Challenges Facing Lipid Guidelines Peter W. F. Wilson, M.D. Emory University

Disclosure Peter W. F. Wilson Grants Sanofi-Aventis—Role of adiposity as a risk factor for heart disease in Framingham participants Liposcience—LDL particle number in US Veterans ATP III: Clinical Management of Metabolic Syndrome The management of metabolic syndrome has two goals: to reduce underlying causes and to treat associated lipid and nonlipid risk factors. Obesity and physical inactivity are underlying risk factors for CHD. If the metabolic syndrome is present after LDL-C has been controlled, then therapeutic lifestyle changes should stress weight reduction and increased physical activity. Weight reduction enhances LDL-C lowering and reduces all of the risk factors of the metabolic syndrome. Regular physical activity reduces VLDL levels and increases HDL-C, and in some people, it lowers LDL-C. Physical activity can also reduce BP and insulin resistance, which are two of the factors associated with the metabolic syndrome, and it can favorably influence cardiovascular function. After the underlying risk factors have been addressed, therapies should be used to treat the lipid and nonlipid risk factors, including hypertension, elevated TG, and low HDL-C. In addition, aspirin should be given to CHD patients to reduce the prothrombotic state.   Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Discussion Items Lipid Measures Recent Evidence Lipids and CVD Current Guidelines Specific Groups Diabetes Mellitus Familial Hypercholesterolemia Hypertriglyceridemia Metabolic Syndrome Therapy

Lipid Research Clinic Program Lipid Measurements Density VLDL 1.006 Non- HDL LDL IDL Total* Bottom* fraction 1.063 HDL* LDLFriedewald = Total - HDL- (Trig/5) (mg/dl)

Serum Lipoprotein Size and Density VLDL 0.095 -- Chylomicrons 1.006 -- 1.020 -- LDL Density (g/ml) HDL-1 IDL 1.060 -- Chylomicron Remnants 1.100 -- HDL-2 HDL-3 1.140 -- Nascent HDL 60 100 140 200 280 400 600 800 1000 Diameter (Angstroms)

Cholesterol Apolipoprotein B-100 Phospholipid Apolipoprotein (a)

Lp(a) Level and Risk for CHD LRC Men 35-59 Years with 7-10 Years Follow-up 4 97.5%C.I./2.5% C.I. 3 Relative Risk Relative Risk for CHD 2 1 0-3.0 3.1-7.2 7.3-15.5 15.6-34.8 34.9-119.8 Lp (a) Quintile (mg/dL) Schaefer JAMA 1994: 274: 1002

Lifetime Risk of CHD By Total Cholesterol Category Framingham Men and Women 63 57 51 42 39 34 36 33 29 43 42 41 21 36 30 26 40 23 24 20 31 34 18 27 19 20 17 15 17 14 Cholesterol (mg/dL) Age (y) Men Women After Lloyd-Jones Arch Intern Med 2003; 163:1966

Cholesterol Trialists Meta-Analysis Prevention of Cardiovascular Disease with LDL-C Lowering Search Investigators: Am Heart J 2007; 157: 815

Cholesterol Trialists Meta-Analysis of Statins Baigent Lancet 2005; 366: 1267

Cholesterol Trialists Cause Specific Mortality with Statins (effect of 1 mmol/l [38.6 mg/dl] reduction)) Baigent Lancet 2005; 366: 1267

Cholesterol Trialists Major CVD Events with Statins (effect of 1 mmol/l [38.6 mg/dl] reduction) Baigent Lancet 2005; 366: 1267

Cholesterol Trialists Proportional reduction in Major Vascular Events and mean absolute LDLcholesterol reduction at 1 year Proportional Reduction in Event Rate Baigent Lancet 2005; 366: 1267

Cholesterol Trialists Proportional reduction in Major Vascular Events and Mean absolute LDL-C reduction at 1 year Baigent Lancet 2005; 366: 1267

Framingham Offspring Men Diabetes and Lipid Extremes Framingham Offspring Men 60 p<0.001 50 Non-Diabetic 40 Diabetic Per cent 30 p<0.001 20 p<0.001 10 HDL-C<35 Total-C 240+ LDL-C 160+ Trig 250+ HDL-C<35 Total-C 240+ Siegel Metabolism 1996; 96: 1267

Framingham Offspring Women Diabetes and Lipid Extremes Framingham Offspring Women 50 p<0.001 Non-Diabetic 40 p<0.001 Diabetic p<0.001 30 Per cent p<0.001 20 10 HDL-C<35 Total-C 240+ LDL-C 160+ Trig 250+ HDL-C<35 Trig 250+ Siegel Metabolism 1996; 96: 1267

CHD Death Risk by non HDL-C, LDL-C, and Diabetes Status ARIC, Framingham, MRFIT Usual Care Relative Risk >100 <100 LDL-C (mg/dL) Non HDL-C (mg/dL) Diabetes Present Diabetes Absent Liu Diabetes Care 2006; 28: 1916

Statins to Prevent CVD in Diabetic Patients Cholesterol Treatment Trialists Meta-Analysis According to Baseline Lipoprotein Measurements 1 mmol/L LDLc effect Kearney Lancet 2008; 371: 117

Statins to Prevent CVD in Diabetic Patients Cholesterol Treatment Trialists Meta-Analysis 1 mmol/L LDLc effect Kearney Lancet 2008; 371: 117

Fibrates and Non-Fatal MI Abourbih Am J Med 2009; 122: 962 20

Fibrates and Mortality Abourbih Am J Med 2009; 122: 962 21

Updated ATP III Cholesterol Guidelines CHD Risk Category Recommended Goals Optional Goals LDL-C (mg/dl) non-HDL-C High risk (CHD or CHD Risk Equivalent) < 100 < 130 < 70 Moderate High risk (++ risk factors, CHD risk 10-20%) < 160 (++ risk factors, CHD risk <10%) Low risk (0-1 risk factors) < 190 Grundy Circulation 2004;110:227

2008 ADA-ACC Consensus Conference Suggested Treatment Goals in Patients with Cardiometabolic Risk and Lipoprotein Abnormalities Risk Category Goals (all in mg/dL) LDL-C Non-HDL-C ApoB Highest-risk including those with 1)known CVD or 2) diabetes plus one or more additional major CVD risk factors* < 70 < 100 < 80 High-risk patients including those with a) no diabetes or known clinical CVD but two or more additional major CVD risk factors* or 2) diabetes but not other major CVD risk factors < 130 < 90 Updated ATP III LDL-C Goals and Cutpoints for Therapy The National Cholesterol Education Program Adult Treatment Panel III (ATP III) defines high-risk patients as those who have CHD or atherosclerotic disease of the blood vessels to the brain or extremities, or diabetes, or multiple (2 or more) risk factors (e.g., smoking, hypertension) that give them a >20% chance of having a heart attack within 10 years. Very high risk patients are those who have cardiovascular disease together with (1) multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (e.g., continued smoking), (2) metabolic syndrome (a constellation of risk factors associated with obesity including high triglycerides and low high-density lipoprotein cholesterol [HDL-C]) and/or (3) acute coronary syndromes such as heart attack. For high-risk patients, the overall goal is to achieve a low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL. But for patients at very high risk, a group that is considered a "subset" of the high-risk category, a therapeutic option is to decrease LDL-C levels to <70 mg/dL. For very high risk patients whose LDL-C levels are already <100 mg/dL, there is also an option to use drug therapy to reach the <70-mg/dL treatment goal. For moderately high risk patients, the goal is to achieve an LDL-C level <130 mg/dL, but it is a therapeutic option to set a lower LDL-C goal of <100 mg/dL and to use drug therapy for LDL-C levels of 100–129 mg/dL to achieve this lower goal. For high-risk or moderately high risk patients, the report advises that LDL-C–lowering drug therapy be sufficient to achieve at least a 30–40% reduction in LDL-C levels. This can be accomplished by taking statins or by combining lower doses of statins with other drugs (bile acid resins, nicotinic acid, or ezetimibe) or with food products containing plant stanols/sterols. For moderately high risk patients with LDL-C levels of 100–129 mg/dL at baseline or on lifestyle therapy, LDL-C–lowering therapy to reach a goal of <100 mg/dL is recommended, and lipid-altering drug therapy to achieve this goal is a therapeutic option. By definition, almost all people with 0–1 risk factor have a 10-year risk <10%. Drug therapy for primary prevention in this patient population is recommended only for those with higher LDL-C levels. Major CHD risk factors include cigarette smoking, blood pressure 140/90 mm Hg or on antihypertensive medication, HDL-C <40 mg/dL (1.0 mmol/L), family history of premature CHD (CHD in male first-degree relative aged <55 years; CHD in female first-degree relative aged <65 years), and age (men 45 years; women 55 years). HDL-C  60 mg/dL (1.6 mmol/L) counts as a "negative" risk factor; its presence removes 1 risk factor from the total count. Framingham risk score may also be used to determine 10-year CHD risk. References: National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421. Grundy SM, Cleeman JI, Bairey Merz CN, et al., for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239. Bays H, Shepherd J.  Diabetes, metabolic syndrome and dyslipidemia. In: Management Strategies in Diabetes.  Hackensack, NJ: Cambridge Medical Publications, 2004:1-28. *Other major risk factors (beyond lipids) include smoking, hypertension, and family history of premature CAD Brunzell JACC 2008; 51: 1512

Criteria Used for Evaluation of Evidence Recommendation Grade Class I Evidence and/or general agreement that a given diagnostic procedure/ treatment is beneficial, useful and effective  Class II Conflicting evidence and /or a divergence of opinion about the usefulness / efficacy of the treatment Class II a Weight of evidence in favour Class II b Usefulness/efficacy less well established   Class III Evidence that the treatment is not useful and in some cases may be harmful Level of Evidence  Level A Data derived from multiple randomized clinical trials (RCT) or meta-analysis Level B Data derived from a single RCT or large non-randomized studies Level C Consensus of opinion by experts and/or small studies, retrospective studies, registries I IIb III IIa A C 24

Canada 2009 Dyslipidemia Guidelines Moderate Risk Level Pharmacological therapy indicated if: LDL-C > 3.5 mmol/L[135 mg/dl] (apoB > 1.00 g/L) TC/HDL-C ratio > 5.0 hsCRP > 2mg/L in men over 50, women over 60 hsCRP should be performed selectively Consider cost/benefit of preventive therapy A C B Genest Can J Cardiol 2009: 25: 567

Canada 2009 Targets for LDL-C (or apoB): In high- and moderate-risk subjects Nearly all clinical trials measure LDL-C as index of therapy. Recommendations: Primary target is LDL-C decrease to < 80 mg/dl/L or 50% relative reduction We recommend apoB < 80 mg/dl as primary alternate target A A Genest Can J Cardiol 2009: 25: 567

Canada 2009 Dyslipidemia Target Levels Risk Level Initiate treatment if: Primary Primary LDL-C Alternate High Consider treatment in all patients CAD,PVD Atherosclerosis Most Pts with Diabetes Fram Risk Score ≥ 20% Reynolds Risk Score ≥ 20% <2 mmol/L (80 mg/dl) Or ↓50% LDL-C ApoB<80 mg/dl Moderate (strive towards ) FRS 10-19% LDLc>135 mg/dl TC/HDL >5.0 hsCRP >2 (men >50, women>60) Family history and hsCRP modulate risk LDLc<80 mg/dl Or ↓50% LDL-C ApoB<80 mg/dl ApoB<80 mg/dl Low FRS<10% LDL-C>5.0mmol/L ↓50% LDL-C A A A A A Genest Can J Cardiol 2009: 25: 567 27

Canada 2009 Dyslipidemia Recommendations Residual Risk (When LDL-C at target) OPTIONAL Secondary Targets Test Cut-point Intervention TC/HDL-C >4.0 Niacin Fibrate Non HDL-C >135 mg/dl [>3.5 mmol/L] Apo B/AI >0.8 Ezetimibe Triglycerides >150 mg/dl [1.7 mmol/L] hsCRP >2.0 mg/L Statin Genest Can J Cardiol 2009: 25: 567 28 28

Targets other than LDL-C (or apoB) After reaching primary targets (LDL-C or apoB) High HDL-C predicts atherosclerosis regression Low HDL-C predicts mortality even when LDL-C < 150 mg/dl (1.8 mmol/L) No specific target HDL-C or triglyceride levels Secondary optional targets unproven to reduce risk Consider secondary optional targets for high-risk patients Genest Can J Cardiol 2009: 25: 567

Canada 2009 Dyslipidemia Risk Assessment and Treatment Targets Initiate/consider treatment if any of the following: Primary Target LDL-C Primary Alternate ApoB HIGH FRS ≥ 20% RRS≥ 20% CAD PVD Atherosclerosis Most Diabetic Patients (consider treatment in all patients) < 2 mmol/L or ↓ LDL-C 50% ApoB < 0.80 Moderate FRS 10-19% LDL-C > 3.5 mmol/L TC/HDL-C > 5.0 hsCRP > 2 mg/L * Family history (strive towards ) LOW FRS < 10% LDL-C > 5.0mmol/L A A A * Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia Genest Can J Cardiol 2009: 25: 567 30 30

Summary Evidence Safety Proven Clinical Efficacy Case control Observational Cohorts Clinical Trials Safety Proven Clinical Efficacy Consideration of long term risk