1 Welcome to You All Dr Sarma works

1 Welcome to You All Dr. Sarma@works

2 Dyslipidemias 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 0. 001 2. 3 1. 9 4. 3 1. 8 0. 01 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 -12

Pathogenesis of ACS Non-Vulnerable Atherosclerotic Plaque

Plaque Rupture with Thrombus

15 Lipid Transport TG E C Apoprotein boat Apo A I and A II for HDL Lp(a) Apo B 100+C+E – VLDL, IDL Chy. microns Dr. Sarma@works Apo B 100 for LDL, Apo B 48+C+A+E –

16 Lipoproteins HDL LDL C T G A I, A II TG C B 100 VLD L CM T C G B 100 + E +C Dr. Sarma@works TG B 48+E+C

17 Cholesterols and Apoproteins • Total Cholesterol Apoprotein • ‘Bad’ Cholesterols type < 200 Apo B – LDLc, IDLc < 100 B 100 or B 100 +E – VLDLc, VLDLr < 30 B 100 + E + C – Lp(a), small LDL < 20 B 100 + (a) HDL 1 and HDL 2 are protective • ‘Good’ Cholesterols – HDL 1, HDL 2, HDL 3 Dr. Sarma@works Apo A type > 50 A I and

18 Particle size & Density Chylomicron s VLDL IDL < 1. 006 < 1. 019 << 1. 006 LDL Small LDL HDL < 1. 063 < 1. 085 < 1. 210 Atherogenicity increases as density increases Dr. Sarma@works

19 Atherogenic Particles Measurements 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 Fastin g

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 < 200 • ‘Good’ Cholesterols – HDL 1, HDL 2, HDL 3 > 50 • ‘Bad’ Cholesterols (Non HDLc) < 150 – LDLc, IDLc < 100 HDL 1 and HDL – VLDLc, VLDLr 2 are protective < Dr. Sarma@works 30

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 High , TG - HIGH Dr. Sarma@works HDL – N, LDL –

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

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 ↓HDL IHJ, 2000, 52: 173 -177 Am J Med, 1998, vol 105(1 A), 48 S-56 S Dr. Sarma@works

27 Look at the risks • Low HDL + High LDL + • LP(a) excess > 30 mg% + LDL high ++ • LP(a) excess > 30 mg% + low HDL +++ • LP(a) excess > 30 mg% + Incr. t. HCy ++++ • LP(a) excess + Incr. t. HCy + low HDL 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 Intestinal epithelial cell Through lymphatic system to the liver Biliary cholesterol MTP CM Cholesteryl esters ACAT (esterification) Free cholesterol Dr. Sarma@works excretion ABCG 5 ABCG 8 29 Dietary cholesterol Luminal cholesterol Bile acid Micellar cholesterol uptake Bays H et al. Expert Opin Pharmacother 2003; 4: 77

30 Cholesterol Absorption Lymph Enterocyte Ezetimibe Cholesterol ACAT Avasimibe Dr. Sarma@works NPC 1 L 1 Cholesteryl ABCG 5/G 8 Ester Intestinal Lumen

31 Fat Absorption Liver Biliary Transport and Storage Duodenu m Jejunum Ileum Colon Dr. Sarma@works

Triglyceride Absorption Lymph Enterocyte 2 Fatty Acid + Monoglyceri de DGAT Triglyceride Dr. Sarma@works Intestinal Lumen 32

Chylomicron Formation Lymph CM apo. B 48 Enterocyte Triglyceride Cholesteryl Ester Dr. Sarma@works Intestinal Lumen 33

34 Structure of HDL Particle A-I CE TG A-II Dr. Sarma@works A-I, A-II = apolipoprotein A-I, A-II; CE = cholesterol ester; TG = triglycerides

35 HDL Types 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 Free Chol. UEC HDL L CAT Enzyme Dr. Sarma@works LIVER EC

37 HDL Metabolism and Reverse Cholesterol Transport Bile A-I FC CE SR-BI Liver A-I LCAT CE CE FC ABC 1 FC Nascent Macrophage HDL Mature HDL ABC 1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin: cholesterol acyltransferase; Dr. Sarma@works SR-BI = scavenger receptor class BI

38 Role of CETP in HDL Metabolism Bile Nascent HDL Mature HDL FC SR-BI Liver LDLR A-I CE Macrophage LCAT CE ABC 1 FC SRA CETP X CE FC CE ion at B xid O 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 ↑ LDL Cholesterol Nephrotic syndrome. Hypothyroidism Obstr. liver disease Anorexia nervosa Acute Int. Porphyria Progestogens Dr. Sarma@works Thiazides ↑ TG Obesity Diabetes Uremia Alcoholism, Smoking Oral contraceptives Beta blockers Pregnancy

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 Dr. Sarma@works • Extended Lipid profile includes

42 Clinical Photoes Tuberous xanthoma. Flat-topped, yellow, firm tumor Xanthelasma. Multiple, longitudinal, creamy-orange, slightly elevated papules on eyelids. Dr. Sarma@works

43 Clinical Photoes Tendinous xanthomas. Large sub-cutaneous tumors adherent to the Achilles tendons. Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules Dr. Sarma@works

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, Dr. Sarma@works Angio

45 Treatment Strategy Lipid Profile, Risk Assessment LDL > 100 Look For Sec. Causes Treat the cause, if found Treatment CHD + Sec. Prevention LDL > 100 Dr. Sarma@works 2 or more RF High Risk NO CHD Primary Prevention < 2 RF LDL < 130 Low Risk LDL <160

46 Treatment Plan - LDLc Clinical Status Goal Diet Drugs No CHD < 2 RF <160 >190 No CHD 2 or more RF <130 >160 CHD Present <100 >130 Dr. Sarma@works For Indians all the values must be 20 mg less

47 Treatment Options • • Dr. Sarma@works 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) ¢ HMG is Hydroxy Methyl Glutaryl 6. Probucol

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 Recommended Intake • Saturated fat < 7% of calories • PUFA fat Up to 10% of calories • MUFA fat Up to 20% of calories • Total fat 25– 35% of calories • Carbohydrate 50– 60% of calories • Fiber 20– 30 DIETARY THERAPY grams per day Dr. Sarma@works • Protein Approx. 15% of

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 (N 1) – Olive oil, Gingili oil • PUFA (N 6) – Soya, Sun Flower oil, GN oil • PUFA (N 3) – Fish oils – Twice a wk ↓ Dr. Sarma@works 76% CAD

Treatment of ↑ LDLc High LDLc Therapeutic Lifestyle Change Drug Therapy of Choice: Statin Add on drug - EZ , Niacin, BAR Dr. Sarma@works 51

Statins – Mechanism of Action Cholester ol synthesis HMGCo A Intracellul ar Cholester ol VLDL Apo LDL receptor VLDL B Apo E Apo B R (B–E receptor) synthesis LDL receptor– mediated hepatic uptake of LDL and VLDL remnants Serum LDLC Serum VLDL remnants Serum IDL Hepatocyt Systemic e Circulation 1. Reduce hepatic cholesterol synthesis Dr. Sarma@works (HMG Co. A), 2. lowering intracellular cholesterol, 3. Upregulation of LDL receptor and 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 -2

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 Co. A Reductase Inhibitors (Statins) Statin Range Dr. Sarma@works Dose Lovastatin Pravastatin Fluvastatin Simvastatin Atorvastatin Rosuvastatin 20 mg Cerivastatin 20– 80 mg 20– 40 mg 20– 80 mg 10– 80 mg 5– 0. 4– 0. 8 mg 55

LDL-C Lowering - Statin Dose Atorvastatin Mean % Change from Baseline 211 mg/dl* 38% Simvastatin 219 mg/dl* 56 Daily Dose 10 mg 28% 20 mg 46% 51% 54% 35% 41% 16% with 3 Titrations 13% 40 mg 80 mg Adapted from Jones P et al. Am J Cardiol 1998; 81: 5 Dr. Sarma@works

HMG Co. A Reductase Inhibitors (Statins) Ø Common side effects Ø Headache, Myalgia, Fatigue, GI intol. Flu-like symptoms Ø Increase in liver enzymes – serious problems are very rare Ø Occurs in 0. 5 to 2. 5% of cases in dosedependent manner Ø Myopathy occurs in 0. 2 to 0. 4% of patients Ø Rare cases of Rhabdomyolysis Ø We can reduce this risk by Ø Cautiously using statins in impaired renal function Dr. Sarma@works Ø Using the lowest effective dose 57

58 Short falls of Statins Ø Effectiveness and community impact are to be improved Ø Rebound increase in lipids and ↑ of events after withdrawal of statin Rx. Ø High rate of discontinuation by patients Ø Differences in the efficacy of different statins Ø They reduce only endogenous lipids – Individual variation Ø Modest effect on TG and HDL, No effect on Lp(a) Ø Dr. Sarma@works No effect on chylomicrons; escape

59 Ezetimibe Lymph Intestinal Lumen Enterocyte Cholesterol ACAT X NPC 1 L 1 Cholesteryl ABCG 5/G 8 Ester Dr. Sarma@works Ezetimibe

60 Dual Inhibition LDL apo. B 100 Liver Stati n Duodenu m X VLDL apo. B 100 X Ezetimibe Jejunu m Ileum CM Remnant apo. B 48 Dr. Sarma@works CM apo. B 48 Colon

Mean % Change in LDL-C from Baseline Ezetimibe Efficacy (“ 10 + 10 = 80”) Dr. Sarma@works Ezt + Ator 10+10 mg (n=65) 61 Atorvastatin 10 mg (n=60) – 37% 20 mg (n=60) – 42% – 53% 40 mg (n=66) 80 mg (n=62) – 45% – 54% P < 0. 01 Ballantyne CM et al. Circulation 2003; 107: 240

Bile Acid Resins: Mechanism of Action Gall Bladder Bile Acid Enterohepatic Terminal Ileum Excretion BA Recirculation Reabsorption of bile acids Cholesterol 7 - hydroxylase Conversion of cholesterol to BA Secretion BA Liver LDL Receptors VLDL and LDL removal Net Effect - LDL-C Dr. Sarma@works 62

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/d. L) Dr. Sarma@works

64 Bile Acid Resins Drug Range Dose 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 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 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 ØSmoking Ø Obesity (visceral fat), Physical inactivity Ø Very high Carbohydrate diet Ø Type II Diabetes Ø Hyper-triglyceridemia Ø Drugs like beta-blockers, androgenic steroids Dr. Sarma@works androgenic progestins 67

Nicotinic Acid – Mechanism of Action Mobilization of FFA Apo B VLDL TG synthesi s Liver VLDL secretio n VLDL Serum VLDL results in reduced lipolysis to LDL Serum LDL HDL Circulatio n Systemic Hepatocyt Systemic e 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 1 g/d 2 g/d 3 g/d Adapted from Knopp RH. N Engl J Med 1999; 341: 4

Nicotinic Acid Products available Ø Immediate-release, 2– 4 g/d, Sustained Release 3 g /d Ø Extended-release (Niaspan®) 1– 2 g/d Ø Best agent to raise HDL-C Ø Reduces coronary events Ø Adverse effects Ø Flushing, itching, headache (immediate-release, Niaspan®) Ø Hepatotoxicity, GI (sustained-release) Ø Activation of peptic ulcer Ø Hyperglycemia and reduced insulin sensitivity Ø Contraindications Dr. Sarma@worksØ Active liver disease or unexplained LFT elevations Ø 70

Coronary heart disease and HDL-C Framingham Heart Study Rate/1000 200 150 100 50 Women 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 HDL cholesterol <47 mg/dl High HDL cholesterol 47 mg/dl Low total cholesterol 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 Risk of CAD over 4 years of follow-up* CHD RR 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 Ø LDL cholesterol is primary target of therapy Ø Weight reduction and increased physical activity (if the metabolic syndrome is present) Ø Non-HDL cholesterol is secondary target of therapy (if triglycerides 200 mg/d. L) Ø Consider nicotinic acid or fibrates (for patients with CHD or CHD risk Dr. Sarma@works

Treatment of ↑ TG High TG Therapeutic Lifestyle Change Drug 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 + 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% > 500 mg% High Diet + drugs Very high Diet + Intensive Rx Dr. Sarma@works NCEP 2002 Guidelines by expert panel on TG

Fenofibrate Mode of Action v Enhances the activity of lipoprotein lipase v Reduces hepatic fatty acid synthesis v Inhibits HMG co-enzyme A reductase activity v Reduces the CETP activity v Increases the LCAT activity v Increases the production of Apo AI and

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 Dr. Sarma@works Contraindications •

80 Fibric Acid Derivatives Drug Clofibrate Bezafibrate BID Dose 1000 mg BID 200 mg Gemfibrozil BID Fenofibrate OD Fenofibrate micronized Dr. Sarma@works 600 mg 200 mg 160 mg

Treatment of ↑ LDL + ↑ TG Combined Therapeutic Lifestyle Change Drug Therapy of Choice : Statin + Fibrate Add on drug – Niacin, BAR Dr. Sarma@works 81

82 Statin + Fibrate Percent Change Simva + Gemfibrozil 16% 230 332 HDL Ator or Simva + Fenofibrate 22% 166 191 38 LDL HDL 34 LDL TG – 39% – 50% – 28% TG – 41% Da Col PG et al. Curr Ther Res Clin Exp 1973; 53: 473 Dr. Sarma@works

83 Statin + Fibrate – Precautions Ø Use statin alone for non-HDL-C goals Ø Use fish oils or niacin rather than fibrates Ø Keep the doses of the statin and fibrate low Ø Dose the fibrate in the AM and the statin in the PM Ø Avoid (or cautiously use) combo in renal impairment Ø Teach the patient to recognize muscle symptoms Ø Discontinue therapy if muscle symptoms are Dr. Sarma@works present and CK is >10 times the upper limit

84 Probucol 1. Probucol (Lorelco) 500 mg 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 DL ↓ H IN AC NI ↑T FIB G RA TE The Three Canons DYSLIPIDEMIA ↑ LDL STATIN Dr. Sarma@works

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 Fibrate Exercise ↑ TG + ↓ HDL Fibrate + Niacin Statin Exercise Statin + E, N, BA, Myo risk ↑ ↑ Dr. Sarma@works ↑ LDL + ↑ TG + ↓ 86

Atherogenecity of small, dense LDL SDL is highly atherogenic. It Ø Generates free radicals Ø Increases trans endothelial filtration Ø Increases susceptibility to oxidation Ø Reduces affinity for the LDL receptor Ø Increased binding to intimal proteoglycan Ø ↑ Formation of pro-aggregators / vasoconstrictors Ø Impaired in vivo ED independent of HDL, LDL, TG

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 Dr. Sarma@works • Nicotinic acid, ? Bezafibrate, Estrogens

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 % Cumulative 60 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/d. L) Austin M et al. Circulation. 1990; 82: 495 -506.

Cumulative Distribution of HDL levels Phenotypes A and B 100 90 80 70 % Cumulative 60 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/d. L) Austin M et al. Circulation. 1990; 82: 495 -506.

Metabolic Syndrome - Characteristics

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 mm. Hg. § 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 B 6 and B 12 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. B 6 and B 12 are to be given on regular basis Dr. Sarma@works

Summary of Drug choice Lipid abnormality type Advised Rx. Remarks ↑ Homocysteine Folic acid B 6 + B 12 helps ↑ Small dense LDL Statin + Fibrate Aggressive Rx. ↑ Little ‘a’ or LP(a) Niacin Statin no effect ↑ Phenotype B Under research DM, Obesity ↓ ↓ in Phenotype A Under research Aerobic exercise Dr. Sarma@works 96

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 Dr. Sarma@works Niacin Niasyn, Nialip, Nicocin 97

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 v Elevated TG v Elevated VLDL v Diabetics must Reduced HDL-C All v v be given Increase in SD-LDL STATIN Decrease in Apo A I v Increase in Apo B v Ratio of Apo A I / Apo B < 1 Dr. Sarma@works

Diabetes Treatment and Lipids Type Rx used Effect on lipids 1. Insulin 2. Metformin 3. Sulfonylureas 4. Glitazones Favourable 5. Acarbose No effect Dr. Sarma@works Favourable Mildly favourable Not favourable 100

Hypertension Treatment and Lipids Type Rx used Effect on lipids 1. Diuretics Unfavourable 2. Indapamide favourable Mildly 3. ACEi and ARB favourable Very 4. Betablockers Unfavourable 5. Ca channel blockers No effect Dr. Sarma@works 101

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 Dyslipidemia and food CHD Avoid salty, savory, preserved food, NV Hypertension, CVA Do the minimum required exercise Diabetes, IR, ↓ HDL, OA Dr. Sarma@works 102

Where are we heading ? ? 2004 20000 B. C. Paleolithic sup. age Neolithic age 19 th century 21 st century Technology has changed a lot in the way Processed Hunting-gathering live foods we subsistence High level of physical activity Animal fats and glucides ¯ Dietary fibre But, we have not Thrifty genotype Sedentary altered our 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. o rg 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 Dr. Sarma@works A HAPPAY NEW YEAR