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Lipid Management in 2013 Are You Up to Date?

Lipid Management in 2013 Are You Up to Date?. 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

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Lipid Management in 2013 Are You Up to Date?

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  1. Lipid Management in 2013Are You Up to Date? 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 October 30, 2007 University Hospitals Heart & Vascular Institute

  2. How Increased Concentration of Apo B Containing Particles Promotes Atherosclerosis ApoB lipoproteinparticles Blood Monocytes bind toadhesion molecules Smooth muscle Inflammatory response Modification Macrophage Foam cell ApoB = apolipoprotein B. 1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551–561. 3. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536–1540. 4. Steinberg D et al. N Engl J Med. 1989;320:915–924.

  3. Atherothrombotic Vascular Disease:Response-to-Retention Model1 Plaque rupture Thinning fibrous cap • Fibrous cap thinning • Plaque rupture and thrombosis • Atherothrombotic vascular disease (eg, MI and stroke) MI = myocardial infarction. 1. Tabas I et al. Circulation. 2007;116:1832–1844.

  4. Atherosclerosis Progression1–3 Plaque rupture and thrombosis (acute coronary event) Fatty streak involving lipoprotein and immune cell infiltration Gradual outward expansion of arterial wall Normal Artery Inward expansion causing luminal narrowing (chronic stable angina) 1. Tabas I et al. Circulation. 2007;116:1832–1844. 2. Hansson GK. N Engl J Med. 2005;352:1685–1695. 3. Jawad E et al. Dis Mon. 2008;54:671–689.

  5. Lipoprotein Physiology Made Simple GI Tract Adipose tissue Food is absorbed and converted to transporter particles 1 Food is consumed Energy storage (starvation) 3 2 Transporter particles 3 Liver Muscle 4 Energy utilization Plasma Disassembles transporter particles to prevent clogged transport pathways Assembles key body maintenance particles, substrates for hormone assembly Cell membranes, Salt and H2O balance Reproductive hormones Vitamins 5 5 GI Tract 7 Liver 6 Refuse eliminated from the body Particles provided that eliminate the refuse Accepts refuse from plasma 8

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

  7. Dietary Priorities in Dyslipidemia • Reduced intake of saturated fat and cholesterol • Increased intake of soluble fiber and plant sterols/stanols • In overweight and obese patients, reduced caloric intake to achieve weight reduction • 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

  8. Adding Soluble Fiber to the Diet • Whole grains • Nuts and seeds • Fruit • Legumes

  9. Adding Plant Sterols and Stanols to the Diet • Goal is 2000-2500 mg daily • Dietary options containing these functional foods • Margarines • OJ • Milk and non-dairy drinks • Breads

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

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

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

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

  14. NCEP ATP III Approach toPrimary 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 1st 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 • Manage lipids based upon the principle of matching treatment intensity to estimated risk Expert Panel, ATP III. Circulation 2002;106:3143-3421

  15. ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Grundy S, et al. Circulation 2004;110:227

  16. 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?

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

  18. Evidence-Based Reviews • 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 • Statin therapy is unassociated with increased risk of cancer • Statin therapy is the most effective means of risk reduction in diabetic patients

  19. 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 • Do not start new patients on 80 mg daily • 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 www.fda.org 6/8/11

  20. Simvastatin Dosing Regulations • 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 20 mg daily: amlodipine, ranolazine, amiodarone www.fda.gov 6/8/11, 12/15/11

  21. Hepatic Function Testing in Patients Receiving Statins • 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) • 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. www.fda.gov 2/28/12

  22. Cognitive Adverse Effects of Statins • 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 • 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 • Consider withdrawing the drug and using alternate therapies when new memory loss is clinically evident www.fda.gov 2/28/12

  23. Changes in Blood Glucose in Patients Receiving Statins • 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 • 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 www.fda.gov 2/28/12

  24. The Metabolic Syndrome andNon-HDL Cholesterol

  25. The Metabolic Syndrome • Requires 3 or more • Waist circumference >35”♀ or 40”♂ • Fasting glucose 100-125 mg/dl • BP ≥130/85 or on anti-HBP meds • HDL-C < 50 mg/dl♀ or <40 mg/dl ♂ • Triglycerides ≥ 150 mg/dl • Increased risk for type 2 DM and CHD • LDL-C is not a good CHD risk predictor in these patients

  26. The Metabolic SyndromeA Growing Cardiometabolic Phenotype in the U.S. Ramjee V, et al. J Am Coll Cardiol. 2011;58:457-463.

  27. Understanding Non-HDL Cholesterol Total Cholesterol VLDL Cholesterol +IDL-C HDL Cholesterol +RLP-C LDL Cholesterol +Lp(a)-C Tg/5 + + Usually Anti-atherogenic Pro-atherogenic Non-HDL-Cholesterol Address only when Tg = 200-499 mg/dl • 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 • When non-HDL-C is >30 mg/dl above LDL-C goal, more intensive lipid therapy is warranted

  28. Appears on all UH lipid profiles when triglycerides are 200-499

  29. Treatment of the Metabolic Syndrome • Treatment of choice is diet and cardiovascular exercise to achieve IBW • Medical therapy is used when diet and exercise does not achieve goals • Goals of lipid therapy depend upon serum triglycerides: • Tg <200: Achieve LDL-C goal • Tg 200-499: 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

  30. Niacin Therapy: Does it Help?

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

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

  33. 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) • 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 40-80 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 • 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

  34. 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 • 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

  35. HPS-2 THRIVE • 25,673 pts in UK, China and Scandinavia with established atherosclerotic vascular disease • 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

  36. HPS-2 THRIVE Results • No benefit on MVE of adding Niacin-laropiprant to aggressive LDL lowering regimen • Increased incidence of serious adverse events (myopathy) in Chinese patients European Heart Journal doi:10.1093/eurheartj/eht055

  37. Newer Drugs for LDL-C Lowering and HDL-C Raising • CETP inhibitors • PCSK9 inhibitors

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

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

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

  41. Mutations Causing Familial Hypercholesterolemia - LDL particles Apo B 4 1 2 Hepatocyte Lysosomal degradation 3  LDL-R Cholesterol Cholesterol 7 alpha hydroxylase 5 PCSK9 + + Bile Sterol Regulatory Element Binding Protein 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 ↓ Statin

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

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