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Hypertriglyceridemia and Cardiovascular Disease Management: The Role of Omega-3 Fatty Acids . William S. Harris, PhD Research Professor of Medicine Sanford School of Medicine University of South Dakota Director, Nutrition and Metabolic Disease Research Institute
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Hypertriglyceridemia and Cardiovascular Disease Management: The Role of Omega-3 Fatty Acids William S. Harris, PhD Research Professor of Medicine Sanford School of Medicine University of South Dakota Director, Nutrition and Metabolic Disease Research Institute Sanford Research/University of South Dakota Sioux Falls, South Dakota
? Key Question How often do you recommend omega-3 fatty acids as treatment for your patients with hypertriglyceridemia? • Frequently • Sometimes • Seldom • Never Use your keypad to vote now!
Faculty Disclosure • Dr Harris:advisor, grants/research support: Monsanto Company; advisor, grants/research support, speakers bureau: Reliant Pharmaceuticals, Inc.; scientific advisor: OmegaMetrix, LLC.
Learning Objectives: Hypertriglyceridemia • Discuss the etiology of hypertriglyceridemia and its potential impact on CVD outcomes • Develop treatment plans to help patients achieve LDL-C, HDL-C, and triglyceride targets through diet, exercise, and drug therapy • Assess the role of omega-3 acid ethyl esters in management of hypertriglyceridemia with regard to efficacy, safety, and concomitant drug use
? Key Question How confident are you in understanding the importance of hypertriglyceridemia in assessing cardiovascular risk? • Very confident • Somewhat confident • Not confident Use your keypad to vote now!
Cardiovascular Disease (CVD): No. 1 Cause of Mortality in US Men and Women Deaths in Thousands, 2002 COPD = coronary obstructive pulmonary disease. American Heart Association. Heart Disease and Stroke Statistics—2005 Update.
Assessing CVD Risk:The Cornerstone of Treatment • Risk factors often cluster in predisposed individuals • CVD risk increases along with the number of abnormalities • Identification of 1 risk factor should prompt the search for others and signal initiation of proactive, aggressive risk-reduction strategies NCEP ATP III. JAMA. 2001;285:2486-2497.
Framingham Point System for Grading Cardiovascular Risk • Risk score based on sum of graded risk factors that defines a 10-year hard CHD (myocardial infarction + CHD death) risk percentage • 10-year risk subcategories: >20% High Moderate 10%-20% <10% Low CHD = coronary heart disease. NCEP ATP III. JAMA 2001;285:2486–2497.
Dyslipidemias Are Risk Factors for CVD Hypertriglyceridemia Elevated LDL Small, dense LDL Atherosclerosis Low HDL Diabetes Hypertension Insulin resistance EndothelialDysfunction Hyperinsulinemia Hypercoagulability Visceral adiposity HDL = high-density lipoprotein; LDL = low-density lipoprotein. Deedwania PC. Am J Med. 1998;105:1S-3S.
Dyslipidemias Are Prominent in Metabolic Syndrome* * Diagnosis is established when ≥3 of these risk factors are present. NCEP ATP III. JAMA. 2001;285:2486-2497.
? Key Question How do the NCEP ATP III guidelines categorize a TG range of 150-199 mg/dL? • Very high • Borderline high • Normal • Low-normal Use your keypad to vote now! NCEP ATP III. JAMA. 2001;285:2486-2497.
TG (mg/dL) <150 Normal 150-199 Borderline high 200-499 High ≥500 Very high ATP III Lipid Classifications • Total cholesterol (mg/dL) <200 Desirable 200-239 Borderline high ≥240 High • LDL (mg/dL) <100 Optimal 130-159 Borderline high 160-189 High • HDL (mg/dL) <40 (M) Low <50 (F) Low ≥60 High NCEP ATP III. JAMA. 2001;285:2486-2497.
? Key Question Elevated TGs at a level requiring intervention present a particular risk for which of the following groups? • Women • Male athletes with no significant family history • Individuals with a family history of early heart disease • Women using oral contraceptives Use your keypad to vote now!
Elevated Triglycerides Increase CHD Risk Framingham Heart Study 2.5 Women 2.0 Men 1.5 Relative Risk for CHD 1.0 0.5 0.0 50 100 150 200 250 300 350 400 TGs in VLDL and IDL For every increase in serum TG level of 89 mg/dL, risk of CHD increases 30% in men and 69% in women2 Meta-analysis of 17 prospective studies VLDL = very low density lipoproteins, IDL = intermediate density lipoprotein. 1. Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. 2. Hokanson JE. Curr Cardiol Rep. 2002;4:488-493.
Increased Risk From TG Is Independent of HDL 17.2 Triglycerides (mg/dL) 18 16 <200 14 200-299 12 ≥300 Odds Ratio 10 7.9 8 6.7 6.1 5.7 6 4.3 3.7 3.1 4 2.2 1.3 1.0 1.1 2 0 <30 30-39 40-49 50+ HDL (mg/dL) TG levels associated with CAD risk are graded and independent. Lipids analyzed from 653 patients with premature familial CAD and 1029 control subjects. Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012.
HDL-C and Coronary Artery Disease Risk 3.0 2.5 2.0 Relative Risk 1.5 25 1.0 45 0.5 65 HDL-C(mg/dL) 85 0.0 100 160 220 LDL-C (mg/dL) Data from Framingham Heart Study (Men) Kwiterovich PO. Am J Cardiol. 1998;82:13Q-21Q.
Lipid Profile Guidelines • Patients with multiple risk factors are candidates for intensified therapy (LDL <100 mg/dL) • Diabetes, aortic aneurysm, symptomatic carotid disease, and peripheral vascular disease are coronary risk equivalents • Complete lipid profile (TC, LDL, HDL, TG) is the preferred initial test • More frequent tests for persons with multiple CHD risk factors • Recommend treatment beyond LDL lowering for TG >199 mg/dL NCEP ATP III. Circulation. 2002;106:3143-3421.
Treating Dyslipidemias:An Overview • Stratify patient’s risk for CVD • Treat individual abnormalities aggressively and proactively • Target therapy toward: • Reducing acquired causes through diet and lifestyle modifications • Treating associated lipid- and non–lipid-based CVD risk factors with lifestyle modifications and pharmacotherapy NCEP ATP III. JAMA. 2001;285:2486-2497.
Pharmacotherapy Commonly Used to Reduce CVD Risk and/or Alter Risk Factors
? Key Question Why do patients continue to have dyslipidemia despite efforts to manage blood lipid levels? • Patients don’t adhere to prescribed treatments • Managed care formulary restraints • Reluctance to use combination therapy • Available treatments are not adequate to control the range of blood lipids • All of the above Use your keypad to vote now!
Hypertriglyceridemia and Risk Management • Causes • Efficacy of pharmacotherapy • Treatment strategies • Role of omega-3 acid ethyl esters
TG-Rich Particles Chylomicron • Non-HDL-C = • total cholesterol – HDL • 2. Non-HDL-C is the sum of all the atherogenic particles VLDL IDL LDL HDL
Secondary Causes Diabetes mellitus Chronic renal failure Nephrotic syndrome Cushing’s disease Lipodystrophy Pregnancy Medication use (eg, corticosteroids, beta-blockers, retinoids, thiazide diuretics, antiretroviral therapy) Causes of Elevated TG Levels • Acquired Causes • Overweight/obesity • Physical inactivity • Smoking • Excess alcohol intake • High carbohydrate intake (>60% of total energy) NCEP ATP III. Circulation. 2002;106:3143-3421.
? Key Question Results of studies have shown that statins can reduce TG levels on average by what percentage? • ≤30% • ≤55% • >60% Use your keypad to vote now! NCEP ATP III. Circulation. 2002;106:3143-3421.
Efficacy of Pharmacotherapy *Administer with caution due to risk of myopathy and rhabdomyolysis. • NCEP ATP III. Circulation. 2002;106:3143-3421; 2. Wierzbicki AS et al. Curr Med Res Opin. 2003;19:155-168.
What Are the Different Types of Treatment That Can Lower Serum TG? • Prescription drugs • Require a prescription • Over-the-counter (OTC) drugs • FDA considers them safe and effective for use without a prescription to treat a medical problem • Dietary supplement • Product taken by mouth that contains a "dietary ingredient" intended to supplement the diet; does not require a prescription www.fda.gov/cder/drugsatfda/glossary.htm#OTC; www.cfsan.fda.gov/~dms/supplmnt.html.
Fibrates Can Lower TG Levels and Increase HDL • How do fibrates work? • Activate transcriptional factors critical for lipid metabolism (peroxisome proliferator-activated receptor alpha [PPAR-α]) • Benefit: reduce cardiovascular event rates in high-risk patients1 with: • Low LDL (<125 mg/dL) or • Combined dyslipidemia (LDL >125 + TG >200) or • Typical diabetic or metabolic syndrome dyslipidemias • Fenofibrate combinations: • With statins in patients with high TG or low HDL once LDL is at goal.2 • With ezetimibe in patients intolerant of statins 1. Robins et al. Diabetes Care. 2003;26:1513-1517; 2. Grundy SM et al. Circulation. 2004;110:227-239.
Niacin for Lipid Management • Raises HDL-C levels and reduces CHD risk, used alone or in combination with statins1-3 • Recommended by NCEP ATP III in combination with statins for patients with high TG or low HDL4 • Side effects include flushing, dizziness, palpitations, tachycardia, gout, hyperglycemia, and nausea 1. Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255; 2. Bays HE et al. Am J Cardiol.2003;91:667-672; 3. Brown BG et al. N Engl J Med. 2001;345:1583-1592; 4. Grundy SM et al. Circulation. 2004;110:227-239.
Omega-3 Acid Ethyl Esters:How Do They Lower TG? • How do they work? • Inhibit synthesis of VLDL and TG in the liver • Increase rate of hepatic fatty acid oxidation • Benefit • Reduce serum TG; lower risk of cardiac sudden death and all-cause mortality; mildly lower BP; reduce inflammatory and thrombotic risk • How used? • 1-4 g/d by mouth, alone or combined with statin; no drug interactions or clinically important adverse effects Berge RK et al. Biochem J. 1999;343:191-197; Covington MB. Am Fam Physician. 2004;70:133-140. Ren B et al. J Biol Chem. 1997;272:26827-26832; Madsen L et al. Lipids. 1999;34:951-963; Willumsen N et al. J Lipid Res. 1993;34:13-22;Harris WS et al. Am J Clin Nutr. 1997;66:254-260; Lu G et al. J Nutr Biochem. 1999;10:151-158.
Omega-3 Acid Ethyl Ester Dosing • 1 g omega-3 acid ethyl ester capsule contains:465 mg EPA + 375 mg DHA • Dose for hypertriglyceridemia (>499 mg/dL) • 4 g: 4 capsules once a day or 2 capsules twice a day with or without meals DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid. Available at: www.omacorrx.com/HCP-OMACOR/OMACOR_Dosing.html. Accessed February 13, 2007.
Clinical Benefits of Omega-3 Fatty Acids Evidence supports use: • Hypertriglyceridemia (2-4 g/d) • Secondary CVD prevention (fish oil capsules) • Rheumatoid arthritis (mild effect) • Hypertension (mild effect) Covington MB. Am Fam Physician. 2004;70:133-140.
? Key Question The NCEP ATP III guidelines recommend drug intervention to reduce TG levels at which level of risk? • Very high ≥500 mg/dL • High 200-499 mg/dL • Borderline high 150-199 mg/dL • Normal <150 mg/dL Use your keypad to vote now! NCEP ATP III. Circulation. 2002;106:3143-3421.
GISSI-Prevenzione Trial (n = 11,324 post-MI)Early Effect on All-Cause Mortality 1.00 Omega-3 Acid Ethyl Esters (850 mg/d) 0.99 0.98 Probability 0.97 0.59 (95% CI, 0.36-0.97) P = .037 Control 0.96 0.95 30 120 360 150 0 90 180 210 270 330 60 240 300 Days Marchioli R et al. Circulation. 2002;105:1897-1903.
NCEP ATP III Definitions of Patient Risk Categories Based on Fasting TG Level National Institutes of Health. 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). NIH Publication No. 02-5215. Bethesda, Md: National Institutes of Health; 2002:VII-3-VII-5, Appendix III-A.
American Heart Association Recommendations Kris-Etherton et al. Circulation. 2002;106:2747-2757.
American Heart Association Evidence-Based Guidelines for Prevention of CVD in Women: 2007 Update • As many as 20% of all coronary events in women occur in the absence of traditional risk factors • Clinical recommendations • As an adjunct to diet, omega-3 fatty acids in capsule form (approximately 850-1000 mg EPA and DHA) may be considered in women with CHD • Higher doses (2-4 g) may be used for treatment of women with high TG levels Ridker PM et al. JAMA. 2007; 297:611-619.
Omega-3 Acid Ethyl Esters Improve the Lipid Profile in Patients With High TG on Simvastatin Simvastatin 10-40 mg/d (average 32 mg/d) NS 350-401 128-164 P <.025* P <.025 P <.0005 P <.005 *after 48 weeks (NS after 24 weeks) Durrington PN et al. Heart. 2001;85:544-548.
NCEP ATP III Recommendations and ADA Standards of Care for Treating Dyslipidemias • Consider adding a fenofibrate, omega-3 acid ethyl esters, or niacin in patients with elevated TG or low HDL after patient has achieved the LDL goal with statin therapy • Combination therapy using statins and other lipid-lowering agents may be necessary ADA. Diabetes Care. 2007;30:S4-S41. Grundy SM et al. Circulation. 2004;110:227-239.
Focused Treatment for Hypertriglyceridemia NCEP ATP III. Circulation. 2002;106:3143-3421.
Focused Treatment for Hypertriglyceridemia (cont’d) NCEP ATP III. Circulation. 2002;106:3143-3421.
Summary: Omega-3 Fatty Acids and Hypertriglyceridemia • Omega-3 fatty acids from fish protect against heart disease • A dose of 4 g/d (acid ethyl esters) effectively lowers TG • Can be safely combined with statins • Have no known drug-drug interactions • May prolong bleeding time in some patients • Are not contaminated with mercury • Endorsed by the American Heart Association Covington MB. Am Fam Physician. 2004;70:133-140.
Case Study 1 • Woman aged 63 years with a history of hypertension and hypercholesterolemia • Current medications: ramipril 10 mg/d; simvastatin 40 mg/d • BMI 33; waist 36 inches; BP 128/82 mm Hg • FBS, TSH: normal • Blood lipids • Total cholesterol: 165 mg/dL • HDL: 35 mg/dL • LDL: 100 mg/dL • TG: 392 mg/dL FBS = fasting blood sugar; TSH = thyroid-stimulating hormone.
Case Study 1 (cont’d) • Framingham score • 4% if nonsmoker • 8% if smoker • Does hypertriglyceridemia present a particular risk to this patient? • Is pharmacotherapy warranted?
? Decision Point How would you modify treatment to focus management of the patient’s persistent dyslipidemia? • Add gemfibrozil • Add fenofibrate • Add niacin • Add omega-3 acid ethyl esters • Advise diet modification and exercise only Use your keypad to vote now!
Case Study 2 • Man aged 40 years; father had MI at age 40 • BMI 25 kg/m2; waist 34 in; BP 126/82 mm Hg • EBCT: calcium score 125 • Thallium stress test: small, reversible abnormality of inferior wall • FBS and TSH: normal • Patient had severe flushing and gout with niacin-ER, backache with simvastatin EBCT = electron beam computed tomography.
Case Study 2 (cont’d) • Total cholesterol: 177 mg/dL • HDL: 27 mg/dL • LDL: 120 mg/dL • TG: 151 mg/dL
? Decision Point Which of the following would you advise to manage his dyslipidemia and improve his cardiovascular risk profile? • Gemfibrozil • Fenofibrate • Omega-3 acid ethyl esters • Fenofibrate/ezetimibe • Fenofibrate/omega-3 acid ethyl esters • Ezetimibe/low dose statin Use your keypad to vote now!