(Reproduced with permission from Toth PP. High-density lipoprotein as a therapeutic target: clinical evidence and treatment strategies. Am J Cardiol 2005;96:50K-58K.)

Dyslipidemia can be the result of abnormalities in gastrointestinal nutrient absorption, serum and intracellular enzyme activities, and/or cell surface receptor expression. A complete fasting (12-14 hours) lipoprotein profile (including LDL, triglyceride, and HDL) should be obtained on anyone screened for dyslipidemia. Because of the relationship between specific lipoprotein fractions and risk for CAD, measuring total cholesterol levels has little clinical relevance.

The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III, 2001) has defined risk-stratified, evidence-based target levels for atherogenic serum lipoproteins (Table 27-1). CAD risk is stratified by evaluating a patient’s cardiovascular risk factor burden (number of risk factors) and, if two or more risk factors are present, calculation of the Framingham risk score. In the setting of primary prevention, low risk is defined as 0-1 risk factor. Moderate and moderately high risk are defined as 2 or more risk factors with a 10-year Framingham risk of 5% to 10% and 10% to 20%, respectively. Patients who are in the high risk category either have CAD (previous history of MI, stable/unstable angina, revascularization with CABG or percutaneous coronary angioplasty) or a CAD risk equivalent, defined as diabetes mellitus, abdominal aortic aneurysm, peripheral vascular disease, significant carotid artery disease (transient ischemic attack or stroke from carotid origin, >50% obstructive atheromatous plaque in carotid artery), or a 10-year Framingham risk that exceeds 20%. The American Heart Association (AHA) also defines chronic kidney disease (glomerular filtration rate [GFR] <60 mL/min/1.73 m²) as a CAD risk equivalent. It is important to calculate the Framingham risk score so as to differentiate moderate, moderately high, and high risk among patients with multiple risk factors and no history of CAD or a CAD risk equivalent. An electronic Framingham risk calculator can be downloaded at www.nhlbi.nih.gov/guidelines/cholesterol. Box 27-1 summarizes established CAD risk factors.

Table 27-1 Low-Density Lipoprotein (LDL) Cholesterol Goals and Thresholds for Initiating Therapeutic Lifestyle Change (TLC) and Pharmacologic Intervention

Targets

In ATP-III the NCEP implemented these conceptual changes: (1) an optimal LDL-C is defined as less than 100 mg/dL for all patients independent of race or gender; (2) an HDL less than 40 mg/dL is now defined as a categorical risk factor for CAD; and (3) it defined target levels for non-HDL-C. Non-HDL-C is defined as total cholesterol minus HDL-C and is an estimate of atherogenic lipoproteins in serum (VLDL + LDL). The risk-stratified target for non-HDL-C is the LDL-C target plus 30 (see Table 27-1). LDL-C reduction is the primary goal of therapy in patients with dyslipidemia. However, in patients with fasting triglyceride (TG) levels greater than 200 mg/dL, non-HDL reduction is the secondary priority of therapy. There is currently no specified target for HDL-C elevation. However, in patients with low HDL-C, it is important to try to raise HDL-C as much as possible. According to a recent AHA Consensus Statement, an HDL-C less than 50 mg/dL in women is now considered low (Mosca et al., 2004). The American Diabetes Association (ADA) advocates HDL-C goals of 40 mg/dL or higher for men and 50 mg/dL or higher for women with diabetes mellitus.

Based on such trials as the Heart Protection Study (Heart Protection Study Collaborative Group, 2002), Treating to New Targets study (LaRosa et al., 2005), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction trial (Cannon et al., 2004), in regard to LDL-C reduction and reducing risk for CAD-related morbidity and mortality, “the lower the better” (Toth, 2004). The NCEP “white paper” recommended that physicians consider treating LDL-C to less than 70 mg/dL and non-HDL-C to less than 100 mg/dL in very-high-risk patients (e.g., recent ACS, diabetic patient with multiple, poorly controlled risk factors) (Grundy et al., 2004). Other therapeutic options include initiating antilipidemic medication with therapeutic lifestyle change if baseline LDL-C is greater than 100 mg/dL in patients with moderately high and high risk; in patients at high risk with baseline LDL-C less than 100 mg/dL, a further reduction of LDL-C by 30% to 40% with medication is a therapeutic option. AHA recommends LDL-C less than 70 mg/dL as a reasonable option for any patient with CAD (Smith et al., 2006).

Nonpharmacologic Interventions

Therapeutic lifestyle change (TLC) is first-line therapy for patients at risk for cardiovascular events. Patients who smoke should stop. The amount of daily consumed cholesterol should be less than 200 mg. Table 27-2 summarizes the distribution of calories from nutrients. Reduced saturated fat and increased consumption of mono- and polyunsaturated fats promote serum LDL-C reduction. The ingestion of viscous fiber and plant stanols decrease cholesterol absorption. Ideally, patients should exercise for 20 to 30 minutes five times per week. Regular exercise promotes weight loss and relieves visceral adiposity and insulin resistance.

Table 27-2 Dietary Recommendations for Therapeutic Lifestyle Change

Dietary Component	Recommended Allowance
Polyunsaturated fat	Up to 10% of total calories
Monounsaturated fat	Up to 20% of total calories
Total fat	25%-35% of total calories
Carbohydrate	50%-60% of total calories
Dietary fiber	20-30 g/day
Protein	About 15% of total calories
Dietary cholesterol	<200 mg/day

Pharmacologic Interventions

Statins

The statins are reversible, competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. HMG-CoA reductase is the rate-limiting step for cholesterol biosynthesis in the liver and systemic tissues. Statins are the most potent agents for reducing serum levels of LDL-C. The statins augment the elimination of atherogenic apoB100-containing lipoproteins (VLDL, VLDL remnants, and LDL) from plasma by upregulating the LDL receptor on the surface of hepatocytes. The statins also reduce VLDL secretion and stimulate apoprotein-AI expression and hepatic HDL secretion.

Many prospective, placebo-controlled clinical trials have shown that the statins significantly reduce rates of MI, stroke, and coronary and all-cause mortality in the primary prevention (Downs et al., 1998) and secondary prevention settings (Scandinavian Simvastatin Survival Study Group, 1994). Statins reduce the frequency of stable and unstable angina and decrease atheromatous plaque progression and, based on intravascular ultrasound measurement (Nissen et al., 2004), quantitative coronary angiography, and high-resolution magnetic resonance imaging (Corti et al., 2002), even stimulate some degree of plaque resorption. The statins reduce cardiovascular events in men and women, blacks and Hispanics, hypertensive and diabetic patients, smokers, and patients over age 70.

Seven statins are currently available. These drugs differ by potency and a number of pharmacokinetic properties. The choice of statin and its dosing depend on the magnitude of LDL-C and non-HDL-C reduction required (baseline vs. risk-stratified NCEP target). The LDL-C–lowering efficacy of the statins is as follows (e.g., Jones et al., 2003):

Rosuvastatin (Crestor): 45%-63% (5-40 mg daily)

Atorvastatin (Lipitor): 26%-60% (10-80 mg daily)

Simvastatin (Zocor): 26%-47% (10-80 mg daily)

Lovastatin (Mevacor): 21%-42% (10-80 mg daily)

Fluvastatin (Lescol): 22%-36% (10-20 mg daily)

Pitavastatin (Livalo): 32%-43% (1-4 mg daily)

Pravastatin (Pravachol): 22%-34% (10-80 mg daily)

Each doubling of a statin’s dose yields an additional 6% reduction, on average, in serum LDL-C (“rule of 6s”). Patients who are heterozygous or homozygous for familial hypercholesterolemia frequently require high potency statins at their highest doses coupled to stringent restriction in dietary lipid ingestion and the addition of one or more other lipid-lowering agents. The statins induce significant reductions in serum TG levels (typically 10%-25%) and modest elevations in serum HDL-C (2%-14%). Unlike the other statins, atorvastatin therapy is associated with decreasing capacity for raising HDL-C as a function of increasing doses. In patients with high baseline serum TG levels (>300 mg/dL), simvastatin and rosuvastatin raise HDL-C up to 18% and 22%, respectively.

The statins display significant differences in their pharmacokinetic profiles. Because of their relatively short half-life (1-4 hours), lovastatin, fluvastatin, pravastatin, and simvastatin should be taken after the evening meal in order to intercept the peak activity of HMG–CoA reductase, which occurs around midnight. Rosuvastatin and atorvastatin can be taken at any time during the day or night because of their long half-life (~19 and 14 hours, respectively). The coadministration of drugs or compounds that inhibit cytochrome P450 3A4 (macrolide antibiotics [erythromycin, clarithromycin], azole-type antifungals [ketoconazole, itraconazole], cyclosporine, HIV protease inhibitors, nefazodone, >1 qt grapefruit juice daily) with atorvastatin, simvastatin, and lovastatin is contraindicated because these statins depend on this P450 isozyme for oxidative modification and elimination (Neuvonen et al., 1998). CYP3A4 inhibition is associated with increased risk for myopathy and hepatotoxicity. The dose of simvastatin should be 20 mg or less daily in patients being treated with amiodarone or verapamil.

Although there is some concern about the potential toxicity of statins, their benefits significantly outweigh their risks. Liver toxicity can occur and is defined as an alanine transaminase (ALT) elevation of three times or more the upper limit of normal (ULN) on two occasions at least 1 month apart. The average risk of hepatotoxicity from statin therapy is approximately 1%, but risk increases as a function of increasing doses. Mild elevations in serum transaminase levels early during the course of therapy are relatively common and usually resolve spontaneously. If hepatotoxicity develops, statin therapy should be discontinued until transaminase levels normalize and therapy with a different statin can be initiated. There is no documented evidence that the statins increase risk for liver failure. The most important adverse event associated with statin therapy is rhabdomyolysis, myoglobinuria, and renal failure. The risk for rhabdomyolysis is less than 0.1%. Symptoms of rhabdomyolysis include worsening muscle pain, proximal weakness, nausea and vomiting, and brownish-red discoloration of urine. The statins can cause myalgia. If a patient develops myalgia or muscle weakness, a serum creatine kinase (CK) level can be obtained. The diagnosis of myopathy is made when CK levels exceed 10 times ULN. When assessing myalgia, it is important to evaluate patients for pain caused by arthritis, tendinopathy, fibromyalgia, and muscle strain induced by exertion.

Ezetimibe

Dietary and biliary sources contribute significantly to serum levels of cholesterol (Fig. 27-2). Although plant sterols and stanols block gastrointestinal (GI) cholesterol absorption, ezetimibe (Zetia) is the first member of a class of lipid-lowering drugs known as cholesterol absorption inhibitors. Mechanistically, ezetimibe inhibits the Niemann-Pick C1 Like-1 protein, which mediates cholesterol and phytosterol transport along the brush border of the jejunal enterocyte (Altmann et al., 2004; Davis et al., 2004). After glucuronidation, ezetimibe undergoes enterohepatic recirculation with negligible systemic exposure. The half-life of ezetimibe is approximately 22 hours. When dosed at 10 mg once daily, ezetimibe reduces serum LDL-C on average by 20%, but up to 24% of patients experience a reduction of 25% or greater (Ballantyne et al., 2004; Davidson et al., 2002). Ezetimibe also decreases TGs by up to 8% and raises HDL-C by up to 4%. Ezetimibe does not decrease the absorption of bile acids, steroid hormones (ethinyl estradiol, progesterone), or such fat-soluble vitamins as vitamins A, D, E, or α- and β-carotenes.

Figure 27-2 Gastrointestinal absorption of dietary and biliary lipid and cholesterol. In the gastrointestinal tract, cholesterol and triglycerides arising from biliary and dietary sources are assimilated with bile salts and phospholipids to form micelles. Micelles transport cholesterol and lipid to the jejunal brush border. Along the enterocyte surface, the sterol transporter known as Niemann Pick C1 Like 1 (NPC1L1) protein is responsible for importing cholesterol and phytosterols into the neurocyte. Once internalized, the cholesterol is esterified to cholesterol esters via the activity of acyl-CoA acyltransferase (ACAT). The esterified cholesterol is packaged with triglycerides, phospholipids, and apoprotein B48 (ApoB48) to form chylomicrons in an assimilation reaction catalyzed by microsomal transfer protein (MTP). The chylomicrons are released into gastrointestinal lacteals which conduct these lipoproteins into the central circulation. Excess intracellular sterols can be excreted back into the GI tract via the activity of the sterol exporter complex ABCG5/G8 (ATP-binding membrane cassette transporter G5/G8).

(Reproduced with permission from Toth PP, Davidson MH. Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 2005;5:455-462.)

The risk of hepatotoxicity with ezetimibe is almost identical to placebo (0.5% vs. 0.3%), and there is no documented evidence of increased risk for myopathy. Fixed-dose ezetimibe is also available in combination with increasing doses of simvastatin (Vytorin; 10/10, 10/20, 10/40, 10/80 mg daily). Ezetimibe can also be safely used in combination with other statins (Toth and Davidson, 2005). The ezetimibe provides additive changes in lipoprotein levels to that observed with statin therapy. The addition of ezetimibe to a statin regimen substantially reduces the likelihood of needing to titrate the statin.

KEY TREATMENT

Statins, fibrates, niacin, omega-3 fish oils, and bile acid sequestration agents to treat dyslipidemia reduce cardiovascular morbidity significantly (SOR: A).

Statins are the most efficacious drugs currently available for reducing serum levels of LDL and significantly impact risk for both cardiovascular morbidity and mortality (SOR: A).

The omega-3 fish oils also appear to impact cardiovascular mortality, although the evidence is not as strong as with statins (SOR: A).

Fibrates have the greatest capacity to reduce serum TGs and reduce cardiovascular morbidity (MI and stroke). The fibrates have not yet been shown to beneficially impact mortality as an independent end point in clinical trials. The fibrates have been shown to reduce rates of atherosclerotic disease progression in both diabetic and nondiabetic patients with CAD (SOR: A).

Niacin raises serum levels of HDL significantly better than other currently available antilipidemic medications, and it also reduces LDL, TGs, and lipoprotein(a) (SOR: A).

Therapy with combinations of drugs (statin-fibrate, statin-niacin, fibrate-niacin, statin-ezetimibe) is frequently required in patients with mixed forms of dyslipidemia and increases the likelihood of therapeutic success. The addition of niacin or omega-3 fish oils to statin therapy does provide incremental cardiovascular risk reduction over statin therapy alone (SOR: A).

The impact of fibrate and ezetimibe adjuvant therapy with a statin is currently being evaluated in prospective, randomized clinical trials.

Potential for Harm

Antilipidemic agents can induce hepatotoxicity and myopathy (SOR: A).

Statins and fibrates may induce transient elevations in serum transaminases and should be discontinued if levels exceed three times ULN. If levels are below this threshold, monitor liver function tests because transaminase levels usually decrease and trend toward normal spontaneously. Often, these drugs are discontinued prematurely to the detriment of patient care (SOR: A).

When combining a statin with a fibrate, use of gemfibrozil should be discouraged because it impairs the glucuronidation and elimination of the statins to varying degrees. This can result in increased risk for hepatotoxicity and rhabdomyolysis (SOR: A). Fenofibrate and fenofibric acid are safer choices in this context.

Patients complaining of myalgias or weakness, especially if escalating, should be monitored for myopathy. The statins and fibrates should be discontinued if serum CK levels exceed 10 times ULN (SOR: A). However, myalgias are common and not necessarily attributable to statin and fibrate use.

In patients presenting with rhabdomyolysis, antilipidemic medications should be discontinued immediately. Patients should be hospitalized, hydrated with intravenous fluids, and provided supportive care.

Hypertension

Key Points

• Hypertension is highly prevalent in men and women and people of all ethnic and racial groups

• Hypertension tends to be undertreated in patients with both complicated and uncomplicated forms.

• In uncomplicated HTN the specific choice of drug is less important than the attainment of goal blood pressure.

Hypertension (HTN) is highly prevalent and is a significant risk factor for CAD, left ventricular hypertrophy (LVH), CHF, PVD, stroke, sudden death, nephropathy, and diabetes mellitus. The incidence of HTN increases as a function of age; patients who are normotensive at age 55 have a 90% risk of developing HTN at some point in their lives. Risk for hypertension is regulated by genetic background (e.g., mutations in cell membrane cation transporters in the renal proximal tubular epithelium and vasculature, cell surface receptors, endocrine influences, calcium handling in smooth muscle cells) and environmental factors. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) provides the current framework for defining and managing HTN in the U.S. population (Chobanian et al., 2003). Table 27-3 summarizes the JNC-7 classification of blood pressure (BP), soon scheduled for revision. The reduction of BP to guideline-specified targets in patients with complicated and uncomplicated HTN substantially reduces risk for acute cardiovascular events, progression of atherosclerosis, and end-organ injury.

Table 27-3 JNC-7 Blood Pressure (BP) Classification

As demonstrated by the Framingham Study, BP is a continuous risk factor for CVD, with no threshold effect yet identified (Vasan et al., 2002). For every increase of 20/10 mm Hg in BP above 115/75 mm Hg, risk for CVD increases twofold. Contrary to a widely held misconception in medicine, among patients older than 50 years, the treatment of systolic blood pressure (SBP) reduces risk for CVD and renal disease significantly more than diastolic blood pressure (DBP). Despite the recognized dangers of HTN and the large number of medications available, only one third of patients are treated to target levels in the United States (Whelton et al., 2002). Hypertension is a defining feature of the metabolic syndrome and usually suggests that the patient has some degree of underlying endothelial dysfunction, with an imbalance between vasodilatory and vasoconstrictive influences impacting the arterial wall.

Recommendations

In response to recent epidemiologic and clinical trial data, JNC-7 made a series of new recommendations for addressing the HTN epidemic, which now includes more than 73.6 million patients in the U.S. alone. Patients with SBP of 120 to 139 mm Hg and DBP of 80 to 89 mm Hg are defined as “prehypertensive” and warrant aggressive lifestyle modification to prevent progression to HTN. It must be assumed that even in this BP range, changes in vessel wall histology and physiology are inducing elevations in BP. Weight reduction, moderation of alcohol intake (2 drinks per day for men, 1 for women), reducing daily sodium intake to 2.4 g/day, increasing aerobic exercise, and the Dietary Approaches to Stop Hypertension (DASH) regimen are all associated with significant reductions in BP (Chobanian et al., 2003). Thiazide diuretics such as hydrochlorothiazide or chlorthalidone, alone or in combination with other antihypertensives, should be used to treat most patients with HTN.

If baseline BP is more than 20/10 mm Hg above target level, initial therapy should consist of two antihypertensive agents (one of which should be a thiazide diuretic unless there is a contraindication) started simultaneously. The majority of patients with HTN will need two or more drugs to achieve adequate control of BP. As demonstrated in the Hypertension Optimization Trial (Hansson et al., 1998), diabetic patients require, on average, 3.4 medications to achieve adequate control. In uncomplicated HTN the BP target is less than 140/90 mm Hg. In patients with diabetes or chronic kidney disease (GFR <60 mL/min/1.73m², baseline serum creatinine >1.5 mg/dL in men or >1.3 mg/dL in women, or albuminuria defined as >300 mg/day on 24-hr urine specimen or 200 mg albumin/g creatine on urine spot check), the BP target is less than 130/80 mm Hg.

A large number of antihypertensive medications are available (Table 27-4). Prevailing expert opinion now contends that, unless there are compelling indications for the use of a specific drug class because of background cardiovascular or renal disease, it makes little difference whether a calcium channel blocker (CCB), beta blocker, angiotensin converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB) is used to initiate therapy in the setting of uncomplicated HTN (Blood Pressure Lowering Treatment Trialists wwwwCollaboration, 2003; Julius et al., 2004; National Institute of Clinical Excellence Guideline 18, 2004; Pepine et al., 2003; Williams, 2005). Risk reduction is predominantly driven by the magnitude of BP reduction, rather than the specific mechanism by which it is achieved. Ideally, pharmacologic intervention will be coupled to lifestyle modification in order to achieve lasting and consistent reductions in BP reduction. If a patient’s BP is greater than 20/10 mm Hg above goal, initiating therapy with a combination preparation increases the likelihood of therapeutic success and patient compliance. The use of combination therapy is also associated with reduced cost. Many ACEI, ARBs, CCBs, centrally acting drugs (e.g., reserpine, methyldopa), and β-blockers are available in combination with fixed doses of hydrochlorothiazide (12-25 mg) and, less often, chlorthalidone. Box 27-2 summarizes combinations of drugs that are efficacious and those associated with undesirable side effect profiles. Box 27-3 summarizes recommendations for attaining BP targets in the more challenging patient.

Table 27-4 Oral Antihypertensive Drugs (Usual Dose Range)

Box 27-3 Ten Tips for Attaining Goal Blood Pressure (BP)

Modified from Flack JM, Nasser SA. Hypertension Pocket Guide. New York, McMahon, 2005.

1. Establish minimum goal BP; when >15/10 mm Hg above goal, BP monotherapy is unlikely to be effective.

2. In most situations, wait 4-6 weeks before titrating BP medications upward.

3. Realize that most hypertensive patients will ultimately require more than one (>1) drug to attain goal BP, especially those with diabetes, obesity, decreased kidney function, or proteinuria.

4. Initiate lifestyle modifications; diet should limit sodium (<2 g/day), saturated fat, cholesterol, and alcohol intake (<2 drinks/day); appropriate aerobic exercise; and weight loss (if indicated).

5. Remember that hypertension is not asymptomatic and that BP medications alleviate more side effects than they cause.

6. Minimize exposure to nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, when kidney function is reduced (<60 mL/min/1.73m²).

7. A diuretic appropriate to the level of kidney function is essential to the multidrug regimen when more than two (>2) antihypertensives are prescribed.

8. Consider using a dihydropyridine and a rate-lowering calcium antagonist in combination when BP is refractory to treatment.

9. Diuretic doses may need to be relatively high (e.g., furosemide, 160 mg/day in divided doses, or metolazone, 10-20 mg/day) when kidney function is <30 mL/min/1.73m².

10. If BP remains above goal on three or more (≥3) antihypertensives (one of which is a diuretic) at near-maximal doses, consider referral to a hypertension specialist or nephrologist.

Patients with BP poorly responsive to even aggressive intervention should be evaluated further for etiologies such as renal arterial stenosis, adrenal and pituitary tumors, poor compliance, thyroid “storm,” and volume overload from acute or chronic renal disease. A broad range of clinical trials have demonstrated that the rate of progression of certain cardiovascular and renal disease states is slowed by the use of particular antihypertensive agents (Chobanian et al., 2003). These constitute “compelling indications” (Table 27-5). In patients requiring inhibition of the renin-angiotensin-aldosterone (RAAS) axis (CHF, CAD, post-MI, nephropathy, LVH), an elevation in serum creatinine of up to 35% is tolerable and is not an indication for discontinuing an ACEI or an ARB. In patients who develop hyperkalemia in response to an ACEI or ARB therapy, consideration should be given to reducing their dosage, adding a thiazide diuretic to promote potassium excretion, reducing potassium intake, or, when necessary, discontinuing the drugs and arranging referral to a nephrologist. Acute hyperkalemia can be managed with oral or rectal Kayexalate, a resin that binds and promotes the excretion of GI potassium. Men with HTN and benign prostatic hypertrophy or low serum HDL can be treated with an alpha-adrenergic blocker. In contrast to α-blockade, which can raise HDL levels by up to 20%, β-blockade is associated with reductions in serum HDL. Beta blockers and thiazide diuretics are both associated with the antagonism of glycemic control. Potassium balance should be monitored regularly in patients receiving combinations of ACEI/ARB with aldosterone antagonists. Blood pressure management should be individualized, with providers paying close attention to potential unwanted side effects that may dampen the benefit of BP reduction.

Table 27-5 JNC-7–Defined Compelling Indications for Use of Specific Antihypertensive Agents in Complicated Hypertension

Hypertensive emergencies increase risk for acute MI, hemorrhagic stroke, encephalopathy, and other adverse events. Table 27-6 summarizes intravenous (IV) medications that can be used to reduce BP rapidly in the acute, emergent setting.

Table 27-6 Parenteral Drugs for Treatment of Hypertensive Emergencies

The results of two prospective trials may impact JNC-8 recommendations. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) an atenolol/hydrochlorothiazide (A/H) regimen was compared to amlodipine/perindopril (A/P) in 19,257 subjects with HTN and three other cardiovascular risk factors. Despite nearly identical BP control, the patients randomized to A/P experienced a 23% lower incidence of fatal/nonfatal stroke, 16% fewer cardiovascular events and procedures, 11% lower all-cause mortality, and 30% less new-onset type 2 diabetes mellitus compared to the A/H regimen over a median follow-up of 5.5 years (Dahlof et al., 2005). In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial, 11,506 hypertensive patients were randomized to treatment with either benazepril/amlodipine (B/A) or benazepril/hydrochlorothiazide (B/H). The primary and secondary composite end points comprised (1) nonfatal MI and stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, coronary revascularization, and cardiovascular mortality; and (2) nonfatal MI and stroke and cardiovascular mortality, respectively (Jamerson et al., 2008). The primary and secondary end points were both reduced more with B/A compared to B/H by 19.6% and 21%, respectively. These trials strongly support the use of ACE inhibition therapy combined with the dihydropyridine amlodipine when managing hypertension. Among patients with established vascular disease or high-risk diabetes mellitus without heart failure, the ONTARGET trial demonstrated that the incidence of cardiovascular events was identical in groups treated with either telmisartan or ramipril (Yusuf et al., 2008). The incidence of angioedema in the telmisartan group was approximately one third of that observed in the ramipril group. Consequently, in patients such as those studied in ONTARGET, it is therapeutically legitimate to treat ACEI-intolerant patients with an ARB.

KEY TREATMENT

If BP is greater than 20/10 mm Hg above target level, two antihypertensives should be started simultaneously, usually including hydrochlorothiazide, although amlodipine is also used with an ACE inhibitor (SOR: A).

The use of combination therapy to treat HTN allows for the interception of multiple mechanisms etiologic for this disorder and increases the likelihood of therapeutic success (SOR: A).

JNC 7 encourages the use of specific antihypertensive agents in the setting of HTN complicated by CHF, CAD, MI, nephropathy, and other forms of CVD (SOR: A).

Lifestyle modification is an important component of HTN management (SOR: A).

Treatment with ACEI and ARBs is associated with decreased risk for new-onset diabetes mellitus in patients with HTN (SOR: A).

The majority of health care providers believe that diastolic BP impacts CVD more than systolic BP; the opposite is true (SOR: A).

Metabolic Syndrome

Key Points

• Metabolic syndrome is an insulin-resistant state associated with visceral adiposity, hypertension, hyperglycemia, dyslipidemia, and a proinflammatory and pro-oxidative state.

• Metabolic syndrome is not a CAD risk equivalent but is associated with heightened risk for CVD and diabetes mellitus.

• Metabolic syndrome should be treated with aggressive lifestyle modification, including weight loss, exercise, smoking cessation, and dietary modification.

Causes and Incidence

The incidence of obesity is rising worldwide. With increased mechanization and changes associated with increased food availability and lower average daily caloric expenditure, people are experiencing continuous weight gain with aging. Being overweight and the development of obesity now constitute the second most important preventable cause of mortality. In the United States, 30% of the population is obese, and 70% is overweight. The incidence of obesity is rising among both genders as well as all racial and ethnic groups. An important consequence of obesity is the development of insulin resistance and the metabolic syndrome (Haffner et al., 1990; Haffner and Taegtmeyer, 2003). The metabolic syndrome (or “syndrome X”) is defined by a constellation of cardiovascular risk factors and is associated with heightened risk for cardiovascular morbidity and mortality. A variety of definitions of the metabolic syndrome have been developed, but the one with the greatest clinical utility is that defined by the NCEP ATP-III (Grundy et al., 2004a, 2004b; Eckel et al., 2005). Waist circumference, blood pressure, fasting blood sugar, and serum TG and HDL levels are used to make the diagnosis (Table 27-7). Once three of the five criteria are met, the diagnosis of metabolic syndrome can be made.

Table 27-7 NCEP ATP-III Criteria for Diagnosing Metabolic Syndrome

Risk Factor	Defining Level
Abdominal obesity	Men: waist >40 inches Women: waist >35 inches
Triglycerides	≥150 mg/dL
High -density lipoprotein cholesterol (HDL-C)	Men: <40 mg/dL Women: <50 mg/dL
Blood pressure	≥130/ ≥85 mm Hg
Fasting glucose	≥100 mg/dL

∗Patients having any three of the above five risk factors meet criteria for the diagnosis of the metabolic syndrome.

From Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (NCEP ATP-III).

Based on data from the Third National Health and Nutrition Examination Survey (NHANES-III), the incidence of metabolic syndrome increases linearly in both men and women as a function of age (Alexander et al., 2003; Ford et al., 2002). Hispanic and Native Americans are disproportionately affected. Current estimates suggest that 24% of the U.S. population have metabolic syndrome. In the Kuopio Ischaemic Heart Disease Risk Factor Study, patients with metabolic syndrome experienced a 3.77- and 2.43-fold increase in risk for coronary heart disease mortality and all-cause mortality, respectively, over 12-year follow-up compared to patients without the metabolic syndrome (Lakka et al., 2002).

Cardiovascular Risk Factors

As waist circumference increases, visceral adiposity increases. Visceral adipose tissue is metabolically highly active. An important conceptual shift has occurred in recent years with respect to how adipose tissue is viewed. It is no longer seen as a passive storage site for excess caloric ingestion. Instead, it is clear that visceral adipose tissue displays many features of an endocrine organ (Bradley et al., 2001; Toth, 2005a) (Fig. 27-3). Visceral adipose tissue produces a variety of inflammatory cytokines (tumor necrosis factor, transforming growth factor-β), interleukins (IL-1, IL-6), and effector molecules that regulate appetite (leptin) as well as insulin sensitivity and resistance (e.g., adiponectin, resistin). As the mass of visceral adipose tissue increases, adiponectin production decreases, which is associated with increased insulin resistance in adipose tissue, skeletal muscle, and the hepatic parenchyma (see Fig. 27-3). As adipose tissue becomes more insulin resistant, the capacity to regulate the catabolism of stored TGs becomes progressively more dysregulated and unresponsive to systemic tissue needs. Serum levels of free fatty acids (FFAs) rise. The portal circulation becomes flooded with FFAs, resulting in both increased TG deposition within the liver (nonalcoholic steatohepatitis [NASH] or fatty liver) (Banerji et al., 1995) and increased VLDL secretion resulting in hypertriglyceridemia. A fatty liver in the absence of excessive alcohol intake is an important marker for insulin resistance and is highly correlated with the magnitude and severity of adiposity (Fig. 27-4). Elevation in FFAs induces progressive deterioration in glycemic control by (1) interfering with normal phosphorylation of the insulin receptor, resulting in less expression of a glucose transporter (GLUT 4) necessary for the internalization and oxidation of serum glucose (Dresner et al., 1999), and (2) the induction of “lipotoxicity,” the process by which FFAs induce premature apoptosis and dropout of pancreatic β-islet cells. Patients experiencing concomitant worsening insulin resistance and progressive loss of insulin-producing capacity experience a continuum of glycemic disturbance, beginning with impaired fasting glucose, then impaired glucose tolerance, and ultimately diabetes mellitus. As serum levels of insulin rise, risk for CAD-related events increases precipitously (Pyorala et al., 1996) (Fig. 27-5). Patients with metabolic syndrome have a threefold to fivefold increased risk for developing diabetes compared to patients without metabolic syndrome.

Figure 27-3 Insulin sensitivity and degree of adiposity.

(From Fujimoto WY, Abbate SL, Kahn SE, et al. The visceral adiposity syndrome in Japanese-American men. Obes Res 1994;2:364-371.)

Figure 27-4 Risk of a major coronary heart disease (CHD)–related event associated with quintile of insulin levels in nondiabetic men enrolled in the Helsinki Policemen Study.

(From Pyorala M, Miettinen H, Laakso M, Pyorala K. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998;98:398-404.)

Figure 27-5 Severity of hepatic fat deposition as visceral adiposity worsens.

(From Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes 1995;19:846-850.)

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