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Lipid Management in 2013 Are You Up to Date?

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Presentation on theme: "Lipid Management in 2013 Are You Up to Date?"— Presentation transcript:

1 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 School of Medicine October 30, 2007 University Hospitals Heart & Vascular Institute 1


3 How Increased Concentration of Apo B Containing Particles Promotes Atherosclerosis
ApoB lipoprotein particles Blood Monocytes bind to adhesion molecules Smooth muscle Inflammatory response Modification Macrophage Excessive atherogenic particle concentration results in gradient driven diffusion of LDL particles into the subendothelial space. These particles are retained by proteoglycans, are modified by oxidation, or in the case of type 2 diabetes, glycosylation, and are then retained by tissue macrophages. As the macrophages become loaded with modified LDL particles they become foam cells, the cells that are pathognomonic for the atherosclerotic process. There is gradual ingress of smooth muscle cells resulting in fibrous cap formation and resultant development of a mature atherosclerotic plaque. Foam cell ApoB = apolipoprotein B. 1. Tabas I et al. Circulation. 2007;116:1832– Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551–561. 3. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536– Steinberg D et al. N Engl J Med. 1989;320:915–924. 1. Tabas I et al. Circulation. 2007;116:1832–1844. 3

4 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) As the atherosclerotic process continues there is progressive ingress of inflammatory cells. Cytokine expression promotes the inflammatory process, which is exacerbated by foam cell death and release of necrotic debris into the subendothelial space. The shoulder of the fibrous cap weakens and finally cracks, resulting in platelet recruitment to the site of endothelial disruption. If the platelet response and recruitment of prothrombotic elements is marked, vascular occlusion may occur, resulting in an acute coronary syndrome. MI = myocardial infarction. 1. Tabas I et al. Circulation. 2007;116:1832–1844. 1. Tabas I et al. Circulation. 2007:116;1832–1844. 4

5 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 This slide reminds us that patients may have extensive subclinical atherosclerosis in the absence of obstruction of the vascular lumen. In those cases in which there are recurrent small plaque ruptures and subsequent repair, progressive obstruction of the lumen may occur and result in angina pectoris. However, in those cases in which a large plaque rupture occurs, an acute coronary syndrome may occur in the absence of pre-existing angina pectoris or other cardiac symptoms. Inward expansion causing luminal narrowing (chronic stable angina) 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. 5

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

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

8 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

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

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

11 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 In the proximal small intestine, dietary glycerol, phytosterols, cholesterol, fatty acids and phospholipids form micelles. When these dietary components are combined with bile acids they are solubilized and form mixed micelles, which are then be absorbed into the duodenal and jejunal enterocyte from the lumen of the small intestine. The consumption of fiber and/or large quantities ( mg daily) of plant sterols and stanols results in impaired mixed micellar absorption, reducing the quantity of dietary cholesterol in chylomicrons, which, in turn, results in delivery of less cholesterol to the liver. Reduced hepatocyte cholesterol concentration increases the expression of LDL receptors. Phopsho;ipids Apo B-48

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

13 LDL-C Lowering Drugs: Mechanisms of Action
Small intestine Liver Proximal Acetyl CoA FFA Apo C1,2,3 NPC1L1 Tg Apo E HMG CoA reductase Micelles Apo B Lomitapide Niacin VLDL Mipo Ezetimibe FFA Statin CE Drugs that lower LDL-C act by a variety of mechanisms. Statins, the most commonly used category of cholesterol lowering drugs, act by inhibiting the activitiy of HMGCoA reductase, the rate-limiting step on cholesterol biosynthesis. Reduced hepatic cholesterol levels result in the increased expression of LDL receptors. Ezetimibe acts in the proximal small intestine to reduce cholesterol absorption by inhibiiting the activitiy of NPC1L1, a protein that facilitates absorption of mixed micelles across the duodenal and jejunal mucosa into the circulation. Bile acid binding resins act by reducing distal small intestinal absorption of cholesterol rich-bile. Both of the intestinally active drugs reduce hepatic cholesterol levels and increase the expression of LDL receptors. Niacin reduces hepatic uptake of free fatty acids from adipose tissue. Free fatty acids are one of the components of triglycerides, which are incorporated into VLDL particles. Fewer VLDL and LDL particles are therefore produced. VLDL Cholesterol Distal Intestinal Bile Acid Transporter Adipose Tissue Bile RLP Resins IDL LDL

14 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

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 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:


17 ATP III Update 2004: Risk Category LDL-C Goal Initiate TLC
LDL-C Goals and Cutpoints for Therapy in Different Risk Categories 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: 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 > 160 mg/dL Lower risk: 0-1 risk factor <160 mg/dL 160 mg/dL >190 mg/dL TLC= Therapeutic lifestyle change The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) 100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is 100 mg/dL, but when risk is very high, an LDL-C goal of 70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2 risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is 130 mg/dL, but an LDL-C goal 100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cut points of therapy. (Circulation. 2004;110: ) Grundy S, et al. Circulation 2004;110:227 17

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 Heart Association National Lipid Association

20 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

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 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 6/8/11

22 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 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 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. 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 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 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 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 2/28/12

26 The Metabolic Syndrome and Non-HDL Cholesterol

27 The Metabolic Syndrome
Requires 3 or more Waist circumference >35”♀ or 40”♂ Fasting glucose 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

28 The Metabolic Syndrome A Growing Cardiometabolic Phenotype in the U.S.
1994 – 2002 2003 – 2010 ∆ (%) MetS 23.7% 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 Obesity 19.8% 33.7% +13.9 Ramjee V, et al. J Am Coll Cardiol. 2011;58: 28


30 Usually Anti-atherogenic
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 = 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

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 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 : 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

33 Niacin Therapy: Does it Help?

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

35 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

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) 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 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

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 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

38 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

39 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: /eurheartj/eht055

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

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

42 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 CE LPL LCAT ABC G1 transporter TG CE TG FC CETP CE TG HDL-2 Apo B CE VLDL, LDL ↑HDL-C ↓LDL-C Fecal elimination

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

44 - Mutations Causing Familial Hypercholesterolemia Hepatocyte
LDL particles - Apo B 4 1 2 Hepatocyte Lysosomal degradation 3  LDL-R Cholesterol Cholesterol 7 alpha hydroxylase 5 +  PCSK9 FH can occur in the setting of one or more mutations that affect the LDL receptor. The most common mutation is an abnormally low number of functioning LDL receptors (1). Other mutations include defective apolipoprotein B (2), resulting in suboptimal binding of LDL particles to the LDL receptor; over-expression of the serine protease, PCSK9, which is responsible for the degradation of the LDL receptor (3); abnormalities of LDL adaptor protein which assures proper fit of apo B containing particles into the clathrin coated pits of the LDL receptor (4); and cholesterol 7 alpha hydoxylase deficiency, the rate limiting step of bile synthesis from cholesterol, resulting in cholesterol loading of hepatocytes (5). 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

45 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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