1. Health Care, Education and Researchwww.billingsclinic.com Updated Cholesterol Management Guidelines Donald Brown, Pharm.D, BCACP May 3 rd, 2014

2. Objectives Brief review of current and newer cholesterol lowering medications Discuss previous guidelines and how they compare to new guidelines Discuss controversy and treatment strategies

3. Pre-Lecture Questions 1.The updated cholesterol management guidelines address managing the statin intolerant patient. –True or False 2.The updated cholesterol management guidelines risk calculator does not address patients less than 40 years old. –True or False 3.Non-statin therapy has no place in managing patients’ cholesterol –True or False

4. The Art of James C. Christensen Image available at: http://www.world-wide-art.com/images/James-Christensen/Low-Tech.jpg

5. Atherogenesis

6. Lipoprotein Metabolism Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

7. Cholesterol Lowering Medication Statins Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

8. Cholesterol Lowering Medication Cholesterol Absorption Inhibitor Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

9. Cholesterol Lowering Medication Bile Acid Sequestrant Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

10. Cholesterol Lowering Medication Niacin Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

11. Cholesterol Lowering Medication Fibrates Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

12. Cholesterol Lowering Medication Fish Oils Image available at: http://pic.pimg.tw/mulicia/8a5d7405327f4b775ba83e725dff57f9.png

13. Current Arsenal Statins Bile acid sequestrants Ezetimibe Fibrates Niacin Rx and OTC fish oil products New –Lomitapide (Juxtapib®) - MTTP inhibitor –Mypomersen (Kynamro®) – antisense oligonucleotide Future? – PCSK9 inhibitors, CETP inhibitors Image available at: http://www.3riversarchery.com/images/medium/6100X.jpg

14. Patient Case # 1 25 year old male with no medical history –No HTN, no DM, no smoking –Has a strong family history of premature CVD Father died of MI at age 42 –BMI = 25 kg/m^2 –TC = 310 mg/dL –HDL-C = 50 mg/dL –TG = 400 mg/dL –LDL-C = 180 mg/dL Question: Should we start treatment?

15. Patient Case #2 64 year old male –No HTN, no DM, no smoking –SBP = 129 mmHg –TC = 180 mg/dL –HDL-C = 70 mg/dL –TG = 130 mg/dL –LDL-C = 84 mg/dL Question: Should we start treatment?

16. SET THE WAY-BACK MACHINE

17. What Are We Used To? Adult Treatment Panel III Guidelines (2001) –Focused on: Primary prevention in patients with multiple risk factors Modifications of lipid classification 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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf.

18. Adult Treatment Panel III Patients with multiple risk factors –Patients with diabetes without CHD Raised to CHD risk level –Used Framingham risk projections –Patient with the Metabolic Syndrome Candidates for intensified TLC 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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf.

19. Adult Treatment Panel III Modified lipid classifications –LDL-C < 100 mg/dL --- optimal –Raised categorical HDL-C < 35 mg/dL to 40 mg/dL –Lowered TG classifications Gives more attention to moderate elevations

20. Adult Treatment Panel III Supported implementing –Complete lipoprotein profile –Use of plant stanols and soluble fiber –Importance of adherence to TLC and medication therapies –Identified importance of treating patients with TG >200 mg/dL (Non-HDL-C) 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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf.

21. Adult Treatment Panel III Primary Target:LDL-C –Goal based on CV risk Secondary Target:Non-HDL-C –When LDL-C goal met and TG ≥ 200 mg/dL –Goal is always the LDL-C goal + 30 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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf.

22. Adult Treatment Panel III Secondary Prevention in patients with established CVD –LDL-C goal: 100 mg/dL, further reduction to 70 mg/dL –If LDL-C < 70 mg/dL is not achievable due to high baseline LDL-C reduction of 50% with statins and/or combination 1.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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf. 2.Smith SC, Jr, et al. J Am Coll Cardiol. 2006;47:2130-2139.

23. Adult Treatment Panel III

24. Framingham Risk Framingham risk score –10 year risk of developing coronary heart disease –Takes into account patient’s: Age Gender Total cholesterol value Smoking status HDL-C value SBP and treatment status 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): executive summary. National Cholesterol Education Program Web site. Available at: http://www.nhlbi.nih.gov/guidelines/ cholesterol/atp3xsum.pdf.

25. A Word About Risk Risk factors –Formation of plaques –Cause plaques to rupture Major Risk Factors: –Cigarette smoking –Hypertension –Low HDL-C –Diabetes

26. Back to Patient Case # 1 25 year old white male with no medical history –No HTN, no DM, no smoking –Has a strong family history of premature CVD Father died of MI at age 42 –BMI = 25 kg/m^2 –TC = 310mg/dL –HDL-C = 50 mg/dL –TG = 400 mg/dL –LDL-C = 180 mg/dL Question: Should we start treatment? ATP III: 1 risk factor, Fram risk ~ 1%

27. Back to Patient Case #2 64 year old white male –No HTN, no DM, no smoking –SBP = 129 mmHg –TC = 180 mg/dL –HDL-C = 70 mg/dL –TG = 130 mg/dL –LDL-C = 84 mg/dL Question: Should we start treatment? ATP III: Age, HDL – risk factor, Fram Risk 5%

28. FAST FORWARD ABOUT 12- YEARS

29. Many Trials/Papers Published HPSIDEALAIM-HIGHPROVE-IT ACCORDHPS-THRIVEASCOT-LLAJUPITER VA-HITPROSPERMETEORCARDS ALLHAT-LLTARBITER-2SEARCHTNT SHARPENHANCEIMPROVE-ITHOPE-3

30. THE AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN HEART ASSOCIATION MANAGEMENT GUIDELINE UPDATE

31. ACC/AHA Guidelines 2013 Non-statin therapies de-emphasized Emphasized lifestyle as the foundation to risk reduction 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

32. What’s New? 1.Focus on ASCVD Risk Reduction: –4 statin benefit groups 2.New perspective on LDL-C and/or Non-HDL-C treatment goals 3.Global risk assessment for primary prevention 4.Safety recommendations 5.Role of biomarkers and non-invasive tests 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

33. 1. Four Statin Benefit Groups Four groups of primary and secondary prevention –Patients with clinical ASCVD –Patients with LDL-C ≥ 190 mg/dL –Patients with DM and no evidence of ASCVD 40 – 75 years old + LDL-C 70 – 189 mg/dL –Patients w/o DM or ASCVD LDL-C 70 – 189 mg/dL + 10-yrsk of ASCVD ≥ 7.5% 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

34. Origins of the Groups Randomized controlled trials –Who should get statin therapy and what intensity –Lowering of LDL-C 30 – 50% or more –Relative reduction in ASCVD risk consistent among various patient groups Statin therapy reduces risk across spectrum of baseline LDL-C > 70 mg/dL 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

35. Defining Statin Intensity What are the statin intensity groups? –High intensity Lowers LDL-C ~ > 50% –Moderate intensity Lowers LDL-C ~ 30 to 50% –Low intensity Lowers LDL-C ~ < 30% 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a Rosuvastatin 20 – 40 mg Atorvastatin 40 – 80 mg Atorvastatin 10 – 20 mg Rosuvastatin 5 – 10 mg Simvastatin 20 – 40 mg Pravastatin 40 – 80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40mg BID Pitavastatin 2 – 4 mg Simvastatin 10 mg Pravastatin 10 – 20 mg Lovastatin 20 mg Fluvastatin 20 – 40 mg Pitavastatin 1 mg

36. Defining Statin Intensity What are the statin intensity groups? –High intensity Lowers LDL-C ~ > 50% –Moderate intensity Lowers LDL-C ~ 30 to 50% –Low intensity Lowers LDL-C ~ < 30% Rosuvastatin 20 – 40 mg Atorvastatin 40 – 80 mg Atorvastatin 10 – 20 mg Rosuvastatin 5 – 10 mg Simvastatin 20 – 40 mg Pravastatin 40 – 80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40mg BID Pitavastatin 2 – 4 mg Simvastatin 10 mg Pravastatin 10 – 20 mg Lovastatin 20 mg Fluvastatin 20 – 40 mg Pitavastatin 1 mg

37. 2. LDL “Goals” Perspective Paradigm shift –New perspective on treatment goals RCT evidence has only shown that ASCVD events are reduced by using the maximum tolerated statin dose The use of non-statin therapy –i.e. ezetimibe and niacin 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

38. LDL “Goals” Perspective Secondary prevention –Evidence only shows support for statin therapy to maximally reduce LDL-C. No support for a target FH w/ LDL-C > 190 mg/dL –May be difficult to achieve goal LDL-C < 100 despite the use of 3 cholesterol-lowering medications However, if patient achieves 50% reduction they are receiving evidence based therapy 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

39. Treatment Goals Type 2 diabetes –Patients 40 – 75 yo the benefits of LDL-C lowering with high-intensity/maximally tolerated statin shown to be substantial –Non statin drugs may be added to address low HDL- C or high TG Estimated 10-yer ASCVD risk ≥ 7.5% –Statins used for primary risk reduction benefits patient across range of LDL-C levels from 70 – 189 mg/dL 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

40. ACC/AHA Risk Calculator Primary prevention –Use of a new pooled cohort equation to estimate 10- year ASCVD risk in both white and black men and women –Identifying patients that will most likely benefit from statin therapy –Who may not benefit Patient-centered approach 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

41. 3. Global Risk Assessment Primary prevention –Use of a new pooled cohort equation –Identifying patients most likely to benefit –Who may not benefit Patient centered-approach –Risk reduction benefit, ADEs, DDIs and patient preference 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

42. ACC/AHA Risk Calculator Takes into account: –Patient Age, gender, ethnicity, SBP, TC, HDL, Smoking status, HTN treatment, Diabetes

43. Risk Calculator Accounts for patient’s –Age, gender, ethnicity, SBP, …

44. Risk Calculator

45. ACC/AHA Risk Calculator Only for Patients 20 - 59

46. Statin Therapy Flowchart

47. Yes…There’s An App For That

48. Safety RCTs identified safety considerations –i.e Pre-Diabetes Management of muscle symptoms Use of pharmacists to aid in the safe use of cholesterol-lowering therapy 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

49. 4. Safety RCTs identified safety considerations –i.e Pre-diabetes Management of muscle symptoms Use of pharmacists to aid in the safe use of cholesterol lowering therapy

50. 5. Biomarkers and Tests Role of biomarkers and non-invasive tests –Included recommendations to consider using LDL-C > 160 mg/dL Evidence of genetic hyperlipidemias Family history hsCRP CAC

51. Biomarkers and Tests Role of Biomarkers and non-invasive tests –Included recommendations to consider using LDL-C > 160 mg/dL Evidence of genetic hyperlipidemias Family history High-sensitivity C-reactive protein ≥ 2mg/L CAC score ≥ 300 Agatston units or ≥ 75 percentile for age, gender, and ethnicity 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a

52. Statin-intolerant Patients Recommend determining causal relationship with statin Investigate other potential causes of muscle symptoms, for instance Stopping and re-starting statin therapy Switch to another statin at a lower dose Does not present what to do with the truly intolerant statin patient

53. CONTROVERSY

54. New Risk Calculator What was the equation/formula used to calculate this risk? –We don’t know, it has not been provided –Not verified in prospective studies –Of course, RCTs cannot be available for every scenario Should not mean a lack of evidence though –Relies heavily on age and gender Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

55. New Risk Calculator What was the equation/formula –Not yet provided –Not verified in prospective studies Of course, RCTs cannot available for every scenario –Should not mean a lack of evidence though –Relies heavily on age and gender

56. More Patients on Statins New calculator could make 30 million more patients eligible for statin therapy Does not address patients younger than 40 or older than 79 years –May ignore early treatment/prevention –May over treat primary prevention patient Lack of risk factors in the calculator –Family history –C-reactive protein –Lp(a) or apoB Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

57. More Patients on Statins 30 million more patients statin eligible Younger than 40 years or older than 70 –May ignore treatment/prevention –May over treat primary prevention patient Lack of risk factors in calculator –Family history, CRP, Lp(a) or apoB Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

58. Quality Measures What could this mean for quality measures –No targets, but insurance companies already look for this Perhaps looking to see if patient taking a statin medication Is lack of LDL-C goals a flaw? Once patient on highest tolerated dose of statin is it really necessary to repeat lipid levels? Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

59. Scatter plot with best-fit lines of major lipid trials (statin and nonstatin trials) for both primary and secondary prevention of coronary heart disease events. RAYMOND C et al. Cleveland Clinic Journal of Medicine 2014;81:11-19 ©2014 by Cleveland Clinic

60. Statin-intolerant Patients Recommend determine causal relationship with statin Investigate other possible causes Stopping and re-starting statin therapy Switch to another statin at a lower dose Truly intolerant statin?

61. Quality Measures What could this mean for quality measures –No targets, but insurance companies Is lack of LDL-C goals a flaw? Necessary to repeat lipid levels? Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

62. Other Contentious Points No period for open comment/critique Apparent lack of attempt to correlate with other guidelines Raymond, C, Cho L, Rocco, M, Hazen SL. New Cholesterol Guidelines: Worth the Wait?. Cleveland Clinic Journal of Medicine.81(1).Jan 2014:11-19. O’Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Available at: http://www.medscape.com/viewarticle/814152#1

63. Back to Patient Case # 1 25 year old male with no medical history –No HTN, no DM, no smoking –Has a strong family history of premature CVD Father died of MI at age 42 –BMI = 25 kg/m^2 –TC = 310 mg/dL –HDL-C = 50 mg/dL –TG = 400 mg/dL –LDL-C = 180 mg/dL Question: Should we start treatment?

64. According to new calculator –Risk calculator does not apply to him Less than 40 years old –Even at 40 his 10-year risk is 3.1% –“Eligible” for statin therapy at 58 years –Comfortable waiting to start therapy?

65. Back to Patient Case #1 According to new guideline calculator –Risk calculator does not apply to him Less than 40 years old So according to the calculator –Even when patient is 40 year old his 10 year risk at that time will still only be 3.1% –When 58 years old patient would then be “eligible” to receive treatment Comfortable waiting starting therapy?

66. Of course you wouldn’t base decision solely on a risk calculator –If difficulty identifying patient for a statin group could use other risks History of premature atherosclerotic cardiovascular disease in first degree relative High sensitivity-reactive protein (CRP) > 2 mg/L Coronary Artery Calcium (CAC) scan

67. Back to Patient Case #2 64 year old male –No HTN, no DM, no smoking –SBP = 129 mmHg –TC = 180 mg/dL –HDL-C = 70 mg/dL –TG = 130 mg/dL –LDL-C = 84 mg/dL Calculated risk = 7.5%

68. Patient Case #3 64 year old male –2 pack per day smoker –Untreated HTN (SBP = 150 mmHg) –TC = 153 mg/dL –HDL-C = 70 mg/dL –TG = 60 mg/dL –LDL-C = 71 mg/dL Calculated risk = 10.5%

69. Summary Of note: –The National Lipid Association does not currently endorse these new guidelines Due to lack of discussion on –Options for those with residual risk or continued elevated LDL-C who are already on maximally tolerated statin –Management of special populations »Patients 75 years »Those with FH »Statin intolerance

70. Summary So, where does this leave us for treating patients? –Likely have more patients that should be on statin therapy due to lower threshold for calculated risk We should be treating diabetics more aggressively Lipid measurements –Still important for measuring adherence, although not specifically recommended in the guidelines

71. Summary Lack of documenting the use of –Non-HDL-C in decision making Probably because no treatment goals –The role of treating high triglycerides –Or whether we should treat other biomarkers like apoB or LDL-particles

72. Summary There is controversy, but… Should be treating diabetics more aggressively TLC remains a cornerstone

73. Post-Lecture Questions 1.The updated cholesterol management guidelines address managing the statin intolerant patient. –True or False 2.The updated cholesterol management guidelines risk calculator does not address patients less than 40 years old. –True or False 3.Non-statin therapy has no place in managing patients’ cholesterol –True or False

74. QUESTIONS/COMMENTS