Hyperlipidemia

1. Hyperlipidemia Yasar Kucukardali Professor Yeditepe University Department of Internel Medicine

2. Objectives • To learn correct management of hyperlipidemia • Review NCEP ATP III Guidelines • Discuss laboratory monitoring

3. Relation between plasma cholesterol concentration and six-year coronary heart disease risk in 361,662 men (ages 35 to 57) screened during the MRFIT study. There is a continuous, positive, graded correlation between the plasma cholesterol concentration and coronary risk. Data from Stamler, J, Wentworth, D, Neaton, JD, JAMA 1986; 256:2823.

6. Cholesterol Essential component of the cell membrane Precursor molecule from which steroid hormones, bile salts, and vitamin D are synthesized Derived from the diet synthesized within the body,mainly in the liver.

7. Dietary sources of Cholesterol Çoklu doymamış YAğlar: Mısır, ayçiçek, soya, susam, fındık, keten tohumu Tekli doymamış yağlar: zeytinyağı Doymuş yağlar: Tereyağ, sade yağ, krema, kaymak, süt, peynir ve etlerin bileşiminde bulunan yağlar

8. Cholesterol circulates as a component of lipoproteins The principal plasma lipoproteins chylomicrons (CMs) very low density lipoproteins (VLDL) low-density lipoproteins (LDL) high-density lipoproteins (HDL) The principal fat in the diet is the triglycerides (TG), which are absorbed in the intestine The lipoproteins are transported in combination with apoproteins (apo), like apo-A, apo-B, and apo-C

10. Clasification Hyperlipidemias are classified as primary or secondary Primary hyperlipidemia have been classified into 5 major groups according to plasma lipoprotein patterns Causes of Sec. Hyperlipidemia • Diet • Hypothyroidism • Nephrotic syndrome • Anorexia nervosa • Obstructive liver disease • Obesity • Diabetes mellitus • Pregnancy • Acute hepatitis • AIDS (protease inhibitors) • Pancreatitis • Hematopoietic diseases (myeloma, Waldenstrom's macroglobulinemia, cryoglobulinemia, hemochromatosis • Systemic lupus erythematousus • drugs like estrogens, corticosteroids, and retinoids

11. Genetic primary hyperlipidemias

12. Symptoms of Hyperlipidemia • Hyperlipidemia usually has no noticeable symptoms and tends to be discovered during routine examination or evaluation for atherosclerotic cardiovascular disease. • Deposits of cholesterol (known as xanthomas) may form under the skin • Individuals with hypertriglyceridemia may develop numerous pimple-like lesions across their body. ** • Extremely high levels of triglycerides may also result in pancreatitis, a severe inflammation of the pancreas that may be life-threatening.

13. DermatologicMarkers of LipidDerangement • Abnormalities of lipid metabolism may favor lipid deposition in the skin and present as xanthomas • Xanthelasma palpebrarum is the commonest type of cutaneous xanthoma • The major lipid stored in xanthomas is esterified cholesterol • However, only about half of the patients with xanthelasma are hyperlipidemic • The most frequent hyperlipidemia associated with xanthelasma is type IIa • Isolated xanthelasmata are often treated with destructive modalities, like trichloroacetic acid, electrocautery, surgical excision, carbon dioxide laser, pulsed dye laser, and erbium:YAG laser

14. Disorders of lipid storage

15. Individuals with hypertriglyceridemia may develop numerous pimple-like lesions across their body

16. NCEP Guidelines • The NCEP Adult Treatment Panel (ATP) first published guidelines for managing hypercholesterolemia in 1988 (ATP I) • Revised them in 1993 (ATP 2) • The latest NCEP report (ATP III) has been published in 2001.

17. managinghypercholesterolemia • Thefirst step is todeterminelipoproteinlevelsafter a 9- to 12-hourfast • Next, coronaryheartdisease (CHD) risk equivalentsandmajor risk factorsshould be established. CHD risk equivalentsinclude clinical CHD symptomaticcarotidarterydisease peripheralarterialdisease abdominalaorticaneurysm diabetes Major risk factors (exclusive of LDL cholesterol) cigarettesmoking hypertension low HDL cholesterol (<40 mg/dL) familyhistory of premature CHD age (men >45 years; women >55 years) • CHD risk equivalentsand risk factorsarethenusedtodeterminethe risk category of thepatient

18. Coronary Equivalents Abdominal Aortic Aneurysm Peripheral Artery Disease Renal Artery Stenosis Carotid Artery Stenosis Cerebral Vascular Disease Diabetes Mellitus • Risk Factors Hypertension HDL <40 mg/dl (>60 mg/dl “negative” risk factor) Family history of premature CAD (male <55 female <65) Male >45, Women >55 Cigarette Smoking

19. Checking lipids • Nonfasting lipid panel • measures HDL and total cholesterol • Fasting lipid panel • Measures HDL, total cholesterol and triglycerides • LDL cholesterol is calculated: • LDL cholesterol = total cholesterol – (HDL + triglycerides/5)

20. When to check lipid panel • Two different Recommendations • Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) • Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides • Repeat testing every 5 years for acceptable values • United States Preventative Services Task Force • Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. • If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained • Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesteral levels or premature cardiovascular disease. • Screeningmay be appropriate in olderpeoplewhohaveneverbeenscreened, althoughscreening a secondorthird time is lessimportant in olderpeoplebecauselipidlevelsarelesslikelytoincreaseafterage 65.

22. NCEP/ATP III • Identify if patient has CAD or equivalent (PAD, DM, AAA, Carotid) • Risk factor assessment (HTN, FHx, Tob, Age & Sex, HDL<40 or >60) • If 2 or more risk factors; do Framingham 10-yr risk assessment.

23. Therapeutic lifestyle changes (TLC) NCEP/ATP III • TLC are considered first-line therapy in the management of high cholesterol • A 3-month trial of TLC should precede the use of drug therapy The essential features of TLC (a) reduced intake of saturated fats [less than 7% of total calories] and cholesterol [less than 200 mg/d] (b) therapeutic options for enhancing LDL lowering - such as plant stanols/sterols [2 g/d] and increased soluble fiber [10-25 g/d; (c) weight reduction (d) increased physical activity

24. Accordingto ATP III, themostcost-effectiveapproachtoprevention of CHD dietmodification exercise weightcontrol cessation of smoking • Cigarettesmoking, leadstoelevatedtriglyceridesandlow HDL levels • Smokingcessationshouldreceive prime emphasis in theclinicalstrategytoreduce CHD risk. • Whilemoderateintakes of alcohol in middle-agedandolderadultsmayreduce risk for CHD, highintakes of alcoholproducemultipleadverseeffects. • Personswho do not drinkshould not be encouragedtoinitiateregularalcoholconsumption. • Physicalactivity as a component of TLC includesenoughmoderateexercisetoexpend at least 200 kcalperday.

25. The NCEP recommends • The use of statins as first-line therapy • BASA's LDL-lowering effects may be enhanced in combination with other cholesterol-lowering medications, particularly statins. • Nicotinic acid is recommended for high-risk patients with low levels of LDL cholesterol, high triglycerides, and low HDL cholesterol - a triad known as atherogenic dyslipidemia. • Fibrates are primarily used for persons with very high triglycerides to reduce risk for acute pancreatitis and for those with dysbetalipoproteinemia.

26. Drugtreatment/Statins • The statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme • Inhibition of HMG-CoA reductase leads to a decrease in intrahepatic cholesterol concentration ,leading to an increase in receptor-mediated LDL catabolism. • The statins also decrease the activity of CETP Thus the overall effect is a small increment in HDL • Statins decrease serum triglycerides. • Statin-induced increased LDL-receptor activity also leads to the enhanced removal of the TG-rich lipoproteins VLDL and IDL. Similarly, increased activity of LDL receptor leads to enhanced uptake of CM remnants, thereby increasing postprandial TG clearance.

27. Drugtreatment/Bile-acidsequestratingagents (BASA) • BASA are anion exchange resins, BASA bind the bile acids, thus impeding their reabsorption and significantly increasing their fecal excretion. • This leads to the depletion of intrahepatic cholesterol, which causes increased expression of LDL receptors. • BASA promote apo-A1 synthesis by an unknown mechanism and tend to raise HDL levels. • BASA nonspecifically bind anions and interfere with absorption of a number of drugs which are anionic at intestinal pH (statins, fenofibrate, corticosteroids, diuretics, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, thyroxine, and digoxin).

28. Drugtreatment/Nicotinicacid (NA) • Plasma FFA are immediate precursors of hepatic and subsequently plasma triglycerides transported in VLDL. • NA is immediately taken up by adipose tissue via a specific high-affinity G-protein-coupled receptor. It then inhibits lipolysis in adipose tissue, resulting in a decrease in plasma FFA • NA, in a dose-dependent way, lowers triglyceride-rich VLDL and cholesterol-rich LDL. • NA is the most potent HDL-raising drug. But the unpleasant side effect of flushing precludes many patients from taking this drug.

29. DrugtreatmentFibricacidderivatives (fibrates) • Fibrates reduce triglycerides through PPARa-mediated reduced expression of apo-CIII, which serves as an inhibitor of lipolytic processing and receptor-mediated clearance. This leads to increased LPL synthesis and enhanced clearance of triglyceride-rich lipoproteins. • Fibrate-mediated increases in HDL are due to PPARa stimulation of apo-AI and apo-AII expression. • Three fibric acid derivatives are currently available Fibrates are primarily used for lowering elevated triglycerides because the LDL cholesterol-lowering effects of fibrates are generally only 10% or less in persons with hypercholesterolemia.

30. Othertherapeutictargets in lipidmetabolism • Ezetimibe blocks uptake of cholesterol into jejunal enterocytes, hence selectively blocking dietary and biliary cholesterol absorption from the gut. It acts by decreasing the intestinal cholesterol supply to the liver, lowering hepatic cholesterol levels and thus inducing LDL receptor expression. Unlike the bile-acid sequestrants, it does not interfere with absorption of fat-soluble drugs. Moreover, ezetimibe does not increase serum TG.

31. Lipid-lowering agents

32. NCEP/ATP III • Treat elevated TG (>150mg/dl) • First lower LDL; if TG still >200 consider adding/increasing drug therapy • But, if TG >500mg/dl, first lower triglycerides to prevent pancreatitis. When they are <500 then return to LDL lowering • Treat HDL <40 after lowering LDL.