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Dyslipidemia and Cardiovascular Risk Reduction: An Evidence-Based Review

Dyslipidemia and Cardiovascular Risk Reduction: An Evidence-Based Review. Robert M. Guthrie, MD Professor of Emergency Medicine Professor of Internal Medicine Professor of Pharmacology The Ohio State University College of Medicine Columbus, Ohio. ?. Key Question.

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Dyslipidemia and Cardiovascular Risk Reduction: An Evidence-Based Review

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  1. Dyslipidemia and Cardiovascular Risk Reduction:An Evidence-Based Review Robert M. Guthrie, MD Professor of Emergency Medicine Professor of Internal Medicine Professor of Pharmacology The Ohio State University College of Medicine Columbus, Ohio

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

  3. Faculty Disclosure • Dr Guthrie: grants/research support: Abbot Laboratories, Boehringer-Ingelheim Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline; speakers bureau: AstraZeneca.

  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 20031 • Total US cost in 2006 = $403.1 billion1 • Associated with high blood levels of cholesterol and other lipids, and low HDL levels1 • Risk assessment, risk reduction1,2 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: 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 NCEP ATP III. JAMA. 2001;285:2486-2497.

  7. Major Risk FactorsOther 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. NCEP ATP III Risk Definitions NCEP ATP III. JAMA. 2001;285:2486-2497.

  9. Risk Assessment:Dyslipidemia and CVD • Framingham risk calculator1,2 • Based on age, sex, total and HDL cholesterol, smoking, BP • Mobile Lipid Clinic3 • Free NCEP ATP III–based tools • Palm® and Windows® • Reynolds risk calculator4 • For healthy women without diabetes 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. Reynolds Risk Score. Available at http://www.reynoldsriskscore.org/default.aspx. Accessed on February 23, 2007.

  10. NCEP ATP III Risk Categories Grundy SM, et al. Circulation. 2004;110:227-239.

  11. Dyslipidemia • Presence of abnormal levels of blood lipids and lipoproteins1 • Diagnosed using fasting lipoprotein profile1 • 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? • Lack of screening and treatment by clinicians • Lack of effective medications • Lack of therapy adherence by patients • 1 and 3 • All of the above Use your keypad to vote now!

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

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

  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 CV: cardiovascular NCEP ATP III. JAMA. 2001;285:2486-2497.

  16. NCEP ATP III 2001Thresholds for LDL-Lowering Therapy 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 TG: triglyceride Grundy SM, et al. Circulation. 2004;110:227-239.

  18. NCEP ATP IIITherapeutic Goals for LDL 1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Grundy SM, et al. Circulation. 2004;110:227-239.

  19. Review of Key Clinical Trials Conducted in 2005 • 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) 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 IDF: International Diabetes Federation 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.

  22. Prevalence of Metabolic Syndrome: NHANES III 1988-1994 Percent Affected 20-29 30-39 40-49 50-59 60-69 70+ Age (years) NHANES III: Third National Health and Nutrition Examination Survey Ford ES, et al. JAMA. 2002;287:356-359.

  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 CVD Diabetes 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 LIFESTYLE CHANGES • Eliminate tobacco exposure • Body mass index <25 kg/m2 • 30 min/d physical activity • Limit alcohol use to 1-2 drinks/d • Top 40% of healthy diet score HTN: hypertension Chiuve SE, et al. Circulation. 2006;114:160-167.

  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 cholesterol1 • 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 LDL2 • Lichtenstein AH, et al. Circulation. 2006;114:82-96. • 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 0 -5 -10 mg/dL mg/dL -15 -20 -25 *Each diet: 6% saturated fat; <150 mg/d cholesterol; no trans fat. Appel LJ, et al. JAMA. 2005;294:2455-2464.

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

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

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

  34. ASTEROID Trial • Intravascular ultrasound (IVUS) was used to assess coronary atherosclerosis • Rosuvastatin (40 mg/d) for 24 months decreased LDL by 53% and increased HDL by 15% • Significant regression of atherosclerosis was seen ASTEROID: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden Nissen SE, et al. JAMA. 2006;295:1556-1565.

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

  36. MERCURY II Trial • More high-risk patients reached their LDL target of <100 mg/dL with rosuvastatin (10 or 20 mg/d) than with atorvastatin (10 or 20 mg/d) or simvastatin (20 or 40 mg/d) • Likewise, more patients at very high risk reached their LDL goal of <70 mg/dL with rosuvastatin than with atorvastatin or simvastatin MERCURY II: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY Ballantyne CM, et al. Am Heart J. 2006;151:975.e1-975.e9.

  37. Other Lipid-Lowering Drugs • Fibrates can decrease triglycerides and increase HDL levels1-3 • Niacin (nicotinic acid) can also decrease triglycerides and increase HDL levels1-3 • Ezetimibe can further decrease LDL levels by selectively inhibiting intestinal absorption of cholesterol1,3 • Bile acid sequestrants may decrease LDL1-3 • Combination therapy may be effective1,3 1. Treat Guidel Med Lett. 2005;3:15-22. 2. NCEP ATP III. JAMA. 2001;285:2486-2497. 3. Grundy SM, et al. Circulation. 2004;110:227-239.

  38. NCEP ATP IIIDrug Therapy Progression 6 wk 6 wk 4-6 mo If goal not met, intensify drug therapy or refer to lipid specialist Continue to monitor response and adherence Begin drug therapy to decrease LDL If goal not met, intensify drug therapy NCEP ATP III. JAMA. 2001;285:2486-2497.

  39. Improving Patients’ Adherence • Simplify medication regimens • Prescribe fewer pills per day1 • Avoid medication switching2 • Help patients remember to take medications • Time pills with events like meals, bedtime3 • Recommend pill boxes, personal alarms • Teach patients about risks and benefits • Offer educational tools, brochures, Web sites • Use follow-up lipid tests to monitor progress4 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.

  40. Improving Patients’ Adherence • Medication adherence drops as costs rise1 • Ask if patients have prescription drug coverage • Identify generic or preferred drugs • Urge patients to raise cost problems over time • Depression can reduce adherence2 • 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.

  41. 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.

  42. Case Study

  43. Case Study • 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/m2; BP 139/82 mm Hg; pulse 72 bpm BMI: bodymassindex

  44. 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

  45. ATP III: Framingham Point Scores to Estimate 10-Year Risk SBP mm Hg If Untreated If Treated Age 20-39 Age40-49 Age50-59 Age60-69 Age70-79 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 <120 120-129 130-139 140-159 160 0 1 2 3 4 0 3 4 5 6 Nonsmoker Smoker 0 9 0 7 0 4 0 2 0 1 Point Total 10-Year Risk, % Age 16 Total C 2 HDL-C 0 Systolic BP (SBP) 4 Smoking status 0 Point total 22 <9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 <1 1 1 1 1 2 2 3 4 5 6 8 11 14 17 22 27 30 HDL mg/dL Points 60 50-59 40-49 <40 -1 0 1 2 Total Cholesterol Age 20-39 Age40-49 Age50-59 Age60-69 Age70-79 <160 160-199 200-239 240-279 280 0 4 8 11 13 0 3 6 8 10 0 2 4 5 7 0 1 2 3 4 0 1 1 2 2 NCEP ATP III. JAMA. 2001;285:2486-2497.

  46. ? Decision Point What is this patient’s risk category? • High • Moderately high • Moderate • Either moderate or moderately high • Lower Use your keypad to vote now!

  47. Therapeutic Considerations • Therapeutic lifestyle changes • First line of treatment • Include dietary modification, exercise, and weight control • Lipid-lowering medications1,2 • Statins are safe and effective,3-5 and significantly reduce risk of CVD and stroke6-8 • Other agents (eg, fibrates, niacin)9 6. NCEP ATP III. JAMA. 2001;285:2486-2497. 7. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. 8. Shepherd J, et al. Lancet. 2002;360:1623-1630. 9. Rubins HB, et al. N Engl J Med. 1999;341:410-418. 1. Grundy SM, et al. Circulation. 2004;110:227-239. 2. Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E. 3. Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463. 4. Helmy T, et al. MedGenMed. 2005;7:8. 5. Pohlel K, et al. Curr Opin Lipidol. 2006;17:54-57.

  48. Therapeutic Considerations • Drug interactions • Calcium channel blockers1 • Antidepressants2 • 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.

  49. Special Populations • Women1 • 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 Americans1 • Highest overall CHD mortality rate • Asian Indians2,3 • 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.

  50. 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

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