2. Metabolic & Endocrine Disease Summit Dyslipidemia and Current Guidleines for Lipid Management Thursday July 28, 2011 Orlando, FL Joyce L. Ross, MSN, CRNP, CS, FPCNA, FNLA Diplomate Accreditation Council for Clinical Lipidology Certified Clinical Lipid Specialist University of Pennsylvania Health System – Retired Joyce@joycerossnp.com 484-614-5027

3. Current Estimates of the Impact of CVD and Dyslipidemia in the US American Heart Association. Heart Disease and Stroke Statistics―2008 Update. Dallas, Texas: American Heart Association; 2008. 1 in 2 adults has total cholesterol ≥200 mg/dL 1 in 3 adults has CVD

4.  # 1 Killer in US since 1900 Prevalence of Cardiovascular Disease 2002 Heart and Stroke Statistical Update. American Heart Association  Effects 1/5 th of the population  Approximately 40% of all first MI’s are fatal  63% of women/50% of men with CAD had no prior knowledge of disease  Every 29 seconds an American suffers a coronary event  Every 60 seconds an American dies from a coronary event

5. CAD = coronary artery disease. Adapted from Levy D et al. In: Textbook of Cardiovascular Medicine. Philadelphia, Pa: Lippincott-Raven; 1998. CHD: The Diagnosis Often Comes Too Late MI or death as initial presentation of CAD Men62% Women46% 010203040506070 Percentage of Patients

6. 40% are absent because death is the sign and symptoms FatiguePoorly localized chest tightness FeverChest pressure or aching PallorArm pressure or aching (5 min or <) Intermittent claudification Dypsnea Mild angina on exertion Lightheadedness ConfusionPalpitations

7. CVD costs the nation $274 billion each year, including health expenditures and lost productivity 2600 people die every single day!!!!!!!!!!!!! How, What and Why????? 13 million Americans have some form of coronary heart disease

8. Risk factors High LDL-C levels Low HDL-C levels Hypertension Diabetes Mellitus Obesity- BMI> or equal 30kg/m2 Smoking Sedentary Lifestyle

9. Dyslipidemia Dyslipidemia is a major risk factor for CHD, the leading cause of death in the United States 1 The World Health Organization estimates that dyslipidemia is associated with >50% of global ischemic heart disease cases and >4 million deaths per year 2 1. Smith DG. Am J Manag Care. 2007;13:S68-S71. 2. World Health Organization. The World Health Report. 2002;4:47-97. CHD = coronary heart disease.

10. Atherosclerosis  Large part of CAD  Plays a tremendous role in mortality, morbidity  Deposition of fat containing plaques that consist of cholesterol and lipids on the innermost layer of the walls of large and medium sized arteries  Progression of atherosclerosis finds its foundation in continued elevation of cholesterol blood levels

11. Causes of Lipid Disorders Primary and Secondary Causes Primary are related to genetics Secondary may be related to medical disorders, and medications, that effect specific parameters of the lipid profile Metabolic endocrine Diabetes Thyroid disease Renal Hepatic drugs Ross, J 2005

12. Focus on Multiple Risk Factors CHD risk equivalents DM, PVD, symptomatic carotid disease, AAA, stroke, TIA Framingham projections of 10-year CHD risk Identify certain patients with multiple risk factors for more intensive treatment Multiple metabolic risk factors metabolic syndrome NCEP ATP III. JAMA. 2001;285:2486-2497. National Cholesterol Education Guidelines ATP III

13. Features of ATP III - Triglycerides Patients with triglycerides  200 mg/dL LDL cholesterol: primary target of therapy Non-HDL cholesterol: secondary target of therapy Non HDL-C = total cholesterol – HDL cholesterol Example: TC 270 minus HDL 50 = 220 non-HDL- C - Should not be higher than 30 points than LDL goal. - If LDL goal 130, non HDL goal = < 130 NCEP ATP III. JAMA. 2001;285:2486-2497

14. Recommendation for Screening/Detection (20 years old) If family history of premature CAD – check lipids at 2 years old Complete lipoprotein profile Fasting – 12 hour recommended Total cholesterol (< 200) LDL (per risk factors) HDL (> 40 men, > 50 women) Triglycerides (<150) NCEP ATP III. JAMA. 2001;285:2486-2497

15. Very low-density lipoprotein Made in the liver TG-rich IDL Non-HDL-C Includes All Atherogenic Apo B- containing Lipoproteins 1,2 Intermediate-density lipoprotein – VLDL remnant Made from VLDL by TG lipolysis TG and cholesterol-rich Low-density lipoprotein Made from IDL by TG lipolysis Cholesterol-rich High TG increases density and atherogenicity 1,2 High-density lipoprotein Removes cholesterol from artery wall Other possible anti-atherogenic effects (eg, anti-inflammatory) 3 1. Chapman MJ, Caslake M. Eur Heart J. 2004;(suppl A):A43-A48. 2. Garg R et al. Prev Cardiol. 2005;8:173-177. 3. Gotto AM, Brinton EA. J Am Coll Cardiol. 2004;43:717-724. VLDL HDL Definition of Non-HDL-C LDL Non-HDL-C = Total Cholesterol minus HDL-C

16. Risk Assessment Step Process Traditional risk factors Framingham 10 year risk assessment when appropriate Assess for metabolic syndrome in all patients NCEP ATP III. JAMA. 2001;285:2486-2497

17. Risk Category CHD and CHD risk equivalents Multiple (2+) risk factors Zero to one risk factor LDL Goal (mg/dL) <100 < 70 * <130 <160 Three Categories of Risk that Modify LDL-Cholesterol Goals NCEP ATP III Update Circulation 2004, 2004;110:227-239

18. Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals Cigarette smoking Hypertension (BP  140/90 mmHg or on antihypertensive medication) Low HDL cholesterol (<40 mg/dL) † Family history of premature CHD CHD in male first degree relative <55 years CHD in female first degree relative <65 years Age (men  45 years; women  55 years) † HDL cholesterol  60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count. NCEP ATP III. JAMA. 2001;285:2486-2497

19. Determination of 10-year CHD Risk Framingham Point Scores For Hard CHD Event Step 1 Calculate traditional risk factors Step 2 Determine 10-year CHD risk from table according to point total Ross, J 2005

20. Framingham Limitations  No consideration of risk with a first degree relative 60% of people with heart disease have established FH risk  No reflection of true risk for older age women  Representation of younger patients at risk still needs examination Focus has been on older than 50 years especially men demonstrated age related risk and plaque development Cardiovascular disease leading cause of death in women

21. AGE Age (years) Male Female 20 - 34 - 9 - 7 35 - 39 - 4 - 3 40 - 44 0 0 45 - 49 3 3 50 - 54 6 6 55 - 59 8 8 60 - 64 10 10 65 - 69 11 12 70 - 74 12 14 75 - 79 13 16 NCEP ATP III. JAMA. 2001;285:2486-2497

22. Total Cholesterol TC 20 - 39 y 40 -49 y 50-59 y 60 - 69 y 70 - 79 y mg/dl M F M F M F M F M F < 160 0 0 0 0 0 0 0 0 0 0 160 - 190 4 4 3 3 2 2 1 1 0 1 200 - 239 7 8 5 6 3 4 1 2 0 1 240 - 279 9 11 6 8 4 5 2 3 1 2  280 11 13 8 10 5 7 3 4 1 2 Smoking Status Nonsmoker 0 0 0 0 0 0 0 0 0 0 Smoker 8 9 5 7 3 4 1 2 1 1 NCEP ATP III. JAMA. 2001;285:2486-2497

23. Blood Pressure Systolic Blood Untreated Treated M F M F < 120 0 0 0 0 120 - 139 0 1 1 3 140 - 159 1 3 2 5 > 160 2 4 3 6 NCEP ATP III. JAMA. 2001;285:2486-2497

24. HDL - Cholesterol HDL-cholesterol (mg/dL) M F > 60 - 1 - 1 50 - 59 0 0 40 - 49 1 1 < 40 2 2 NCEP ATP III. JAMA. 2001;285:2486-2497

25. 10 - Year CHD Based on Point Count Male Female Point total 10 year risk (%) Point total 10 year risk (%) < 0 < 1 < 9 < 1 0 1 9 1 1 1 10 1 2 1 11 1 3 1 12 1 4 1 13 2 5 2 14 2 6 2 15 3 7 3 16 4 8 4 17 5 9 5 18 6 10 6 19 8 11 8 20 11 12 10 21 14 13 12 22 17 14 16 23 22 15 20 24 27 16 25 > 25 > 30 > 17 > 30 NCEP ATP III. JAMA. 2001;285:2486-2497

26. ATP III: Risk Is More Than Elevated LDL-C Expert Panel. JAMA 2001; Grundy et al. Circulation 2005; 112:2735-52. Metabolic Syndrome Elevated LDL-C Waist Circumference Low levels of HDL-C Elevated BP Elevated TG Elevated Fasting Glucose Easily measured variables

27. ATP III and Metabolic Syndrome ATP III draws attention to the importance of the metabolic syndrome Provides a working definition of this syndrome for the first time Those with metabolic syndrome are at increased risk for development of DM CHD plus increased mortality in general Ross, J 2005 Adapted from NCEP ATP III. JAMA. 2001;285:2486-2497

28. Diagnosis of metabolic syndrome Defined as any pathophysiologic dysfunction that results in a loss of metabolic control of homeostasis in the body ATP III gives specific criteria for the syndrome but does not go as far as to call it a CAD equivalent Components of the syndrome discussed in terms of risk factors and defining levels

29. Diagnosis is established when 3 of These risk factors are present Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. > 102 cm (>40 in) >88 cm (>35 in) Abdominal obesity (Waist circumference)  110 mg/dL Fasting glucose Blood pressure <40 mg/dL/ <50 g/dL 130/85 mm/Hg HDL-C Men/Women  150 mg/dL TG Men & Women Defining LevelRisk Factor

30. 0 1 2 3 4 CVD * CHD † 012345 Mortality hazard ratio Number of Metabolic Syndrome Criteria * Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C, recreational/nonrecreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke † Similar adjustments except for prevalent stroke Ford ES. Atherosclerosis 2004;173:309-314 Metabolic Syndrome: Risk of Death CHD=Coronary heart disease, CVD=Cardiovascular disease Risk is Proportional to the Number of ATP III Criteria

31. Role of Insulin Resistance and Compensatory Hyperinsulinemia Genetics Environment Insulin Resistance Hyperinsulinemia Glucose Uric Acid Dyslipidemia Hemodynamic Hemostatic Metabolism elevated TG increased PP Lipemia decreased HDL small, dense LDL LDL Oxidation Coronary Heart Disease Decreased clearance Sympathetic Response Sodium retention & Increased BP Increased PAI I & fibrinogen Increased Glucose Levels = diabetes American Journal of Epidemiology 2000; 152(10): 897-907Sakkinen PA, Wahl P, Cushman M, et al

33. What is the pathophysiology of an MI? (What is the last straw?) Is it the last Donut Pizza Hamburger with cheese French fries ??????????? Bad Luck ? Poor parental choices? A series of chemical events?

34. The Damage from Cholesterol and other factors assert their influence on the CONTRIBUTING FACTORS IN VASCULAR DISEASE lifestyle cholesterol HTN genetics diabetes novel risk factors Ross, J 2005

35. Endothelium (Gateway to the Cardiovascular System) Largest organ in the body Largest organ in the body Total surface = 6 tennis courts Total surface = 6 tennis courts Total mass = 5 normal hearts Total mass = 5 normal hearts Total weight = 1800 G Total weight = 1800 G Total # of cell = 1 trillion Total # of cell = 1 trillion Living Organ that forms a barrier between the blood and the tissues Living Organ that forms a barrier between the blood and the tissues

36. One layer cell liner of blood vessels Lies between the lumen of arteries and vascular smooth muscle Maintaining arterial vascular, tone and structure Mediation of inflammatory and immune mechanisms Coagulation (fibrinolysis, retardation of platelet and leukocyte adhesion)

37. Endothelial Dysfunction Foam Cells Fatty Streak Intermediate LesionAtheroma Fibrous Plaque Complicated Lesion/Rupture From first decadeFrom third decade From fourth decade Growth mainly by lipid accumulation Smooth muscle & collagen Thrombosis, hematoma Non-obstructive plaque Endothelium Plaque Cap

38. Apolipoprotein B (ApoB) LDL Particle Density – Pattern A & B Serves as an identification protein for specific receptors located on hepatic and peripheral cells involved in lipoprotein metabolism Produced in the liver Useful in patients with borderline LDL cholesterol levels especially if there is a family history of premature disease Adapted from Prev Cardio 1999:2:105-114 Diagram: Ross J 2005

39. Atherogenic Changes Associated with Triglycerides Low HDL-C Increased VLDL Remnants Coagulation changes Increased PAI-1 Increased fibrinogen Increased Chylomicron Remnants Small dense LDL particles HYPERTRIGLYCERIDEMIA Vascular Biology Working Group

40. Serum TG Levels: NCEP/ATP III Goals and Cutpoints Classification Serum TG Level (mg/dL) Normal<150 Borderline High150-199 High200-499 Very High≥500 Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

41. Elevated Trigycerides contributing factors Contributing factors Obesity and overweight Physical inactivity Excess ETOH intake High carbohydrate diets Genetic disorders FCHL Hyperlipidemia FH Familial dysbetalipoproteninemia Several diseases Type 2 DM Chronic renal failure Nephrotic syndrome Medications Corticosteroids, estrogens Retinoids Higher doses of beta- adrenergic blocking agents Protease inhibitors tomoxifin

42. Risk of CHD by Triglyceride Level: The Framingham Heart Study Castelli WP. Am J Cardiol. 1992;70:3H-9H. n=5,127 Triglyceride level (mg/dL)

43. Antioxidative Activity Antithrombotic Activity Other Antiatherogenic Actions of HDL Reverse Cholesterol Transport Cellular Cholesterol Efflux Antiapoptotic Activity Antiinflammatory Activity HDL Antiinfectious Activity Chapman MJ, et al. Curr Med. Res Opin. 2004,20:1253-1268. Assmann G, et al. Annu Rev Med. 2003,53:321-41. Endothelial Repair Vasodilatory Activity

44. Hs CRP - CRP is an acute phase reactant High levels associated with increased vascular events, MI, CVA Assay precisely measures low levels of CRP Inflammation is part of the sequence of events for MI most studies demonstrate A 3 - 4 fold increased risk associated with the highest quartile compared with the lowest levels stronger prediction when combined with the lipid panel shown to be decreased with statin therapy and Niacin Inflammation in Atherothrombosis: How to Use High-Sensitivity C-Reactive Protein (hsCRP) in Clinical Paul M. Ridker, MD, MPH.Am Heart Hosp J (2004) 2;4 Suppl 1:4-9

45. Recommendations for Use: hs-CRP in Clinical Practice Not recommended for routine screening of entire population In patients at intermediate risk (10% to 20% CHD risk per 10 years): – hs-CRP may help direct further evaluation and therapy in primary prevention In patients with stable coronary disease, acute coronary syndromes: – hs-CRP measurement may be useful as an independent marker of prognosis for recurrent events

46. Ross J 2005

47. The elbow and feet of the ARH patient showing xanthomas at 10 years of age (a,b). Complete regression of xanthomas shown at the age of 23 (c,d). S. Lind et al., J Int Med 2004; 256: 406-12 Eruptive Xanthomas Before and After Zetia + Statin

48. TREATMENT OF ASSIGNED RISK Use standard guidelines by the appropriate experts in the field Many will offer suggestions that include the other aspects of cardiovascular risk ALL plans begin with Therapeutic Lifestyle Management (TLC)

49. Involve the patient Enhanced communication improves patient adherence, outcomes, and satisfaction Barrier PA et al. Mayo Clin Proc. 2003;78:211-4. Patient-centered approach facilitates identification of risk conditions Provider-centered approach may lead to missed diagnoses and poor adherence

50. Integrative medicine framework Edelman D et al. J Gen Intern Med. 2006;21:728-34. Mind-body approaches Physical activity Group sessions Individual sessions Improved health behaviors Nutrition Health self-education Multidimensional, patient-centered, individualized

51. Effecting Change Change Agents Educative process The past does not equal the future The process of pain and pleasure What do changes mean to the patient Setting reachable goals Partnering for progress Contracts Support Change the attitude = Change in behavior Ross J 2004

52. Therapeutic Lifestyle Interventions Weight reduction – enhances LDL-C lowering – reduces metabolic syndrome risk factors Increased physical activity reduces VLDL levels, raises HDL-C, lowers LDL-C levels lowers blood pressure reduces insulin resistance Dietary carbohydrate restrictions periodic assessments of dietary changes Metabolic Syndrome and Subclinical Atherosclerosis

53. Therapeutic Lifestyle Changes in LDL-Lowering Therapy Major Features TLC Diet Reduced intake of cholesterol-raising nutrients (same as previous Step II Diet) Saturated fats <7% of total calories Dietary cholesterol <200 mg per day LDL-lowering therapeutic options Plant stanols/sterols (2 g per day) Viscous (soluble) fiber (10 – 25 g per day) Weight reduction Increased physical activity Adapted from NCEP ATP III. JAMA. 2001;285:2486-2497

54. Obesity Chronic, relapsing disease characterized by an excessive accumulation of body fat It is heterogeneous Genetic Environmental Metabolic Behavioral Associated with multiple risk factors that lead to morbidity and mortality American Heart Association has classified obesity as a chronic illness major, modifiable risk factor for CAD

55. 1. Wing RR, et al. Arch Intern Med. 1987;147:1749–1753. 2. Goldstein DJ. Int J Obes. 1992;16:397–415. 3. Thomas PR, ed. Weighing the Options. 1995. Health Benefits of Weight Loss Weight loss of 5%–10% in obese individuals with type 2 diabetes, hypertension or dyslipidemia resulted in: Improved glycemic control 1 Reduced blood pressure 2 Improved lipid profile 2 “Several studies demonstrate that small losses...help reduce obesity-related comorbidities and that improvements in these risk factors persist with maintenance of these modest weight losses.” 3 — Institute of Medicine

56. Lifestyle Modification: NHLBI Recommendations Assess patient readiness and motivate the patient Diet: – 500–1000 kcal/day deficit for loss of 1–2 pounds per week – Reducing dietary fat along with calories can help Physical activity goal: – Moderate activity for 30–45 minutes, 3 to 5 times per week to start, increasing to  30 minutes most or all days of the week National Institutes of Health. Obes Res. 1998;6(suppl 2):51S–209S.

57. Risk Reduction Therapy Risk Behavior % Mortality – 10 years Smoke Cessation 35 – 45 % LDL Reduction to goal 25 – 35 % BP management to goal 10 – 15 % ASA 10 % ACE Inhibitor Use 20 – 30 % Weight Loss 20 % Exercise 20 % Grundy 9/2000

58. Problems with Smoking  Reduced HDL  reduces O2 in the blood  constricts arteries  damages the blood vessels Ross J 2004

59. Atherogenic dyslipidemia is an important target of therapy for CV risk management, and commonly occurs in patients with the metabolic syndrome and/or diabetes A substantial proportion of patients with atherogenic dyslipidemia are not at lipid goals Guidelines recommend non-HDL-C as a secondary target in patients with atherogenic dyslipidemia, including combination therapy with a fibrate and statin Atherogenic Dyslipidemia as a Target of Therapy

60. Features of Patients With the Metabolic Syndrome or Type 2 Diabetes CharacteristicNo MS/No DMMSDM Waist circumference, cm89108*109* LDL-C, mg/dL124129*122* † HDL-C, mg/dL5440*44* † TG, mg/dL105214*220* † Fasting glucose, mg/dL93100*175* ‡ SBP/DBP, mmHg118/71134*/77*134*/71* ‡ Prevalent CVD, %5.213.626.7 Malik S et al. Diabetes Care. 2005;28:690-693. * P<0.0001 compared with no MS/no DM; † P<0.01 comparing MS with DM; ‡ P<0.0001 comparing MS with DM. Atherogenic dyslipidemia is common in patients with metabolic syndrome (MS), including type 2 diabetes (DM)

61. Lipid Therapy Options for Dyslipidemia 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. 2. Zetia® (ezetimibe) [package insert]. Merck/Schering-Plough Pharmaceuticals. North Wales, PA; 2008. 3. Lovaza™ (omega-3-acid ethyl esters) capsules [package insert]. Reliant Pharmaceuticals. Durham, NC; 2007. Drug ClassLDL-CHDL-CTGKey Limitations Statins 1 ↓ 18%–55%↑ 5%–15%↓ 7%–30%Myositis, ↑ LFTs Bile acid sequestrants 1 ↓ 15%–30%↑ 3%–5%No effect or ↑ Upper/lower GI complaints (eg, constipation) Nicotinic acid 1 ↓ 5%–25%↑ 15%–35%↓ 20%–50% Flushing, hyperglycemia, hyperuricemia/gout Fibric acid derivatives 1 ↓ 5%–20%↑ 10%–20%↓ 20%–50% Upper GI complaints, myopathy Cholesterol- absorption inhibitors 2 ↓ 18%↑ 1%↓ 8% ↑ LFTs in combination with statins; lack of outcomes data Omega-3 fatty acids 3 * ↑ 45%↑ 9%↓ 45% ↑ LDL-C; lack of outcomes data * Based on use in patients with very high TG levels (≥500 mg/dL).

62. Agents that reduce TGs Lifestyle management Exercise – as powerful as any medication if applied appropriately Dietary changes Reduction of carbohydrates Reduced amounts of fruit juice, soda with sugar Medications Fibrates – Gemfibrozil, Fenofibrates Niacin (Niaspan) HMG Co reductase Inhibitors (all) Fish Oil

63. Medications Fibrates Drugs of choice for increased VLDL Safe in combination with statins if renal function normal Effects on Lipids increase/decrease LDL decrease TGs increase HDL Fenofibrate (now 4 ) much more efficacious and safer than previous fibrates Fenofibrate decreases TGs 32 - 53 %, HDL increased by 2 - 26 % Gemfibrozil decreased TG ’ s 31 - 35 %, HDL increased by 6 - 10 %

64. Niacin Mechanism of action poorly understood Decreased VLDL production Niacin Effects decreases LDL, shifts LDL density gradient to larger, buoyant increases HDL decreases VLDL, shifts to more buoyant type B-3 Vitamin First used to lower chol. In 1955 Agents: IR Niacin SL Niacin Extended release - Niaspan Effect on Cholesterol decreases TC, TG, increased HDL, lowers LDL

65. F i s h O i l used as modifier for lipid profile, specifically triglyceride levels, using various doses daily can have some GI issues when starting can titrate up to about 9 grams daily best taken with food Need to be cautious with Anticoagulants  Coumadin  Warfarin Antiplatelet Drugs  ASA  NSAIDS  Ticlid  Plavix

66. Fish Oil Potential mechanisms for reduction of CV Risk Reduce susceptibility of the heart to ventricular arrhythmia Anti-thrombogenic Reduce Triglycerides (fasting & postprandial) Retard growth of atherosclerotic plaque Reduce adhesion molecule expression Reduce platelet-derived growth factor Anti-inflammatory Promote nitric oxide induced endothelial relaxation Mildly hypotensive Recommend combination of EPA & DHA Etherston et al.Circulation(106):2747 2002

67. Prescription Fish Oil Omacor EPA/DHA rich fish oil capsule Was used in the study that encouraged AHA Recommendation to add fish oil to all patients with Known CAD One gram capsule cardio protection – 1 grams daily to reduce TGs – 4 grams daily

68. Ezetimibe The first in a new class of lipid-lowering compounds that: Selectively inhibits the intestinal absorptionof cholesterol and related phytosterols

69. STATINS: Mechanism of Action Inhibit the rate-limiting enzyme HMG-CoA in cholesterol biosynthesis The associated decrease in synthesis stimulates production of LDL receptors Also possible increased removal of VLDL and IDL remnants which accounts for some decrease in triglycerides Other effects

70. Current Research theories with HMG Co-reductase inhibitors anti-inflammatory effects plaque stabilization decreased thrombus formation endothelial restoration

71. NEWSFLASH !!!!! All Statins Are Not Created Equal How are they different ? strength at starting dose way the body metabolizes it hydro/lipophilic

72. Taking a walk on the Cytochrome P450 Pathway Ross J 2004

73. Role of CYP450 3A4 in Drug Metabolism Responsible for converting lipophilic substrates to water-soluble products to facilitate urinary excretion High potential for drug-drug interactions, as approximately 50% of drugs are metabolized by this enzyme Hydrophilic agents do not require clinically significant metabolism through this pathway Wilson. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. Hardman et al, eds. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2003:3-30.

74. Dose Efficacy of Statin-Based Therapies for LDL-C Reduction (%) 1 Dose Efficacy in STELLAR 1* Drug10 mg20 mg40 mg80 mg CRESTOR ® (rosuvastatin calcium)465255 Lipitor ® (atorvastatin calcium)37434851 Pravachol ® (pravastatin sodium) 202430* Zocor ® (simvastatin)28353946 Vytorin TM (ezetimibe 10 mg/simvastatin)* reduces LDL-C by 46% to 59% 2* Data derived from the prescribing information for Vytorin

75. Safety: Looking at the Data From Another Perspective: If You Put 1,000 Patients on Aspirin and a Statin... Aspirin (81 mg) You can expect ~25 (10 - 40) hemorrhagic CVAs annually You can expect ~135 (70 - 200) major GI bleeds annually Statin You can expect 2 cases of mild rhabdomyolysis annually No cases of liver failure No deaths Lauer MS, et al. N Engl J Med 2002:346;1468-1474. Law MR, et al. BMJ 2003:326:1423. A Lot of fear and mis-perspection taking place, causing our patients not to take statins or not taking enough statin to reach goal

76. Combination Therapies for Hypertriglyceridemia Fibrates & statin therapy Niacin & statin therapy Zetia and Statin therapy Prescription omega-3 fatty acids & statin

77. Advicor First and new combination therapy utilizing Lovastatin and Niaspan Helps met ATP III guidelines Modifies LDL, HDL, TG, and Lp(a) Once nightly dosing Data from 748 patients exposed for 1 years and almost 400 for 2 years revealed that it is safe and well tolerated. Elevated LFTs > 3 X ULN occurred in < 1% at doses of 2000/40 or less NIASPAN® [package insert]. Miami, Fla: Kos Pharmaceuticals, Inc.; 2003. Morgan JM et al. J Cardiovasc Pharmacol Ther. 1996;1:195-202

78. Vytorin Combination of Zocor Zetia Enhanced LDL lowering than with just statin therapy Cost effective in one product Outcome studies not completed Ross, J 2004

79. Combination Therapy: Adding Fibrate to a Statin Better  TG and  HDL-C  non-HDL-C PROS May  myositis/ myopathy risk  cost and complexity  LDL particle size Potential for other drug interactions CONS  apo B  VLDL Grundy SM. Am J Cardiol. 2005;95:462-468. Jones PH. Am J Cardiol. 2005;95:120-122.

80. Combination Therapy Fibrate and statin monotherapy increase the risk of myositis or myopathy, and have been associated with rhabdomyolysis. Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are co- administered with a statin (with a significantly higher rate observed for gemfibrozil). The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.

81. WARNING: The combined use of fibrates and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure Fibrate Class Labeling Regarding Concomitant Statin Therapy

82. Number of Reports of Rhabdomyolysis for Fibrate/Statin Therapies (1998 to 2002) Medication No. Cases Reported* No. Prescriptions Dispensed † No. Cases reported per Million Prescriptions Fenofibrate With cerivastatin With other statins Fenofibrate total 14 2 16 100,000 3,419,000 3,519,000 140 0.58 4.5 Gemfibrozil With cerivastatin With other statins Gemfibrozil total 533 57 590 116,000 6,641,000 6,757,000 4600 8.6 87 15x increase Jones PH, Davidson MH. Am J Cardiol. 2005;95:120-122. *Food and Drug Administration’s Adverse Event Reporting System (January1, 1998 to March 31, 2002). † Calculated from data from the National Prescription Audit Plus Report, IMS Health (January 1, 1998 to March 31, 2002), and a Verispan, LLC Concomitancy Report (January 1, 1998 to March 31, 2002).

83. Case Study

84. 60-Year-Old Woman With Type 2 Diabetes and a History of Chronic Pancreatitis Patient profile: 60-year-old woman with well-controlled type 2 diabetes of 3 years’ duration and a history of chronic pancreatitis presents for a new patient examination Social history: She smokes 1 pack/day and drinks alcohol moderately

85. 60-Year-Old Woman With Type 2 Diabetes and a History of Chronic Pancreatitis (cont’d) Current medications Amlodipine 5 mg Glipizide 10 mg Metformin 1000 mg BID Simvastatin 40 mg Physical findings BMI: 36 kg/m 2 Waist circumference: 41 in (104 cm) Blood pressure: 141/90 mm Hg Lipid profile TC: 250 mg/dL HDL-C: 36 mg/dL LDL-C: 100 mg/dL TG: 570 mg/dL

86. What is her risk for any CV event in the next 10 years? 1. 2% 2. 8% 3. 17% 4. 22% 5. ≥30% 6. Not necessary to calculate

87. Age (y) Points 20-34-7 35-39-3 40-440 45-493 50-546 55-598 60-6410 65-6912 70-7414 75-7916 TCAge (y) (mg/dL)20-3940-4950-5960-6970-79 <16000000 160-19943210 200-23986421 240 -279118532  280 1310742 Step 2: TC HDL-C (mg/dL)  60 50-5940-49<40 Points 012 Step 3: HDL-C Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Framingham Risk Scoring (Women)

88. Framingham Risk Scoring (Women) (cont’d) Systolic BP (mm Hg) Points (Untreated ) Points (Treated ) <12000 120-12913 130-13924 140-15935  160 46 Age (y) 20-3940-4950-5960-6970-79 Nonsmok er 00000 Smoker97421 Points10-Yr Risk Point s 10-Yr Risk <9<1%142% 91%153% 101%164% 111%175% 121%186% 132%198% 2011% 2114% 2217% 2322% 2427%  25  30% 87 Step 4: Systolic Blood Pressure Step 5: Smoking Status Step 6: Add up the Points Step 7: Calculate Risk of CHD Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.

89. Diagnosis is established when 3 of These risk factors are present Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. > 102 cm (>40 in) >88 cm (>35 in) Abdominal obesity (Waist circumference) Special levels now for Asian population  110 mg/dL Fasting glucose Blood pressure <40 mg/dL/ <50 g/dL 130/85 mm/Hg HDL-C Men/Women  150 mg/dL TG Men & Women Defining LevelRisk Factor

90. Which of the following would you consider adding to this particular patient's regimen? 1. Fenofibrates 2. Niacin 3. Pravastatin 4. Prescription omega-3 fatty acids 5. Absorption Inhibitor

91. Treatment Plan Patient was treated with prescription omega-3 fatty acids, 4 g daily for 3 months Continued statin treatment at same dose Compliant with low-fat diet and lost 10 pounds Diabetes remained under control Blood pressure to 134/90 mm Hg Continue lifestyle management Stop Smoking Return for follow up in 3 months Lipid profile at 3-month follow-up: TC: 210 mg/dL; HDL: 36 mg/dL; LDL: 103 mg/dL; TG: 355 mg/dL, Non-HDL 174, glucose 118, HbA1c 7.0, renal and liver functions WNLs

92. 3-Month Follow-up Patient was continued with prescription omega-3 fatty acids, 4 g daily Changed statin to Rosuvastatin 20 mg No change with diabetic medication Blood pressure medications unchanged but added ACE Continue with lifestyle management Stop Smoking Lipid profile at 3-month follow-up: On Return TC: 140 mg/dL; HDL: 40 mg/dL; LDL: 65 mg/dL; TG: 165 mg/dL, Non-HDL not necessary since TGs are < 200, glucose 104, HbA1c 6.9, liver and kidney function normal. BP 122/78 91

93. Take Home Message Dyslipidemias are an important CVD risk factor Patients who are at LDL-C goal with statin therapy and still have hypertriglyceridemia remain at increased risk for CVD Niacin, fibrates, and prescription omega-3 fatty acids are approved agents for lowering TG levels Studies have shown that combination therapies using niacin + statin, omega-3 fatty acids + statin, and fibrates + statin are effective at reducing TG levels 92

94. NCEP ATP III Current Guidelines Provide Direction on How to Treat Patients With Dyslipidemia The first priority of treatment is to lower LDL-C – The first line of drug therapy to manage LDL-C is statins – In high-risk patients, the LDL-C goal is <100 mg/dL – Optional goal of LDL-C to <70 mg/dL for patients considered to be at very high risk If LDL-C at goal but TG ≥200 mg/dL – Non-HDL-C is a second target of therapy – Combining a fibrate or nicotinic acid with an LDL-C-lowering drug can be considered TG ≥150 mg/dL defined as borderline high and should be addressed A specific goal for HDL-C is not specified – HDL-C <40 mg/dL is defined as low – Treatment of low HDL-C should be considered for high-risk patients

95. We have our work cut out for us Many to work with who need our care and expertise ARE YOU UP & READY TO MEET THE CHALLENGE ?