1. Management of Hyperlipidemia Mark P. Woodruff, M.D. Creighton Cardiac Center November 9, 2005

2. 2 Management of Hyperlipidemia Prevent or delay the onset of CAD in patients without known disease –primary prevention Prevent or delay recurrent events in patients with CAD –secondary prevention

3. 3 Lipid Hypothesis LDL cholesterol is key factor in CAD and other CVD Supported by: –epidemiological studies –animal studies –human case studies (familial hypercholesterolemia) –interventional studies (drug, lifestyle, surgical)

4. TM © 1999 Professional Postgraduate Services ® 0 5 10 15 20 25 30 (2.60)(3.25)(3.90)(4.50)(5.15)(5.80)(6.45)(7.10)(7.75)(8.40)(9.05) Cholesterol and CHD: Seven Countries Study TC mg/dL (mmol/L) CHD mortality rates (%) Verschuren WMM et al. JAMA. 1995;274:131-136. 100125150175200225250275300325350 Northern Europe United States Southern Europe, Inland Southern Europe, Mediterranean Siberia Japan

5. 5 LDL Reduction Proven to reduce cardiac events and other vascular events (stroke) Proven to reduce total mortality in certain groups Proven to be safe with long term treatment

6. 6 Hyperlipidemia? Treat only the highest 10% LDL –Account for only 20% of CHD events In PROVE-IT (pts with ACS) –Median pre-treatment LDL was ~106 Definition of hyperlipidemia evolves

7. TM © 1999 Professional Postgraduate Services ® -9 -47 -9 -20 -14 -23 -8.5 -19 -11 -34 -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 %+%+ Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. * Net difference between treatment and control groups (P values are for events). TC *CHD events * N=number enrolled. Early Primary-Prevention Trials: Overview WHO: Clofibrate N=15,745, P<0.05 Oslo: Diet/smoking cessation N=1,232, P=0.02 Upjohn: Colestipol N=2,278, P  0.02 LRC-CPPT: Cholestyramine N=3,806, P<0.05 HHS: Gemfibrozil N=4,081, P<0.02

8. TM © 1999 Professional Postgraduate Services ® Early Secondary-Prevention Trials: Overview Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. * Net difference between treatment and control groups (P values are for events). N=number enrolled; ns=not significant. TC *CHD events * CDP: Niacin (n=1,119) N=8,341, P=ns CDP: Clofibrate (n=1,103) N=8,341, P=ns Stockholm: Clofibrate + niacin N=555, P=ns POSCH: Partial ileal bypass N=838, P<0.001 %+%+

9. TM © 1999 Professional Postgraduate Services ® -20 -26 5 -31 -33 -22 -25 -35 8 -34 -42 -30 -20 -28 5 -24 -20 -9 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 WOSCOPS (N=6,595)4S (N=4,444)CARE (N=4,159) N=number enrolled. TC LDL-C HDL-C 1 o prevention 2 o prevention Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin Trials Nonfatal MI/CHD death CHD death All-cause mortality %+%+

10. TM © 1999 Professional Postgraduate Services ® 4S: Effects of Cholesterol Lowering on Noncoronary Ischemic Symptoms and Angina Pedersen TR et al. Am J Cardiol. 1998;81:333-335. Fraction of patients Months Simvastatin Placebo Intermittent ClaudicationCarotid Bruit AnginaCerebrovascular Events

11. Brown BG et al. Circulation. 1993;87:1781-1791. * As defined by the comparison between the change in the treated group vs the change in the control. FATSFATSSTARSHARPLCAS (nicotinic acid(lovastatin(diet + resin)(diet + + colestipol)+ colestipol)fluvastatin) Event Reduction in Angiographic Plaque Regression Trials +% stenosis* Event reduction (%)%

12. JAMA 291; 9 Nissen et.al., 3/3/04

13. TM © 1999 Professional Postgraduate Services ® Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995. Angiographically Inapparent Atheroma

14. JAMA 291; 9 Nissen et.al., 3/3/04

16. PROVE-IT

17. NEJM 350;15 Cannon et.al. 4/8/04

18. PROVE-IT: Final LDL cholesterol level LDL cholesterol level Pravastatin 40 mg (IQR) (n=1973) Atorvastatin 80 mg (IQR) (n=2003) p Final LDL cholesterol (mg/dL) 95 (79-113) 62 (50-79)<0.001 Cannon CP et al. N Engl J Med 2004. Available at: http://www.nejm.org. IQR=Interquartile range

19. PROVE-IT NEJM 350;15 Cannon et.al. 4/8/04

20. So What Is Optimal LDL? Neonates: LDL 30-70 Indigenous populations: LDL 50-75 –Often long lived without CVD Healthy, wild primates: LDL 40-80

21. Optimal LDL? Scan fig 2 JACC Vol. 43, No. 11, 2004 O’Keefe, Jr. et al.

22. Optimal LDL? Scan fig 3 JACC Vol. 43, No. 11, 2004 O’Keefe, Jr. et al.

23. Optimal LDL? JACC Vol. 43, No. 11, 2004 O’Keefe, Jr. et al.

24. Normal Fatty Streak Fibrous Plaque Occlusive Atherosclerotic Plaque Plaque Rupture/ Fissure & Thrombosis MI Stroke Critical Leg Ischemia Clinically Silent CoronaryDeath Increasing Age Effort Angina Claudication UnstableAngina Atherosclerosis: A Progressive Process Courtesy of P Ganz.

25. Libby P. Circulation. 1995;91:2844-2850. Characteristics of Plaques Prone to Rupture –T lymphocyte – Macrophage foam cell (tissue factor + ) – “Activated” intimal SMC (HLA-DR + ) –Normal medial SMC “Stable” plaque “Vulnerable” plaque Lumen area of detail Media Fibrous cap Lumen Lipid core Lipid core

26. Libby P. Circulation. 1995;91:2844-2850. Proposed Mechanisms of Event Reduction by Lipid-Lowering Therapy Improved endothelium-dependent vasodilationImproved endothelium-dependent vasodilation Stabilization of atherosclerotic lesionsStabilization of atherosclerotic lesions –especially nonobstructive, vulnerable plaques Reduction in inflammatory stimuliReduction in inflammatory stimuli –lipoproteins and modified lipoproteins Prevention, slowed progression, or regression of atherosclerotic lesionsPrevention, slowed progression, or regression of atherosclerotic lesions

27. Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program www.nhlbi.nih.gov

28. Updated ATP III 2004 HPS, MIRACL, REVERSAL, PROVE-IT

29. 29 Screening All adults > 20 yrs, every 5 years or when increased risk is noted Fasting lipid profile –measure total cholesterol, HDL and triglycerides –presumably all TG in VLDL in fasting state Friedewald equation: LDL = TC - [ TG/5 + HDL]  TG/5 = VLDL –not valid if TG > 300-400 –can directly measure LDL Non-HDL cholesterol = Total cholesterol – HDL

30. 30 ATP III Lipid and Lipoprotein Classification LDL Cholesterol: The primary target of therapy <100 (<70)Optimal 100–129Near optimal/above optimal 130–159Borderline high 160–189High  190Very high

31. 31 ATP III Lipid and Lipoprotein Classification (continued) HDL Cholesterol (mg/dL) <40 Low  60 High

32. 32 ATP III Lipid and Lipoprotein Classification (continued) Total Cholesterol (mg/dL) <200Desirable 200–239Borderline high  240High

33. 33 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) Metabolic syndrome † HDL cholesterol  60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.

34. Cost Effectiveness Issues Therapeutic lifestyle changes (TLC)Therapeutic lifestyle changes (TLC) –Most cost-effective therapy Drug therapyDrug therapy –Dominant factor affecting costs –Cost effectiveness: one factor in the decision for drug therapy –Declining price of drugs: increases cost effectiveness

35. 35 Highest Risk for Cardiac Events Highest risk is for those with CAD –>20% per 10 yrs for another event –Most will die from a vascular event

36. 36 CHD Risk Equivalents Risk for major coronary events equal to that in established CHD 10-year risk for hard CHD >20% Hard CHD = myocardial infarction + coronary death

37. 37 Diabetes as a CHD Risk Equivalent 10-year risk for CHD  20% High mortality with established CHD –High mortality with acute MI –High mortality post acute MI

38. 38 CHD Risk Equivalents Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) Diabetes Multiple risk factors that confer a 10-year risk for CHD >20%

39. 39 Risk Category CHD and CHD risk equivalents Multiple (2+) risk factors Zero to one risk factor LDL Goal (mg/dL) <100 Optional goal <70 <130 <160 Three Categories of Risk that Modify LDL-Cholesterol Goals

40. 40 LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) CHD or CHD Risk Equivalents (10-year risk >20%) <100 (option <70)  100  100 (<100 consider drug) 2+ Risk Factors (10-year risk  20%) <130 (in higher risk consider <100)  130 10-year risk 10–20%:  130 (consider if 100-129) 10-year risk <10%:  160 0–1 Risk Factor<160  160  190 (160–189: LDL-lowering drug optional)

41. 41 Drug Therapy HMG CoA Reductase Inhibitors (Statins) Reduce LDL-C 18–55% & TG 7–30% Raise HDL-C 5–15% Anti-inflammatory effect Major side effects –Myopathy –Increased liver enzymes

42. 42 HMG CoA Reductase Inhibitors (Statins) (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Reduce coronary procedures (PTCA/CABG) Reduce stroke Reduce total mortality

43. 43

44. 44 Drug Therapy Bile Acid Sequestrants Major actions –Reduce LDL-C 15 – 30% –Raise HDL-C 3 – 5% –May increase TG Side effects –GI distress/constipation –Decreased absorption of other drugs Contraindications –Dysbetalipoproteinemia –Raised TG (especially >400 mg/dL)

45. 45 Bile Acid Sequestrants (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality

46. 46 Drug Therapy Nicotinic Acid Major actions –Lowers LDL-C 5–25% –Lowers TG 20–50% –Raises HDL-C 15–35% Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity Contraindications: liver disease, severe gout, peptic ulcer

47. 47 Nicotinic Acid (continued) Demonstrated Therapeutic Benefits Reduces major coronary events Possible reduction in total mortality

48. 48 Drug Therapy Fibric Acids Major actions –Lower LDL-C 5–20% (with normal TG) –May raise LDL-C (with high TG) –Lower TG 20–50% –Raise HDL-C 10–20% Side effects: dyspepsia, gallstones, myopathy –Interaction with statins, less with fenofibrate Contraindications: Severe renal or hepatic disease

49. 49 Fibric Acids (continued) Demonstrated Therapeutic Benefits Reduce progression of coronary lesions Reduce major coronary events

50. 50 Ezetimibe Decrease cholesterol uptake at the brush border of the intestine Reduces LDL by ~ 10-15% Well tolerated Useful in combination But…no studies showing benefit –But will increase chance of getting to goal LDL

51. 51 LDL-cholesterol goal: <100 mg/dL –Optional goal <70 Most patients require drug therapy to achieve goal First, achieve LDL-cholesterol goal –Statin considered first line drug Second, modify other lipid abnormalities Treat other risk factors Secondary Prevention: Drug Therapy for CHD and CHD Risk Equivalents

52. 52 Patients Hospitalized for Coronary Events or Procedures Measure LDL-C within 24 hours Consider starting all patients on a statin –Definitely if LDL >100 –Start with dose that will likely reduce LDL by 30-40% Start lifestyle therapies simultaneously with drug Reevaluate in 4-8 weeks Secondary Prevention: Drug Therapy for CHD and CHD Risk Equivalents (continued)

53. Slide Source LipidsOnline www.lipidsonline.org Therapy more likely to be initiated by physician Therapy more likely to be continued by physician long term Patients less likely to be concerned about side effects/monitoring Patients more likely to view therapy as essential (heart medication) Patients more likely to be compliant (lower discontinuation rates) Patient more likely to achieve LDL cholesterol <100 mg/dl Early event reduction in ACS patients not missed Fonarow GC et al. Circulation 2001;103:2768-2770. In-Hospital Initiation of Lipid- Lowering Therapy: The Time is NOW

54. Slide Source LipidsOnline www.lipidsonline.org CHD Patient Treatment Gap: Community Pearson TA et al. Arch Intern Med 2000;160:459-467. 18 Provider awareness does not equal successful implementation 95 Physician Awareness of NCEP Guidelines Patient Treated to Goal Percent

55. Slide Source LipidsOnline www.lipidsonline.org Number of US Adults Eligible for Statin Treatment Based on New Evidence CategoryPatients CAD12,600,000 PVD4,000,000 CVD4,600,000 Diabetes17,000,000 Total38,200,000

56. 56 LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) CHD or CHD Risk Equivalents (10-year risk >20%) <100 (option <70)  100  100 (<100 consider drug) 2+ Risk Factors (10-year risk  20%) <130 (in higher risk consider <100)  130 10-year risk 10–20%:  130 (consider if 100-129) 10-year risk <10%:  160 0–1 Risk Factor<160  160  190 (160–189: LDL-lowering drug optional)

57. 57 Primary Prevention Estimate risk  Don’t like to treat patient if they are not destined to develop the disease  Do years and years and years of treatment benefit?  At what cost? Use other risk predictors?  CRP  Coronary calcium scores  Carotid ultrasound

58. 58 Drug Therapy for Primary Prevention Initiate therapeutic lifestyle changes Initiate LDL-lowering drug therapy (after 3 months of lifestyle therapies) Usual drug options –Statins –Bile acid sequestrant, nicotinic acid, fibrates Continue therapeutic lifestyle changes Return visit in about 6 weeks

59. 59 Progression of Drug Therapy in Primary Prevention If LDL goal not achieved, intensify LDL-lowering therapy If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist Monitor response and adherence to therapy Start statin or bile acid sequestrant or nicotinic acid Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid 6 wks Q 4-6 mo If LDL goal achieved, treat other lipid risk factors Initiate LDL- lowering drug therapy

60. ATP III Guidelines Specific Dyslipidemias

61. 61 Specific Dyslipidemias: Very High LDL Cholesterol (  190 mg/dL) Causes and Diagnosis Genetic disorders –Monogenic familial hypercholesterolemia –Familial defective apolipoprotein B- 100 –Polygenic hypercholesterolemia Family testing to detect affected relatives

62. 62 Specific Dyslipidemias: Very High LDL Cholesterol (  190 mg/dL) (continued) Management LDL-lowering drugs –Statins (higher doses) –Statins combined with bile acid sequestrants, nicotinic acid and or ezetimibe Plasmapheresis, liver transplant

63. 63 Specific Dyslipidemias: Elevated Triglycerides Classification of Serum Triglycerides Normal <150 mg/dL Borderline high150–199 mg/dL High200–499 mg/dL Very high  500 mg/dL

64. 64 Specific Dyslipidemias: Elevated Triglycerides (  150 mg/dL) Causes of Elevated Triglycerides Obesity and overweight Physical inactivity Cigarette smoking Excess alcohol intake

65. 65 Specific Dyslipidemias: Elevated Triglycerides Causes of Elevated Triglycerides (continued) High carbohydrate diets (>60% of energy intake) Several diseases (type 2 diabetes, chronic renal failure, nephrotic syndrome) Certain drugs (corticosteroids, estrogens, retinoids, higher doses of beta-blockers) Various genetic dyslipidemias

66. 66 Specific Dyslipidemias: Elevated Triglycerides (continued) Independent risk factor for CHD –weakens with multivariate analysis –partially degraded VLDL i.e. remnant lipoprotein is atherogenic Non-HDL cholesterol = VLDL + LDL = TC – HDL –goal of non-HDL chol = LDL goal + 30  so for CAD pt it is 130

67. 67 ATP III: The Metabolic Syndrome* *Diagnosis is established when  3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is  BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. <40 mg/dL <50 mg/dL Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women  110 mg/dL Fasting glucose  130/  85 mm Hg Blood pressure HDL-C  150 mg/dL TG Abdominal obesity † (Waist circumference ‡ ) Defining LevelRisk Factor

68. 68 ATP III: Management of Diabetic Dyslipidemia Primary target of therapy: identification of LDL-C; goal for persons with diabetes: <100 mg/dL Therapeutic options: –LDL-C 100–129 mg/dL: increase intensity of TLC; add drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid); intensify risk factor control –LDL-C  130 mg/dL: simultaneously initiate TLC and LDL-C–lowering drugs TG  200 mg/dL: non–HDL-C* becomes secondary target Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. Note: Diabetic dyslipidemia is essentially atherogenic dyslipidemia in persons with type 2 diabetes. *Non–HDL-C goal is set at 30 mg/dL higher than LDL-C goal.

69. 69 Specific Dyslipidemias: Elevated Triglycerides Management of Very High Triglycerides (  500 mg/dL) Goal of therapy: prevent acute pancreatitis Very low fat diets (  15% of caloric intake) Triglyceride-lowering drug usually required (fibrate or nicotinic acid) Reduce triglycerides before LDL lowering

70. 70 Specific Dyslipidemias: Low HDL Cholesterol Causes of Low HDL Cholesterol (<40 mg/dL) Elevated triglycerides Obesity Physical inactivity Type 2 diabetes Cigarette smoking Very high carbohydrate intakes (>60% energy) Certain drugs (beta-blockers, anabolic steroids, progestational agents)

71. 71 Specific Dyslipidemias: Low HDL Cholesterol Management of Low HDL Cholesterol LDL cholesterol is primary target of therapy Weight reduction and increased physical activity (if the metabolic syndrome is present) Non-HDL cholesterol is secondary target of therapy (if triglycerides  200 mg/dL) Consider nicotinic acid or fibrates (for patients with CHD or CHD risk equivalents)

72. 72 Interventions to Improve Adherence Focus on the patient Simplify medication regimens Provide explicit patient instruction Use good counseling techniques to teach the patient how to follow the prescribed treatment Use systems to reinforce adherence and maintain contact with the patient

73. 73 Interventions to Improve Adherence Focus on the patient (continued) Encourage the support of family and friends Reinforce and reward adherence Increase visits for patients unable to achieve treatment goal Increase the convenience and access to care Involve patients in their care through self- monitoring

74. 74 Interventions to Improve Adherence (continued) Focus on the Physician and Medical Office Teach physicians to implement lipid treatment guidelines Use reminders to prompt physicians to attend to lipid management Use patients to prompt preventive care

75. 75 Management of Hyperlipidemia Treatment is effective and safe Diagnosis is easy –Measure lipid profile Assess risk of patient Treatment based on the risk –LDL reduction is mainstay and statins are the most effective drug