Dyslipidemia

Dyslipidemia 

is elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides; low high-density lipoprotein (HDL) cholesterol; or a combination of these abnormalities.

PATHOPHYSIOLOGY

• Cholesterol, triglycerides, and phospholipids are transported in blood as complexes of lipids and proteins (lipoproteins). Elevated total and LDL cholesterol and reduced HDL cholesterol are associated with development of coronary heart disease (CHD).

• Risk factors such as oxidized LDL, mechanical injury to endothelium, and excessive homocysteine can lead to endothelial dysfunction and cellular interactions culminating in atherosclerosis. Eventual clinical outcomes may include angina, myocardial infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death.

• Atherosclerotic lesions arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL recruits monocytes into the artery wall, which transform into macrophages that accelerate LDL oxidation. Oxidized LDL provokes an inflammatory response mediated by chemoattractants and cytokines.

• Repeated injury and repair within an atherosclerotic plaque eventually lead to a fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells. Maintenance of the fibrous plaque is critical to prevent plaque rupture and coronary thrombosis.

• Primary or genetic lipoprotein disorders are classified into six categories: I (chylomicrons), IIa (LDL), IIb (LDL + very-low-density lipoprotein [VLDL]), III (intermediatedensity lipoprotein), IV (VLDL), and V (VLDL + chylomicrons). Secondary forms of dyslipidemia also exist, and several drug classes may affect lipid levels (eg, progestins, thiazide diuretics, glucocorticoids, β-blockers, isotretinoin, protease inhibitors, cyclosporine, mirtazapine, and sirolimus).

• The primary defect in familial hypercholesterolemia is inability to bind LDL to the LDL receptor (LDL-R). This leads to a lack of LDL degradation by cells and unregulated biosynthesis of cholesterol.

CLINICAL PRESENTATION

• Most patients are asymptomatic for many years. Symptomatic patients may complain of chest pain, palpitations, sweating, anxiety, shortness of breath, abdominal pain, or loss of consciousness or difficulty with speech or movement.

• Depending on the lipoprotein abnormality, signs on physical examination may include cutaneous xanthomas, peripheral polyneuropathy, high blood pressure, and increased body mass index or waist size.

DIAGNOSIS

• Measure fasting lipoprotein profile (total cholesterol, LDL, HDL, triglycerides) in all adults 20 years of age or older at least once every 5 years.

• Measure plasma cholesterol, triglyceride, and HDL levels after a 12-hour fast because triglycerides may be elevated in nonfasting individuals; total cholesterol is only modestly affected by fasting.

• Two determinations, 1 to 8 weeks apart are recommended to minimize variability and obtain a reliable baseline. If the total cholesterol is greater than 200 mg/dL (>5.17 mmol/L), a second determination is recommended, and if the values are greater than 30 mg/dL (>0.78 mmol/L) apart, use the average of three values History and physical examination should assess: 

(1) presence or absence of cardiovascular risk factors or definite cardiovascular disease; 

(2) family history ofpremature cardiovascular disease or lipid disorders; 

(3) presence or absence of secondary causes of dyslipidemia, including concurrent medications; and (4) presence or absence of xanthomas, abdominal pain, or history of pancreatitis, renal or liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack).

• Diabetes mellitus and the metabolic syndrome are considered CHD risk equivalents; their presence in patients without known CHD is associated with the same level of risk as patients without them but having confirmed CHD.

• Lipoprotein electrophoresis is sometimes performed to determine which class of lipoproteins is involved. If the triglycerides are less than 400 mg/dL (4.52 mmol/L), and neither type III dyslipidemia nor chylomicrons are detected by electrophoresis, then one can calculate VLDL and LDL concentrations: VLDL = triglycerides ÷ 5; LDL= total cholesterol – (VLDL + HDL). Initial testing uses total cholesterol for case finding, but subsequent management decisions should be based on LDL.

TREATMENT

• Goals of Treatment: Lower total and LDL cholesterol to reduce the risk of first or recurrent events such as MI, angina, heart failure, ischemic stroke, or peripheral arterial disease.

GENERAL APPROACH

• The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends that fasting lipoprotein profile and risk factor assessment be used in initial classification of adults.

• If the total cholesterol is less than 200 mg/dL (>5.17 mmol/L), then the patient has a desirable blood cholesterol level (Table 8–1). If the HDL is also greater than 40 mg/dL (>1.03 mmol/L), no further follow-up is recommended for patients without known CHD and who have fewer than two risk factors (Table 8–2). In patients with borderline-high blood cholesterol (200–239 mg/dL; 5.17–6.18 mmol/L), assessment of risk factors is needed to more clearly define disease risk.

Decisions regarding classification and management are based on the LDL cholesterol levels 

• Four risk categories modify the goals and modalities of LDL-lowering therapy:

1. Highest risk = Known CHD or CHD risk equivalents; risk for coronary events is at least as high as for established CHD (ie, >20% per 10 years, or 2% per year).

2. Moderately high risk = 2 or more risk factors in which 10-year risk for CHD is 10% to 20%.

3. Moderate risk = 2 or more risk factors and a 10-year risk of 10% or less.

4. Lowest risk = 0 to 1 risk factor, which is usually associated with a 10-year CHD risk of less than 10%.

NONPHARMACOLOGIC THERAPY

• Begin therapeutic lifestyle changes (TLCs) on the first visit, including dietary therapy, weight reduction, and increased physical activity. Advise overweight patients to lose 10% of body weight. Encourage physical activity of moderate intensity 30 minutes a day for most days of the week. Assist patients with smoking cessation and control of hypertension.

• The objectives of dietary therapy are to progressively decrease intake of total fat, saturated fat, and cholesterol and to achieve a desirable body weight 

• Increased intake of soluble fiber (oat bran, pectins, psyllium) can reduce total and LDL cholesterol by 5% to 20%. However, they have little effect on HDL-C or triglycerides. Fiber products may also be useful in managing constipation associated with bile acid resins (BARs).

• Fish oil supplementation reduces triglycerides and VLDL-C, but it either has no effect on total and LDL-C or may elevate these fractions. Other actions of fish oil may account for any cardioprotective effects.

• Ingestion of 2 to 3 g daily of plant sterols reduces LDL by 6% to 15%. They are usually available in commercial margarines.

• If all recommended dietary changes were instituted, the estimated average reduction in LDL would range from 20% to 30%.

PHARMACOLOGIC THERAPY

Bile Acid Resins

• BARs (cholestyramine, colestipol, colesevelam) bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic cholesterol pool increases cholesterol biosynthesis and the number of LDL-Rs on hepatocyte membranes, which enhances the rate of catabolism from plasma and lowers LDL levels. Increased hepatic cholesterol biosynthesis may be paralleled by increased hepatic VLDL production; consequently, BARs may aggravate hypertriglyceridemia in patients with combined dyslipidemia.

• BARs are useful in treating primary hypercholesterolemia (familial hypercholesterolemia, familial combined dyslipidemia, and type IIa hyperlipoproteinemia).

• Common GI complaints include constipation, bloating, epigastric fullness, nausea, and flatulence. They can be managed by increasing fluid intake, increasing dietary bulk, and using stool softeners.

• The gritty texture and bulk may be minimized by mixing the powder with orange drink or juice. Colestipol may have better palatability than cholestyramine because it is odorless and tasteless. Tablet forms may help improve adherence.

• Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D, E, and K; hypernatremia and hyperchloremia; GI obstruction; and reduced bioavailability of acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Drug interactions may be avoided by alternating administration times with an interval of 6 hours or more between the BARs and other drugs.

Niacin

• Niacin (nicotinic acid) reduces hepatic synthesis of VLDL, which in turn reduces synthesis of LDL. Niacin also increases HDL by reducing its catabolism.

• The principal use of niacin is for mixed dyslipidemia or as a second-line agent in combination therapy for hypercholesterolemia. It is a first-line agent or alternative for treatment of hypertriglyceridemia and diabetic dyslipidemia.

• Cutaneous flushing and itching appear to be prostaglandin mediated and can be reduced by taking aspirin 325 mg shortly before niacin ingestion. Taking the niacin dose with meals and slowly titrating the dose upward may minimize these effects. Concomitant alcohol and hot drinks may magnify the flushing and pruritus from niacin, and they should be avoided at the time of ingestion. GI intolerance is also a common problem.

• Laboratory abnormalities may include elevated liver function tests, hyperuricemia, and hyperglycemia. Niacin-associated hepatitis is more common with sustainedrelease preparations, and their use should be restricted to patients intolerant of regular- release products. Niacin is contraindicated in patients with active liver disease, and it may exacerbate preexisting gout and diabetes.

• Niaspan is a prescription-only, extended-release niacin formulation with pharmacokinetics intermediate between prompt- and sustained-release products. It has fewer dermatologic reactions and a low risk of hepatotoxicity. Combination with statins can produce large reductions in LDL and increases in HDL.

• Nicotinamide should not be used in the treatment of dyslipidemia because it does not effectively lower cholesterol or triglyceride levels.

HMG-CoA Reductase Inhibitors

• Statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Reduced LD synthesis and enhanced LDL catabolism mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects.

• When used as monotherapy, statins are the most potent total and LDL cholesterol– lowering agents and among the best tolerated. Total and LDL cholesterol are reduced in a dose-related fashion by 30% or more when added to dietary therapy.

• Combination therapy with a statin and a BAR is rational because the numbers of LDL-Rs are increased, leading to greater degradation of LDL cholesterol; intracellular synthesis of cholesterol is inhibited; and enterohepatic recycling of bile acids is interrupted.

• Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined with a statin or other drug.

• Constipation occurs in less than 10% of patients taking statins. Other adverse effects include elevated alanine aminotransferase, elevated creatine kinase levels, myopathy, and, rarely, rhabdomyolysis.

Fibric Acids

• Fibrate monotherapy (gemfibrozil, fenofibrate, clofibrate) is effective in reducing VLDL, but a reciprocal rise in LDL may occur, and total cholesterol values may remain relatively unchanged. Plasma HDL concentrations may rise 10% to 15% or more with fibrates.

• Gemfibrozil reduces synthesis of VLDL and, to a lesser extent, apolipoprotein B with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins from plasma. Clofibrate is less effective than gemfibrozil or niacin in reducing VLDL production.

• GI complaints occur in 3% to 5% of patients. Rash, dizziness, and transient elevations in transaminase levels and alkaline phosphatase may also occur. Gemfibrozil and probably fenofibrate enhance gallstone formation rarely.

• A myositis syndrome of myalgia, weakness, stiffness, malaise, and elevations in creatine kinase and aspartate aminotransferase may occur and seems to be more common in patients with renal insufficiency.

• Fibrates may potentiate the effects of oral anticoagulants, and the international normalized ratio (INR) should be monitored very closely with this combination.

Ezetimibe

• Ezetimibe interferes with absorption of cholesterol from the brush border of the intestine, making it a good choice for adjunctive therapy. It is approved as monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in ~18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated; ~4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone.

Fish Oil Supplementation

• Diets high in omega-3 polyunsaturated fatty acids (from fish oil), most commonly eicosapentaenoic acid (EPA), reduce cholesterol, triglycerides, LDL, and VLDL and may elevate HDL cholesterol.

• Fish oil supplementation may be most useful in patients with hypertriglyceridemia, but its role in treatment is not well defined.

• LOVAZA (omega-3-acid ethyl esters) is a prescription form of concentrated fish oil EPA 465 mg and docosahexaenoic acid 375 mg. The daily dose is 4 g, which can be taken as four 1-g capsules once daily or two 1-g capsules twice daily. This product lowers triglycerides by 14% to 30% and raises HDL by ~10%.

• Complications of fish oil supplementation such as thrombocytopenia and bleeding disorders have been noted, especially with high doses (EPA 15–30 g/day).

TREATMENT RECOMMENDATIONS

• Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomicrons derived from dietary fat with the subsequent reduction in plasma triglycerides. Total daily fat intake should be no more than 10 to 25 g, or ~15% of total calories. Secondary causes of hypertriglyceridemia should be excluded, and, if present, the underlying disorder should be treated appropriately.

• Primary hypercholesterolemia (familial hypercholesterolemia, familial combined dyslipidemia, and type IIa hyperlipoproteinemia) is treated with BARs, statins, niacin, or ezetimibe.

• Combined hyperlipoproteinemia (type IIb) may be treated with statins, niacin, or gemfibrozil to lower LDL-C without elevating VLDL and triglycerides. Niacin is the most effective agent and may be combined with a BAR. A BAR alone in this disorder may elevate VLDL and triglycerides, and their use as single agents for treating combined hyperlipoproteinemia should be avoided.

• Type III hyperlipoproteinemia may be treated with fibrates or niacin. Although fibrates have been suggested as the drugs of choice, niacin is a reasonable alternative because of the lack of data supporting a cardiovascular mortality benefit from fibrates and because of potentially serious adverse effects. Fish oil supplementation may be an alternative therapy.

• Type V hyperlipoproteinemia requires stringent restriction of dietary fat intake. Drug therapy with fibrates or niacin is indicated if the response to diet alone is inadequate. Medium-chain triglycerides, which are absorbed without chylomicron formation may be used as a dietary supplement for caloric intake if needed for both types I and V.

Combination Drug Therapy

• Combination therapy may be considered after adequate trials of monotherapy and for patients documented to be adherent to the prescribed regimen. Two or three lipoprotein profiles at 6-week intervals should confirm the lack of response prior to initiation of combination therapy.

• Screen carefully for contraindications and drug interactions with combined therapy, and consider the extra cost of drug product and monitoring.

• In general, a statin plus a BAR or niacin plus a BAR provides the greatest reduction in total and LDL cholesterol.

• Regimens intended to increase HDL levels should include either gemfibrozil or niacin, bearing in mind that statins combined with either of these drugs may result in a greater incidence of hepatotoxicity or myositis.

• Familial combined dyslipidemia may respond better to a fibrate and a statin than to a fibrate and a BAR.

TREATMENT OF HYPERTRIGLYCERIDEMIA

• Lipoprotein pattern types I, III, IV, and V are associated with hypertriglyceridemia, and these primary lipoprotein disorders should be excluded prior to implementing therapy.

• A family history positive for CHD is important in identifying patients at risk for premature atherosclerosis. If a patient with CHD has elevated triglycerides, the associated abnormality is probably a contributing factor to CHD and should be treated.

• High serum triglycerides (see Table 8–1) should be treated by achieving desirable body weight, consumption of a low saturated fat and cholesterol diet, regular exercise, smoking cessation, and restriction of alcohol (in select patients).

• The sum of LDL and VLDL (termed non-HDL [total cholesterol – HDL]) is a secondary therapeutic target in persons with high triglycerides (≥200 mg/dL [≥2.26 mmol/L). The goal for non-HDL with high serum triglycerides is set at 30 mg/dL (0.78 mmol/L) higher than that for LDL on the premise that a VLDL level less than or equal to 30 mg/dL (0.78 mmol/L) is normal.

• Drug therapy with niacin should be considered in patients with borderline-high triglycerides but with risk factors of established CHD, family history of premature CHD, concomitant LDL elevation or low HDL, and genetic forms of hypertriglyceridemia associated with CHD. Alternative therapies include gemfibrozil or fenofibrate, statins, and fish oil. The goal of therapy is to lower triglycerides and VLDL particles that may be atherogenic, increase HDL, and reduce LDL.

• Very high triglycerides are associated with pancreatitis and other adverse consequences. Management includes dietary fat restriction (10–20% of calories as fat), weight loss, alcohol restriction, and treatment of coexisting disorders (eg, diabetes). Drug therapy includes gemfibrozil or fenofibrate, niacin, and higher-potency statins (atorvastatin, pitavastatin, rosuvastatin, and simvastatin). Successful treatment is defined as reduction in triglycerides to less than 500 mg/dL (5.65 mmol/L).

TREATMENT OF LOW HDL CHOLESTEROL

• Low HDL cholesterol is a strong independent risk predictor of CHD. ATP III redefined low HDL cholesterol as less than 40 mg/dL (<1.03 mmol/L) but specified no goal for HDL raising. In low HDL, the primary target remains LDL, but treatment emphasis shifts to weight reduction, increased physical activity, and smoking cessation, and to fibrates and niacin if drug therapy is required.

TREATMENT OF DIABETIC DYSLIPIDEMIA

• Diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL, and minimally elevated LDL. Small, dense LDL (pattern B) in diabetes is more atherogenic than larger, more buoyant forms of LDL (pattern A).

• ATP III considers diabetes to be a CHD risk equivalent, and the primary target is to lower the LDL to less than 100 mg/dL (<2.59 mmol/L). When LDL is greater than 130 mg/dL (>3.36 mmol/L), most patients require simultaneous TLCs and drug therapy. When LDL is between 100 and 129 mg/dL (2.59 and 3.34 mmol/L), intensifying glycemic control, adding drugs for atherogenic dyslipidemia (fibrates and niacin) and intensifying LDL-lowering therapy are options. Statins are considered by many to be the drugs of choice because the primary target is LDL.

EVALUATION OF THERAPEUTIC OUTCOMES

• Short-term evaluation of therapy for dyslipidemia is based on response to diet and drug treatment as measured by total cholesterol, LDL-C, HDL-C, and triglycerides.

• Many patients treated for primary dyslipidemia have no symptoms or clinical manifestations of a genetic lipid disorder (eg, xanthomas), and monitoring may be solely laboratory based.

• In patients treated for secondary intervention, symptoms of atherosclerotic cardiovascular disease, such as angina and intermittent claudication, may improve over months to years. Xanthomas or other external manifestations of dyslipidemia should regress with therapy.

• Obtain lipid measurements in the fasting state to minimize interference from chylomicrons. Monitoring is needed every few months during dosage titration. Once the patient is stable, monitoring at intervals of 6 months to 1 year is sufficient.

• Patients on BAR therapy should have a fasting panel checked every 4 to 8 weeks until a stable dose is reached; check triglycerides at a stable dose to ensure they have not increased.

• Niacin requires baseline tests of liver function (alanine aminotransferase), uric acid, and glucose. Repeat tests are appropriate at doses of 1,000 to 1,500 mg/day. Symptoms of myopathy or diabetes should be investigated and may require creatine kinase or glucose determinations. Patients with diabetes may require more frequent monitoring.

• Patients receiving statins should have a fasting lipid panel 4 to 8 weeks after the initial dose or dose changes. Obtain liver function tests at baseline and periodically thereafter. Some experts believe that monitoring for hepatotoxicity and myopathy should be triggered by symptoms.

• For patients with multiple risk factors and established CHD, evaluate for progress in managing other risk factors such as BP control, smoking cessation, exercise and weight control, and glycemic control (if diabetic).

• Evaluation of dietary therapy with diet diaries and recall survey instruments allows information about diet to be collected in a systematic fashion and may improve patient adherence to dietary recommendations.