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1 Welcome to You All Dr.Sarma@works 2 Dyslipidemias Dx. and Rx. Dr.Sarma RVSN, M.D., M.Sc (Canada) Consultant in Medicine and Chest, President IMA – Tiruvallur Branch # 3, Jayanagar, Tiruvallur – 602 001 +91 98940 60593, (4116) 260593 Dr.Sarma@works 3 CD ROM Available The contents of today’s presentation are available in a CD-ROM format for computer and VCD player use. This CD, in addition, contains our talks on ECG, Asthma, COPD, Hypertension Rx. also Dr.Sarma@works 4 National Cholesterol Education Program - NCEP Adult Treatment Panel III (ATP III) Guidelines -2002 Updated October 2004 Dr.Sarma@works 5 Guidelines that aren’t implemented never work Dr.Sarma@works CHD Risk Factors ranking - PROCAM Study Risk factor Smoking LDL cholesterol (mg%) > 100 but < 160 > 160 Hypertension (SBP > 140; DBP > 90) HDL cholesterol (mg%) 40 to 55 < 40 Triglycerides (mg%) 105- 167 >167 Fasting blood glucose (mg%) 110 - 126 > 126 Family history of MI Relative risk P Value 2.3 0.001 1.9 4.3 1.8 0.01 0.001 0.001 1.7 2.7 0.01 0.001 1.6 2.6 0.01 0.001 1.4 1.9 1.4 0.05 0.01 0.05 7 Emerging Risk Factors 1. Lipoprotein (a) 2. Homocysteine 3. Prothrombotic factors 4. Pro-inflammatory factors 5. Metabolic syndrome 6. Sub-clinical atherosclerosis Dr.Sarma@works 8 CHD Risk Equivalents 1. Diabetes Mellitus 2. Peripheral Vascular Disease 3. > 20% in Framingham risk score 4. Carotid atheroma 5. Reno-vascular Disease All forms of AVD Dr.Sarma@works 9 AVD – Clinical Manifestations Organ Condition Impairment Clinical Presentation Heart Coronary Heart Disease (CHD) Ischemia Infarction Angina Pectoris Myocardial Infarction Brain Cerebro vascular Disease (CVD) Ischemia Infarction Transient Ischemia attack Stroke Kidney Reno vascular Disease (RVD) Ischemia Infarction Renal HT, Renal impairment Renal Failure Ischemia Infarction Intermittent Claudication Gangrene Leg Peripheral Vascular Muscles Disease (PVD) For every thing the common denominator is ED Dr.Sarma@works 10 Progression of Atherosclerosis Dr.Sarma@works Lipid Peroxidation LDL, IDL Not normally taken up by the vessel wall ROS – Free radicals and Pro-oxidants Oxidized LDL, IDL Freely enters the vessel wall Endothelium Scavenger pathway Foam Cells Atherosclerosis Dr.Sarma@works Macrophages Cytokines, GF 11 The Havoc by LDL at the endothelium Vessel Lumen Monocyte LDL Adhesion Molecules Cytokines Macrophage MCP-1 LDL Modified LDL Foam Cell Endothelium Intima Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Ross R. N Engl J Med 1999;340:115-126. Pathogenesis of ACS Non-Vulnerable Atherosclerotic Plaque Vulnerable Atherosclerotic Plaque Plaque Rupture with Thrombus 15 Lipid Transport TG EC Apoprotein boat Apo A I and A II for HDL Apo B100+C+E – VLDL, IDL Dr.Sarma@works Apo B100 for LDL, Lp(a) Apo B48+C+A+E – Chy. microns 16 Lipoproteins HDL LDL C T G A I, A II TG C B 100 VLDL CM TG C B 100 + E +C Dr.Sarma@works TG B 48+E+C 17 Cholesterols and Apoproteins • Total Cholesterol • ‘Bad’ Cholesterols – LDLc, IDLc – VLDLc, VLDLr – Lp(a), small LDL < 200 Apoprotein Apo B type < 100 < 30 < 20 B100 or B100 +E B100 + E + C B100 + (a) • ‘Good’ Cholesterols – HDL 1, HDL 2, HDL 3 Apo A type > 50 A I and A II HDL 1 and HDL 2 are protective Dr.Sarma@works 18 Particle size & Density Chylomicrons VLDL IDL << 1.006 < 1.006 < 1.019 LDL Small LDL HDL < 1.063 < 1.085 < 1.210 Atherogenicity increases as density increases Dr.Sarma@works 19 Atherogenic Particles Measurements VLDL VLDLR Apolipoprotein B Non-HDL-C IDL LDL SDL TG-rich lipoproteins Dr.Sarma@works 20 Two Types of Lipids LIPIDS IN BLOOD TOTAL CHOLESTEROL GOOD CHOLESTEROL HDL 1 and HDL 2 Dr.Sarma@works TRIGLYCERIDES BAD CHOLESTEROL LDL, ( IDL, VLDL, Lp(a)) 21 Lipid Profile Report LIPIDS ESTIMATED TOTAL CHOLESTEROL (TC) HDLc LDLc VLDLc TRIGLYCERIDES (TG) Chylomicrons PP Dr.Sarma@works VLDL Fasting 22 Lipid Calculations A. Total Cholesterol 200 HDL Cholesterol 50 LDL Cholesterol (TC –(HDL+VLDL)) VLDL Cholesterol (1/5 of TG) B. Triglycerides Dr.Sarma@works 120 30 150 23 The Good and Bad • Total Cholesterol • ‘Good’ Cholesterols – HDL 1, HDL 2, HDL 3 • ‘Bad’ Cholesterols (Non HDLc) – LDLc, IDLc – VLDLc, VLDLr – Lp(a), small LDL < 200 > 50 < 150 < 100 < 30 < 20 HDL 1 and HDL 2 are protective Dr.Sarma@works 24 How it should be reported ? Lipid type tested Patient Normal 260 200 HDLc (athero-protective) 55 55 LDLc + other atherogenic 155 100 Non-HDLc (atherogenic) 205 130 Ratio of TC ÷ HDLc 4.73 4 Triglycerides (TG) 250 150 Total Cholesterol (TC) Interpretation Dr.Sarma@works HDL – N, LDL – High , TG - HIGH 25 Today’s Safer Values • • • • • • • • • Dr.Sarma@works Total Cholesterol < 200 Triglycerides < 150 LDL Cholesterol < 100 HDL Cholesterol > 50 (for women 55) Bad Cholesterols the lower the better Good Cholesterols the higher the better Non HDL Cholesterol < 130 Lp(a) values < 20 Homocysteine < 14 μ mols per liter 26 Indian Specialty A. Isolated low LDL B. Isolated low HDL C. Isolated high TG 32.90% 21.35% 10.45% ↑TG ↑LDL The Triad IHJ, 2000, 52: 173-177 Am J Med, 1998, vol 105(1A), 48S-56S Dr.Sarma@works ↓HDL 27 Look at the risks • • • • • • • • Low HDL + High LDL LP(a) excess > 30 mg% LP(a) excess > 30 mg% + LDL high LP(a) excess > 30 mg% + low HDL LP(a) excess > 30 mg% + Incr. tHCy LP(a) excess + Incr. tHCy + low HDL Circulating lipids are one aspects Tissue lipid content is more important + + ++ +++ ++++ +++++ J. Atherosclerosis : Hopkins PN, 1997 – 17, 2792 Dr.Sarma@works Relative risk of CHD Additive Effect Smoking 4.5 16 1.6 3 SBP >160 5 6 4 Dyslipidemia With DM all risks are doubled Dr.Sarma@works 28 Intestinal Cholesterol Absorption Through lymphatic system to the liver Intestinal epithelial cell MTP CM Cholesteryl esters ACAT (esterification) Free cholesterol Dr.Sarma@works Biliary cholesterol excretion ABCG5 ABCG8 Dietary cholesterol Luminal cholesterol Bile acid Micellar cholesterol uptake Bays H et al. Expert Opin Pharmacother 2003;4:779-790. 29 30 Cholesterol Absorption Lymph Enterocyte Ezetimibe Cholesterol ACAT Avasimibe Dr.Sarma@works NPC1L1 Cholesteryl ABCG5/G8 Ester Intestinal Lumen 31 Fat Absorption Liver Duodenum Biliary Transport and Storage Jejunum Ileum Colon Dr.Sarma@works 32 Triglyceride Absorption Lymph Enterocyte 2 Fatty Acid + Monoglyceride DGAT Triglyceride Dr.Sarma@works Intestinal Lumen 33 Chylomicron Formation Lymph CM apoB48 Enterocyte Triglyceride Cholesteryl Ester Dr.Sarma@works Intestinal Lumen 34 Structure of HDL Particle A-I A-I CE TG A-II A-I, A-II = apolipoprotein A-I, A-II; CE = cholesterol ester; TG = triglycerides Dr.Sarma@works 35 HDL Types A-I A-I CE CE CE A-II HDL 1 HDL 2 APO A I Protective Dr.Sarma@works A-II HDL 3 Alcohol increases 36 Reverse Cholesterol Transport MF in Vascular Endothelium LIVER EC Free Chol. UEC HDL L CAT Enzyme Dr.Sarma@works 37 HDL Metabolism and Reverse Cholesterol Transport Bile A-I F C CE LCAT SR-BI Liver A-I CE CE FC ABC1 FC Nascent Macrophage HDL Mature HDL ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI Dr.Sarma@works 38 Role of CETP in HDL Metabolism Bile Nascent HDL A-I Mature HDL FC CE SR-BI Liver A-I LDLR Macrophage LCAT CE FC CETP ABC1 FC CE SRA X CE B VLDL/LDL Torcitrapib Dr.Sarma@works CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein 39 Hyperlipidemias Primary 5% Familial & genetic Secondary 95% Dr.Sarma@works 40 Secondary Hyperlipidemia Dr.Sarma@works ↑ LDL Cholesterol Nephrotic syndrome. Hypothyroidism Obstr. liver disease Anorexia nervosa Acute Int. Porphyria Progestogens ↑ TG Obesity Diabetes Uremia Alcoholism, Smoking Oral contraceptives Beta blockers Thiazides Anabolic steroids Pregnancy Steroids, Thiazides 41 Clinical Action • Presence of secondary causes of Hyperlipidemia – Order for full lipid profile (LP) – HT also • Presence of hyperlipidemia – increased TG or EC – Investigate for all secondary causes • For all above 20 years once in every 5 years • For those above 45 yrs – once in 2 years • For those with already known lipid abnormality follow-up every 3-6 months • Extended Lipid profile includes Homocysteine, LP(a), SD-LDL, ALP, Apo A and Apo B, HS-CRP Dr.Sarma@works 42 Clinical Photoes Tuberous xanthoma. Flat-topped, yellow, firm tumor Xanthelasma. Multiple, longitudinal, creamyorange, slightly elevated papules on eyelids . Dr.Sarma@works 43 Clinical Photoes Tendinous xanthomas. Large subcutaneous tumors adherent to the Achilles tendons. Dr.Sarma@works Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules 44 Evaluation 1. History of eruptive xanthomas, Abd. pain 2. H/o wt. gain, DM, estrogens, Alcohol, Ex. 3. Fasting Lipid profile (TC, LDL, HDL, TG) 4. OGTT, TSH, Liver & Renal Function tests 5. CHD assessment by ECG, TMT, Angio 6. Risk factor assessment, Family H/o P.CHD Dr.Sarma@works 45 Treatment Strategy Lipid Profile, Risk Assessment LDL > 100 Look For Sec. Causes Treat the cause, if found Treatment NO CHD CHD + Primary Prevention Sec. Prevention 2 or more RF LDL > 100 Dr.Sarma@works High Risk < 2 RF Low Risk LDL < 130 LDL <160 46 Treatment Plan - LDLc Clinical Status Goal Diet Drugs No CHD < 2 RF <160 >160 >190 No CHD 2 or more RF <130 >130 >160 CHD Present <100 >100 >130 For Indians all the values must be 20 mg less Dr.Sarma@works 47 Treatment Options • • Diet – Two step approach Drug therapy 1. HMG¢ co A Reductase Inhibitors 2. Fibric Acid derivatives 3. Nicotinic Acid 4. Ezetimibe 5. Bile Acid binding Resins (BAR) 6. Probucol ¢ Dr.Sarma@works HMG is Hydroxy Methyl Glutaryl 48 New Treatments Drug therapy 1. Colesevelam (BAR) 2. Phytosterols 3. Avasimibe – ACAT inhibitor 4. Torcetrapib – CETP inhibitor 5. Drugs decreasing Apo B synthesis Dr.Sarma@works 49 Therapeutic Lifestyle Changes - TLC • • • • • • • • Nutrient Saturated fat PUFA fat MUFA fat Total fat Carbohydrate Fiber Protein Cholesterol Recommended Intake < 7% of calories Up to 10% of calories Up to 20% of calories 25–35% of calories 50–60% of calories 20–30 grams per day Approx. 15% of calories Less than 200 mg/day DIETARY THERAPY Dr.Sarma@works 50 Our dietary fats • SFA (saturated) – meet and diary products, coconut oil, Kernel, Ghee, Butter, Palm oil, • Trans fatty acids in vanaspati, chocolates confectionaries, baked, deep fat fried food • MUFA (N1) – Olive oil, Gingili oil • PUFA (N6) – Soya, Sun Flower oil, GN oil • PUFA (N3) – Fish oils – Twice a wk ↓ 76% CAD • Legumes, fruits, olive oil – ↓ all cause mortality Dr.Sarma@works Treatment of ↑ LDLc High LDLc Therapeutic Lifestyle Change Drug Therapy Therapy of Choice: Statin Add on drug - EZ , Niacin, BAR Dr.Sarma@works 51 Statins – Mechanism of Action Cholesterol synthesis HMGCoA Intracellular Cholesterol VLDL LDL receptor VLDL Apo B R Apo E (B–E receptor) synthesis Apo B LDL LDL receptor–mediated hepatic uptake of LDL and VLDL remnants Serum LDL-C Serum VLDL remnants Serum IDL Hepatocyte Dr.Sarma@works 1. 2. 3. 4. Systemic Circulation Reduce hepatic cholesterol synthesis (HMG CoA), lowering intracellular cholesterol, Upregulation of LDL receptor and ↑ the uptake of non-HDL from circulation. 52 CHD Risk Reduction – Statin Therapy Endpoints 53 Relative Risk Reduction (%) +20 0 –5 –10–15–20–25–30–35–40–45–50 Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina Dr.Sarma@works La Rosa JC et al. JAMA 1999;282:2340-2346. 54 Time course of Statin effects LDL-C lowered* Inflammation reduced Endothelial function restored Days Dr.Sarma@works Vulnerable plaques stabilized Ischemic episodes reduced * Time course established Cardiac events reduced* Years HMG CoA Reductase Inhibitors (Statins) Dr.Sarma@works Statin Dose Range Lovastatin 20–80 mg Pravastatin 20–40 mg Fluvastatin 20–80 mg Simvastatin 20–80 mg Atorvastatin 10–80 mg Rosuvastatin 5–20 mg Cerivastatin 0.4–0.8 mg 55 56 LDL-C Lowering - Statin Dose Atorvastatin 211 mg/dl* Simvastatin 219 mg/dl* Daily Dose 0% -10% -20% 38% 20 mg -30% -40% 46% -50% 51% 54% -60% 10 mg 28% 35% 41% 16% with 3 Titrations 13 % 40 mg 80 mg Adapted from Jones P et al. Am J Cardiol 1998;81:582-587. Dr.Sarma@works 57 HMG CoA Reductase Inhibitors (Statins) Common side effects Headache, Myalgia, Fatigue, GI intol. Flu-like symptoms Increase in liver enzymes – serious problems are very rare Occurs in 0.5 to 2.5% of cases in dose-dependent manner Myopathy occurs in 0.2 to 0.4% of patients Rare cases of Rhabdomyolysis We can reduce this risk by Cautiously using statins in impaired renal function Using the lowest effective dose Cautiously combining statins with fibrates Muscle toxicity requires the discontinuation of statin Dr.Sarma@works 58 Short falls of Statins Effectiveness and community impact are to be improved Rebound increase in lipids and ↑ of events after withdrawal of statin Rx. High rate of discontinuation by patients Differences in the efficacy of different statins They reduce only endogenous lipids – Individual variation Modest effect on TG and HDL, No effect on Lp(a) No effect on chylomicrons; escape phenomenon Dr.Sarma@works 59 Ezetimibe Lymph Enterocyte Cholesterol ACAT Intestinal Lumen X NPC1L1 Cholesteryl ABCG5/G8 Ester Dr.Sarma@works Ezetimibe 60 Dual Inhibition LDL apoB100 Liver Statin Duodenum X VLDL apoB100 X Ezetimibe Jejunum Ileum CM Remnant apoB48 Dr.Sarma@works CM apoB48 Colon 61 Ezetimibe Efficacy (“10 + 10 = 80”) 0% Ezt + Ator 10+10 mg (n=65) Atorvastatin 10 mg (n=60) 20 mg (n=60) 40 mg (n=66) 80 mg (n=62) -10% -20% -30% –37% -40% -50% –42% –53% –45% –54% -60% P < 0.01 Dr.Sarma@works Ballantyne CM et al. Circulation 2003;107:2409-2415. 62 Bile Acid Resins: Mechanism of Action Cholesterol 7- hydroxylase Gall Bladder Bile Acid Conversion of cholesterol to BA BA Secretion Enterohepatic Recirculation Terminal Ileum BA Excretion Reabsorption of bile acids Net Effect - LDL-C Dr.Sarma@works Liver LDL Receptors VLDL and LDL removal 63 Bile Acid Resins (BAR) Major actions • Reduce LDLc by 15–30% • Raise HDLc by 3–5% • May increase TG Side effects • GI distress / constipation / nausea • Decreased absorption of other drugs Contra indications • Dysbetalipoproteinemia, • Biliary Obstruction • Raised TG (especially >400 mg/dL) Dr.Sarma@works 64 Bile Acid Resins Drug Dose Range Cholestyramine 4–16 g Colestipol 5–20 g Colesevelam 2.6–3.8 g Dr.Sarma@works Treatment of ↓ HDLc Low HDLc Therapeutic Lifestyle Change Drug Therapy Therapy of Choice : Niacin Add on drug - Finofibrate Dr.Sarma@works 65 The CADI study [Coronary Artery Disease in Asian Indians] 14% of Asian Indian males & 5% of females have Optimal HDL Prevalence of coronary heart disease and its risk factors in Asian Indians Atherosclerosis , Rosemount , IL Oct 6-11 , 1991 120 100 80 60 40 20 0 86 95 14 5 Asian Indian females Asian Indian males % with < optimal level of HDL-C % with an optimal HDL-C levels In Indian patients with CAD, High TG levels are found more often than high cholesterol levels. Journal, Ind. Acad. clin. med vol 2 Jul-Sept 2001 Causes of Low HDL Smoking Obesity (visceral fat), Physical inactivity Very high Carbohydrate diet Type II Diabetes Hyper-triglyceridemia Drugs like beta-blockers, androgenic steroids and androgenic progestins Dr.Sarma@works 67 Nicotinic Acid – Mechanism of Action Mobilization of FFA Apo B VLDL TG synthesis VLDL VLDL secretion Serum VLDL results in reduced lipolysis to LDL Serum LDL LDL HDL Liver Circulation Hepatocyte Systemic Circulation Decreases hepatic production of VLDL and of apo B Dr.Sarma@works 68 Effect of Niacin on Lipoproteins 35% 69 HDL-C with crystalline niacin 25% HDL-C with Niaspan® 12.5% Baseline LDL-C with Niaspan® LDL-C with crystalline niacin -15% TG with Niaspan® -30% TG with crystalline niacin 0 Dr.Sarma@works 1g/d 2g/d 3g/d Adapted from Knopp RH. N Engl J Med 1999;341:498-511.. Nicotinic Acid Products available Immediate-release, 2–4 g/d, Sustained Release 3 g /d Extended-release (Niaspan®) 1–2 g/d Best agent to raise HDL-C Reduces coronary events Adverse effects Flushing, itching, headache (immediate-release, Niaspan®) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity Contraindications Active liver disease or unexplained LFT elevations Peptic ulcer disease Dr.Sarma@works 70 Coronary heart disease and HDL-C Framingham Heart Study 200 Rate/1000 150 100 Women 50 Men 0 <25 25–34 35–44 45–54 55–64 65–74 75+ HDL-C (mg/dl) Gordon, Castelli et al. Am J Med 1977; 62: 707–714 Relative risks of MI The Physicians Health Study 3.78 3.21 2.41 1.00 Low total cholesterol <212 mg/dl Low HDL cholesterol <47 mg/dl High HDL cholesterol 47 mg/dl High total cholesterol 212 mg/dl Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381 HDL-C vs LDL-C as a predictor of CHD risk CHD RR Risk of CAD over 4 years of follow-up* 3 2.5 2 HDL-C 1.5 25 mg/dl 45 mg/dl 65 mg/dl 85 mg/dl 1 0.5 0 100 mg/dl 160 mg/dl 220 mg/dl LDL-C *Men aged 50–70 Gordon, Castelli et al. Am J Med 1977; 62: 707–714 74 Management of Low HDLc LDL cholesterol is primary target of therapy Weight reduction and increased physical activity (if the metabolic syndrome is present) Non-HDL cholesterol is secondary target of therapy (if triglycerides 200 mg/dL) Consider nicotinic acid or fibrates (for patients with CHD or CHD risk equivalents) Dr.Sarma@works Treatment of ↑ TG High TG Therapeutic Lifestyle Change Drug Therapy Therapy of Choice : Fibrate Add on drug – Statin, Niacin Dr.Sarma@works 75 76 Treatment Strategy Fasting TG Level ↑Fasting TG Level TG >150, No CHD TG > 150, CHD + TG > 500, CHD +/- TG < 150 Normal < 2 RF Diet Modify 2 or > RF Diet + Fibrate Diet + Fibrate + Niacin Diet + Fibrate + Statin Dr.Sarma@works 77 Triglycerides TG Level Classification Treatment < 150 mg% Normal TG No Rx. 150 to 200 mg% Borderline high Diet alone 201 to 500 mg% High Diet + drugs > 500 mg% Very high Diet + Intensive Rx NCEP 2002 Guidelines by expert panel on TG Dr.Sarma@works Fenofibrate Mode of Action Enhances the activity of lipoprotein lipase Reduces hepatic fatty acid synthesis Inhibits HMG co-enzyme A reductase activity Reduces the CETP activity Increases the LCAT activity Increases the production of Apo AI and Apo A II 79 Fibric Acid Derivatives • Major actions – Lower TG 20–50%,↓VLDL synthesis – Raise HDL-C 10–20% – ↓ LDL (TG is N), ↑ LDL (TG is ↑) – Increase the SDL particle size (less athero) • Side effects Dyspepsia, gallstones, myopathy, Abn. LFT • Contraindications Severe renal or hepatic / biliary disease Dr.Sarma@works 80 Fibric Acid Derivatives Drug Clofibrate Bezafibrate Gemfibrozil Fenofibrate Fenofibrate micronized Dr.Sarma@works Dose 1000 mg BID 200 mg BID 600 mg BID 200 mg OD 160 mg OD Treatment of ↑ LDL + ↑ TG Combined Therapeutic Lifestyle Change Drug Therapy Therapy of Choice : Statin + Fibrate Add on drug – Niacin, BAR Dr.Sarma@works 81 82 Statin + Fibrate Simva + Gemfibrozil Percent Change 30 20 10 16% 230 332 0 -10 -20 -30 -40 -50 -60 Ator or Simva + Fenofibrate HDL 166 191 38 LDL 22% HDL 34 LDL TG –39% –28% TG –41% –50% Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482. Dr.Sarma@works 83 Statin + Fibrate – Precautions Use statin alone for non-HDL-C goals Use fish oils or niacin rather than fibrates Keep the doses of the statin and fibrate low Dose the fibrate in the AM and the statin in the PM Avoid (or cautiously use) combo in renal impairment Teach the patient to recognize muscle symptoms Dr.Sarma@works Discontinue therapy if muscle symptoms are present and CK is >10 times the upper limit of normal 84 Probucol 1. Probucol (Lorelco) 500mg b.i.d with food 2. Third line drug – erratic effect on LDL & HDL 3. Lowers Cholesterol and the only drug which regresses xanthomas 4. It is an antioxidant of LDL 5. Diarrohea, flatulence, nausea, increases QTc 6. Can be combined with BAR Dr.Sarma@works 85 The Three Canons DYSLIPIDEMIA ↑ LDL - STATIN Dr.Sarma@works 86 Summary of Drug choice Lipid abnormality type First choice Additional Remarks ↑ LDL Statin Ezetimibe Myopathy ↑ ↑ TG Fibrate Niacin ↓ CHO intake ↓ HDL Niacin Fibrate Exercise ↑ LDL + ↑ TG Statin + Fibrate Niacin Myo risk ↑ ↑ ↑ LDL + ↓ HDL Statin + Niacin Exercise ↑ TG + ↓ HDL Fibrate + Niacin Statin ↑ LDL + ↑ TG + ↓ HDL Statin + Fibrate E, N, BA, FO Myo risk ↑ ↑ ↑ Dr.Sarma@works Fibrate Exercise Atherogenecity of small, dense LDL SDL is highly atherogenic. It Generates free radicals Increases trans endothelial filtration Increases susceptibility to oxidation Reduces affinity for the LDL receptor Increased binding to intimal proteoglycan ↑ Formation of pro-aggregators / vasoconstrictors Impaired in vivo ED independent of HDL, LDL, TG Circulation, 2000, 102: 716-721 88 Lp(a) or Little‘a’ • • • • • Similar to LDL molecule Apo B + additional Apo ‘a’ attached by S=S bond Primary determinant is genetic Normal value 20 mg %, > 30 high risk It competes with plasminogen because of its structural similarity and so interferes with plasmin synthesis and thrombolytic pathway • Nicotinic acid, ? Bezafibrate, Estrogens ↓it Dr.Sarma@works Phenotype B or ALP This ALP or phenotype B is present and seen in most often • Insulin resistant individuals • Diabetics • Obese persons • Sedentary life style More prevalent in India Apo A I ÷ Apo B will be < 1 Cumulative Distribution of TG Levels Phenotypes A and B 100 90 80 70 % Cumulative60 frequency 50 40 Phenotype A Phenotype B 30 20 10 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 500 TG (mg/dL) Austin M et al. Circulation. 1990;82:495-506. Cumulative Distribution of HDL levels Phenotypes A and B 100 90 80 70 % Cumulative60 frequency 50 Phenotype A Phenotype B 40 30 20 20 25 30 35 40 45 50 55 60 65 70 75 80 HDL-C (mg/dL) Austin M et al. Circulation. 1990;82:495-506. Metabolic Syndrome - Characteristics Hypertriglyceridemia Low HDL-cholesterol Elevated apolipoprotein B Small, dense LDL particles Inflammatory profile Insulin resistance Hyperinsulinemia Glucose intolerance Impaired fibrinolysis Endothelial dysfunction These features can lead to type 2 diabetes, hypertension and cardiovascular disease The interaction between our current genotype and our present day life style and eating habits places us at very high risk of having this phenotype B that makes us highly susceptible to Atherosclerosis. Journal of Internal Medicine 2003:254(2):114-25 ATP-III Criteria for Metabolic Syndrome Abdominal obesity (waist circumference): men >100 cm (40 in); women >88 cm (35 in) Triglycerides > 150 mg/dl HDL cholesterol: men < 40 mg/dl; women < 50 mg/dl Blood pressure > 130/ 85 mmHg. Fasting glucose > 110 mg/dl Diagnosis of metabolic syndrome is made when 3 or more of the risk determinants shown above are present. 95 Homocysteine • Normal value is up to 15 μ mols./L • Folic acid, Vitamin B6 and B12 are essential for the normal transulfuration and remethylation cycles • Excess of homocystine generates oxidative stress on the cell membranes. DNA and protein denaturation through ROS formation • Folic acid 5 mg/ day + Vit. B6 and B12 are to be given on regular basis Dr.Sarma@works 96 Summary of Drug choice Lipid abnormality type Advised Rx. Remarks ↑ Homocysteine Folic acid B6 + B12 helps ↑ Small dense LDL Statin + Fibrate Aggressive Rx. ↑ Little ‘a’ or LP(a) Niacin ↑ Phenotype B Under research DM, Obesity ↓ ↓ in Phenotype A Under research Aerobic exercise Dr.Sarma@works Statin no effect 97 Some Brand Names Drug class Brand name Atorvastatin TG-TOR, Storvas, Avastin, Atcor Simvastatin Sim, Simvotin, Simcard, Simvas Atorvastatin + Ezetimibe TG tor Z, Storvas Z, Ezetimibe Ezedoc, Ezee, Ezet Fenofibrate Lipicard, Fibrate, Finolip, Stanlip Gemfibrozyl Lopid, Lipizyl, Normolip, Losterol Niacin Niasyn, Nialip, Nicocin Dr.Sarma@works 98 Atherosclerosis and IR and DM Hypertension Obesity Hyperinsulinemia Insulin Resistance Diabetes Hypertriglyceridemia Small, dense LDL Low HDL Hypercoagulability Dr.Sarma@works Atherosclerosis 99 Dyslipidemia in IR and DM Elevated TG Elevated VLDL Reduced HDL-C All Diabetics must be given STATIN Increase in SD-LDL Decrease in Apo A I Increase in Apo B Ratio of Apo A I / Apo B < 1 Dr.Sarma@works 100 Diabetes Treatment and Lipids Type Rx used Effect on lipids 1. Insulin Favourable 2. Metformin Mildly favourable 3. Sulfonylureas Not favourable 4. Glitazones Favourable 5. Acarbose No effect Dr.Sarma@works 101 Hypertension Treatment and Lipids Type Rx used Effect on lipids 1. Diuretics Unfavourable 2. Indapamide Mildly favourable 3. ACEi and ARB Very favourable 4. Betablockers Unfavourable 5. Ca channel blockers No effect Dr.Sarma@works Who is to be blamed ?? We do not care at all to We soon end up having Restrict diet, over eat CHO, sweet toothed Over weight and obesity Eat more fruits, fiber, vegetables Atherosclerosis and AVD Avoid fatty, crunchy, munchy tasty food Dyslipidemia and CHD Avoid salty, savory, preserved food, NV Hypertension, CVA Do the minimum required exercise Diabetes, IR, ↓ HDL, OA Take enough milk and milk products, Ca Osteoporosis & fractures Quit smoking and abstain from alcohol What not ! Control worry, anger, vengeance, jealousy Mental & physical illness Dr.Sarma@works 102 Where are we heading ? ? 20000 B.C. 2004 Paleolithic sup. age Neolithic age 19th century 21st century Technology has changedProcessed a lot in the way we live Hunting-gathering subsistence High level of physical activity But, we have not Thrifty genotype foods Animal fats and glucides ¯ Dietary fibre Sedentary altered our life life style Susceptibility genotype Journal of internal medicine 2003:254(2):114-25 We have to pay the very heavy price !! What could be prevented, we treat or leave 105 Web Resources on Lipids www.lipidsonline.org www.hypertensiononline.org www.ncbi.nlm.nih.gov www.univ baylor.org Dr.Sarma@works 106 CD ROM Available The contents of today’s presentation are available in a CD-ROM format for computer and VCD player use. This CD, in addition, contains our talks on ECG, Asthma, COPD, Hypertension Rx. also Dr.Sarma@works 107 Wishing YOU all A HAPPAY NEW YEAR Dr.Sarma@works