic, and blood pressure control on cardiovascular events in patients with type 2 diabetes. A subset of these patients (ACCORD EYE) was examined to assess the effects of this control on the progression of diabetic retinopathy (DR). Previous studies had shown mixed results of the effect of tight glycemic control on DR. In the ACCORD EYE study, the tight control of glycemia resulted in a 33% reduction in the relative risk of progression of DR. Using simvastatin plus fenofibrate for dyslipidemia control yielded a 40% reduction in the risk of DR progression. Tight blood pressure control did not appear to affect DR progression in ACCORD. Previous studies (eg, FIELD) have also suggested a possible protective effect of fenofibrate in DR.

Statin use may be associated with a reduction in intraocular pressure and potentially a protective effect against glaucoma. Additional clinical research is needed. Patients with ocular hypertension or glaucoma being treated with topical timolol have a small but significant elevation of serum LDL and reduction in HDL, but do not appear to have increased mortality.

The relationship of statin use to age-related macular degeneration (AMD) is unresolved. Several population-based studies (ARIC, MELBOURNE, Blue Mountains) have suggested that the use of statins is associated with a decreased risk of advanced AMD, whereas other studies (Beaver Dam) suggest there is no change in AMD risk with statin use. Other studies have suggested an increase in the risk of developing neovascular, or “wet,” AMD in individuals who

smoke or have other cardiac risk factors. All of these studies are limited by either small sample size or lack of randomized prospective data on the use of statins. Therefore, more data are required to assess the nature of this relationship. Corneal arcus, a nonreversible lipid deposit at the corneal limbus, is associated with age and hyperlipidemia. In the Blue Mountains Eye Study, the presence of arcus in persons aged 49 years and older was associated with higher total cholesterol and triglyceride levels.

Finally, statins do not appear to increase the risk of cataracts. In fact, some recent studies (eg, Blue Mountains) have suggested a protective effect.

American Academy of Ophthalmology website; www.aao.org. American Heart Association website; www.americanheart.org. CardioSource. American College of Cardiology website; www.acc.org. European Society of Cardiology website; www.escardio.org.

Fong DS, Poon KY. Recent statin use and cataract surgery. Am J Ophthalmol. 2012;153(2):222–228.e1.

Klein R, Knudtson MD, Klein BE. Statin use and the five-year incidence and progression of age-related macular degeneration. Am J Ophthalmol. 2007;144(1):1–6.

Müskens RP, Wolfs RC, Witteman JC, et al. Topical beta-blockers and mortality. Ophthalmology. 2008;115(11):2037–2043. Song J, Deng PF, Stinnett SS, Epstein DL, Rao PV. Effects of cholesterol-lowering statins on the aqueous humor outflow

pathway. Invest Ophthalmol Vis Sci. 2005;46(7):2424–2432.

Tan JS, Mitchell P, Rochtchina E, Wang JJ. Statin use and the long-term risk of incident cataract: The Blue Mountains Eye Study. Am J Ophthalmol. 2007;143(4):687–689.