Dyslipidemia PDF

Dyslipidemia Harith Al-Qazaz Definition Dyslipidemia is defined as elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides; low high-density lipoprotein (HDL) cholesterol; or a combination of these abnormalities. Dyslipidemia, plays a major role in atheros...

Dyslipidemia Harith Al-Qazaz Definition Dyslipidemia is defined as elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides; low high-density lipoprotein (HDL) cholesterol; or a combination of these abnormalities. Dyslipidemia, plays a major role in atherosclerosis and plaque formation leading to coronary heart disease (CHD) as well as other forms of atherosclerotic cardiovascular disease (ASCVD), such as carotid and peripheral artery disease. CHD is the leading cause of death in adults and It is also the chief cause of premature, permanent disability PATHOPHYSIOLOGY Cholesterol and Lipoprotein Metabolism Cholesterol, an essential substance manufactured by most cells in the body, is used to maintain cell wall integrity and for the biosynthesis of bile acids and steroid hormones. Cholesterol, triglycerides, and phospholipids circulate in the blood as lipoproteins. The major lipoproteins are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and high-density lipoprotein (HDL). A measured total cholesterol is the total cholesterol molecules in all these major lipoproteins. The estimated value of LDL cholesterol is found using the Friedewald equation (after fasting for 9–12 hours): LDL cholesterol (mg/dL) = total cholesterol – (HDL cholesterol + triglycerides/5), when lipids are expressed in units of mg/dL; LDL cholesterol (mmol/L) = total cholesterol – (HDL cholesterol + triglycerides/2.2), when lipids are expressed in units of mmol/L PATHOPHYSIOLOGY Cholesterol and Lipoprotein Metabolism This formula becomes inaccurate if serum triglycerides are greater than 400 mg/dL (4.52 mmol/L), if chylomicrons are present, or the patient has familial dysbetalipoproteinemia. In each of these cases, LDL cholesterol must be directly measured, which can be done for any patient at most laboratoriess. More recently, some laboratories have transitioned to using the Martin-Hopkins equation to estimate LDL cholesterol instead of the Friedewald equation. The Martin-Hopkins equation is calculated as: LDL cholesterol = total cholesterol – HDL cholesterol – triglyceride/adjustable factor Biosynthesis of cholesterol is directly regulated by the amount of cholesterol present in an individual. Therefore, higher ingestion of cholesterol through food consumption results in decreased production of endogenous cholesterol in the liver. In the liver, cholesterol is produced through the mevalonate pathway and the 3-Hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) is converted to mevalonate by HMG-CoA reductase (site of action for statins). PATHOPHYSIOLOGY Elevated total and LDL cholesterol and reduced HDL cholesterol are associated with development of coronary heart disease (CHD). Eventual clinical outcomes may include angina, myocardial infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 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. PATHOPHYSIOLOGY Primary dyslipidemias include genetic defects resulting in hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and disorders of HDL-C metabolism and an excess of lipoproteins. These disorders have an increased risk of premature ASCVD due to significant elevations in cholesterol levels. In homozygous and heterozygous familial hypercholesterolemia (FH), the primary defect is the inability to bind LDL-C to LDL-C receptors. This leads to lack of LDL-C degradation by cells and unregulated biosynthesis of cholesterol. Secondary forms of dyslipidemia also exist, and several drug classes may elevate cholesterol levels (eg, progestins, thiazide diuretics, glucocorticoids, β- blockers, isotretinoin, protease inhibitors, cyclosporine and mirtazapine). CLINICAL PRESENTATION Dyslipidemia is usually asymptomatic. Corneal arcus of the eye and xanthomas may be seen in patients with genetic disorders that cause a marked increase in serum LDL cholesterol (> 250 mg/dL). Symptomatic patients may complain of chest pain, palpitations, sweating, anxiety, shortness of breath, or abdominal pain. They may also experience difficulty with speech or movement or loss of consciousness. 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 Indications for Lipid Panel All adults more than 20 years of age should be screened at least every 5 years using a fasting blood sample to obtain a lipid profile (total cholesterol, non-HDL cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides). A non-fasting lipid profile can be used for risk assessment for most patients for primary and secondary prevention assessment. If the triglycerides are elevated in the non-fasting state, then it may be necessary to recheck a fasting lipid profile to assess LDL cholesterol, but non- HDL cholesterol can accurately be assessed irrespective of fasting state. Diagnosis Lipid Panel Children between 2 and 20 years old should be screened for high cholesterol if their parents have premature CHD (male first-degree relatives < 55 years old and female first-degree relatives < 65 years old) or if one of their parents has a total cholesterol greater than 240 mg/dL. Elevated non-HDL cholesterol or elevated LDL cholesterol exceeding 70 mg/dL above the target level should have an assessment of ASCVD risk if 40 to 75 years of age and a primary prevention patient without diabetes. Serum triglycerides exceeding 150 mg/dL and serum HDL cholesterol less than 40 mg/dL in men and less than 50 mg/dL in women may increase risk of ASCVD and should be evaluated. Indications for Other Tests Conditions that may produce lipid abnormalities should be screened for using appropriate tests. If present, these conditions should be properly addressed as they can be secondary causes for dyslipidemia. Diagnosis History and physical examination should assess: (1) presence or absence of cardiovascular risk factors (2) family history of premature cardiovascular disease or lipid disorders; (3) presence or absence of secondary causes of dyslipidemia; 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. 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. (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, pectin) can reduce total and LDL cholesterol by 5% to 20%. Fish oil supplementation reduces triglycerides and VLDL-C, but it either has no effect on total and LDL-C or may elevate these fractions. Ingestion of 2 to 3 g daily of plant sterols reduces LDL by 6% to 15%. They are usually available in commercial margarines. PHARMACOLOGIC THERAPY The rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Isolation of a specific inhibitor of this enzyme resulted in the first marketed statin called lovastatin. By reducing cholesterol synthesis, statins were shown to up-regulate the LDL receptor. The ACC/AHA Guidelines identify four groups of patients targeted for statin treatment, including: Established clinical ASCVD (secondary prevention) Primary elevation of LDL levels 190 mg/dL or higher Diabetes mellitus (DM), age 40 to 75 years, with LDL levels 70 to 189 mg/dL Primary prevention without DM, age 40 to 75 years, with an estimated 10-year risk of 7.5% or greater, and LDL levels 70 to 189 mg/dL PHARMACOLOGIC THERAPY HMG-CoA Reductase Inhibitors Statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) Inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Reduced LDL 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. PHARMACOLOGIC THERAPY Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut 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, and 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. 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. PHARMACOLOGIC THERAPY Bile Acid Resins BARs (cholestyramine, colestipol, and 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. Common GI complaints include constipation, bloating, epigastric fullness, nausea, and flatulence. PHARMACOLOGIC THERAPY 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. Laboratory abnormalities may include elevated liver function tests, hyperuricemia, and hyperglycemia. PHARMACOLOGIC THERAPY 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. 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. PHARMACOLOGIC THERAPY 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. Mipomersen Mipomersen is an inhibitor of apolipoprotein B-100 synthesis. It is indicated as an adjunct to lipid-lowering medications and diet to reduce LDL-cholesterol, apolipoprotein B, total cholesterol, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia. PHARMACOLOGIC THERAPY Lomitapide Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces the amount of cholesterol that the liver and intestines assemble and secrete into the circulation. It is indicated as an adjunct to diet and other lipid-lowering treatments to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia. Proprotein Convertase Subtilisin9 (PCSK9) Inhibitors (Alirocumab, Evolocumab) These drugs are indicated as an adjunct to diet and maximally tolerated lipid-lowering therapy for adults with heterozygous familial hypercholesterolemia or ASCVD who require additional lowering of LDL cholesterol. TREATMENT RECOMMENDATIONS It is highly recommended that Total daily fat intake should be no more than 10 to 25 g, or ~15% of total calories. Primary hypercholesterolemia (familial hypercholesterolemia, familial combined dyslipidemia, and hyperlipoproteinemia) is treated with BARs, statins, niacin, or ezetimibe. Combined hyperlipoproteinemia may be treated with statins, niacin, or gemfibrozil to lower LDL-C without elevating VLDL and triglycerides. Fish oil supplementation may be an alternative therapy. Drug therapy with fibrates or niacin is indicated if the response to diet alone is inadequate. TREATMENT RECOMMENDATIONS TREATMENT OF HYPERTRIGLYCERIDEMIA 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 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. 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. TREATMENT RECOMMENDATIONS TREATMENT OF LOW HDL CHOLESTEROL Low HDL cholesterol is a strong independent risk predictor of CHD. 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.