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Sheraton Miami Mart Hotel Miami, Florida April 5, 2008

Sheraton Miami Mart Hotel Miami, Florida April 5, 2008. 2008. Symposia Series 1. 1. 1. Targeting Hypertriglyceridemia to Reduce Cardiovascular Disease Risk: Understanding and Applying Emerging Science. Emma Meagher, MD Associate Professor of Medicine and Pharmacology

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Sheraton Miami Mart Hotel Miami, Florida April 5, 2008

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  1. Sheraton Miami Mart Hotel Miami, Florida April 5, 2008 2008 Symposia Series 1 1 1

  2. Targeting Hypertriglyceridemia to Reduce Cardiovascular Disease Risk: Understanding and Applying Emerging Science Emma Meagher, MD Associate Professor of Medicine and Pharmacology Vice Chief, Division of Experimental Therapeutics University of Pennsylvania School of Medicine Associate Director, Cardiovascular Risk Intervention Program University of Pennsylvania Health System Philadelphia, Pennsylvania

  3. 7 How likely are you to discuss hypertriglyceridemia as a cardiovascular risk in patients at risk for CVD? • Very likely • Likely • Somewhat likely • Not likely Use your keypad to vote now! CVD = cardiovascular disease.

  4. Dr Meagher has no relevant financial relationships with any commercial interests to disclose Faculty Disclosure

  5. Learning Objectives • Review lipid management guidelines, including target goals for LDL-C, HDL-C, and TGs • Define the significance of hypertriglyceridemia in the context of CVD and lipid metabolism • Select appropriate treatment for managing CVD risk in patients with hypertriglyceridemia HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride.

  6. Dyslipidemia • Dyslipidemia is a major risk factor for CHD, the leading cause of death in the United States1 • The World Health Organization estimates that dyslipidemia is associated with >50% of global ischemic heart disease cases and >4 million deaths per year2 CHD = coronary heart disease. 1. Smith DG. Am J Manag Care. 2007;13:S68-S71. 2. World Health Organization. The World Health Report. 2002;4:47-97.

  7. CVD Mortality • Dyslipidemia leads to atherosclerosis, a progressive disease and a leading cause of CVD morbidity and mortality Deaths per 100,000 National Heart, Lung and Blood Institute. Morbidity & Mortality: 1998 Chartbook on Cardiovascular, Lung, and Blood Diseases. Rockville, Maryland: US Department of Health and Human Services, National Institutes of Health, 1998.

  8. DyslipidemiaCan We Prevent This Cascade of Events? Complicated Lesions/Rupture Intermediate Lesions Fibrous Plaque Foam Cells Fatty Streak Atheroma From First Decade From Third Decade From Fourth Decade Growth Mainly by Lipid Accumulation Smooth Muscle and Collagen Thrombosis Hematoma Adapted from Pepine CJ. Am J Cardiol. 1998;82(Suppl. 10A);23S-27S..

  9. Major Statin Trials: CHD Events Occur in Patients Treated With Statins 28.0 19.4 Patients Experiencing Major CHD Events (%) 15.9 13.2 12.3 11.8 10.9 10.2 8.7 7.9 6.8 5.5 AFCAPS/ TexCAPS6 4S1 LIPID2 CARE3 HPS4 WOSCOPS5 4444 9014 4159 20 536 6595 6605 N -35% -25% -28% -29% -26% -25%  LDL-C Secondary High Risk Primary 1. 4S Group. Lancet. 1994;344:1383-1389; 2. LIPID Study Group. N Engl J Med. 1998;339:1349-1357; 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307; 6. Downs JR, et al. JAMA. 1998;279:1615-1622.

  10. Hypertriglyceridemia:Recognized Risk Factor for CVD • In 2002, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recognized hypertriglyceridemia as a risk factor for CVD and set treatment goals Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

  11. Serum TG Levels: NCEP/ATP III Goals and Cutpoints Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

  12. Treatment Objectives for Elevated TG Levels: NCEP Guidelines • High TG: At Risk for CHD • Primary objective: LDL-C reduction • Secondary objective: Non-HDL-C reduction TG 200-499 mg/dL • Very High TG: At Riskfor CHD, • Pancreatitis • Primary objective: TG reduction • Secondary objective: LDL-C and non–HDL-C reduction TG ≥500 mg/dL Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

  13. LDL-C and Non–HDL-C Goals in Patients With TG  200 mg/dL Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

  14. TG-rich lipoproteins Non–HDL-C Lipoprotein Particles Non–HDL-C = TC Minus HDL-C VLDL VLDLR IDL LDL Small, dense LDL Goal for non–HDL-C is 30 mg/dL higher than for LDL-C goal IDL = intermediate-density lipoprotein; TC = total cholesterol; VLDL = very low-density lipoprotein; VLDLR = very low-density lipoprotein remnant. Figure courtesy of Vera Bittner, MD, MSPH Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). NIH Publication No. 02-5215; September 2002.

  15. Lipoprotein Particle Quantity Is a Predictor of Risk Fewer Particles More Particles LDL= 130 mg/dL Apo B More Apo B Cholesterol Ester • Correlates with: • TC 198 mg/dL • LDL-C 130 mg/dL • TG 90 mg/dL • HDL-C 50 mg/dL • Non–HDL-C 148 mg/dL • Correlates with: • TC 210 mg/dL • LDL-C 130 mg/dL • TG 250 mg/dL • HDL-C 30 mg/dL • Non–HDL-C 180 mg/dL Apo = apolipoprotein. Adapted from Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

  16. Lipid MetabolismDyslipidemia and Particle Size: The Role of CETP Visceral Adiposopathy Renal Clearance Small,Dense HDL TG HDL Cholesterol Ester FFA TG CETP TG VLDL Lipases Small, Dense LDL CETP TG Cholesterol Ester Fatty Liver LDL Lipases TG CETP = cholesterol ester transfer protein; FFA = free fatty acid. Bays H, et al. Expert Opin Pharmacother. 2003;4:1901-1938.

  17. Case Study

  18. 54-Year-Old Man With Hypertension • Patient profile: a 54-year-old married white man. He is a retired chief executive who travels often and eats mostly at restaurants. For the past 5 years, he had hypertension that is now treated with amlodipine • Social history: He is a nonsmoker with a long-term weight problem, addressed with jogging, walking his dog regularly, and playing golf • Family history: Father died at a young age in a car accident; mother died in her 80s of cancer

  19. 54-Year-Old Man With Hypertension (cont’d) • Current medications • Amlodipine 5 mg/d • Sildenafil 50 mg prn • Physical findings • BMI: 28 kg/m2 • Waist circumference: 41 in (104 cm) • Blood pressure: 150/88 mm Hg • Lipid profile • TC: 220 mg/dL • HDL-C: 36 mg/dL • LDL-C: 122 mg/dL • TG: 310 mg/dL BMI = body mass index.

  20. 7 Would you use Framingham risk scoring to assess this patient’s CVD risk? • Yes • No Use your keypad to vote now!

  21. 7 Which of the following criteria are used to measure CVD risk using Framingham risk scoring? • BMI • Family history • Serum LDL-C level • Serum TG level • TC • Waist circumference Use your keypad to vote now!

  22. 7 What is this patient’s risk* for any CV event in the next 10 years? • 5% • 10% • 12% • 25% • ≥30% Use your keypad to vote now! *Based on Framingham risk scoring.

  23. Framingham Risk Scoring (Men) Step 1: Age (y) Step 2: TC Step 3: HDL-C Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.

  24. Framingham Risk Scoring (Men) (cont’d) Step 4: Systolic Blood Pressure Step 7: Calculate Risk of CHD Step 5: Smoking Status Step 6: Add Up thePoints BP = blood pressure. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.

  25. 7 Which of the following would you consider as the first choice to add to this patient's regimen? • Bile acid sequestrant • Ezetimibe • Fenofibrate • Niacin • Prescription omega-3 fatty acids • Statin Use your keypad to vote now!

  26. Treatment Decision • The patient has a Framingham risk score of 13, which is associated with a 10-year risk of 12% • Patient was started on atorvastatin 20 mg daily and a low-fat diet • More aggressive management of his high TG level and low HDL-C level is indicated • Patient’s blood pressure also remains elevated and HCTZ 25 mg daily was added. Continued exercise, low-fat diet, and lifestyle modification were reinforced HCTZ = hydrochlorothiazide.

  27. TGs and CVD Risk • There is evidence that high levels of TGs are associated with increased CVD risk

  28. The Framingham Heart Study: Risk of CHD Increases With TG Level Men Women 3 2.5 2 Relative CHD Risk 1.5 1 0.5 0 400 50 100 150 200 250 300 350 N = 5127 patients with no history of CHD. TG Level (mg/dL) Castelli WP. Am J Cardiol. 1992;70:3H-9H.

  29. The Münster Study: A Prospective Study of CHD Risk (PROCAM) Low Levels of HDL-C Significantly Increase CHD Risk Elevated Levels of TG Significantly Increase CHD Risk TG HDL-C Relative CHD Risk HDL-C (mg/dL) TG (mg/dL) 8-year follow-up of 4639 men with no history of myocardial infarction or stroke Assmann G, et al. Am J Cardiol. 1996;77:1179-1184.

  30. Plasma TG Levels Correlate to CAD Risk TG Levels (adjusted for HDL) Are Independently Associated With Premature Familial CAD* *TG odds ratio adjusted for HDL-C as a continuous variable. 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.

  31. TGs and Pancreatitis • Hypertriglyceridemia is a risk factor for pancreatitis • 12% to 38% of patients presenting with acute pancreatitis had markedly elevated TG levels Toskes PP. Gastroenterol Clin North Am. 1990;19:783-791.

  32. Case Study

  33. 60-Year-Old Woman With Type 2 Diabetes and a History of Chronic Pancreatitis • Patient profile: 60-year-old woman with well-controlled type 2 diabetes of 3 years’ duration and a history of chronic pancreatitis presents for a new patient examination • Social history: She smokes 1 pack/day and drinks alcohol moderately

  34. 60-Year-Old Woman WithType 2 Diabetes and a History of Chronic Pancreatitis (cont’d) • Current medications • Amlodipine 5 mg • Glipizide 10 mg • Metformin 1000 mg BID • Simvastatin 40 mg • Physical findings • BMI: 36 kg/m2 • Waist circumference: 41 in (104 cm) • Blood pressure: 141/90 mm Hg • Lipid profile • TC: 250 mg/dL • HDL-C: 36 mg/dL • LDL-C: 100 mg/dL • TG: 570 mg/dL

  35. 7 What is her risk* for any CV event in the next 10 years? • 2% • 8% • 17% • 22% • ≥30% Use your keypad to vote now! *Based on Framingham risk scoring.

  36. 7 Which of the following are monotherapies for hypertriglyceridemia? • Fenofibrates • Niacin • Prescription omega-3 fatty acids • Statins • All of the above Use your keypad to vote now!

  37. 7 Which of the following would you consider adding to this patient's regimen? • Fenofibrates • Niacin • Pravastatin • Prescription omega-3 fatty acids Use your keypad to vote now!

  38. 3-Month Follow-up • Patient was treated with prescription omega-3 fatty acids, 3 g daily for 3 months • Continued statin treatment at same dose • Compliant with low-fat diet and lost 10 pounds • Diabetes remained under control • Blood pressure improved to 135/85 mm Hg • Lipid profile at 3-month follow-up: TC: 210 mg/dL; HDL: 36 mg/dL; LDL: 103 mg/dL; TG: 355 mg/dL

  39. Omega-3 fatty acid Control Omega-3 fatty acid Control Omega-3 fatty acid Control Omega-3 fatty acid Control GISSI-Prevenzione Study:Effects of Omega-3 Fatty Acids on Serum Lipids LDL-C TC mg/dL mg/dL HDL-C TG mg/dL mg/dL 0 6 12 18 30 42 0 6 12 18 30 42 Months Months Marchioli R, et al. Circulation 2002;105:1897-1903.

  40. GISSI-Prevenzione Study: Effects of Omega-3 Fatty Acids on All-Cause Mortality 1.00 0.99 Omega-3 fatty acids 0.98 Probability of Survival 0.97 0.59 (95% CI = .36-.97)P = .037 Control 0.96 0.95 150 30 120 360 0 180 210 270 330 90 240 300 60 Days Marchioli R, et al. Circulation. 2002;105:1897-1903.

  41. Effects on VLDL Triglyceride Metabolism: Prescription Omega-3 + + LPL Cholesterol Triglyceride FFA IDL VLDL LDL P-OM3 FFA Adipose Chylomicrons LPL FFA = free fatty acid; LPL = lipoprotein lipase. Adapted with permission from Dunbar RL, Rader DJ. Cleve Clin J Med. 2005;72:661-680. Chylomicron remnants

  42. Combination Therapies for Hypertriglyceridemia • Niacin + statin • Fibrates + statin • Prescription omega-3 fatty acids + statin

  43. COMPELL Study:Niacin ER/Statin Combination Therapy N = 292; 12 weeks *P <.05 vs atorvastatin + niacin ER Atorvastatin 40 mg + niacin ER 2 g Rosuvastatin 20 mg + niacin ER 1 g Simvastatin 40 mg + ezetimibe 10 mg * Rosuvastatin 40 mg * Change From Baseline (%) * * TG Lp(a) LDL-C HDL-C Lp(a) = lipoprotein A. McKenney JM, et al. Atherosclerosis. 2007;192:432-437.

  44. SAFARI Study:Fenofibrate + Statin Combination Therapy * Change from baseline (%) * * * HDL-C VLDL-C LDL-C TG N = 618*P <.001 vs simvastatin. Grundy SM , et al. Am J Cardiol. 2005;95:462-468.

  45. JELIS Study: Prescription Omega-3 Fatty Acids + Statin Reduce Major Coronary Events 4% P =.011 The primary end point was significantly lower in the EPA + statin group compared with the statin-only group a 19% reduction 3.5% 3% 2.8% Major coronary events* 2% 1% Statin only(n = 9319) EPA + statin(n = 9326) 0% *Sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and coronary artery bypass graft/percutaneous coronary intervention; mean follow-up 4.6 years EPA = eicosapentaenoic acid. Yokoyama M, et al. Lancet 2007;369:1090-1098.

  46. COMBOS Study:(COMBination of Prescription Omega-3s and Simvastatin) Placebo + simvastatin 40 mg/d P-OM3 4 g/d + simvastatin 40 mg/d Non- HDL-C 5 LDL-C HDL-C Apo B VLDL-C TG 0 0.7 3.4* –1.2 –2.2 –1.9 –5 –2.8 –4.2† –6.3 –7.2 –10 –9.0* Median Change From Baseline (%) Additional changes to baseline simvastatin therapy –15 –20 –25 –27.5* –29.5* –30 P-OM3 is not indicated for the treatment of TGs from 200-499 mg/dL in combination with a statin *P <.0001 between groups; †P = .023 between groups Davidson MH, et al. Clin Ther. 2007;29:1354-1367.

  47. Q & A 57

  48. PCE Takeaways

  49. PCE Takeaways • Hypertriglyceridemia is an important CVD risk factor • Patients who are at LDL-C goal with statin therapy and still have hypertriglyceridemia remain at increased risk for CVD • Niacin, fibrates, and prescription omega-3 fatty acids are approved agents for lowering TG levels • Studies have shown that combination therapies using niacin + statin, omega-3 fatty acids + statin, and fibrates + statin are effective at reducing TG levels

  50. 7 How likely will you be to discuss hypertriglyceridemia as a cardiovascular risk in your patients at risk for CVD? • Very likely • Likely • Somewhat likely • Not likely Use your keypad to vote now! CVD = cardiovascular disease.

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