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Dyslipidemia and Atherosclerosis

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



5 Pre-β HDL

6 TRIG CHOL LDL IDL VLDL Adipose Heart Muscle Other Tissues
Dietary Fat g/day (98% absorbed) free fatty acids Chylomicron Apo B-48 (Apo A-I) “LDL Pathway” LDL Receptors Adipose Heart Muscle Lipoprotein Lipase Dietary Cholesterol 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 HMG CoA Reductase Hepatic Lipase apo E LDL Other Tissues intestine, skin, adrenal, ovary, testes, atheroma / macrophages VLDL Apo C’s Apo B-100 Apo E IDL TRIG ketone bodies CO2, H2O pre-β1 HDL (two apo A-I) pre-β2 HDL (+PL=disc) pre-β3 HDL (+UC in disc) HDL3 PL FC LCAT HDL2b Hepatic Lipase HDL2a CE CETP TG

7 Familial Hypercholesterolemia (FH)

8 Hypercholesterolemia
½ normal LDL Receptors Adipose Heart Muscle Lipoprotein Lipase Bile Acids CHOL ffa VLDL TRIG “LDL Pathway” HMG CoA Reductase Other Tissues ketone bodies CO2, H2O  IDL HDL Familial Hypercholesterolemia (heterozygous) Statins  LDL



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

12 What FH May Mean for a Family
40 ♥ 373 Affected Age at MI Total Chol Key 47 ♥ 42 218 38 ♥ 34 ♥ 347 40 ♥ 373 41 ♥ 45 ♥ 334 16 284 18 94 20 182 42 180 31 158 12 132 17 157 18 285 19 130 21 311 22 135 6 291 13 344 14 118 15 255

13 “Pure” Hypercholesterolemia Monogenic Syndromes
Familial hypercholesterolemia (FH) LDL receptor mutations (over 800 distinct types) 1/500 in general population (heterozygotes) Familial defective apo B (FDB) (minority of FH) Ligand defect not receptor defect 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 Common Genetics poorly defined Mechanisms poorly defined (likely includes hyperabsorbers) Generally milder than FH Diet-induced Very common Generally much milder than FH “Secondary” causes Hypothyroidism—rel. common in elderly but ↑LDL mild Other (rare hepatic and renal abn., etc.)

15 VLDL overproduction Associated Lipid Abnormalities:
Mild-moderate ↑VLDL-C/Plasma TG Mild-moderate ↓HDL-C Small, dense LDL (and HDL) Mild ↑LDL-C 1o 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 aging Almost always helped by weight loss


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

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 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 National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

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

22 Slide 10 Type 2 diabetes is associated with a marked increase in the risk of coronary heart disease. It has been debated whether patients with diabetes who have not had myocardial infarctions should be treated as aggressively for cardiovascular risk factors as patients who have had myocardial infarctions. The seven-year incidence of myocardial infarction (fatal and nonfatal) among 1,373 non-diabetic subjects was compared with the incidence among 1,059 diabetic subjects, all from a Finnish population-based study. The seven-year incidence rates of myocardial infarction in non-diabetic subjects with and without prior myocardial infarction at baseline were 18.8% and 3.5%, respectively (P<0.001). The seven-year incidence rates of myocardial infarction in diabetic subjects with and without prior myocardial infraction at base line were % and 20.2%, respectively (P<0.001). The data suggest that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as non-diabetic patients with previous myocardial infarction. These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in non-diabetic patients with prior myocardial infarction.

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

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

25 >102 cm (>40 in) >88 cm (>35 in)
ATP III: Insulin Resistance Syndrome (“The Metabolic” Syndrome* ICD ) <40 mg/dL <50 mg/dL Men Women >102 cm (>40 in) >88 cm (>35 in) 100 mg/dL Fasting glucose 130/85 mm Hg Blood pressure HDL-C 150 mg/dL TG Abdominal obesity† (Waist circumference‡) Defining Level Risk Factor ATP III: THE METABOLIC SYNDROME n        According to the guidelines, diagnosis of the metabolic syndrome is made when three or more of the risk factors shown on this slide are present. It is worth noting that for purposes of defining a risk factor for the metabolic syndrome ATP III raises the HDL-C cutpoint to <50 mg/dL for women. Such an adjustment again reflects the propensity of women to have higher HDL-C than men in the first place. After appropriate control of LDL-C levels is attained, ATP III recommends that physicians focus on weight reduction and increased physical activity in those persons who exhibit evidence of the syndrome. Focusing on these two management practices also targets two underlying risk factors for CHD: obesity or overweight, and physical inactivity. n        Weight reduction accomplishes two goals: enhances LDL-C reduction and reduces all risk factors for the metabolic syndrome. Because abdominal obesity is more highly correlated with metabolic risk factors than is an elevated body mass index, measuring the waist circumference is recommended to identify the body weight component of the metabolic syndrome. Note that some men develop metabolic risk factors when waist circumference is only marginally increased ( cm [37-39 in]). (For recommended approaches to reducing overweight and obesity in patients, physicians are referred to the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults from the NHLBI Obesity Education Initiative [1998].) n        Regular physical activity has numerous cardiovascular benefits, according to the guidelines—among them reduction of VLDL-C levels, increase of HDL-C levels, and, in some persons, a decrease in LDL-C levels. It also can reduce blood pressure and insulin resistance. Thus, the guidelines recommend that any management plan for high serum cholesterol incorporates regular physical activity. (See the US Surgeon General’s Report on Physical Activity for evidence base for this recommendation.) n        The following therapies directed against the lipid and nonlipid risk factors of the metabolic syndrome will also reduce CHD risk: treatment of hypertension; treatment of elevated TG and low HDL-C; and use of aspirin in patients with CHD (although ATP III points out that no specific guidelines have been established for aspirin use in primary prevention). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: *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:

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: Morganroth J, Levy RI, Fredrickson DS. Ann Intern Med 1975; 82:

28 TG and HDL vs. Risk of Premature CAD 653 cases, 1029 controls
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):

29 CHD Events vs. LDL-C: Statin and Non-Statin Trials
30 4S-PI 25 GREACE-UC 2° Prevention HPS 2o-Pl 4S-Rx 20 POSCH-Pl Percent with CHD event HPS 2o-Rx 15 LIPID-PI GREACE-Rx 1° Prevention LIPID-Rx CARE-PI 10 WOSCOPS-PI CARE--Rx POSCH—Rx AFCAPS/ TexCAPS-PI CPPT-Pl 5 CPPT--Rx HPS 1o-Rx HPS 1o-Pl WOS COPS-Rx AFCAPS/ TexCAPS-Rx 90 110 130 150 170 190 210 LDL-C at follow-up (mg/dL)

30 NCEP ATP Update—2004 Risk Category Risk Factors LDL-C Goal
Lower RF <160 Mod/Mod-High >2 RF, FRS <20% <130 High CVD alone or FRS >20% <100 Very High CVD+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: 2o prev as younger; 1o prev+DM=high risk; other, use clinical judgment Non-HDL-C: use if TG>200; goal as LDL-C+30 *Therapeutic option: use clinical judgment Grundy, et al. Implications of Recent Clinical Trials for NCEP ATP III. Circ. July 13, 2004;110:

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 1o 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 Clinical Judgment for NCEP ATP Update—2004 (per Dr. E. A. Brinton)
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 Rx, subtract if fears atherosclerosis)

34 Choice of HMG-CoA Reductase Inhibitors (“Statins”)
1. Lovastatin (Mevacor, Altoprev, generic)—events (1o prev.), longer experience, generic and extended release available 2. Pravastatin (Pravachol)—v. good event  data (1o and 2o prevention), safer in combo? 3. Simvastatin (Zocor)—best 2o prev. data, DM/2o 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, 2o 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
Intensive Lifestyle Changes and CAD Reversal (Ornish D, et al. JAMA 1998; 280:2001) p = p = 0.001

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

38 Finnish Mental Hospital Study Age-adjusted death-rates (per 1000 person-years)
Males Females CHD Total Hospital N, diet 5.7 34.6 4.0 31.1 Hospital N, control 13.0 38.8 7.7 32.1 Hospital K, control 15.2 40.2 8.1 25.9 Hospital K, diet 7.5 35.1 6.5 30.7 Pooled diet 6.6 34.8 5.2 30.9 Pooled control 14.1 39.5 7.9 29.0 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*
Patient 2: LDL-C: 100 mg/dL HDL-C: 25 mg/dL Patient 1: LDL-C: 220 mg/dL HDL-C: 45 mg/dL RR of CHD After 4 yr CHD Risk: HDL-C vs LDL-C as Predictor1 The Framingham Heart Study showed that the lower the level of HDL-C, the greater the risk of a coronary event, regardless of LDL-C level. In fact, a person with a “desirable” LDL-C of 100 mg/dL but a low HDL-C of 25 mg/dL has the same risk for an event as a person with an LDL-C of 220 mg/dL and an HDL-C of 45 mg/dL.1 Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. HDL-C (mg/dL) LDL-C (mg/dL) *Data represent men age 50–70 yr from the Framingham Study. Adapted from and reprinted with permission from Castelli WP. Can J Cardiol. 1988;4(suppl A):5A.

43 Rx Changes HDL and TC/HDL are Best predictors of CHD Risk Reduction
Univariate Regression R2 In univariate methods, the rank order of R2 values was total cholesterol (TC)/HDL > HDL > non-HDL > TC > LDL > TG, using either curvilinear relationship (shown here) or linear relationship. Changes in HDL-inclusive parameters (TC/HDL-C, HDL-C, and non-HDL) were consistently the best predictors of CHD risk reduction. The weakest association was between percent change in TG and CHD events. There was a relatively modest association between percent change in LDL and RRR in CHD. In a multivariate model, only percent change in HDL-C (p<0.001) and TC (p=0.015) were independently predictive of RRR in CHD. The relationships between percent change in LDL-C and TG and RRR in CHD were of borderline significance (p=0.1 and p=0.06 for LDL-C and TG, respectively). Similar results were obtained examining the various possible combinations of the relationships between percent and absolute on-treatment changes in lipid parameters and the relative and absolute CHD risk reduction in either linear or curvilinear models. Study Limitations The clinical trials examined vary in their size, patient population, lipid-altering agents used, and duration of therapy and follow-up. The definition of CHD endpoint was not consistent across all trials. The vast majority of patients enrolled in these trials were male. Study Conclusions Changes in HDL-C and HDL-C–inclusive parameters are the strongest predictors of CHD risk reduction in lipid intervention trials. This supports the hypothesis that intervention-induced increases in HDL-C levels significantly contribute to reduction in CHD risk. 1. Alsheikh-Ali AA, Abourjaily HM, Stanek E, McGovern M, Kuvin JT, Karas RH. Increases in HDL-cholesterol are the strongest predictors of risk reduction in lipid intervention trials. Poster presented at: American Heart Association Scientific Sessions 2004; November 7-10, 2004; New Orleans, La. N=44,170; total CHD events = 3869 R2 denotes the proportion of variance. TC = total cholesterol. 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
Bile Macrophage Mature HDL Nascent HDL A-I A-I UC CE CE LCAT PL Liver PL&UC UC CE ABCA1 SR-BI SR-A CETP LDL-R Oxidation CE B Role of CETP in HDL Metabolism This slide shows the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), described in the previous slide, together with another important pathway of reverse cholesterol transport involving the action of plasma CE transfer protein (CETP). CE can be transferred from HDL to apolipoprotein (apo) B-containing proteins, such as very-low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs), by CETP. Through uptake of LDL by the liver via hepatic LDL receptors, cholesterol can then be returned to the liver, where it may eventually be excreted as bile. (This slide also illustrates the current belief that only modified apoB-containing proteins are taken up by macrophages. “Oxidation” is given as an example of modification.) References Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1841–1851. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34:1255–1274. Steinberg D. A docking receptor for HDL cholesterol esters. Science. 1996;271:460–461. VLDL/LDL 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:

46 Oxidized LDL HPODE HPETE 12-Lipoxygenase


48 Medications which Raise HDL-C Levels
Agent HDL-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% Slide 32. Effects of drugs on HDL-C levels A number of pharmacologic agents will also increase low HDL-C. Niacin provides the greatest increase in HDL-C. Reference: Belalcazar LM, Ballantyne CM. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol. Prog Cardiovasc Dis 1998;41: Belalcazar LM et al. Progress in Cardiovascular Disease 1998;41:

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

50 CDP at 6 yr: Nonfatal MI by Baseline FBG*
Relative Hazard 0.70 0.74 0.73 0.44 Placebo Niacin Event Rate (%) 126 mg/dL *Z for interaction = –0.35. Indicates homogeneity Canner PL et al. Am J Cardiol 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 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) mg CaCO3 (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 Not recommended for atheroprevention! Types
Niacinamide/Nicotinamide Acipimox Inositol Hexaniacinate Lipid Effects Few or none Evidence for CHD Prevention None Not recommended for atheroprevention!

54 Use med Rx to ↑HDL only in 2o and high-risk 1o prev
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 Rx 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 2o and high-risk 1o prev

55 TG and HDL vs. Risk of Premature CAD 653 cases, 1029 controls
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):

56 LDL Phenotypes/Patterns A and B (B=SD LDL) vs. Plasma TG
100 90 80 70 % Cumulative frequency 60 50 40 Phenotype A 30 Phenotype B 20 10 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:

57 Extra Atherogenicity of Small Dense LDL (pattern B)
↓LDL-R uptake, ↑ Levels & Modific. Endothelial Chemoattractants LDL ENDOTHELIUM Monocyte Through endothelium easier LDL Macrophage Stays on matrix longer Mildly oxidized Macrophage More readily oxidized Small, dense LDL binds with poor affinity to the LDL receptor, and therefore, remains in plasma for prolonged periods. Macrophage uptake of small, dense LDL may result from the action of oxygen free radicals on these particles. Small, dense LDL possesses low degrees of oxidative resistance and are more susceptible to oxidative modification. As a result, cholesterol-rich, macrophage foam cells may form. Macrophage foam cells are characteristic of lipid-rich plaques. They also secrete many factors that contribute to the proatherogenic, proinflammatory, and prothrombogenic activities. Chapman MJ, et al. Eur Heart J. 1998;19(suppl A):A24-A30. FOAM CELL Smooth Muscle Cell Highly oxidized And Associates w/ Metabolic Syndrome/DM: ↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid.

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 Advanced Lipid Profiles—Which?
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

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

63 Gemfibrozil (Lopid and generic) vs
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 Lipid Efficacy of Omega-3 AEE is Similar to Fenofibrate
Efficacy Comparison in Patients with TG ≥ 500 mg/dL Relative Difference vs. Placebo Omega-3 AEE Fenofibrate TG HDL-C CHOL VLDL-C LDL-C TG HDL-C CHOL VLDL-C LDL-C 50% 50% 30% 30% 10% 10% -10% -10% -30% -30% -50% -50% -70% -70% Source: Omacor® Prescribing Information; Antara® 130 mg Prescribing Information.

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

67 GISSI-Prevenzione Trial Omega-3 Acid Ethyl Esters Reduce All-Cause and Sudden Death
1.00 0.99 Omega-3 AEE 0.98 0.59 (95% CI ) P=0.037 Probability 0.97 Control 0.96 0.95 30 60 90 120 150 180 210 240 270 300 330 360 Days GISSI-Prevenzione Trial - Early Effect on All-Cause Mortality Control Omacor® RR P-Value All-Cause Mortality 10.6% 8.4% 21% 0.0064 Sudden Death 3.3% 1.8% 44% 0.0006 Marchioli R, et al., Circulation 2002;105:

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):

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
# Trials N % Δ Total % Δ CVD % Δ non-CVD Statins 35 53K ↓13%* ↓22%* ↓3% Omega-3 14 10K ↓23%* ↓32%* Fibrates 17 14K 0% ↓7% ↑13%* *p< M Studer, et al. Arch Int Med 2005;165:

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 Rx 2o factors Treat all TG > 500 for pancreatitis & athero Treat to <150 if 2o 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 < <190 No CHD, 2+ risk factors < <160 CHD/CHD risk equivalent < <130 CVD + DM/MS/Cigs/ACS < <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.


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
Why? Rx yes/no? More aggressive Rx? Specific Rx When? 1o Prevention Intermediate-Risk 2o Prevention, CVD: W/ normal lipid profile Severe beyond risk factors Progression despite “adequate” Rx 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 (1o Prev) CAC by CT Carotid US Ankle Brachial Index (SBP ankle/SBP arm <.9)

78 Combination Therapy Statin + Other Med

79 L-TAP: Majority of CHD Patients Do Not Reach NCEP LDL-C Goal
25 n = 1,460 20 18 16.6 14.4 15 13 11.2 % of patients 9.9 9.4 10 7.9 5  >160 LDL-C (mg/dL) on-treatment Pearson TA et al. Arch Intern Med. 2000;160: Other L-TAP data courtesy of TA Pearson.

80 Example of Statin Titration and Failure to Attain Optimal LDL-C
Starting LDL-C 220 mg, 40% Lowering at Statin 10 mg 250 200 LDL-C 150 100 Optimal 50 20 40 60 80 100 Statin dose (mg)

81 Statin Titration: Potential for Side Effects at Maximum Dose
Atorvastatin Lovastatin Simvastatin 2.5 2.0 4  2.3  1.5 1.7  Elevated transaminases (% of patients) 1.0 0.5 The efficacy of statins is dose dependent1; high doses may be required for maximum LDL-C reduction. High doses of statins may, however, also induce raised liver enzymes, and studies have shown that transaminase levels may increase by more than three times the upper limit of normal in a significant number of patients.2,3 The increased risk of adverse events may, therefore, outweigh the clinical benefits achieved by increasing the statin dose. Titrating the dose of atorvastatin from 40 mg to 80 mg, for example, decreases LDL from 50% to 60%, but concomitantly increases the incidence of elevated transaminase levels from 0.6% to 2.3% of patients.4 References 1. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81: 582–7. 2. Dujovne CA, Chremos AN, Pool JL et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin. Am J Med 1991; 91 (Suppl 1B): 25–30. 3. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53: 828–47. 4. Lipitor™ (atorvastatin calcium) Tablets (package insert). Pontypool, UK: Parke-Davis: 1999. 10 20 40 80 20 40 80 20 40 80 Statin dose (mg) 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.

82 More vs. Less Aggressive LDL-C Lowering Rx
Study LDL-C LowRx LDL-C HiRx Add'lLDL↓ Add’lCHD↓ Safety Prove-IT 95 mg/dl 62 mg/dl 35% 16% 3x ↑ALT A to Z 81 mg/dl 66 mg/dl 18% 11% 9x ↑myop* TNT 101 mg/dl 77 mg/dl 24% 22% 6x ↑ALT IDEAL 103 mg/dl 82 mg/dl 20% 2x ↑myalg 9x ↑ALT Prove-IT: Prava 40 vs. Atorva 80. NEJM, 2004;350: A to Z: Simva 20 vs. Simva 80. JAMA, 2004;292: TNT: Atorva 10 vs. Atorva 80. NEJM, March 8, 2005. IDEAL: Simva vs. Atorva 80. JAMA 2005; 294: *Included patients w/ ARF, EtOH abuse and on meds interfering w/ statin metabolism.

83 CAD Events in the 4S Trial
Majority of CAD Events Occur Despite Statin Rx: Need for Further Rx Improvement CAD Events in the 4S Trial 30% ↓CAD w/ statin % with CAD event 70% CAD events not prevented Despite the significant reduction in the incidence of CAD with LDL-C lowering, there is clearly a need for improvement. Significant reduction in LDL-C with simvastatin in the 4S trial reduced CAD events by approximately 30%, leaving a residual risk of 70% among patients receiving therapy. Placebo Simvastatin Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:

84 Event Reduction With Monotherapy Versus Combination Therapy
WOSCOPS 6595 4S 4444 CARE 4159 HPS 20,536 ASCOT 19341 FATS (10 Y) 176 Trial N Reduction in CV Events (%) -31 -34 -24 -25 -36 Among the statin trials, CV events have been reduced on average from 24% to 36%. Trials using combination therapy targeting multiple lipid abnormalities have led to greater reductions in CV events. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333: Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. Sever PS, Dahlof B, Poulter NR, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet. 2003;361: Brown BG, Brockenbrough A, Zhao X-Q, et al. Very intensive lipid therapy with lovastatin, niacin, and colestipol for prevention of death and myocardial infarction: a 10-year Familial Atherosclerosis Treatment Study (FATS) follow-up [abstract]. Circulation. 1998;98(suppl I):I-635. Abstract 3341. -72 1. Shepherd J, et al. N Engl J Med. 1995;333: ; 2. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: ; 3. Sacks FM, et al. N Engl J Med. 1996;335: ; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Sever PS, et al. Lancet. 2003;361: ; 6. Brown BG, et al. Circulation. 1998;98(suppl I):I-635.

85 HATS: Angiographic and Clinical Endpoints After 3 Years
89% reduction 25 20 15 10 5 Mean Change in Stenosis, % Composite Event Rate, % * The HDL-Atherosclerosis Treatment Study (HATS) was a 3-year double-blind, placebo-controlled, NHLBI-sponsored study that, in part, evaluated niacin therapy of HDL-C management in patients also on an LDL-C–lowering statin regimen. The study included 160 patients with coronary artery disease (CAD) who had low HDL-C and normal LDL-C levels. Patients were randomly assigned to 1 of 4 regimens – statin (S; simvastatin) and niacin (N), S and N plus antioxidant vitamins (AV), antioxidants, or placebo. For the purpose of this graph, we will be discussing the effects of N on HDL-C parameters. Niacin was started at 250 mg twice daily and increased linearly to 1000 mg twice daily at 4 weeks; the mean dose was 2.4 g/d. Antioxidants (total daily doses: 800 IU vitamin E, 1000 mg vitamin C, 25 mg -carotene, and 10 µg selenium) were given twice daily. The primary outcomes were angiographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, MI, stroke, or revascularization). Patients receiving N had a significant increase in HDL-C of 26%. The addition of AV blunted the magnitude of this increase in HDL-C. For the angiographic primary endpoint – the change in severity of the most severe stenosis in 9 proximal coronary segments – slight regression was observed with the addition of N (-0.4%) and progression was slowed with N and AV (+0.7%) treatment when compared to placebo (+3.9% mean change in stenosis). The composite clinical endpoint of death from coronary causes, confirmed MI or stroke, or revascularization was reduced by 89% in patients treated with N compared with placebo (p=0.04). There were no statistically significant differences in clinical endpoints in the group receiving both N and AV compared with placebo. The authors concluded that the addition of N in CAD patients with low HDL-C and “normal” LDL-C resulted in slight regression of coronary atherosclerosis and a significant reduction (89%) in clinical coronary events over 3 years compared with placebo. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345: 9 Proximal Lesions Coronary Death, MI, Stroke, or Revascularization HATS = HDL-C-Atherosclerosis Treatment Study; S = simvastatin; N = niacin; AV = antioxidant vitamins. *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:

86 Niacin ER 1g/d Placebo

87 Ezetimibe + Atorvastatin 10 mg (n=65)
Ezetimibe + Atorvastatin 10 mg: Greater LDL-C Reduction vs. Atorvastatin 20 or 40 mg Alone Atorvastatin Ezetimibe + Atorvastatin 10 mg (n=65) 10 mg (n=60) 20 mg (n=60) 40 mg (n=66) 80 mg (n=62) Key Point: Adding ZETIATM (ezetimibe) to the lowest dose of atorvastatin (10 mg) was more effective than atorvastatin 10 mg, 20 mg, or 40 mg in lowering LDL-C. P<0.01

88 Ezetimibe/Simvastatin vs. Atorvastatin LDL-C Lowering
10 20 40 80 10/10 10/20 10/40 10/80 % Reduction from baseline at wk 6 Davidson M, McGarry T, Bettis R, et al. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40: * * * * *P0.001 vs atorvastatin at corresponding dose. Ballantyne et al. J Am Coll Cardiol. 2004;43(suppl A):480A.

89 Ezetimibe With Fenofibrate in Hypercholesterolemia
-5 -10 -10.1 -15 Placebo (n=8) -13.5 Mean % LDL-C reduction after 14 d -20 Fenofibrate 200 mg (n=8) -25 -22.3 Ezetimibe 10 mg -30 (n=8) In a small study, 32 hypercholesterolemic patients were randomized to receive placebo, fenofibrate 200 mg, ezetimibe 10 mg, or the combination of fenofibrate 200 mg and ezetimibe 10 mg. After 2 weeks of therapy, the LDL-C reduction with a combination of ezetimibe and fenofibrate was significantly greater than in any other arm (36.3% vs 22.3% with ezetimibe alone vs 13.5% with fenofibrate alone vs 10.1% with placebo; P<0.03 vs placebo or either drug alone). -35 Ezetimibe 10 mg + -36.3 fenofibrate 200 mg -40 (n=8) *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. Kosoglou T, Fruchart J-C, Guillaume M, et al. Coadministration of ezetimibe and fenofibrate leads to favorable effects on Apo CII and LDL-C subfractions. 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

92 Suggested Main Points:
1) Statistics show overwhelmingly that cardiovascular disease (CVD) – and not cancer – is the major health concern for postmenopausal women. In fact, 1 in 2 women will eventually die of heart disease or stroke; but only 1 in 25 women will die because of breast cancer.1 The incidence of heart disease, including coronary artery disease and stroke, is rare in premenopausal women. However, heart disease is the most frequent cause of death in women over the age of 50.2,3 2) Although there has been a gradual and pronounced decrease in cardiovascular deaths in this country, the decrease has not occurred equally among men and women. Since 1984, death rates for men have dropped, while cardiovascular death rates for women have increased.1 3) It is possible that estrogen replacement at menopause could have an impact on these mortality curves. Currently, however, only 16% of women receive HRT after natural menopause, and 50% of these stop therapy within a year. Thus, treatment must become widespread before it might have a visible impact on mortality trends. Despite the impact of CVD, only 35% of women in a recent survey related heart disease to menopause.4 References: 1) 1997 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association 2) National Center for Health Statistics. Vital Statistics of the United States. 1992, Vol II – Mortality, Part A. Hyattsville, Md: US Dept of Health and Human Services, Public Health Service; DHHS publication 3) SEER Cancer Statistics Review Miller et al, eds. National Cancer Institute, 1997. 4) Wyeth-Ayerst Fourth Annual Menopause Report

93 Incidence of Cardiovascular Events in Women Before and After the Menopause
350 300 Average Age at Menopause 250 Incidence / 100,000 200 150 100 50 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 >65 Age Range F. B. Hu et al. New Engl J Med, 2000; 343:530-7 In postmenopausal women, atherosclerosis is a disease of estrogen deficiency

94 Risk of Cardiac Events/Death in Estrogen Users in 6 Large Observational Studies
Relative Risks and 95%Confidence Intervals 0.0 0.5 1.0 1.5 2.0 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 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 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 *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 WHI: Percent CHD Events by Year
HR = 1.29 95% nCI = 1.02–1.63 95% aCI = 0.85–1.97 Hazard Year Ratio P = NS for trend over time. This figure compares yearly rates (annualized percent) of CHD events in the CEE/MPA and placebo groups. Annualized percent represents the percent of women experiencing first time CHD events in the patient group during that particular year. For example, an annualized percent of 0.29 represents 29% of women in that treatment group who had not previously had a CHD event having one during that year. The annualized percent of CHD events in both the CEE/MPA and placebo group were variable, with a notable decrease in events in the placebo group at year 5. The table to the right of the line graph lists the HRs for total CHD events with CEE/MPA use on a year-to-year basis. Statistical tests for linear trends with time since randomization detected no significant trend over time for CHD; however, the WHI investigators note that these time-trend results should be viewed cautiously because the number of CHD cases in each year were small, the data for later years are incomplete, and risk comparisons in later years are limited to women who were not diagnosed with CHD in previous years For the entire follow-up period examined, overall HR for CHD was 1.29, with a significant 95% nominal CI of 1.02–1.63. Year *Includes 8 silent MIs. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:

97 Early vs. Late Estrogen Effects on the Natural History of Atherosclerosis
Adventitia MMP-9 Fibrous Cap Fibrous Cap Media Internal Elastic Lamina Fibrous Cap Plaque Plaque Fatty Streak/Plaque Plaque Necrotic Core Necrotic Core Estrogen Effects in Atherogenesis  LDL oxidation   LDL atherogenicity  LDL binding/accum   lesion progression  CAMs   monocyte adhesion/  macrophage accumulation  MCP-1 and TNFa  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 In order to assimilate the available data on estrogen and CHD, it is necessary to understand the natural history of atherosclerosis and any role estrogens may play in that history. It is now widely held that atherosclerotic lesions mainly result from a complex mechanism of events leading from endothelial injury and activation of the inflammatory system.1 The progression of atherosclerosis is shown in the illustrations above. Atherogenesis, or the initial appearance of fatty streaks/plaques, is followed by the appearance of a fibrous cap, plaque growth, and progression into necrosis.2 Some of the protective effects of estrogen on atherogenesis include the following: 1) decreased LDL oxidation, and thereby decreased LDL atherogenicity3; 2) decreased levels of cell adhesion molecules and cytokines commonly associated with inflammatory cell interactions4; 3) decreased proliferation and migration of smooth muscle cells, resulting in the inhibition of lesion progression5,6; and 4) an increase in endothelial function through promotion of rapid endothelial-dependent vasodilation.4 When plaques are already established, however, the effects of estrogen are no longer beneficial. Studies have suggested that estrogens may have the potential to increase plaque instability, through increased inflammation and increased release of matrix metalloproteinases, degradative enzymes that destabilize existing atherosclerotic plaques.7,8 In addition, estrogens may increase neovascularization and thereby may increase the likelihood of plaque hemorrhage.9,10 Loss of estrogen benefits in established atherosclerosis may also be attributable to diminished ER expression. Post and colleagues11 have reported a greater degree of methylation of the ER gene in atherosclerotic plaques compared with normal aorta. Increased methylation of the ER gene reduces its expression, and therefore results in a decreased cellular ability to respond to estrogens. Loss of estrogen benefits may also be related to decreased vascular responsivity. The ability of arteries to dilate in response to decreased blood flow is an important part of cardiovascular health. Herrington et al12 found that older women, particularly those with elevated cardiovascular risk factors, had lost their ability to respond to ERT/HRT with dilation as described for younger women.4 CAMs = cell adhesion molecules; SMC = smooth muscle cell; MMP = matrix metalloproteinase. A complete list of references for this slide can be found in the accompanying document titled “Cardiovascular References.”

98 Timing of CEE Start vs. Anti-atherosclerosis Effect (Nonhuman Primates)
Plaque Area (Relative to Placebo) Ovariectomy 70% Decrease1,2 Healthy diet CEE + atherogenic diet Atherogenic diet * 50% Decrease3 CEE + atherogenic diet ** Atherogenic diet + No CEE 2 years Healthy Diet + CEE Healthy diet 0% No change4 Premenopause Postmenopause 1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6. 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17: 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-7. 4Williams JK, et al. Arterioscler Thromb Vasc Biol. 1995;15: *Like Obs. HRT trials **Like HERS/WHI

99 Timing of HRT Start vs. Effects on CVD:
Extrapolation of WHI Results (E+P Arm) 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 5 10 15 20 25 30 Years Postmenopause at Randomization <10 10-19 Zero-Year RR=0.62 *Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)

100 Effect of Estrogen Dose on Risk for CHD
Nurses’ Health Study, Hormone Use Multivariate-adjusted RR (95% CI) Person-years of Follow-up Cases (n) Never 0.3 mg* 0.625 mg* 1.25 mg 313,661 19,964 116,150 39,026 609 19 99 41 1.0 0.58 ( ) 0.54 ( ) 0.70 ( ) RR = relative risk for current vs. never users. Grodstein F, et al. Ann Intern Med. 2000;133:

101 Effect of Estrogen Dose on Risk for Stroke
Nurses’ Health Study, Hormone Use Multivariate-adjusted RR (95% CI) Person-years of Follow-up Cases (n) Never 0.3 mg* 0.625 mg* 1.25 mg 313,661 19,964 116,150 39,026 290 9 124 46 1.0 0.54 ( ) 1.35 ( ) 1.63 ( ) RR = relative risk for current vs. never users. Grodstein F, et al. Ann Intern Med. 2000;133:

102 WHI Scorecard: $600M Later…
“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)

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 Lipoprotein Effects of Major Lipid Rx Classes: Summary
Factor Statins BAS CAI Fibrates Niacin ↓LDL-C +++ ++ +/- ↑LDL size - ? ↓TG + ↓Remnant ++? ↓Lp(a) ↑HDL +/++

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