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Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine.

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Presentation on theme: "Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine."— Presentation transcript:

1 Dyslipidemia and Atherosclerosis Eliot A. Brinton, M.D. Associate Professor Cardiovascular Genetics Division of Cardiology Department of Internal Medicine University of Utah School of Medicine

2 HDL2 HDL3 LDL IDL VLDL Chylomicron 1.006 plasma pre-β HDL Lipoproteins by Size and Density



5 Pre-β HDL

6 AdiposeHeartMuscle Lipoprotein Lipase HMG CoA Reductase Dietary Cholesterol 100-500 mg/day (40-50% absorbed) Bile acids 300 mg Cholesterol 600 mg Biliary Chol. 700 mg/day Bile Acids 20 g/day 98.5%reabsorbed TRIG ketone bodies CO 2, H 2 O OtherTissues intestine, skin, adrenal, ovary, testes, atheroma / macrophages macrophages VLDL Apo C’s Apo B-100 Apo E IDL Hepatic Lipase apo E LDL pre-β 1 HDL (two apo A-I) pre-β 2 HDL (+PL=disc) pre-β 3 HDL (+UC in disc) HDL 3 PLFC LCAT PLFC “LDL Pathway” LDL Receptors CETP TG CE HDL 2a HDL 2b HepaticLipase CHOL Dietary Fat 60-100 g/day (98% absorbed) free fatty acids Chylomicron Apo B-48 (Apo A-I)

7 Familial Hypercholesterolemia (FH)

8  LDL AdiposeHeartMuscle Lipoprotein Lipase Bile Acids CHOL ffa VLDL TRIG “LDL Pathway” HMG CoA Reductase OtherTissues ketone bodies CO 2, H 2 O  IDL HDL HDL FamilialHypercholesterolemia(heterozygous) ½ normal LDL Receptors Statins



11 Non-Fatal CAD in FH (Utah) vs. General U.S. Population

12 What FH May Mean for a Family 45 ♥ 334 47 ♥ 42218 38 ♥ 34 ♥ 347 40 ♥ 373 41 ♥ 34 ♥ 16284189420182 4218031158 1213217157182851913021311221356291133441411815255 40 ♥ 373 Affected Age at MI Total Chol Key

13 “Pure” Hypercholesterolemia Monogenic Syndromes ­Familial hypercholesterolemia (FH) LDL receptor mutations (over 800 distinct types)LDL receptor mutations (over 800 distinct types) 1/500 in general population (heterozygotes)1/500 in general population (heterozygotes) ­Familial defective apo B (FDB) (minority of FH) Ligand defect not receptor defectLigand defect not receptor defect Apo B mutations (3500, etc.)Apo B mutations (3500, etc.) ­PCSK9 mutations (rel rare, 1/50 FH families) ­Autosomal recessive hypercholest. (v. rare)

14 “Pure” Hypercholesterolemia Other causes ­Polygenic hypercholesterolemia Very CommonVery Common Genetics poorly definedGenetics poorly defined Mechanisms poorly defined (likely includes hyperabsorbers)Mechanisms poorly defined (likely includes hyperabsorbers) Generally milder than FHGenerally milder than FH ­Diet-induced Very commonVery common Generally much milder than FHGenerally much milder than FH ­“Secondary” causes Hypothyroidism—rel. common in elderly but ↑LDL mildHypothyroidism—rel. common in elderly but ↑LDL mild Other (rare hepatic and renal abn., etc.)Other (rare hepatic and renal abn., etc.)

15 VLDL overproduction ­Associated Lipid Abnormalities: Mild-moderate ↑VLDL-C/Plasma TGMild-moderate ↑VLDL-C/Plasma TG Mild-moderate ↓HDL-CMild-moderate ↓HDL-C Small, dense LDL (and HDL)Small, dense LDL (and HDL) Mild ↑LDL-CMild ↑LDL-C ­1 o mechanism of familial combined hyperlipidemia (FCHL) and familial HTG (mechanism of difference unclear) ­Strongly associated with central adiposity: Major mechanism for ↑TC and ↑TG with agingMajor mechanism for ↑TC and ↑TG with aging Almost always helped by weight lossAlmost always helped by weight loss


17 Metabolic Syndrome DM-2 FCHL ↑Apo B ??? ? “Classic” DM-2 “Isolated” ↑Apo B “Isolated” Metabolic Syndrome Adapted from John Brunzell, personal communication, 2005 Overlap Among Metabolic Syndrome, Diabetes Mellitus-2, ↑Apo B and FCHL

18 Despite Elegant Science of Abnormalities of Lipoprotein Metabolism, Treatment of Dyslipidemias is Nearly Always Just According to Lipid Levels!

19 Atheroprevention in Diabetes Mellitus

20 National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. Atherosclerosis in Diabetes ~80% of all diabetic mortality –75% from coronary atherosclerosis –25% from cerebral or peripheral vascular disease >75% of all hospitalizations for diabetic complications >50% of patients with newly diagnosed type 2 diabetes already have CHD

21 Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic Men Multiple Risk Factor Intervention Trial (MRFIT) Rate/1000 1 2 3 4 5 Serum Cholesterol Quintile Bierman EL, Arteriosder Thromb, June 1992 Based on data from J. Stamler ● ● ● ● ● ● ● ● ● ●


23 Diabetes and glucose intolerance vs. cardiovascular mortality Men Women Bedford Study, Keen, et al. Lancet. 2:505–508, 1965. 10 year CVD mortality (%) Normal IGT DMNormalIGTDM 40-5960+ Age (years)

24 HBP  Inflam, cytokines  insulin  Gluc/DM (ox/glycox)  TG Dense LDL Low HDL  Coag. Endothelial dysfunction Insulin Resistance Interrelationship Between Obesity, Insulin Resistance, DM and Atherosclerosis Obesity, etc. Atherosclerosis

25 ATP III: Insulin Resistance Syndrome (“The Metabolic” Syndrome* ICD9 277.7) *  3 risk factors = Insulin Resistance † Abdominal obesity is more highly correlated with metabolic risk factors than is  BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. <40 mg/dL <50 mg/dL Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women  100 mg/dL Fasting glucose  130/  85 mm Hg Blood pressure HDL-C  150 mg/dL TG Abdominal obesity † (Waist circumference ‡ ) Defining LevelRisk Factor

26 Insulin Resistance Syndrome Prevalence: NHANES III Data; ATP III Criteria 24% of total US Population (47 million pts) 32% of US Hispanics 26% higher Hispanic women vs. men 57% higher in Black women vs. men 43% of total population > 60 y old Ford E, et al JAMA 287:356-9, 2002

27 Fredrickson Type III (Familial Dysbetalipoproteinemia) Definition ­TGRL remnant (IDL) excess ­VLDL-C/Plasma TG  0.30, TG >150 mg/dl ­Apo E 2/2 + other abn (VLDL overprod?); or apo E deficiency ­Palmar (flat and orange) and/or tuberoeruptive (elbow) xanthomas Prevalence and Athero Risk ­193 NIH referrals for TG >190 mg/dl and familial  lipids, 49 (25%!) had type III. ­37% of these type III patients had CAD (average onset of 38 yo) Fredrickson DS, Morganroth J, Levy RI. Ann Intern Med 1975; 82:150-157 Morganroth J, Levy RI, Fredrickson DS. Ann Intern Med 1975; 82:158-174

28 TG and HDL vs. Risk of Premature CAD 653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM, cigarette smoking and LDL cholesterol Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.

29 LDL-C at follow-up (mg/dL) 0 5 10 15 20 25 30 90110130150170190210 Percent with CHD event CARE--Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI 2° Prevention 1° Prevention WOSCOPS-PI WOS COPS-Rx AFCAPS/ TexCAPS-Rx AFCAPS/ TexCAPS-PI GREACE-UC GREACE-Rx HPS 2 o -Pl CPPT-Pl CPPT--Rx POSCH-Pl POSCH—Rx HPS 2 o -Rx HPS 1 o -Pl HPS 1 o -Rx CHD Events vs. LDL-C: Statin and Non-Statin Trials

30 NCEP ATP Update—2004 Risk CategoryRisk FactorsLDL-C Goal Lower 0-1 RF <160 Mod/Mod-High>2 RF, FRS <20% <130 HighCVD alone or FRS >20% <100 Very HighCVD+DM, MS, ↑↑RF, ACS <70* In High and Very High Risk categories – –Consider statin Rx even if already at goal – –Consider combination Rx—statin + fibrate or niacin—if TG>200+NHDL- C>130 or HDL-C<40 Statin Rx for 30-40% ↓LDL-C (R-5, A-10, S-20, F,L,P-40) in > mod. high risk vs. don’t use lower doses 65-80 yrs: 2 o prev as younger; 1 o prev+DM=high risk; other, use clinical judgment Non-HDL-C: use if TG>200; goal as LDL-C+30 Grundy, et al. Implications of Recent Clinical Trials for NCEP ATP III. Circ. July 13, 2004;110:227-239. *Therapeutic option: use clinical judgment

31 More Aggressive Lipid Treatment “BEIGE” Broader use of treatment (TLC and meds) Earlier use of medications (may not wait for TLC) Increased intensity of Rx Getting to goal Evaluation of progress, follow-up (esp. compliance which is <50% at 1 year!!!) Modified from AM Gotto AHA mtg 11/05

32 Factors Not Included in the Framingham Risk Score CVD (FRS designed for 1 o prevention) Diabetes Mellitus (FRS not used in DM in ATP III) Metabolic Syndrome (TG, glucose, obesity, DBP) Family History of CHD Emerging risk factors Diet and exercise Higher risk in non-Caucasians Further risk increase above 79 years old Risk beyond 10 years in future (underestimates risk in young adults)

33 May adjust the LDL-C goal from NCEP table up or down by 30 mg/dl per: 1. Position within risk category (add if  risk, subtract if  ), or factors not in Framingham score (e.g. DM, IR) 2. Overall health (add if  quality/ quantity, subtract if  ) 3. Patient’s wishes (add if fears R x, subtract if fears atherosclerosis) Clinical Judgment for NCEP ATP Update—2004 (per Dr. E. A. Brinton)

34 Choice of HMG-CoA Reductase Inhibitors (“Statins”) 1. Lovastatin (Mevacor, Altoprev, generic)—  events (1 o prev.), longer experience, generic and extended release available 2. Pravastatin (Pravachol)—v. good event  data (1 o and 2 o prevention), safer in combo? 3. Simvastatin (Zocor)—best 2 o prev. data, DM/2 o prev. indication (any LDL-C),  max efficacy, cost effective (  events) 4. Fluvastatin (Lescol)—  athero and events, cost effective (low- mod lowering), safer in combo? 5. Atorvastatin (Lipitor)—good event  data (A80 > P40 or A10, 2 o prev),  max effic., cost eff. (mid  LDL-C), good  CRP 6. Rosuvastatin (Crestor)—  max efficacy, v. cost-effective ($17/mo for ½ of R40 qod), event data pending, safety = other statins, good  CRP, better resp. to added ezet?

35 Diet (Medical Nutrition Therapy, MNT), and Lifestyle (Therapeutic Lifestyle Change, TLC) for Atheroprevention

36 Intensive Lifestyle Changes and CAD Reversal (Ornish D, et al. JAMA 1998; 280:2001) p = 0.02 p = 0.001

37 Finnish Mental Hospital Study Study Design and Serum Cholesterol Diet changed in hospital N Diets reversed Data for males shown here. Total in each hospital about 3500. About 70- 75% remained in hospital all 12 years Miettinen M, et al. Lancet 1972; ii: 835

38 Finnish Mental Hospital Study Age-adjusted death-rates (per 1000 person-years) MalesFemales CHDTotalCHDTotal Hospital N, diet 5.734.64.031.1 Hospital N, control Hospital K, control Hospital K, diet 7.535.16.530.7 Pooled diet 6.634.85.230.9 Pooled control Miettinen M, et al. Lancet 1972; ii: 835

39 Non-Medical Treatments (TLC) for Dyslipidemias Diet (MNT) Low saturated fat (5-10% ↓LDL-C); low cholesterol? Whole grains, fruits, vegetables, legumes, non-fat dairy? hard water? (~5% ↓LDL-C) Supplements –Plant sterol/stanol ester margarine (5-10% ↓LDL-C) –Soluble fibers (~5% ↓LDL-C) –Red Yeast Rice/Cholestin (lovastatin + other statins?)—% ↓LDL-C & safety issues not well documented –Niacin (Rx effective but AHA recommends against DS NA for lipids) –Fish oil (Rx effective but AHA and FDA against DS ω-3 at TG ↓doses, DS ok anti-plt) –Flaxseed oil (little conversion to EPA/DHA, few data, ok for vegans) –Phospholipids, garlic, biotin, etc. not well documented –Folate, B6, B12—↓Hcy but ↓CVD not seen yet

40 Non-Medical Treatments for Dyslipidemias (cont.) Exercise How? (aerobic, anaerobic, stretching all beneficial) How often? (2/wk to constant) What benefits? –↓Obesity, ↑mood/↓depression, ↓insomnia, –Plasma factors: ↓TG, ↑HDL-C, ↑ LDL size?, ↓Glucose, ↓CRP? –↑Collateral vessels –↓CVD (but protection not absolute) –↑Longevity Smoking Cessation Will to quit essential Non-medical treatment effective (hypnosis, behavior modif.) Several good medications available

41 Atheroprevention Beyond LDL-C and Statin Monotherapy: Non-Statin Treatment

42 CHD Risk Prediction by HDL-C vs. LDL-C* LDL-C (mg/dL) HDL-C (mg/dL) Adapted from and reprinted with permission from Castelli WP. Can J Cardiol. 1988;4(suppl A):5A. RR of CHD After 4 yr *Data represent men age 50–70 yr from the Framingham Study. Patient 2: LDL-C: 100 mg/dL HDL-C: 25 mg/dL Patient 1: LDL-C: 220 mg/dL HDL-C: 45 mg/dL

43 Univariate Regression R2R2 N=44,170; total CHD events = 3869 R 2 denotes the proportion of variance. TC = total cholesterol. Rx Changes HDL and TC/HDL are Best predictors of CHD Risk Reduction Alsheikh-Ali AA, et al. Increases in HDL-C are the strongest predictors of risk reduction in lipid intervention trials [poster]. AHA Scientific Sessions 2004; November; New Orleans, La.

44 Hypothesized Antiatherogenic Mechanisms of HDL Reverse cholesterol transport Antioxidant effects Anti-inflammatory effects Anti-thrombotic effects? Direct blocking of LDL effects? Other?

45 Reverse Cholesterol Transport A-I Liver CE UC PL&UC LCAT UC Bile SR-BI A-I ABCA1 Macrophage CE B CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein Adapted from C Cuchel et al. Art Thromb & Vasc Biol 2003;23:1710-12 LDL-R VLDL/LDL CETP Mature HDL Nascent HDL CE SR-A Oxidation PL

46 12-Lipoxygenase HPODEHPETE OxidizedLDL


48 Medications which Raise HDL-C Levels AgentHDL-C Effect Nicotinic acid  15-35% Fibrates  5-20% Statins  5-15% TZD’s (esp pio)  5-20% Estrogens  10-25%  -blockers  10-20% Alcohol  5-10% Belalcazar LM et al. Progress in Cardiovascular Disease 1998;41:151-174.

49 Effect of Niaspan on Lipids and Glycemic Control in Patients with Diabetes Mellitus (ADVENT) Grundy et al, Arch Int Med 162:1568-76, 2002 * median values

50 CDP at 6 yr: Nonfatal MI by Baseline FBG* mg/dL Relative Hazard 0.700.740.730.44 *Z for interaction = –0.35. Indicates homogeneity Event Rate (%)  126 Placebo Niacin Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.

51 Niacin Reduces MI Regardless of Increase in Fasting Glucose Change in FPG (baseline to 1yr) CDP data. Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.

52 Maximizing Niacin Tolerability Niacin ER (Niaspan), or ERNL (Advicor), far less flushing than IR (?SR qd?) Take with –ASA 325mg (buffered, not enteric-coated) vs. Alka- Seltzer –Diphenhydramine (Benadryl) 25-50 mg –CaCO 3 (Tum) vs. snack (vs. buffered ASA) Gradual uptitration (1 mo each at 500 and 1000 mg/d, re-do if off > 2 wks) Avoid with: EtOH, hot liquids, spicy foods Consider dosing in am (vs. hs) Watch glucose (also uric acid/gout, GI Sx if Hx) Remind pt: flushing not harmful, niacin is a vitamin, D/C antioxidants!

53 No-Flush Niacins Types Niacinamide/Nicotinamide Acipimox Inositol Hexaniacinate Lipid Effects Few or none Evidence for CHD Prevention None Not recommended for atheroprevention!

54 HDL- Clinical Summary Levels--Basal vs. Intervention 1. HDL is protective, but 2. Lowering it may not be bad (e.g. good diet), and 3. Raising it may not be good (data not definitive) 4. LDL/HDL ratio estimates risk but confuses R x Treatment (goal >40 mg/dl in men >50 in women) 1. Not Diet (bad diet is bad, high mono unproven) 2. Not Ethanol (adverse events, bene. unproven) 3. Lifestyle: wt loss, exercise, smoking cessation 4. Meds: niacin (↑effective but ↑Sx), fibrates, statins or TZD’s (less effective but fewer Sx) Use med Rx to ↑HDL only in 2 o and high-risk 1 o prev

55 TG and HDL vs. Risk of Premature CAD 653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM, cigarette smoking and LDL cholesterol Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.

56 0 10 20 30 40 50 60 70 80 90 100 20406080100120140160180200220240260280300500 Phenotype A Phenotype B % Cumulative frequency TG (mg/dL) Austin M et al. Circulation. 1990;82:495-506. LDL Phenotypes/Patterns A and B (B=SD LDL) vs. Plasma TG

57 Extra Atherogenicity of Small Dense LDL (pattern B) Endothelial Chemoattractants FOAM CELL Highly oxidized Smooth Muscle Cell Mildly oxidized Macrophag e LDL ENDOTHELIUM Monocyte Macrophage Through endothelium easier Stays on matrix longer More readily oxidized Associates w/ Metabolic Syndrome/DM: ↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid. ↓LDL-R uptake, ↑ Levels & Modific. And

58 LDL-C Doubly Underestimates CHD Risk with Small-Dense LDL More particles/LDL-C →higher LDL particle # than suspected –e.g. LDL-C 100 → ↑risk ≈ 120 mg/dl More atherogenic/LDL particle than large LDL –e.g. LDL-C 120 ↑risk ≈ 140 mg/dl LDL-C looks low but CHD risk is high

59 Test (method) Berkley Heart Lab (GGE), Lipo Print LipoProfile/ LipoScience (NMR) VAP/Atherotech (Ultracentrifugation) Pro/Con Established method, well validated, rel. pricey ($99-$240 and up, a la carte) More affordable (~$120), new method but well validated, LDL particle #, no extras Established method, well validated, CDC std, very affordable ($45-$90), MetSynd, Lp(a)-chol gratis Advanced Lipid Profiles— Which?

60 Rx of Small, Dense LDL Increase LDL Size Niacin Fibrates TZDs Lower LDL-C Statins Niacin, CAI, BAS, fenofibrate Rx Insulin Resistance Diet, exercise, weight loss TZD’s Metformin? ACEI’s?

61 Non-Pharmacological Approaches to Hypertriglyceridemia Consider secondary causes (increased frequency) –Poorly controlled diabetes mellitus –Hypothyroidism –Corticosteroids / Cushing’s –Isotretinoin (Accutane) (rarely a problem) Weight loss, exercise Avoid sugar and high carbohydrate diet Fish and fish oil Little or NO ALCOHOL Change oral estrogen to patch or discontinue

62 Lipid Effects: Fenofibrate vs Simvastatin Mean (%) change from baseline Steinmetz A et al., J Cardiovasc Pharmacol 1996 Apr;27 Suppl:S63-70 Double-blind, randomized, controlled 12 week trial Type IIa and IIb Patients -20 -25 -21 -35 -41 -17 +18 +15 -10 +4 -25 0 P=0.05 P=0.001 P=0.015P=0.001

63 Gemfibrozil (Lopid and generic) vs. Fenofibrate (TriCor, Antara, Tryglide, generic) Favor Gemfibrozil Cost (generic) Availability (generic) Better CHD event ↓ data (Helsinki & VA- HIT) Favor Fenofibrate Statin compatibility Dosed qd w or w/o meal (ease & compliance) Better lipid effects (esp. ↑HDL, ↓LDL) ↓Fibrinogen ↓Atherosclerosis (DAIS) ↓Athero events (FIELD)

64 Niacin vs. Fibrates for Mixed Dyslipidemia, DM & Met. Synd. Favoring Fibrates Exc ↓TG OK ↑HDL OK ↓LDL (feno only) No flushing No increase in glucose levels No increase in gout/uric acid No increase in Hcy ↓CHD event data (gemfib, trend w/ feno) Some ↓Lp(a) (feno) Favoring Niacin Exc ↑HDL-C OK ↓LDL OK ↓TG Fewer GI Sx (N & V) Better Lp(a) lowering ↓CHD event data (CDP) Better ↓CHD event data in combo w/ statin and/or BAS ↓Total mortality Better compatibility w/ statin (vs. gemfib.) Statin combo tablet (ERNL, Advicor)

65 Efficacy Comparison in Patients with TG ≥ 500 mg/dL Relative Difference vs. Placebo Source: Omacor ® Prescribing Information; Antara ® 130 mg Prescribing Information. Omega-3 AEEFenofibrate Lipid Efficacy of Omega-3 AEE is Similar to Fenofibrate -70% -50% -30% -10% 10% 30% 50% TGHDL-CCHOLVLDL-CLDL-C -70% -50% -30% -10% 10% 30% 50% TGHDL-CCHOLVLDL-CLDL-C

66 Dose-Range of Omega-3 FA Effect on Triglycerides TG 177-442 mg/dL at baseline; 8-week treatment Source: Data on file at Pronova/Reliant. ---------Dose of O3AEEs --------- % Change TG (mg/dL)

67 GISSI-Prevenzione Trial Omega-3 Acid Ethyl Esters Reduce All-Cause and Sudden Death ControlOmacor ® RRP-Value All-Cause Mortality10.6%8.4%21%0.0064 Sudden Death3.3%1.8%44%0.0006 Days 1.00 0.99 0.98 0.97 0.96 0.95 Probability 330210 150 60 0 90 180270 30120 240300 360 0.59 (95% CI 0.36- 0.97) P=0.037 Omega-3 AEE Control Marchioli R, et al., Circulation 2002;105:1897-1903.

68 Non-Lipid Atherosclerosis and Cardiac Effects of Omega-3 FA ↓Malignant ventricular arrhythmias (via cardiac membrane enrichment) ↑ICD triggering (malignant ventr. arrhythmias) ↓Heart rate and ↑HR variability (via ↑parasympathetic tone, altered cytokine levels?) ↑Endothelial relaxation (via ↑NO &↑NO independent mech.) ↓Blood Pressure Anti-proliferative effect/ ↓smooth- muscle cell proliferation Antithrombotic effects (↓platelet reactivity, ↓AA) ↓Plasma viscosity Anti-inflammatory effects –↓Inflammatory cytokines (interleukins, TNF) –↓Mitogens –↓Cell-adhesion molecule expression –Altered eicosanoid synthesis (↓AA) ↑PON (antioxidant on HDL) ↓CHF? ↓Sudden Death ↓Total and CVD mortality Holub BJ, CMAJ 2002;166(5):608-15.

69 Suggestions for Improving Omega-3 FA Tolerability Use O3-AEE’s – fewer capsules, fewer impurities Take at start of meal Freeze/refrigerate capsules (PI says no) Gradual uptitration

70 Mortality Effects of Lipid Rx Rx# Trials N% Δ Total % Δ CVD % Δ non- CVD Statins3553K↓13%*↓22%*↓3% Omega-31410K↓23%*↓32%*↓3% Fibrates1714K0%↓7%↑13%* *p<0.01. M Studer, et al. Arch Int Med 2005;165:725-36. ----------Mortality----------

71 Fibrates vs. Omega-3 to Rx HTG and Prevent Atherosclerosis Favoring Fibrates More conventional ↓CVD Better ↑HDL-C & ↓LDL-C Non-lipid benefits? Good statin compatibility (feno only, FIELD) More convenient (fewer capsules) No fishy burping Favoring Omega-3 More natural ↓CVD and ↓total mortality Non-lipid benefits? No transaminase contraindic. No precaution w/ statins No warfarin interaction Less nausea and vomiting Bottom line: Either is good as first-line Both often needed in combination!

72 Hypertriglyceridemia Drug Treatment When—After diet and R x 2 o factors Treat all TG > 500 for pancreatitis & athero Treat to <150 if 2 o prevention, DM/IR or other  athero risk How Gemfibrozil/Fenofibrate—easier, more effective Niacin—cheap/easy, best if  HDL-C and/or  LDL-C Statins—consider, especially if  LDL-C Omega-3 oils, effective in high doses TZDs (pioglitazone > rosiglitazone)

73 Use Non-HDL-C Instead of LDL-C if TG > 200 (ATP III) LDL-C Target Non-HDL-C Target Patient Category (mg/dL) (mg/dL) No CHD, 0-1 risk factors < 160 <190 No CHD, 2+ risk factors < 130 <160 CHD/CHD risk equivalent < 100 <130 CVD + DM/MS/Cigs/ACS < 70 <100 Non-HDL-C goal = LDL-C goal + 30 Rx to ↓Non-HDL-C: If TG <~400 Rx as LDL-C If TG >~400 Rx as HTG

74 Hepatic Source of Inflammatory Markers: CRP, Fibrinogen, SAA Rader. N Engl J Med 2000;343:1179. CRP Fibrinogen SAA


76 Lp(a)—Summary Pro-atherogenic/pro-thrombotic factor Genetically determined Not lowered by most treatments: –Diet –Exercise –Weight loss –Statins, –Bile acid resins, –Gemfibrozil Rx options: –Lower Lp(a)  Niacin  Estrogen  Fenofibrate? –Extra LDL-C lowering

77 Suggested Use of Emerging CHD Risk-Factor Tests Blood Tests SD LDL Apo B vs. LDL # vs. Non HDL-C CRP (vs. Met. Synd.) Lp(a) Microalb’uria, GFR Hcy RLP-C LpPLA2 (PLAC) Arterial Tests (1 o Prev) CAC by CT Carotid US Ankle Brachial Index (SBP ankle/SBP arm <.9) Why? Rx yes/no? More aggressive Rx? Specific Rx When? 1 o Prevention –Intermediate-Risk 2 o Prevention, CVD: –W/ normal lipid profile –Severe beyond risk factors –Progression despite “adequate” Rx

78 Combination Therapy Statin + Other Med

79 18 9.9 13 14.4 11.2 9.4 7.9 16.6 0 5 10 15 20 25 % of patients  100 101- 111- 121- 131- 141- 151- >160 110 120 130 140 150 160 LDL-C (mg/dL) on-treatment n = 1,460 L-TAP: Majority of CHD Patients Do Not Reach NCEP LDL-C Goal Pearson TA et al. Arch Intern Med. 2000;160:459-467. Other L-TAP data courtesy of TA Pearson.

80 Statin dose (mg) LDL-C Example of Statin Titration and Failure to Attain Optimal LDL-C Starting LDL-C 220 mg, 40% Lowering at Statin 10 mg Optimal 50 100 150 200 250 020406080100

81 20 mg includes pts on 40 mg (37%). This does not represent data from a comparative study. Data from prescribing information for atorvastatin, lovastatin, simvastatin. Statin Titration: Potential for Side Effects at Maximum Dose 20408010204080 0 0.5 1.0 1.5 2.0 2.5 Elevated transaminases (% of patients) 8040 1.7  4  2.3  20 Statin dose (mg) Atorvastatin Lovastatin Simvastatin

82 More vs. Less Aggressive LDL-C Lowering Rx StudyLDL-C LowRx LDL-C HiRx Add'l LDL↓ Add’l CHD↓ Safety Prove-IT95 mg/dl62 mg/dl35%16%3x ↑ALT A to Z81 mg/dl66 mg/dl18%11%9x ↑myop* TNT101 mg/dl77 mg/dl24%22%6x ↑ALT IDEAL103 mg/dl82 mg/dl20%11%2x ↑myalg 9x ↑ALT Prove-IT: Prava 40 vs. Atorva 80. NEJM, 2004;350:1495-1504. A to Z: Simva 20 vs. Simva 80. JAMA, 2004;292:1307-1316. TNT: Atorva 10 vs. Atorva 80. NEJM, March 8, 2005. IDEAL: Simva 20-40 vs. Atorva 80. JAMA 2005; 294:2437-2445. *Included patients w/ ARF, EtOH abuse and on meds interfering w/ statin metabolism.

83 Majority of CAD Events Occur Despite Statin Rx: Need for Further Rx Improvement Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383. % with CAD event 30% ↓ CAD w/ statin 70% CAD events not prevented CAD Events in the 4S Trial PlaceboSimvastatin

84 Event Reduction With Monotherapy Versus Combination Therapy -31-36 ASCOT 19341 WOSCOPS 6595 FATS (10 Y) 176 4S 4444 Trial N -72 -34-25 HPS 20,536 Reduction in CV Events (%) CARE 4159 -24 1. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307; 2. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Sever PS, et al. Lancet. 2003;361:1149-58; 6. Brown BG, et al. Circulation. 1998;98(suppl I):I-635.

85 HATS: Angiographic and Clinical Endpoints After 3 Years Coronary Death, MI, Stroke, or Revascularization Mean Change in Stenosis, % Composite Event Rate, % 9 Proximal Lesions 25 20 15 10 5 0 *p<0.001 vs. placebo; † p<0.005 vs. placebo; ‡ p=0.04 vs. placebo. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. HATS = HDL-C-Atherosclerosis Treatment Study; S = simvastatin; N = niacin; AV = antioxidant vitamins. * † ‡ 89% reduction

86 Placebo Niacin ER 1g/d

87 Ezetimibe + Atorvastatin 10 mg: Greater LDL-C Reduction vs. Atorvastatin 20 or 40 mg Alone P<0.01 Ezetimibe + Atorvastatin 10 mg (n=65) 10 mg (n=60) 20 mg (n=60) 40 mg (n=66) 80 mg (n=62) Atorvastatin

88 % Reduction from baseline at wk 6 Ezetimibe/simvastatinAtorvastatin 102080 10/1010/2010/4010/80 40 *P  0.001 vs atorvastatin at corresponding dose. Ballantyne et al.J Am Coll Cardiol. 2004;43(suppl A):480A. Ballantyne et al. J Am Coll Cardiol. 2004;43(suppl A):480A. * * * * Ezetimibe/Simvastatin vs. Atorvastatin LDL-C Lowering

89 Ezetimibe With Fenofibrate in Hypercholesterolemia -13.5 -22.3 -36.3 -10.1 -40 -35 -30 -25 -20 -15 -10 -5 0 Placebo (n=8) Fenofibrate 200 mg (n=8) Ezetimibe 10 mg (n=8) Ezetimibe 10 mg + fenofibrate 200 mg (n=8) Mean % LDL-C reduction after 14 d † *Ezetimibe is not yet indicated for combination use with fenofibrate or any other non-statin lipid agent. † P<0.03 vs placebo or either drug alone. Kosoglou et al. European Atherosclerosis Society Meeting, Glasgow, Scotland, 2001.

90 Statin Mono Rx vs. Combination Rx Favoring Combo Rx Better LDL-C lowering Better non-LDL effects (HDL-C, TG, CRP, other?) Likely better CVD event reduction Complementary mechanisms Favoring Statin Mono Rx Nearly comparable LDL-C↓ (esp. w/ rosuva.) Simpler (less AE risk) Less expensive (esp. rosuva.)

91 Atheroprevention in Postmenopausal Women


93 Incidence of Cardiovascular Events in Women Before and After the Menopause 0 50 100 150 200 250 300 350 Incidence / 100,000 20-2425-2930-3435-3940-4445-4950-5455-59 60-64 >65 Age Range F. B. Hu et al. New Engl J Med, 2000; 343:530-7 Average Age at Menopause In postmenopausal women, atherosclerosis is a disease of estrogen deficiency

94 Risk of Cardiac Events/Death in Estrogen Users in 6 Large Observational Studies 2.0 Relative Risks and 95%Confidence Intervals 95%Confidence Intervals Bush, T. L. et al., Lipid Research Clinics Follow-up Study Circulation 75:1102, 1987 Bush, T. L. et al., Lipid Research Clinics Follow-up Study Circulation 75:1102, 1987 Grodstein, F. et al., Nurses Health Study N Engl J Med 335:453, 1996 Grodstein, F. et al., Nurses Health Study N Engl J Med 335:453, 1996 Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988 Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988 Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992 Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992 Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990* Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990* Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994 Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994 *Deaths from circulatory diseases

95 Rationale for the Randomized HRT Trials (HERS&WHI) Supposed to verify observational studies: –peri-menopausal start Instead studied –late post-menopausal start

96 Hazard Year Ratio 1 1.78 2 1.15 3 1.06 4 0.99 5 2.38 6+ 0.78 Year WHI: Percent CHD Events by Year P = NS for trend over time. HR = 1.29 95% nCI = 1.02–1.63 95% aCI = 0.85–1.97 *Includes 8 silent MIs. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

97 Early vs. Late Estrogen Effects on the Natural History of Atherosclerosis Adventitia Media Fatty Streak/Plaque Internal Elastic Lamina Necrotic Core Plaque Fibrous Cap Plaque Necrotic Core Plaque Fibrous Cap MMP-9 Estrogen Effects in Atherogenesis  LDL oxidation   LDL atherogenicity  LDL binding/accum   lesion progression  CAMs   monocyte adhesion/  macrophage accumulation  MCP-1 and TNF   SMC proliferation   lesion progression  Endothelial function   vasodilation Estrogen Effects in Established Plaques  MMP expression   PQ instability/rupture  Thrombosis   Event # and severity Loss of Estrogen Benefits (when HRT started after prolonged estrogen deficiency)  Expression of estrogen receptors  Vascular responsivity Benefits of estrogen early in atherogenesis Adverse effects of estrogen in vulnerable plaque CAMs = cell adhesion molecules; SMC = smooth muscle cell; MMP = matrix metalloproteinase.

98 1 Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6. 2 Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21. 3 Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-7. 4 Williams JK, et al. Arterioscler Thromb Vasc Biol. 1995;15:827-36. PremenopausePostmenopause Ovariectomy 70% Decrease 1,2 Healthy diet CEE + atherogenic diet Plaque Area (Relative to Placebo) 50% Decrease 3 Atherogenic diet CEE + atherogenic diet 0% No change 4 Healthy diet Atherogenic diet + No CEE 2 years Healthy Diet + CEE Timing of CEE Start vs. Anti-atherosclerosis Effect ( Nonhuman Primates) * ** * Like Obs. HRT trials ** Like HERS/WHI

99 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 Risk Ratio for CVD 051015202530 Years Postmenopause at Randomization <10 10-19 ≥ 20 *Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3) Zero-Year RR=0.62 Timing of HRT Start vs. Effects on CVD: Extrapolation of WHI Results (E+P Arm)

100 Nurses’ Health Study, 1980-1996 Never 0.3 mg* 0.625 mg*  1.25 mg 1.0 0.58 (0.37-0.92) 0.54 (0.44-0.67) 0.70 (0.51-0.97) 609199941 Hormone Use Multivariate-adjusted RR (95% CI) Cases (n) Person-years of Follow-up Grodstein F, et al. Ann Intern Med. 2000;133:933-41. 313,66119,964116,15039,026 RR = relative risk for current vs. never users. Effect of Estrogen Dose on Risk for CHD

101 Nurses’ Health Study, 1980-1996 Never 0.3 mg* 0.625 mg*  1.25 mg 1.0 0.54 (0.28-1.06) 1.35 (1.08-1.68) 1.63 (1.18-2.26) 290912446 Hormone Use Multivariate-adjusted RR (95% CI) Cases (n) Person-years of Follow-up Grodstein F, et al. Ann Intern Med. 2000;133:933-41. 313,66119,964116,15039,026 RR = relative risk for current vs. never users. Effect of Estrogen Dose on Risk for Stroke

102 “Because of the excellent study design of WHI there is now consensus that CEE+MPA should not be started in older women to prevent heart disease.”—Good for <10% of ERT “Whether benefit would be seen if women initiated hormones …at… menopause was not addressed in the WHI.” —Nothing learned about >90% of ERT(!) “We need new clinical trials to test the hypothesis not addressed by the WHI—that younger women who initiate hormones…at the time their own estrogen levels drop will eventually…have less heart disease.”—KEEPS under way ML Stefanick, Kronos Longevity Kronicle 2004;3(7);6-11. What to do while we await relevant RCT data? Choice A: Use best current evidence which is: early-start, long-term/lifetime ERT/HRT benefits most women! Choice B: D/C ERT/HRT (assume WHI applies to all women) WHI Scorecard: $600M Later…

103 HRT in Postmenopausal Women: State of the Art 2005 HRT is good in most women –All perimenopausal women should be considered for HRT (early start) esp if estr. defic Sx present –Low-dose oral CEE/MPA usually best (if tolerated); –Oral or patch estradiol are good alternatives –Continue life-long (unless/until adverse event—VTE, etc.) Current dogma (D/C of HRT after 1-5 y) is likely harmful Late-start HRT usually bad Caveat: HRT does not have FDA indication for CHD prevention

104 FactorStatinsBASCAIFibratesNiacin ↓LDL-C+++++ +/-++ ↑LDL size-??++ ↓TG++-++++++ ↓Remnant++-++?+++ ↓Lp(a)-??+/-+++ ↑HDL++/-++/+++++ Lipoprotein Effects of Major Lipid Rx Classes: Summary

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