1. Dyslipidemia and Cardiovascular Risk Reduction: An Evidence-Based Review Latha Palaniappan, MD, MS Adjunct Clinical Assistant Professor Department of Internal Medicine, Clinical Epidemiology Stanford Prevention Research Center Stanford University School of Medicine Stanford, California

2. Key Question What percentage of your patients with dyslipidemia who are receiving statin therapy alone achieve LDL goal? 1. ≤25% 2. 26%-50% 3. 51%-75% 4. 76%-100% Use your keypad to vote now! ?

3. Faculty Disclosure  Dr Palaniappan has no relevant financial relationships with any commercial interests to disclose.

4. Learning Objectives  Discuss current guidelines for the management of dyslipidemia  Describe the results of recent clinical trials relevant to the management of dyslipidemia  State lipid goals according to patients’ level of cardiovascular risk

5. Cardiovascular Disease (CVD)  Leading cause of death in the United States  37% of all US deaths in 2003 1  Total US cost in 2006 = $403.1 billion 1  Associated with high blood levels of cholesterol and other lipids, and low HDL levels 1  Risk assessment, risk reduction 1,2 HDL: high-density lipoprotein 1. Thom T, et al. Circulation. 2006;113:e85-e151. 2. NCEP ATP III. JAMA. 2001;285:2486-2497.

6. NCEP ATP III Risk Determinants  LDL level  CHD or CHD risk equivalents:  Other clinical atherosclerotic disease  Diabetes  Multiple other risk factors contributing to a Framingham 10-year risk of CHD >20%  Other major risk factors NCEP ATP III. JAMA. 2001;285:2486-2497. NCEP ATP III: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) LDL: low-density lipoprotein CHD: coronary heart disease

7. Major Risk Factors Other Than LDL and CHD  Cigarette smoking  Hypertension  BP ≥140/90 mm Hg or on antihypertensive medication  Low HDL level  <40 mg/dL  Family history of premature CHD  Male first-degree relative <55 years  Female first-degree relative <65 years  Age  Men ≥45 years  Women ≥55 years BP: blood pressure NCEP ATP III. JAMA. 2001;285:2486-2497.

8. TestOptimal Borderline High Risk High Risk Very High Risk Total Cholesterol <200200-239≥240 LDL<100130-159160-189≥190 HDL≥6040-59<40 Triglycerides<150150-199200-499≥500 NCEP ATP III Risk Definitions NCEP ATP III. JAMA. 2001;285:2486-2497.

9. Risk Assessment: Dyslipidemia and CVD  Framingham risk calculator 1,2  Based on age, sex, total and HDL cholesterol, smoking, BP  Mobile Lipid Clinic 3  Free NCEP ATP III–based tools  Palm ® and Windows ® 1. Risk assessment tool for estimating 10-year risk of developing hard CHD (myocardial infarction and coronary death). Available at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof. Accessed on January 17, 2007. 2. Grundy SM, et al. J Am Coll Cardiol. 1999;34:1348-1359. 3. Mobile Lipid Clinic. Available at http://www.mobilelipidclinic.com/DesktopDefault.aspx. Accessed on January 17, 2007.4.

10. NCEP ATP III Risk Categories Risk CategoryCriteria Low risk0-1 risk factor Moderate risk ≥ 2 risk factors; 10-year risk <10% Moderately high risk ≥ 2 risk factors; 10-year risk 10%-20% High risk CHD or CHD risk equivalents; 10-year risk >20% Grundy SM, et al. Circulation. 2004;110:227-239.

11. Dyslipidemia  Presence of abnormal levels of blood lipids and lipoproteins 1  Diagnosed using fasting lipoprotein profile 1  Nearly 40% of US adults have LDL levels ≥130 mg/dL (borderline high or higher) 2 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Thom T, et al. Circulation. 2006;113:e85-e151.

12. Key Question Why do so many patients have high lipid levels? 1. Lack of screening and treatment by clinicians 2. Lack of effective medications 3. Lack of therapy adherence by patients 4. 1 and 3 5. All of the above Use your keypad to vote now! ?

13. Problem: Low Success Rates in Achieving Lipid Goals Pearson TA, et al. Arch Intern Med. 2000;160:459-467. % Patient Success Risk Groups

14. Problem: Patients’ Adherence to Statin Therapy Huser MA, et al. Adv Ther. 2005;22:163-171. Overall Persistence (%)

15. NCEP Guidelines in a Nutshell  Identify individuals at high risk of CV events:  10-year risk >20%  10-year risk 10%-20%  Start therapeutic lifestyle changes and/or medication  Adjust intensity of therapy to individual risk level  Monitor progress to goal lipid control Adherence is always a factor NCEP ATP III. JAMA. 2001;285:2486-2497. CV: cardiovascular

16. NCEP ATP III 2001 Thresholds for LDL-Lowering Therapy TLC (mg/dL) Consider Drug Therapy (mg/dL) Low Risk0-1 risk factor≥160 ≥190 (optional at 160-189) Moderate Risk  2 risk factors; 10-year risk <10% ≥130 ≥160 (optional at 130-159) Moderately High Risk  2 risk factors; 10-year risk 10%-20% ≥130 (optional at 100-129) High Risk CHD or CHD risk equivalents; 10-year risk >20% ≥100 ≥130 ≥100 (optional at <100) TLC: therapeutic lifestyle changes 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Grundy SM, et al. Circulation. 2004;110:227-239.

17. NCEP ATP III Thresholds: Update 2004  Very high-risk patients  LDL ≥100 mg/dL consider drug therapy  LDL goal <70 mg/dL a therapeutic option  Moderately high-risk patients  LDL goal <100 mg/dL a therapeutic option  High-risk and moderately high-risk patients  30%-40% reduction in LDL recommended  High-risk patients with high TG or low HDL levels  Consider fibrate or nicotinic acid  High-risk or moderately high-risk patients with lifestyle-related risk factors  Therapeutic lifestyle change regardless of LDL Grundy SM, et al. Circulation. 2004;110:227-239. TG: triglyceride

18. NCEP ATP III Therapeutic Goals for LDL Risk CategoryLDL Goal (mg/dL) Low risk 0 to 1 risk factor <160 Moderate risk  2 risk factors; 10-year risk <10% <130 Moderately high risk  2 risk factors; 10-year risk 10%-20% <130 (optional goal <100) High risk CHD or CHD risk equivalents; 10-year risk >20% <100 (optional goal <70, especially for very high-risk patients) 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Grundy SM, et al. Circulation. 2004;110:227-239.

19. New Optional Goal for High-Risk Patients  Persons with diabetes and CHD should be treated aggressively with statins, even if they are not otherwise at high risk  The first line of therapy should continue to be statins rather than fibrates (which are still useful in combination therapy) Risk CategoryLDL Goal (mg/dL) High risk CHD or CHD risk equivalents; 10-year risk >20% <77 Cheng AY, Leiter LA. Curr Opin Cardiol. 2006;21:400-404.

20. Importance of Individualized Dyslipidemia Management  Dyslipidemia is a complex disease caused by the interplay of genetic, dietary, and physiologic factors  Dyslipidemia often occurs concurrently with other medical conditions  Treatment strategy is evolving based on new data

21. Metabolic Syndrome Definitions: NCEP ATP III and IDF Components NCEP ATP III 1 ≥3 Components IDF 2 WC + ≥2 Components Waist circumference (WC) ≥102 cm (40˝) in men; ≥88 cm (35˝) in women Europid ≥94 cm (37˝) (men); ≥80 cm (31.5˝) (women) South Asians ≥90 cm (35.5˝) (men); ≥80 cm (31.5˝) (women) Japanese ≥90 cm (35.5˝) (men); ≥80 cm (31.5˝) (women) Triglycerides (mg/dL)≥150 HDL (mg/dL)<40 (men); <50 (women) BP (mm Hg)Systolic ≥130 or diastolic ≥85 Fasting plasma glucose (mg/dL) ≥100 1. Grundy SM, et al. Circulation. 2005;112:2735-2752. 2. International Diabetes Federation. Rationale for new IDF worldwide definition of metabolic syndrome. Available at http://www.idf.org/webdata/docs/Metabolic_syndrome_rationale.pdf. Accessed on February 3, 2007. IDF: International Diabetes Federation

22. Prevalence of Metabolic Syndrome: NHANES III 1988-1994 Percent Affected 20-2930-3940-4950-5960-6970+ Age (years) Ford ES, et al. JAMA. 2002;287:356-359. NHANES III: Third National Health and Nutrition Examination Survey

23. Metabolic Syndrome Prevalence by Race and Ethnicity % Affected Ford ES, et al. JAMA. 2002;287:356-359.

24. Pattern of Dyslipidemia in Type 2 Diabetes   Triglycerides   HDL  Qualitative changes in LDL  Higher proportion of smaller and denser LDL particles susceptible to oxidation and atherogenicity  Mean LDL levels not different in high-risk patients with or without diabetes, but important risk factor Haffner SM. Diabetes Care. 2004;27(suppl 1):S68-S71.

25. Prevalence of Dyslipidemia in Patients With Type 2 Diabetes Affected (%) Total C  200 mg/dL LDL-C  100 mg/dL HDL-C  40 mg/dL Triglycerides  150 mg/dL C: cholesterol Saaddine JB, et al. Ann Intern Med. 2006;144:465-474.

26. American Diabetes Association Lipid Treatment Goals  Decrease triglycerides to <150 mg/dL  Increase HDL to >40 mg/dL in men and >50 mg/dL in women Diabetes without overt CVDDiabetes with overt CVD LDL <100 mg/dL 30%-40% reduction with statin for patients >40 years, regardless of baseline LDL LDL <70 mg/dL an option 30%-40% reduction with statin therapy for all patients American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4-S42.

27. Therapeutic Lifestyle Changes  Adherence to 5 healthful lifestyles reduced coronary events by ≈62% in 16 years  Lifestyle changes reduced coronary events by 57% in men taking medications for HTN or dyslipidemia  Men who adopted 2 lifestyle changes had 27% lower risk than those who did not HTN: hypertension Chiuve SE, et al. Circulation. 2006;114:160-167. LIFESTYLE CHANGES  Eliminate tobacco exposure  Body mass index <25 kg/m 2  30 min/d physical activity  Limit alcohol use to 1-2 drinks/d  Top 40% of healthy diet score

28. Lifestyle Modifications  Physical activity  Get regular exercise  Reduce “screen time”; increase daily activity  Avoidance of tobacco  Weight control  Track weight and caloric intake  Reduce food portion size  Healthful diet Lichtenstein AH, et al. Circulation. 2006;114:82-96.

29. Dietary Modifications Improve Lipid Profiles  Limit intake of saturated fat, trans fat, and cholesterol 1  Choose lean meats, fish, and vegetable alternatives  Choose fat-free and low-fat dairy products  Limit intake of partially hydrogenated fats  Dietary changes can significantly decrease LDL 2 1. Lichtenstein AH, et al. Circulation. 2006;114:82-96. 2. Appel LJ, et al. JAMA. 2005;294:2455-2464.

30. Effects of Three Healthful Diets* on LDL Levels All (n = 161) Baseline mean = 129.2 mg/dL LDL ≥130 mg/dL (n = 75) Baseline mean = 156.7 mg/dL CARB PROT UNSAT CARB PROT UNSAT *Each diet: 6% saturated fat; <150 mg/d cholesterol; no trans fat. Appel LJ, et al. JAMA. 2005;294:2455-2464. mg/dL -25 -20 -15 -10 -5 0

31. Key Question What is your next step if lifestyle changes don’t decrease lipid levels to goal? 1. Use a bile acid sequestrant 2. Use a fibrate 3. Use a statin 4. Use niacin (nicotinic acid) 5. Use ezetimibe Use your keypad to vote now! ?

32. MRC/BHF Heart Protection Study Coronary Mortality Nonfatal MI Major Coronary Events Stroke Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. Reduction of Major Vascular Events (%) MI: myocardial infarction MRC/BHF: Medical Research Council/British Heart Foundation

33. ASCOT-LLA Trial Sever PS, et al. Lancet. 2003;361:1149-1158. Nonfatal MI + Fatal CHD Total CV Events Total Coronary Events Stroke ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm Reduction of Major Vascular Events (%)

34. Cholesterol Treatment Trialists’ (CTT) Meta-Analysis Baigent C, et al. Lancet. 2005;366:1267-1278. All-Cause Mortality Major Vascular Events Coronary Mortality Stroke Reduction in Incidence ( %)

35. Agents That Affect Lipid Metabolism 1,2 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Knopp RH, et al. Eur Heart J. 2003;24:729-741. Drug ClassLDL-CHDL-CTG Statins  18%-55%  5%-15%  7%-30% Bile acid sequestrants  15%-30%  3%-5% No change Nicotinic acid  5%-25%  15%-35%  20%-50% Fibric acids  5%-20%  10%-20%  20%-50% Ezetimibe  18%  1%  2%

36. NCEP ATP III Drug Therapy Progression NCEP ATP III. JAMA. 2001;285:2486-2497. 6 wk4-6 mo If goal not met, intensify drug therapy 6 wk If goal not met, intensify drug therapy or refer to lipid specialist Begin drug therapy to decrease LDL Continue to monitor response and adherence

37. Improving Patients’ Adherence  Simplify medication regimens  Prescribe fewer pills per day 1  Avoid medication switching 2  Help patients remember to take medications  Time pills with events like meals, bedtime 3  Recommend pill boxes, personal alarms  Teach patients about risks and benefits  Offer educational tools, brochures, Web sites  Use follow-up lipid tests to monitor progress 4 1. Iskedjian M, et al. Clin Ther. 2002;24:302-316. 2. Thiebaud P, et al. Am J Manag Care. 2005;11:670-674. 3. Branin JJ. Home Health Care Serv Q. 2001;20:1-16. 4. Benner JS, et al. Pharmacoeconomics. 2004;22(suppl 3):13-23.

38. Improving Patients’ Adherence  Medication adherence drops as costs rise 1  Ask if patients have prescription drug coverage  Identify generic or preferred drugs  Urge patients to raise cost problems over time  Depression can reduce adherence 2  Look for and ask about signs of depression  Treat and/or refer depressed patients for counseling 1. Shrank WH, et al. Arch Intern Med. 2006;166:332-337. 2. Stilley CS, et al. Ann Behav Med. 2004;27:117-124.

39. Share Decision Making  A patient-clinician partnership based on mutual respect and trust improves medication adherence  Ask patients how they understand their condition and the need to treat it  Listen and probe for perceived barriers  Customize your suggestions to their needs  Enlist family members as advocates Piette JD, et al. Arch Intern Med. 2005;165:1749-1755.

40. Case Study

41.  76-year-old white nonsmoking woman  History of hypertension, depression  Current medications:  Diltiazem 240 mg qd  Nefazodone 150 mg bid  Examination: Height 5′6″; weight 146 lb; BMI 23.6 kg/m 2 ; BP 139/82 mm Hg; pulse 72 bpm BMI: body mass index

42. Laboratory Results  Creatinine: 1.4 mg/dL  Lipid panel  Total cholesterol: 245 mg/dL  LDL: 156 mg/dL  HDL: 59 mg/dL  Triglycerides: 148 mg/dL

43. ATP III: Framingham Point Scores to Estimate 10-Year Risk Age Points 20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 -7 -3 0 3 6 8 10 12 14 16 SBP mm Hg If Untreated <120 120-129 130-139 140-159  160 0123401234 If Treated 0345603456 HDL mg/dL Points  60 50-59 40-49 <40 0 1 2 Total Cholesterol <160 160-199 200-239 240-279  280 0 4 8 11 13 0 3 6 8 10 0245702457 0123401234 0112201122 Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 NCEP ATP III. JAMA. 2001;285:2486-2497. Point Total 10-Year Risk, % <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  25 <1 1 2 3 4 5 6 8 11 14 17 22 27  30 Age 20-39 Nonsmoker Smoker 0909 Age 50-59 0404 Age 60-69 0202 Age 70-79 0101 Age 40-49 0707 Age 16 Total C 2 HDL-C 0 Systolic BP (SBP) 4 Smoking status 0 Point total 22

44. Decision Point What is this patient’s risk category? 1. High 2. Moderately high 3. Moderate 4. Either moderate or moderately high 5. Lower Use your keypad to vote now! ?

45. Therapeutic Considerations  Therapeutic lifestyle changes  First line of treatment  Include dietary modification, exercise, and weight control  Lipid-lowering medications 1,2  Statins are first line of drug treatment and significantly reduce risk of CVD and stroke 3-5  Other agents (eg, fibrates, niacin, ezetimibe) 1,2,6 1.Grundy SM, et al. Circulation. 2004;110:227-239. 2.Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E. 3.NCEP ATP III. JAMA. 2001;285:2486-2497. 4.Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. 5.Shepherd J, et al. Lancet. 2002;360:1623-1630. 6.Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463.

46. Therapeutic Considerations  Statins are effective and safe in the elderly 1-3  Monitor for side effects (liver, muscle) 1,4  Consider drug & food interactions 1,4  Consider liver and kidney function 1,4  Other agents (eg, fibrates, niacin) 1,5  Differences in tolerability among fibrates 1  Fibrates have different drug interactions than statins 1  Also consider liver and kidney function 1 1.Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463. 2.Helmy T, et al. Med Gen Med. 2005;7:8. 3.Pohlel K, et al. Curr Opin Lipidol. 2006;17:54-57. 4.Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E. 5.Rubins HB, et al. N Engl J Med. 1999;341:410-418.

47. Therapeutic Considerations  Drug interactions  Calcium channel blockers 1  Antidepressants 2  Others (eg, warfarin) 3  Comorbid conditions  Regular monitoring of hepatic, renal function  Decreased renal function 1. Herman RJ. CMAJ. 1999;161:1281-1286. 2. Karnik NS, Maldonado JR. Psychosomatics. 2005;46:565-568. 3. Treat Guidel Med Lett. 2005;3:15-22.

48. Special Populations  Women 1  CHD delayed 10 to 15 years versus men  Premature CHD risk associated with multiple risk factors and metabolic syndrome  Treatment approach should be similar for women and men  African Americans 1  Highest overall CHD mortality rate  Asian Indians 2,3  Increased risk of metabolic syndrome and CHD versus whites 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Misra A, Vikram NK. Curr Sci. 2002;83:1483-1494. 3. Enas EA, et al. Indian Heart J. 1996;48:343-353.

49. Conclusions  Improving patients’ adherence will improve clinical outcomes  Optimal results require both lifestyle and medical interventions  Lipid-lowering therapy must be tailored to the individual patient  Risk determines lipid goals  Comorbid conditions influence treatment

50. Q & A

51. PCE Takeaways

52. 1. Use risk calculation tools 2. Identify appropriate goals based on risk… and treat to goal! 3. Appreciate the unique profile of diabetic patients with dyslipidemia 4. Address common barriers to adherence and modify treatment regimen accordingly

53. Key Question How important are intravascular ultrasound data when conveying information linking medical treatment to atherosclerosis regression to patients? 1. Extremely important 2. Very important 3. Somewhat important 4. Not very important Use your keypad to vote now! ?