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October 30, 2007University Hospitals Heart & Vascular Institute Carl E. Orringer, MD, FACC Harrington Chair in Preventive Cardiovascular Medicine University.

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Presentation on theme: "October 30, 2007University Hospitals Heart & Vascular Institute Carl E. Orringer, MD, FACC Harrington Chair in Preventive Cardiovascular Medicine University."— Presentation transcript:

1 October 30, 2007University Hospitals Heart & Vascular Institute Carl E. Orringer, MD, FACC Harrington Chair in Preventive Cardiovascular Medicine University Hospitals Case Medical Center Harrington Heart and Vascular Institute Associate Professor of Medicine Case Western Reserve University School of Medicine Lipid Management in 2013 Are You Up to Date?

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3 How Increased Concentration of Apo B Containing Particles Promotes Atherosclerosis Blood ApoB lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response ApoB = apolipoprotein B. 1. Tabas I et al. Circulation. 2007;116:1832– Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551– Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536– Steinberg D et al. N Engl J Med. 1989;320:915–924.

4 Fibrous cap thinning Plaque rupture and thrombosis Atherothrombotic vascular disease (eg, MI and stroke) Plaque rupture Thinning fibrous cap MI = myocardial infarction. 1. Tabas I et al. Circulation. 2007;116:1832–1844. Atherothrombotic Vascular Disease: Response-to-Retention Model 1

5 Atherosclerosis Progression 1–3 1. Tabas I et al. Circulation. 2007;116:1832– Hansson GK. N Engl J Med. 2005;352:1685– Jawad E et al. Dis Mon. 2008;54:671–689. Normal Artery Fatty streak involving lipoprotein and immune cell infiltration Gradual outward expansion of arterial wall Plaque rupture and thrombosis (acute coronary event) Inward expansion causing luminal narrowing (chronic stable angina)

6 Food is consumed Food is absorbed and converted to transporter particles Muscle Energy storage (starvation) Disassembles transporter particles to prevent clogged transport pathways Assembles key body maintenance particles, substrates for hormone assembly Cell membranes, Salt and H 2 O balance Reproductive hormones Vitamins Particles provided that eliminate the refuse Lipoprotein Physiology Made Simple GI Tract Plasma Adipose tissue Liver GI Tract Refuse eliminated from the body Liver Accepts refuse from plasma Transporter particles Energy utilization 3 3

7 Glycerol Phytosterols Cholesterol Fatty acids Bile acids Phospholipids Micelles Intestinal lumen Duodenal/ Jejunal enterocyte Cholesterol CE Apo B-48 Fatty acids Triglycerides Chylomicron Lymphatics Plasma Lipoprotein lipase CM remnant Free fatty acids Muscle Adipose Tissue Phospholipids Cholesterol Surface Components Apo E Liver CM remnants degradation VLDL E B-100 C2 LDL IDL B-100 E SRB1 receptor Macrophage NPC1L1 ABCG5 ABCG8 Acetate Glycerol Glucose Phospholipids MTP ACAT FC Gallbladder Bile acids VLDL B-100 E C2 LDL receptor ( CM ) CM HDL To HDL CMR E3 HDL Cell membranes Hormones B-48 Vitamins FC A1A2 CETP E3 B-48 C3 A1 A2 A4 C (trace) E (trace) B-48 CM C E A4 Remnant receptor LDL-Related protein VLDL remnants

8 Dietary Priorities in Dyslipidemia Reduced intake of saturated fat and cholesterol Reduced intake of saturated fat and cholesterol Increased intake of soluble fiber and plant sterols/stanols Increased intake of soluble fiber and plant sterols/stanols In overweight and obese patients, reduced caloric intake to achieve weight reduction In overweight and obese patients, reduced caloric intake to achieve weight reduction In hypertriglyceridemic patients, same as above plus reduced intake of simple carbohydrates In hypertriglyceridemic patients, same as above plus reduced intake of simple carbohydrates Greatest impact of diet tends to be in overweight or obese patients with atherogenic dyslipidemia Greatest impact of diet tends to be in overweight or obese patients with atherogenic dyslipidemia

9 Adding Soluble Fiber to the Diet Whole grains Whole grains Nuts and seeds Nuts and seeds Fruit Fruit Legumes Legumes

10 Adding Plant Sterols and Stanols to the Diet Goal is mg daily Goal is mg daily Dietary options containing these functional foods Dietary options containing these functional foods Margarines Margarines OJ OJ Milk and non-dairy drinks Milk and non-dairy drinks Breads Breads

11 Intestinal Lumen Glycerol Phytosterols Cholesterol Fatty acids Phospholipids Mixed Micelles NPC1L1 Cholesterol Glycerol + 3 FA Triglycerides Phopsho;ipids Apo B-48 Microsomal triglyceride transfer protein Duodenum and Jejunal Enterocyte Chylomicron Plant sterols and stanols Mechanism of Action of Plant Sterols/Stanols and Fiber Soluble fiber Bile acids Micelles

12 LDL-C Lowering Drug Therapy Statins Statins Ezetimibe Ezetimibe Resins Resins High-dose niacin High-dose niacin Lomitapide Lomitapide Mipomersin Mipomersin Microsomal triglyceride transport protein Microsomal triglyceride transport protein Intestinal bile acid transporter Intestinal bile acid transporter NPC1L1 NPC1L1 Adipose tissue Adipose tissue Apo B Apo B HMGCoA Reductase HMGCoA Reductase Match Drug with Site of Action

13 LDL-C Lowering Drugs: Mechanisms of Action Small intestine Proximal Micelles NPC1L1 Bile Intestinal Bile Acid Transporter Ezetimibe Resins Acetyl CoA Cholesterol HMG CoA reductase Statin FFA Tg CE Apo B VLDL Liver Adipose Tissue FFA Niacin VLDL RLP LDL IDL Distal Apo E Apo C1,2,3 Lomitapide Mipo

14 What’s New in Lipids in 2013 NCEP ATP 3 transitions to NCEP ATP4 NCEP ATP 3 transitions to NCEP ATP4 Update on dietary and drug therapy for lipid disorders Update on dietary and drug therapy for lipid disorders Increased emphasis on the metabolic syndrome Increased emphasis on the metabolic syndrome Questions about role of niacin in treatment of atherosclerotic vascular disease Questions about role of niacin in treatment of atherosclerotic vascular disease New approaches to LDL-C lowering and HDL-C raising therapy New approaches to LDL-C lowering and HDL-C raising therapy

15 NCEP ATP III Approach to Primary Prevention of CHD Count traditional risk factors: cigarette smoking; HBP or on Rx for HBP; HDL-C <40 mg/dl; family Hx premature CHD in 1 st degree relatives (♂<55, ♀<65); age (males ≥45, females ≥55) Count traditional risk factors: cigarette smoking; HBP or on Rx for HBP; HDL-C <40 mg/dl; family Hx premature CHD in 1 st degree relatives (♂<55, ♀<65); age (males ≥45, females ≥55) Use Framingham risk scoring to estimate CHD risk for those with 2 or more risk factors Use Framingham risk scoring to estimate CHD risk for those with 2 or more risk factors Manage lipids based upon the principle of matching treatment intensity to estimated risk Manage lipids based upon the principle of matching treatment intensity to estimated risk Expert Panel, ATP III. Circulation 2002;106:

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17 Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Very High risk: ACS, or CHD w/ DM,multiple CRF <70 mg/dL  70 mg/dL > 70 mg/dL High risk: CHD or CHD risk equivalents (10-year risk >20%) If LDL <100 mg/dl <100 mg/dL (optional goal: <70 mg/dL) Goal <70 mg/dl  100 mg/dL > 100 mg/dL ( 100 mg/dL (<100 mg/dL: consider drug Rx) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) <100 mg/dL  130 mg/dL > 130 mg/dL ( mg/dL: consider drug Rx) Moderate risk: 2+ risk factors ( risk <10%) <130 mg/dL  130 mg/dL > 160 mg/dL Lower risk: 0-1 risk factor <160 mg/dL  160 mg/dL >190 mg/dL ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Grundy S, et al. Circulation 2004;110:227

18 Step 1: NHLBI Critical Review of the Literature 1. What is the evidence that treatment to specific LDL-C and non-HDL-C goals reduces outcomes in atherosclerotic cardiovascular disease in primary and secondary prevention? 2. What is the evidence for efficacy and safety of statins, resins, fibrates, cholesterol absorption inhibitors and niacin?

19 Step 2: Collaboration of Experts to Translate Literature Review into Guidelines American College of Cardiology Foundation American College of Cardiology Foundation American Heart Association American Heart Association National Lipid Association National Lipid Association

20 Evidence-Based Reviews Statin therapy reduces relative risk of CHD events in all groups, regardless of Framingham Risk score Statin therapy reduces relative risk of CHD events in all groups, regardless of Framingham Risk score High-dose statin is more beneficial than low or moderate dose statin therapy High-dose statin is more beneficial than low or moderate dose statin therapy Statin therapy is unassociated with increased risk of cancer Statin therapy is unassociated with increased risk of cancer Statin therapy is the most effective means of risk reduction in diabetic patients Statin therapy is the most effective means of risk reduction in diabetic patients

21 Restrictions on Simvastatin 80 mg Use 80 mg daily dose only in those who have been on that dose for ≥ 12 months and have not experienced toxicity Use 80 mg daily dose only in those who have been on that dose for ≥ 12 months and have not experienced toxicity Do not start new patients on 80 mg daily Do not start new patients on 80 mg daily Treat patients who require >40 mg with an alternate lipid-altering therapy Treat patients who require >40 mg with an alternate lipid-altering therapy Switch patients who need to be started on a drug interacting with simvastatin to an alternate statin Switch patients who need to be started on a drug interacting with simvastatin to an alternate statin 6/8/11

22 Simvastatin Dosing Regulations Contraindicated: itraconazole, ketoconazole, posconazole, erythromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine and danazol Contraindicated: itraconazole, ketoconazole, posconazole, erythromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine and danazol Do not exceed 10 mg daily: diltiazem, verapamil Do not exceed 10 mg daily: diltiazem, verapamil Do not exceed 20 mg daily: amlodipine, ranolazine, amiodarone Do not exceed 20 mg daily: amlodipine, ranolazine, amiodarone 6/8/11, 12/15/11

23 Hepatic Function Testing in Patients Receiving Statins Traditionally ALT and AST have been routinely measured during statin maintenance therapy Traditionally ALT and AST have been routinely measured during statin maintenance therapy Irreversible hepatic damage due to statins is extremely rare and likely idiosyncratic (less than 2 per one million patient-years) Irreversible hepatic damage due to statins is extremely rare and likely idiosyncratic (less than 2 per one million patient-years) There are no data to support routine LFT monitoring to identify such patients There are no data to support routine LFT monitoring to identify such patients FDA therefore recommends only baseline hepatic function studies and follow-up testing as clinically warranted; routine LFT monitoring is no longer recommended. FDA therefore recommends only baseline hepatic function studies and follow-up testing as clinically warranted; routine LFT monitoring is no longer recommended. 2/28/12

24 Cognitive Adverse Effects of Statins Occasional patients over age 50 experience notable, but ill-defined memory impairment that resolves upon discontinuation of statin therapy Occasional patients over age 50 experience notable, but ill-defined memory impairment that resolves upon discontinuation of statin therapy Such memory impairment may occur at any time during statin therapy Such memory impairment may occur at any time during statin therapy There is no association between statin therapy and Alzheimer’s dementia There is no association between statin therapy and Alzheimer’s dementia There is no association between memory loss and specific statin, dose, patient’s age or any specific drug- drug interaction There is no association between memory loss and specific statin, dose, patient’s age or any specific drug- drug interaction Consider withdrawing the drug and using alternate therapies when new memory loss is clinically evident Consider withdrawing the drug and using alternate therapies when new memory loss is clinically evident 2/28/12

25 Changes in Blood Glucose in Patients Receiving Statins JUPITER reported an increased incidence of investigator reported diabetes in the rosuvastatin treated patients JUPITER reported an increased incidence of investigator reported diabetes in the rosuvastatin treated patients A meta analysis of 13 statin trials reported a 9% increased risk of incident diabetes A meta analysis of 13 statin trials reported a 9% increased risk of incident diabetes Statin labels have now been revised to reflect that statin therapy may be associated with a rise in HgbA1C and fasting plasma glucose Statin labels have now been revised to reflect that statin therapy may be associated with a rise in HgbA1C and fasting plasma glucose Consensus is that benefits of statin therapy in appropirate patients far outweighs DM risk Consensus is that benefits of statin therapy in appropirate patients far outweighs DM risk 2/28/12

26 The Metabolic Syndrome and Non-HDL Cholesterol

27 The Metabolic Syndrome Requires 3 or more Requires 3 or more Waist circumference >35”♀ or 40”♂ Waist circumference >35”♀ or 40”♂ Fasting glucose mg/dl Fasting glucose mg/dl BP ≥130/85 or on anti-HBP meds BP ≥130/85 or on anti-HBP meds HDL-C < 50 mg/dl♀ or <40 mg/dl ♂ HDL-C < 50 mg/dl♀ or <40 mg/dl ♂ Triglycerides ≥ 150 mg/dl Triglycerides ≥ 150 mg/dl Increased risk for type 2 DM and CHD Increased risk for type 2 DM and CHD LDL-C is not a good CHD risk predictor in these patients LDL-C is not a good CHD risk predictor in these patients

28 The Metabolic Syndrome A Growing Cardiometabolic Phenotype in the U.S – – 2010 ∆ (%) MetS23.7%34.0%+10.3 High TG 27.0%33.0%+6.0 High TG and low HDL-C 2.1%4.8%+2.7 Type II diabetes mellitus 7.9%10.7%+2.8 Impaired fasting glucose 6.1%25.9%+19.8 Obesity19.8%33.7%+13.9 Ramjee V, et al. J Am Coll Cardiol. 2011;58:

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30 Non-HDL-C = Total cholesterol – [HDL-C]; or [LDL-C] + [VLDL-C] Non-HDL-C = Total cholesterol – [HDL-C]; or [LDL-C] + [VLDL-C] Goal for non-HDL-C is <30 mg/dl above LDL-C goal because desirable Tg is <150 mg/dl Goal for non-HDL-C is <30 mg/dl above LDL-C goal because desirable Tg is <150 mg/dl When non-HDL-C is >30 mg/dl above LDL-C goal, more intensive lipid therapy is warranted When non-HDL-C is >30 mg/dl above LDL-C goal, more intensive lipid therapy is warranted Total Cholesterol HDL Cholesterol LDL Cholesterol VLDL Cholesterol Usually Anti-atherogenic ++ Pro-atherogenic Non-HDL-Cholesterol Address only when Tg = mg/dl Tg/5 Understanding Non-HDL Cholesterol +IDL-C +RLP-C +Lp(a)-C

31 Appears on all UH lipid profiles when triglycerides are

32 Treatment of the Metabolic Syndrome Treatment of choice is diet and cardiovascular exercise to achieve IBW Treatment of choice is diet and cardiovascular exercise to achieve IBW Medical therapy is used when diet and exercise does not achieve goals Medical therapy is used when diet and exercise does not achieve goals Goals of lipid therapy depend upon serum triglycerides: Goals of lipid therapy depend upon serum triglycerides: Tg <200: Achieve LDL-C goal Tg <200: Achieve LDL-C goal Tg : Achieve LDL-C goal, then non-HDL-C goal Tg : Achieve LDL-C goal, then non-HDL-C goal Tg ≥500: Lower Tg to <500; then achieve LDL-C goal and then non-HDL-C goal Tg ≥500: Lower Tg to <500; then achieve LDL-C goal and then non-HDL-C goal

33 Niacin Therapy: Does it Help?

34 Lipid Effects of Niacin Raises HDL-C Raises HDL-C Lowers triglycerides Lowers triglycerides In high doses lowers LDL-C In high doses lowers LDL-C Lowers Lp(a) Lowers Lp(a)

35 Earlier Studies on Niacin Reduced risk of non-fatal MI in post MI men in pre-statin era Reduced risk of non-fatal MI in post MI men in pre-statin era Reduced angiographic CAD progression in combination with statin therapy Reduced angiographic CAD progression in combination with statin therapy Reduced CIMT when used in combination with a statin Reduced CIMT when used in combination with a statin

36 AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events 3414 subjects, age ≥ 45 yrs with established ASCVD (documented CHD, cerebrovascular or carotid disease or symptomatic PAD) 3414 subjects, age ≥ 45 yrs with established ASCVD (documented CHD, cerebrovascular or carotid disease or symptomatic PAD) Documented atherogenic dyslipidemia (LDL-C ≤ 160 mg/dl; HDL-C ≤ 40 mg/dl in men or ≤ 50 mg/dl in women; and triglycerides ≥ 150 mg/dl or ≤ 400 mg/dl) Documented atherogenic dyslipidemia (LDL-C ≤ 160 mg/dl; HDL-C ≤ 40 mg/dl in men or ≤ 50 mg/dl in women; and triglycerides ≥ 150 mg/dl or ≤ 400 mg/dl) All patients received simvastatin to achieve LDL-C mg/dl and if necessary, ezetimibe 10 mg daily All patients received simvastatin to achieve LDL-C mg/dl and if necessary, ezetimibe 10 mg daily Subjects randomized to receive Niacin E-R 2000 mg daily, or if not tolerated,1500 mg daily; or placebo Subjects randomized to receive Niacin E-R 2000 mg daily, or if not tolerated,1500 mg daily; or placebo Primary outcome: Composite endpoint of CHD death, non- fatal MI; ischemic stroke; hosp. for NSTE ACS; or symptom- driven coronary or cerebrovascular revascularization Primary outcome: Composite endpoint of CHD death, non- fatal MI; ischemic stroke; hosp. for NSTE ACS; or symptom- driven coronary or cerebrovascular revascularization Study enrollment began September 2005 Study enrollment began September 2005

37 AIM-HIGH: Study Prematurely Terminated 5/26/11: US FDA reports early termination of trial due to lack of benefit of niacin vs. placebo when added to that achieved with simvastatin or simvastatin plus ezetimibe 5/26/11: US FDA reports early termination of trial due to lack of benefit of niacin vs. placebo when added to that achieved with simvastatin or simvastatin plus ezetimibe Small, unexplained increase in ischemic strokes in niacin arm vs. placebo (28 strokes [1.6%] versus 12 strokes [0.7%] in niacin versus placebo arms. Small, unexplained increase in ischemic strokes in niacin arm vs. placebo (28 strokes [1.6%] versus 12 strokes [0.7%] in niacin versus placebo arms. Role that niacin played in these strokes is uncertain as 9 of the strokes in the niacin group occurred in subjects who d/c’d niacin 2 months to 4 years before their strokes Role that niacin played in these strokes is uncertain as 9 of the strokes in the niacin group occurred in subjects who d/c’d niacin 2 months to 4 years before their strokes

38 HPS-2 THRIVE 25,673 pts in UK, China and Scandinavia with established atherosclerotic vascular disease 25,673 pts in UK, China and Scandinavia with established atherosclerotic vascular disease All received simvastatin ± ezetimibe to lower TC to ≤ 135 mg/dl. All received simvastatin ± ezetimibe to lower TC to ≤ 135 mg/dl. Patients randomized to receive niacin 2g daily + laropiprant 40 mg daily and followed for major vascular events for medain follow-up of 4 years Patients randomized to receive niacin 2g daily + laropiprant 40 mg daily and followed for major vascular events for medain follow-up of 4 years

39 HPS-2 THRIVE Results No benefit on MVE of adding Niacin- laropiprant to aggressive LDL lowering regimen No benefit on MVE of adding Niacin- laropiprant to aggressive LDL lowering regimen Increased incidence of serious adverse events (myopathy) in Chinese patients Increased incidence of serious adverse events (myopathy) in Chinese patients European Heart Journal doi: /eurheartj/eht055

40 Newer Drugs for LDL-C Lowering and HDL-C Raising CETP inhibitors CETP inhibitors PCSK9 inhibitors PCSK9 inhibitors

41 Small Intestine Liver Macrophage ABC A1 transporter ABC G1 transporter Apo A1 FC Pre-β HDL Phospholipids (PL) TG CE HDL-2 Lecithin cholesteryl Acyltransferase (LCAT) PL Apolipoproteins FC TG CE TG CETP LDL -R SR-B1 CE VLDL, LDL Apo B FC Bile Basic HDL Metabolism TG CE Fecal elimination HDL-3 LCAT CE TG VLDL, Remnant particles PL

42 Small Intestine Liver Macrophage ABC A1 transporter ABC G1 transporter Apo A1 FC Pre-β HDL Phospholipids CE TG HDL-2 Lecithin cholesteryl acyltransferase PL Apolipoproteins Lipoprotein lipase FC CE TG CE TG CETP LDL -R SR-B1 CE VLDL, LDL Apo B FC Bile Effect of CETP Inhibition CE TG Fecal elimination HDL-3 LCATLPL ↑HDL-C ↓LDL-C

43 CETP inhibitors Torcetrapib Torcetrapib Improved lipids, increased mortality Improved lipids, increased mortality Dalcetrapib Dalcetrapib No reduction in events post MI No reduction in events post MI Anacetrapib Anacetrapib Evacetrapib Evacetrapib

44 Sterol Regulatory Element Binding Protein  LDL-R  PCSK9 Cholesterol Lysosomal degradation LDL particles Apo B Mutations Causing Familial Hypercholesterolemia 1. Abnormal # or function of LDL-R 2. Defective apo B 3. PCSK9 overexpression 4. Abnormality of LDL adaptor protein (ARH) 5. Chol 7 alpha OH ase ↓ Cholesterol 7 alpha hydroxylase Statin Hepatocyte Bile

45 PCSK9 Inhibitors Subcutaneously administred Subcutaneously administred Dosing is every 2 or every 4 weeks Dosing is every 2 or every 4 weeks Reduces LDL-C by about 60-70% Reduces LDL-C by about 60-70% Has been shown to lower LDL-C in statin intolerant patients, patients with FH Has been shown to lower LDL-C in statin intolerant patients, patients with FH Ongoing trials assesing safety and efficacy in reducing CHD events Ongoing trials assesing safety and efficacy in reducing CHD events


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