Cholesterol. Objectives. Case #1. Case #2 8/6/2012 CHOLESTEROL BASICS: A REVIEW. Cholesterol Basics ATP 3 guidelines

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1 Objectives Cholesterol Ben Brown MD July 2012 With thanks to Fasih Hameed MD & Wendy Kohatsu MD Cholesterol Basics ATP 3 guidelines Two tools how to use with your patients. Lifestyle Management Meds: Basics One special case-expanded lipid panel. Case #1 38 yo Hispanic male, fam hx of CVD, 198 lbs, BMI 32. Case #2 58 yo woman, slender, healthy eater with h/o ischemic stroke age 58. Year later, ischemic bowel. CHOLESTEROL BASICS: A REVIEW Lp(a) = 162 1

2 Why do we even have Cholesterol? 1.Plasma Membranes 2.Myelinated structures in the CNS 3.Inner Mitochondrial Membranes 4.Bile Acids 5.Steroid Hormones and Sex Hormones 6.Ergosterol (UV skin) Vit D3 How do lipids go bad 1.Endothelium damage HTN/Stress 2.Oxidized LDL, Glycocylated LDL and Foam Cells = more atherogenic Sticky (Also acetylated LDL) Macrophages 3.Plaque and rupture Anatomy of the Atherosclerotic Plaque Lumen Intima Media Lipid Core Elastic laminæ Fibrous cap Shoulder Internal External Cholesterol General What is the Best Lipid predictor of CHD in Framingham Study? a. Total Cholesterol b.ldl c.hdl d. Hs-CRP e. TC/HDL ratio 2

3 Cholesterol General What is the Best Lipid predictor of CHD in Framingham Study? a. Total Cholesterol b.ldl c.hdl d. Hs-CRP e. TC/HDL ratio Cholesterol General Total Cholesterol/HDL ratio (TC/HDL) TC/HDL ratio 1 unit = CHD risk by 60% Eg: TC/HDL ratio of <4 is normal 6 = 120% increased risk 3 = 60% decreased risk ATP 3 GUIDELINES TWO TOOLS: AT A GLANCE AND IPHONE APP (?ANDROID) Out patient Management-Case Healthy 48 y/o woman routine screen reveals an LDL of TC 255/L 171/H63/TG180? 3

4 CASES: WORK TOGETHER WITH GUIDELINES 4

5 CASE 1 CASE 2 CASE 3 CASE 4 CASE 5 CASE 6 5

6 Name three TLC recommendations Therapeutic Lifestyle Changes in LDL-Lowering Therapy TLC Diet Reduced intake of cholesterol-raising food Saturated fats <7% of total calories Dietary cholesterol <200 mg per day LDL-lowering therapeutic options Plant stanols/sterols (2 g per day) Viscous (soluble) fiber (10 25 g per day) Weight management Increased physical activity Plant Stanols/sterols 8 RCT s Cholesterol absorption reduced by 50% ~ Dose of 1-3 grams sterol esters/day LDL cholesterol drop of 6-15% 6

7 Fiber Soluble fiber has greater LDL lowering potential Examples of soluble fiber: oats, barley, psyllium, nopales, beans 3-5% lowering of LDL w/10 g soluble fiber/d Total fiber intake inversely related to CHD grams/day Circulation 2002;106:3143 Fiber Grain consumption was inversely correlated with elevated CRP levels. Whole grains contain fiber, lignans, magnesium, zinc, B vitamins, and vitamin E Inverse relationship between dietary fiber and risk of elevated CRP Greater protection was seen at total fiber level > 22 grams/day. Eur J Clin Nutr 2005; 59: Am J Clin Nutr 2006; 83(4): Food Sources Soluble Fiber Oatmeal Legumes such as beans and peas Carrots Apples Pears Nuts Barley Flax seed Oranges Psyllium husk Wendy s Brief Nutrition Advice 1) Double your veggies! 2) At least 25 grams fiber per day 3) Get good oils Also handout on residency web site DM, Inflammation (CRP) and Fiber Study of 522 diabetic patients 15 grams of dietary fiber for every 1000 calories daily (with lifestyle changes = moderate exercise Significantly reduced CRP by 27%. Diabetologia 2009; 52:

8 ATP III :Therapeutic Lifestyle Changes Nutrient Recommended Intake Saturated fat Less than 7% of total kcals Polyunsaturated fat Up to 10% Monounsaturated fat Up to 20% Total fat 25 35% Carbohydrate 50 60% Fiber grams per day Protein ~15% of total kcals Cholesterol Less than 200 mg/day Total calories (energy) Balance energy intake and expenditure to maintain desirable weight/ prevent weight gain Return to later Step 8: ID Metabolic syndrome defined as A. A waist circumference of M/W? B. Triglycerides of? C. HDL M/W? D. BP S/D? E. Fasting glucose? F. And How many do you need? ATP III Guidelines Drug Therapy 8

9 Progression of Drug Therapy in Primary Prevention Initiate LDLlowering drug therapy If LDL goal not If LDL goal achieved, 6 wks not achieved, 6 wks intensify drug Q 4-6 intensify therapy or mo LDL-lowering refer to a lipid therapy specialist Monitor response and adherence to therapy Start statin or bile acid sequestrant or nicotinic acid Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid If LDL goal achieved, treat other lipid risk factors Drug Therapy 1) HMG CoA Reductase Inhibitors (Statins) Reduce LDL-C 18 55% & TG 7 30% Raise HDL-C 5 15% Major side effects Myopathy Increased liver enzymes Contraindications Absolute: liver disease Relative: use with certain drugs HMG CoA Reductase Inhibitors (Statins) (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Reduce coronary procedures (PTCA/CABG) Reduce stroke Reduce total mortality Statins: Drug-Nutrient Side Effects Nutrients Depleted Coenzyme Q10: Statins inhibit the enzyme HMG CoA reductase that is required to make cholesterol and Coenzyme Q10. Could explain myalgia, exercise intolerance, myoglobuinuria Also, Selenium, Zinc, Copper Lower serum PUFA s and alter the relative % of omega 6:3 fats Drug Therapy 2) Bile Acid Sequestrants Ex: cholestyramine, colestipol, colesevelam Major actions Reduce LDL-C 15 30% Raise HDL-C 3 5% May increase TG Contraindications Dysbetalipoproteinemia Raised TG (especially >400 mg/dl) Arch Neurol 2004;61(6):889 Nutr Metab Cardiovasc Dis 2005; 15(1): 36 9

10 Bile Acid Sequestrants (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Side effects GI distress/constipation Decreased absorption of other drugs Decreases beta-carotene, calcium, folate, Fe, Mg, Vit B12, D, E, K & zinc (cholestyramine) 3) Nicotinic Acid Drug Therapy Major actions Lowers LDL-C 5 25% Lowers TG 20 50% Raises HDL-C 15 35% Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Contraindications: liver disease, severe gout, peptic ulcer Nicotinic Acid Nicotinic Acid (continued) Drug Form Range Immediate release (crystalline) Extended release Sustained release Dose g 1 2 g 1 2 g Demonstrated Therapeutic Benefits Reduces major coronary events Possible reduction in total mortality 4) Fibric Acids Drug Therapy Example: gemfibrozil, fenofibrate, clofibrate Major actions Lower LDL-C 5 20% (with normal TG) May raise LDL-C (with high TG) Lower TG 20 50% Raise HDL-C 10 20% Contraindications: Severe renal or hepatic disease Fibric Acids (continued) Demonstrated Therapeutic Benefits Reduce progression of coronary lesions Reduce major coronary events Side effects: dyspepsia, gallstones, myopathy Drug-nutrient interactions: Decrease CoQ10 also, Vitamin E, (fenofibrate incr s homocysteine) 10

11 Cholesterol General Balanced LDL-C levels 1.Human Infants 40-60mg/dL 2.Primates 60mg/dL 3.South American tribes 60mg/dL 4.RCCT s with statins demonstrate reductions in CHD, MI, ischemic CVA, CHF, CRI and other CVD with LDL-C reductions to 60mg/dL Anxious 50y/o middle eastern man with multiple comorbidities, lipids normal, tells you he has a very Strong Fhx of early heart disease (3 relatives died in late 40 s MI s). SPECIAL CASES: EXPANDED LIPID PANEL (MORE LATER) Why bother with more testing? 1. Understand pathophysiology: understand innovation Better assess specific patients 2. Not all lipids are the same risk: impact of LDL size & number HDL subtypes 3. Other Risk Factors missed with typical lipid panel FHx early CADz and close to normal lipids Metabolic Syndrome and need more info to change Catching INFLAMMATION early & preventing disease 11

12 Expanded Lipid Profiles Lipoprotein Particle Analysis (LPP) Spectracell Berkeley HeartLab (BHL) NMR: Liposcience VAP: Atherotec **Quest: Lipid/HSCRP/Lipo(a)/hom ocysteine/apob What s Different Other Risk Factors ATP III Lipid Tests 1. TC 2. LDL 3. Non-HDL Chol 4. HDL chol 5. VLDL 6. Chol/hdl ratio 7. TG New stuff 1.Hs-CRP 2.Homocysteine 3.Lipoprotein (a) 4.Apolipoprotein B 5.Some do other tests (HDL-2, -3 subtypes, small-dense LDL pattern, etc) Homocysteine ApoB Lp(a) Effect of LDL size and number Different types of HDL Why inflammation is important Homocysteine Apo B Normal < 10.0 umol/l Methylation Functions primarily to protect DNA How to help For most Mediterranean Diet adequate, if still a problem may need supplementation B6 25 micrograms/d B micrograms/d Folate 800micrograms/d (may need as methyl THF) Normal level < 60 mg/dl 12

13 LipoProtein (a) Objectives Lp(a) is an inherited abnormal protein attached to LDL. Normal level < 30 mg/dl Lp(a) increases coagulation and triples CVD risk. Treatment options: Niacin NAC Cholesterol Basics: a review Know ATP 3 guidelines Two tools how to use with your patients. Know what Lifestyle Management means and how to do it in the context of an office visit. Know Meds: Basics Know one special case when you want to go the extra step-expanded lipid panel. Avocado Small randomized cross-over trial, N = 15 Other considerations High avocado diet (20-35% total kcals) TC -8.2% (p<0.05) One avocado per day (yum!) Apo (B) HDL stable High complex carb diet (AHA step III) 20% fat TC -4.9% (ns) No avocado :-( Apo (B) no change HDL 14% Am J Clin Nutr 1992; 56:671. Eggs RCT n = 49 2 eggs per day x 6 weeks NO CHANGE in TC (204, 205) No signif change in LDL (124, 129) Control group was oatmeal* and TC 194, LDL 116 Intl J Cardiol 2005; 99(1):

14 Red Yeast Rice Statin vs. Lifestyle + Supplements n = 74 patients, randomized for 3 months LDL reduction with Red Yeast Rice 12 week trial, n = mg RYR vs placebo LDL 23% (175 to 135 mg/dl) TG 15% (146 to 124 mg/dl) Simvastatin 40 mg + AHA handouts on diet and exercise Lifestyle counseling -- weekly with group Red yeast rice (up to 3.6 grams/d) Fish oil 3.8 g (EPA + DHA) P <0.05 Am J Clin Nutr 1999;68:231 Mayo Clin Proc 2008;83(7):758 Statin vs. Lifestyle + Supplements Simvastatin 40 mg LDL-C 40% Lifestyle + Supp s LDL-C 42% TG 9% TG 29% (p<0.05) Mayo Clin Proc 2008;83(7):758 LDL: particle size and number Small LDL= pattern B Bigger is Better Small LDL is the bad guy why? it goes across the endothelium more readily absorbed by macrophages more readily Less is more (better) ApoB ( one per particle) scientifically accepted measurement for LDL particle number. Can be used to Monitor statin therapy requires. 14

15 HDL Inflammation HDL 2 (a and b) Again bigger is better HDL 3 Smaller less protective Hs-CRP Inflammatory marker Better then ESR and leucocytes for predicting vascular events Lp-PLA2 Slightly more specific for vascular inflammation Low risk <200 mg/ml Low Risk level < 1.0 mg/l 72 y/o woman obese, htn, IGT, depression. What is my risk of heart disease or stroke? How do you answer this question? Can you do it in a way that furthers the patients motivation to change and is affordable? Case # 3 Thoughts after test How to treat Routine lipid panel At Goal HDL = 65 VLDL = 18 Chol/HDL ratio =3.2 TG s = 90 moderate risk TC = 211 LDL = 128 Non-HDL chol = 146 Advanced Risk Markers High Risk hscrp = 4.88[<1] sd-ldl = 36.2[20] Moderate Risk Apo B 113[<60] Homocysteine 11.2(<10) At Goal Lp-PLA (<200) NCEP ATC diet with goal of dropping 5-10% weight Lower carbohydrate, higher fiber diet Omega 3 fats; substitute olive oil Screen for DM, hypothyroidism Lower LDL* 15

16 Back to Case #1 38 yo Hispanic male, fam hx of CVD, 198 lbs, BMI 32. Rx: Exercising more; walking Watching portion sizes, esp carbs 20 lb weight loss Still has TG 264; starting fenofibrate in addn. Back to Case #2 58 yowoman, slender, healthy eater with h/o ischemic stroke age 58. Year later, ischemic bowel. Lp(a) = 108[nl<30], ApoB= 176[<60] Rx: Adamantly refusing pharmaceutical Rx Trial of niacin failed miserably despite very low dose Now considering NAC, +/-red yeast rice Summary Know the ATP III (Adult Treatment Panel) guidelines. Know when to get extra testing Be familiar with basic lifestyle counseling Wendy s nutrition advice 1) Double your veggies! 2) At least 25 grams fiber per day 3) Get good oils Know your basic cholesterol medication categories 16

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