11Non-Fatal CAD in FH (Utah) vs. General U.S. Population
12What FH May Mean for a Family 40 ♥373AffectedAge at MITotal CholKey47 ♥4221838 ♥34 ♥34740 ♥37341 ♥45 ♥3341628418942018242180311581213217157182851913021311221356291133441411815255
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 defectApo B mutations (3500, etc.)PCSK9 mutations (rel rare, 1/50 FH families)Autosomal recessive hypercholest. (v. rare)
14“Pure” Hypercholesterolemia Other causes Polygenic hypercholesterolemiaVery CommonGenetics poorly definedMechanisms poorly defined (likely includes hyperabsorbers)Generally milder than FHDiet-inducedVery commonGenerally much milder than FH“Secondary” causesHypothyroidism—rel. common in elderly but ↑LDL mildOther (rare hepatic and renal abn., etc.)
15VLDL overproduction Associated Lipid Abnormalities: Mild-moderate ↑VLDL-C/Plasma TGMild-moderate ↓HDL-CSmall, dense LDL (and HDL)Mild ↑LDL-C1o 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 agingAlmost always helped by weight loss
17Overlap Among Metabolic Syndrome, Diabetes Mellitus-2, ↑Apo B and FCHL ?DM-2“Classic” DM-2“Isolated”MetabolicSyndrome↑Apo B???FCHL“Isolated”↑Apo BAdapted from John Brunzell, personal communication, 2005
18Despite Elegant Science of Abnormalities of Lipoprotein Metabolism, Treatment of Dyslipidemias is Nearly Always Just According to Lipid Levels!
20Atherosclerosis in Diabetes ~80% of all diabetic mortality75% from coronary atherosclerosis25% from cerebral or peripheral vascular disease>75% of all hospitalizations for diabetic complications>50% of patients with newly diagnosed type 2 diabetes already have CHDNational Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
21Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic Men Multiple Risk Factor Intervention Trial (MRFIT)●●●●Rate/1000●●●●●●Serum Cholesterol QuintileBierman EL, Arteriosder Thromb, June 1992Based on data from J. Stamler
22Slide 10Type 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.
23Diabetes and glucose intolerance vs. cardiovascular mortality MenWomen10 year CVD mortality (%)Normal IGT DM Normal IGT DMAge (years)Bedford Study, Keen, et al. Lancet. 2:505–508, 1965.
25>102 cm (>40 in) >88 cm (>35 in) ATP III: Insulin Resistance Syndrome (“The Metabolic” Syndrome* ICD )<40 mg/dL <50 mg/dLMen Women>102 cm (>40 in) >88 cm (>35 in)100 mg/dLFasting glucose130/85 mm HgBlood pressureHDL-C150 mg/dLTGAbdominal obesity† (Waist circumference‡)Defining LevelRisk FactorATP III: THE METABOLIC SYNDROMEn 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 .)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:
26Insulin Resistance Syndrome Prevalence: NHANES III Data; ATP III Criteria 24% of total US Population (47 million pts)32% of US Hispanics26% higher Hispanic women vs. men57% higher in Black women vs. men43% of total population > 60 y oldFord E, et al JAMA 287:356-9, 2002
27Fredrickson Type III (Familial Dysbetalipoproteinemia) DefinitionTGRL remnant (IDL) excessVLDL-C/Plasma TG 0.30, TG >150 mg/dlApo E 2/2 + other abn (VLDL overprod?); or apo E deficiencyPalmar (flat and orange) and/or tuberoeruptive (elbow) xanthomasPrevalence and Athero Risk193 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:
28TG 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 cholesterolHopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):
29CHD Events vs. LDL-C: Statin and Non-Statin Trials 304S-PI25GREACE-UC2° PreventionHPS 2o-Pl4S-Rx20POSCH-PlPercent withCHD eventHPS2o-Rx15LIPID-PIGREACE-Rx1° PreventionLIPID-RxCARE-PI10WOSCOPS-PICARE--RxPOSCH—RxAFCAPS/TexCAPS-PICPPT-Pl5CPPT--RxHPS 1o-RxHPS1o-PlWOSCOPS-RxAFCAPS/TexCAPS-Rx90110130150170190210LDL-Cat follow-up (mg/dL)
30NCEP ATP Update—2004 Risk Category Risk Factors LDL-C Goal Lower RF <160Mod/Mod-High >2 RF, FRS <20% <130High CVD alone or FRS >20% <100Very High CVD+DM, MS, ↑↑RF, ACS <70*In High and Very High Risk categoriesConsider statin Rx even if already at goalConsider combination Rx—statin + fibrate or niacin—if TG>200+NHDL-C>130 or HDL-C<40Statin 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 doses65-80 yrs: 2o prev as younger; 1o prev+DM=high risk; other, use clinical judgmentNon-HDL-C: use if TG>200; goal as LDL-C+30*Therapeutic option: use clinical judgmentGrundy, et al. Implications of Recent Clinical Trials for NCEP ATP III. Circ. July 13, 2004;110:
31More Aggressive Lipid Treatment “BEIGE”Broader use of treatment (TLC and meds)Earlier use of medications (may not wait for TLC)Increased intensity of RxGetting to goalEvaluation of progress, follow-up (esp. compliance which is <50% at 1 year!!!)Modified from AM Gotto AHA mtg 11/05
32Factors 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 CHDEmerging risk factorsDiet and exerciseHigher risk in non-CaucasiansFurther risk increase above 79 years oldRisk beyond 10 years in future (underestimates risk in young adults)
33Clinical Judgment for NCEP ATP Update—2004 (per Dr. E. A. Brinton) May adjust the LDL-C goal from NCEP tableup 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)
34Choice of HMG-CoA Reductase Inhibitors (“Statins”) 1. Lovastatin (Mevacor, Altoprev, generic)—events (1o prev.), longer experience, generic and extended release available2. 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 CRP6. 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?
35Diet (Medical Nutrition Therapy, MNT), and Lifestyle (Therapeutic Lifestyle Change, TLC) for Atheroprevention
36Intensive 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
37Finnish Mental Hospital Study Study Design and Serum Cholesterol Diets reversedData for males shown here. Total in each hospital about About 70-75% remained in hospital all 12 yearsDiet changed in hospital NMiettinen M, et al. Lancet 1972; ii: 835
38Finnish Mental Hospital Study Age-adjusted death-rates (per 1000 person-years) MalesFemalesCHDTotalHospital N, diet5.734.64.031.1Hospital N, control13.038.87.732.1Hospital K, control126.96.36.199.9Hospital K, diet7.535.16.530.7Pooled diet6.6188.8.131.52Pooled control184.108.40.2069.0Miettinen M, et al. Lancet 1972; ii: 835
39Non-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)SupplementsPlant 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 documentedNiacin (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 documentedFolate, B6, B12—↓Hcy but ↓CVD not seen yet
40Non-Medical Treatments for Dyslipidemias (cont.) ExerciseHow? (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)↑LongevitySmoking CessationWill to quit essentialNon-medical treatment effective (hypnosis, behavior modif.)Several good medications available
41Atheroprevention Beyond LDL-C and Statin Monotherapy: Non-Statin Treatment
42CHD Risk Prediction by HDL-C vs. LDL-C* Patient 2:LDL-C: 100 mg/dLHDL-C: 25 mg/dLPatient 1:LDL-C: 220 mg/dLHDL-C: 45 mg/dLRR of CHD After 4 yrCHD Risk: HDL-C vs LDL-C as Predictor1The 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.1Castelli 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.
43Rx Changes HDL and TC/HDL are Best predictors of CHD Risk Reduction Univariate RegressionR2In 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 LimitationsThe 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 ConclusionsChanges 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 = 3869R2 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.
44Hypothesized Antiatherogenic Mechanisms of HDL Reverse cholesterol transportAntioxidant effectsAnti-inflammatory effectsAnti-thrombotic effects?Direct blocking of LDL effects?Other?
45Reverse Cholesterol Transport BileMacrophageMature HDLNascent HDLA-IA-IUCCECELCATPLLiverPL&UCUCCEABCA1SR-BISR-ACETPLDL-ROxidationCEBRole of CETP in HDL MetabolismThis 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.)ReferencesHavel 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/LDLCETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoproteinAdapted from C Cuchel et al. Art Thromb & Vasc Biol 2003;23:
48Medications which Raise HDL-C Levels Agent HDL-C EffectNicotinic 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 levelsA 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 CardiovascularDisease 1998;41:
49Effect of Niaspan on Lipids and Glycemic Control in Patients with Diabetes Mellitus (ADVENT) * median valuesGrundy et al, Arch Int Med 162: , 2002
50CDP at 6 yr: Nonfatal MI by Baseline FBG* RelativeHazard0.700.740.730.44PlaceboNiacinEvent Rate (%)126mg/dL*Z for interaction = –0.35. Indicates homogeneityCanner PL et al. Am J Cardiol Jan 15;95(2):254-7.
51Niacin 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.
52Maximizing Niacin Tolerability Niacin ER (Niaspan), or ERNL (Advicor), far less flushing than IR (?SR qd?)Take withASA 325mg (buffered, not enteric-coated) vs. Alka-SeltzerDiphenhydramine (Benadryl) mgCaCO3 (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 foodsConsider 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!
53No-Flush Niacins Not recommended for atheroprevention! Types Niacinamide/NicotinamideAcipimoxInositol HexaniacinateLipid EffectsFew or noneEvidence for CHD PreventionNoneNot recommended for atheroprevention!
54Use med Rx to ↑HDL only in 2o and high-risk 1o prev HDL- Clinical SummaryLevels--Basal vs. Intervention1. HDL is protective, but2. Lowering it may not be bad (e.g. good diet), and3. Raising it may not be good (data not definitive)4. LDL/HDL ratio estimates risk but confuses RxTreatment (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 cessation4. 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
55TG 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 cholesterolHopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):
56LDL Phenotypes/Patterns A and B (B=SD LDL) vs. Plasma TG 100908070% Cumulative frequency605040Phenotype A30Phenotype B201020406080100120140160180200220240260280300500TG (mg/dL)Austin M et al. Circulation. 1990;82:
57Extra Atherogenicity of Small Dense LDL (pattern B) ↓LDL-R uptake,↑ Levels & Modific.EndothelialChemoattractantsLDLENDOTHELIUMMonocyteThrough endothelium easierLDLMacrophageStays onmatrix longerMildly oxidizedMacrophageMore readily oxidizedSmall, 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 CELLSmooth Muscle CellHighly oxidizedAndAssociates w/ Metabolic Syndrome/DM:↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid.
58LDL-C Doubly Underestimates CHD Risk with Small-Dense LDL More particles/LDL-C →higher LDL particle # than suspectede.g. LDL-C 100 → ↑risk ≈ 120 mg/dlMore atherogenic/LDL particle than large LDLe.g. LDL-C 120 ↑risk ≈ 140 mg/dlLDL-C looks low but CHD risk is high
59Advanced Lipid Profiles—Which? Test (method)Berkley Heart Lab (GGE), Lipo PrintLipoProfile/ LipoScience (NMR)VAP/Atherotech (Ultracentrifugation)Pro/ConEstablished method, well validated, rel. pricey ($99-$240 and up, a la carte)More affordable (~$120), new method but well validated, LDL particle #, no extrasEstablished method, well validated, CDC std, very affordable ($45-$90), MetSynd, Lp(a)-chol gratis
61Non-Pharmacological Approaches to Hypertriglyceridemia Consider secondary causes (increased frequency)Poorly controlled diabetes mellitusHypothyroidismCorticosteroids / Cushing’sIsotretinoin (Accutane) (rarely a problem)Weight loss, exerciseAvoid sugar and high carbohydrate dietFish and fish oilLittle or NO ALCOHOLChange oral estrogen to patch or discontinue
62Lipid Effects: Fenofibrate vs Simvastatin Double-blind, randomized, controlled 12 week trialType IIa and IIb Patients+18+15+4-10Mean (%) change from baseline-17-20-21-25-25-35-41P=0.05P=0.001P=0.001P=0.015P=0.001P=0.001Steinmetz A et al., J Cardiovasc Pharmacol 1996 Apr;27 Suppl:S63-70
63Gemfibrozil (Lopid and generic) vs Gemfibrozil (Lopid and generic) vs. Fenofibrate (TriCor, Antara, Tryglide, generic)Favor GemfibrozilCost (generic)Availability (generic)Better CHD event ↓ data (Helsinki & VA-HIT)Favor FenofibrateStatin compatibilityDosed qd w or w/o meal (ease & compliance)Better lipid effects (esp. ↑HDL, ↓LDL)↓Fibrinogen↓Atherosclerosis (DAIS)↓Athero events (FIELD)
64Niacin vs. Fibrates for Mixed Dyslipidemia, DM & Met. Synd. Favoring FibratesExc ↓TGOK ↑HDLOK ↓LDL (feno only)No flushingNo increase in glucose levelsNo increase in gout/uric acidNo increase in Hcy↓CHD event data (gemfib, trend w/ feno)Some ↓Lp(a) (feno)Favoring NiacinExc ↑HDL-COK ↓LDLOK ↓TGFewer GI Sx (N & V)Better Lp(a) lowering↓CHD event data (CDP)Better ↓CHD event data in combo w/ statin and/or BAS↓Total mortalityBetter compatibility w/ statin (vs. gemfib.)Statin combo tablet (ERNL, Advicor)
65Lipid Efficacy of Omega-3 AEE is Similar to Fenofibrate Efficacy Comparison in Patients with TG ≥ 500 mg/dLRelative Difference vs. PlaceboOmega-3 AEEFenofibrateTGHDL-CCHOLVLDL-CLDL-CTGHDL-CCHOLVLDL-CLDL-C50%50%30%30%10%10%-10%-10%-30%-30%-50%-50%-70%-70%Source: Omacor® Prescribing Information; Antara® 130 mg Prescribing Information.
66Dose-Range of Omega-3 FA Effect on Triglycerides Dose of O3AEEs% Change TG (mg/dL)ADD STUDY TITLE IF AVAILABLETG mg/dL at baseline; 8-week treatmentSource: Data on file at Pronova/Reliant.
67GISSI-Prevenzione Trial Omega-3 Acid Ethyl Esters Reduce All-Cause and Sudden Death 1.000.99Omega-3 AEE0.980.59 (95% CI ) P=0.037Probability0.97Control0.960.95306090120150180210240270300330360DaysGISSI-Prevenzione Trial - Early Effect on All-Cause MortalityControlOmacor®RRP-ValueAll-Cause Mortality10.6%8.4%21%0.0064Sudden Death3.3%1.8%44%0.0006Marchioli R, et al., Circulation 2002;105:
69Suggestions for Improving Omega-3 FA Tolerability Use O3-AEE’s – fewer capsules, fewer impuritiesTake at start of mealFreeze/refrigerate capsules (PI says no)Gradual uptitration
70Mortality Effects of Lipid Rx # TrialsN% Δ Total% Δ CVD% Δ non-CVDStatins3553K↓13%*↓22%*↓3%Omega-31410K↓23%*↓32%*Fibrates1714K0%↓7%↑13%**p< M Studer, et al. Arch Int Med 2005;165:
71Fibrates vs. Omega-3 to Rx HTG and Prevent Atherosclerosis Favoring FibratesMore conventional↓CVDBetter ↑HDL-C & ↓LDL-CNon-lipid benefits?Good statin compatibility (feno only, FIELD)More convenient (fewer capsules)No fishy burpingFavoring Omega-3More natural↓CVD and ↓total mortalityNon-lipid benefits?No transaminase contraindic.No precaution w/ statinsNo warfarin interactionLess nausea and vomitingBottom line:Either is good as first-lineBoth often needed in combination!
72Hypertriglyceridemia Drug Treatment When—After diet and Rx 2o factorsTreat all TG > 500 for pancreatitis & atheroTreat to <150 if 2o prevention, DM/IR or other athero riskHowGemfibrozil/Fenofibrate—easier, more effectiveNiacin—cheap/easy, best if HDL-C and/or LDL-CStatins—consider, especially if LDL-COmega-3 oils, effective in high dosesTZDs (pioglitazone > rosiglitazone)
76Lp(a)—Summary Pro-atherogenic/pro-thrombotic factor Genetically determinedNot lowered by most treatments:DietExerciseWeight lossStatins,Bile acid resins,GemfibrozilRx options:Lower Lp(a)NiacinEstrogenFenofibrate?Extra LDL-C lowering
77Suggested Use of Emerging CHD Risk-Factor Tests Why?Rx yes/no?More aggressive Rx?Specific RxWhen?1o PreventionIntermediate-Risk2o Prevention, CVD:W/ normal lipid profileSevere beyond risk factorsProgression despite “adequate” RxBlood TestsSD LDLApo B vs. LDL # vs. Non HDL-CCRP (vs. Met. Synd.)Lp(a)Microalb’uria, GFRHcyRLP-CLpPLA2 (PLAC)Arterial Tests (1o Prev)CAC by CTCarotid USAnkle Brachial Index (SBP ankle/SBP arm <.9)
79L-TAP: Majority of CHD Patients Do Not Reach NCEP LDL-C Goal 25n = 1,460201816.614.4151311.2% ofpatients9.99.4107.95 >160LDL-C (mg/dL) on-treatmentPearson TA et al. Arch Intern Med. 2000;160:Other L-TAP data courtesy of TA Pearson.
80Example of Statin Titration and Failure to Attain Optimal LDL-C Starting LDL-C 220 mg, 40% Lowering at Statin 10 mg250200LDL-C150100Optimal5020406080100Statin dose (mg)
81Statin Titration: Potential for Side Effects at Maximum Dose AtorvastatinLovastatinSimvastatin2.52.04 2.3 1.51.7 Elevated transaminases(% of patients)1.00.5The 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.2,3The 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.4References1. 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: 1999.10204080204080204080Statin 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.
82More vs. Less Aggressive LDL-C Lowering Rx StudyLDL-C LowRxLDL-C HiRxAdd'lLDL↓Add’lCHD↓SafetyProve-IT95 mg/dl62 mg/dl35%16%3x ↑ALTA to Z81 mg/dl66 mg/dl18%11%9x ↑myop*TNT101 mg/dl77 mg/dl24%22%6x ↑ALTIDEAL103 mg/dl82 mg/dl20%2x ↑myalg 9x ↑ALTProve-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.
83CAD Events in the 4S Trial Majority of CAD Events Occur Despite Statin Rx: Need for Further Rx ImprovementCAD Events in the 4S Trial30% ↓CAD w/ statin% with CAD event70% CAD events not preventedDespite 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.PlaceboSimvastatinScandinavian 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:
84Event Reduction With Monotherapy Versus Combination Therapy WOSCOPS 65954S 4444CARE 4159HPS 20,536ASCOT19341FATS (10 Y)176Trial NReduction in CV Events (%)-31-34-24-25-36Among 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.-721. 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.
85HATS: Angiographic and Clinical Endpoints After 3 Years 89% reduction252015105Mean 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 LesionsCoronary Death, MI, Stroke, or RevascularizationHATS = 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:
87Ezetimibe + Atorvastatin 10 mg (n=65) Ezetimibe + Atorvastatin 10 mg: Greater LDL-C Reduction vs. Atorvastatin 20 or 40 mg AloneAtorvastatinEzetimibe + 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
88Ezetimibe/Simvastatin vs. Atorvastatin LDL-C Lowering 1020408010/1010/2010/4010/80% Reduction from baseline at wk 6Davidson M, McGarry T, Bettis R, et al. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40:*****P0.001 vs atorvastatin at corresponding dose.Ballantyne et al. J Am Coll Cardiol. 2004;43(suppl A):480A.
89Ezetimibe With Fenofibrate in Hypercholesterolemia -5-10-10.1-15Placebo (n=8)-13.5Mean % LDL-C reduction after 14 d-20Fenofibrate 200 mg(n=8)-25-22.3Ezetimibe 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).-35Ezetimibe 10 mg +-36.3fenofibrate 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.
92Suggested 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 50.2,32) 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.13) 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.4References:1) 1997 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association2) 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 publication3) SEER Cancer Statistics Review Miller et al, eds. National Cancer Institute, 1997.4) Wyeth-Ayerst Fourth Annual Menopause Report
93Incidence of Cardiovascular Events in Women Before and After the Menopause 350300Average Ageat Menopause250Incidence / 100,0002001501005020-2425-2930-3435-3940-4445-4950-5455-5960-64>65Age RangeF. B. Hu et al. New Engl J Med, 2000; 343:530-7In postmenopausal women, atherosclerosis is a disease of estrogen deficiency
94Risk of Cardiac Events/Death in Estrogen Users in 6 Large Observational Studies Relative Risks and95%Confidence Intervals0.00.51.01.52.0Bush, T. L. et al., Lipid Research ClinicsFollow-up Study Circulation 75:1102, 1987Grodstein, F. et al., Nurses Health StudyN Engl J Med 335:453, 1996Criqui, M. H. et al., Rancho Bernardo StudyAm J Epidemiol 128:606, 1988Falkeborn, M. et al., Uppsala Health CareRegion Br J Obstet Gynaecol 99: 821, 1992Hunt, K. et al., British Menopausal HormoneStudy Br J Obstet Gynaecol 97:1080, 1990*Psaty, B. M. et al. Group Health Cooperative ofPuget Sound Arch Intern Med 154:1333, 1994*Deaths from circulatory diseases
95Rationale for the Randomized HRT Trials (HERS&WHI) Supposed to verify observational studies:peri-menopausal startInstead studiedlate post-menopausal start
96WHI: Percent CHD Events by Year HR = 1.2995% nCI = 1.02–1.6395% aCI = 0.85–1.97Hazard Year RatioP = 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 yearsFor 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:
97Early vs. Late Estrogen Effects on the Natural History of Atherosclerosis AdventitiaMMP-9Fibrous CapFibrous CapMediaInternal Elastic LaminaFibrous CapPlaquePlaqueFatty Streak/PlaquePlaqueNecrotic CoreNecrotic CoreEstrogen 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 vasodilationEstrogen Effects in Established Plaques MMP expression PQ instability/rupture Thrombosis Event # and severityLoss of Estrogen Benefits (when HRT started after prolonged estrogen deficiency) Expression of estrogen receptors Vascular responsivityBenefits of estrogen early in atherogenesisAdverse effects of estrogen in vulnerable plaqueIn 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.1The 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.2Some 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.4When 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.9,10Loss 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.4CAMs = 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.”
98Timing of CEE Start vs. Anti-atherosclerosis Effect (Nonhuman Primates) Plaque Area(Relative to Placebo)Ovariectomy70%Decrease1,2Healthy dietCEE + atherogenic dietAtherogenic diet*50%Decrease3CEE + atherogenic diet**Atherogenic diet+ No CEE 2 yearsHealthy Diet+ CEEHealthy diet0%No change4PremenopausePostmenopause1Clarkson 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
99Timing of HRT Start vs. Effects on CVD: Extrapolation of WHI Results (E+P Arm)0.00.20.40.60.81.01.21.41.61.82.02.22.42.6Risk Ratio for CVD51015202530Years Postmenopause at Randomization<1010-19≥Zero-YearRR=0.62*Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)
100Effect of Estrogen Dose on Risk for CHD Nurses’ Health Study,HormoneUseMultivariate-adjusted RR (95% CI)Person-yearsof Follow-upCases(n)Never0.3 mg*0.625 mg*1.25 mg313,66119,964116,15039,0266091999411.00.58 ( )0.54 ( )0.70 ( )RR = relative risk for current vs. never users.Grodstein F, et al. Ann Intern Med. 2000;133:
101Effect of Estrogen Dose on Risk for Stroke Nurses’ Health Study,HormoneUseMultivariate-adjusted RR (95% CI)Person-yearsof Follow-upCases(n)Never0.3 mg*0.625 mg*1.25 mg313,66119,964116,15039,0262909124461.00.54 ( )1.35 ( )1.63 ( )RR = relative risk for current vs. never users.Grodstein F, et al. Ann Intern Med. 2000;133:
102WHI 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 wayML 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)
103HRT in Postmenopausal Women: State of the Art 2005 HRT is good in most womenAll perimenopausal women should be considered for HRT (early start) esp if estr. defic Sx presentLow-dose oral CEE/MPA usually best (if tolerated);Oral or patch estradiol are good alternativesContinue life-long (unless/until adverse event—VTE, etc.)Current dogma (D/C of HRT after 1-5 y) is likely harmfulLate-start HRT usually badCaveat: HRT does not haveFDA indication for CHD prevention
104Lipoprotein Effects of Major Lipid Rx Classes: Summary FactorStatinsBASCAIFibratesNiacin↓LDL-C++++++/-↑LDL size-?↓TG+↓Remnant++?↓Lp(a)↑HDL+/++