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  1. 1. Mixed Dyslipidemia – Attenuating risk- treatment beyond LDL. Michael Davidson, MD Executive Medical Director Radiant Research; Director Preventive Cardiology Center; Professor of Medicine Rush University Medical Center Chicago, IL. Christie Ballantyne, MD Professor of Atherosclerosis and Lipoprotein Research; Director Center for Cardiovascular Disease Prevention Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, TX.
  2. 2. Residual Cardiovascular Risk in Major Statin Trials 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. 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.  LDL-C N 4444 4159 20 536 6595 6605 9014 -35% -28% -29% -26% -25% -25% Secondary High Risk Primary Patients Experiencing Major CHD Events, % 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/ TexCAPS 6 19.4 12.3 10.2 8.7 5.5 6.8 28.0 15.9 13.2 11.8 7.9 10.9 CHD events occur in patients treated with statins
  3. 3. HDL-C* (mg/dL) Major CVD Events, % Patients With LDL-C ≤ 80 mg/dL on Atorvastatin 80 mg n = 4874 *On-treatment level (3 months) Barter P, et al. Poster ACC. 2006. Abstract 914-203. ≤ 40 41-50 51-60 >60 P < 0.0001 for Inverse Relationship Treating to New Targets (TNT) Study Low HDL-C Increases CVD Risk Even if LDL-C Levels Are Well-Controlled
  4. 4. <ul><li>Pathophysiology </li></ul><ul><li>Patients with high triglycerides: </li></ul><ul><li>Increase in VLDL remnants </li></ul><ul><li>Increase in IDL </li></ul><ul><li>Small, dense LDL </li></ul><ul><li>Lp-PLA2 and Apo-CIII - pro-atherogenic </li></ul><ul><li>Even on statins – these patients have increased risk </li></ul><ul><li>What is optimum TG level? </li></ul><ul><li>Guidelines : < 150 </li></ul><ul><li>In patients with coronary disease, worsening disease, recurrent symptoms, <100 may be optimal. </li></ul><ul><li>TG/HDL Ratio = 3.5 </li></ul>Lp-PLA2: lipoprotein-associated phospholipase A2 APO-CIII: Apolipoprotein CIII
  5. 5. <ul><li>Beyond LDL as a Target </li></ul><ul><li>Addressed in guidelines as concept of &quot;non-HDL-cholesterol&quot; </li></ul><ul><li>Not a new concept: Helsinki Heart Study of 1987 entry criteria was high levels of non-HDL-C 1 </li></ul><ul><li>Target non-HDL < 100 (but not routinely on lab request slip) </li></ul><ul><li>ADA Expert Panel: Patients with type 2 diabetes and other risk factors should also have non-HDL < 100; apoB goal < 90 mg/dl, LDL particle number < 1000 2 </li></ul>1. Frick et al. N Engl J Med. 1987;317:1237-1245. 2. Brunzell et al. Diabetes Care 31: 811-822
  6. 6. Non–HDL-C Superior to LDL-C in Predicting CHD Risk Liu J, et al . Am J Cardiol. 2006;98:1363-1368. Non–HDL-C, mg/dL Relative CHD Risk LDL-C, mg/dL <ul><li>Within non-HDL-C levels, no association was found between LDL-C and the risk for CHD. </li></ul><ul><li>In contrast, a strong positive and graded association between non–HDL-C and risk for CHD occurred within every level of LDL-C </li></ul><ul><li>Non–HDL-C is a stronger predictor of CHD risk than LDL-C </li></ul>
  7. 7. Residual CVD Risk in Patients Treated With Intensive Statin Therapy Standard statin therapy Intensive high-dose statin therapy PROVE IT-TIMI 22 1 IDEAL 2 TNT 3 N LDL-C,* mg/dL 1 Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. 2 Pedersen TR, et al. JAMA. 2005;294:2437-2445. 3 LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435. 4162 8888 10 001 95 *Mean or median LDL-C after treatment 62 104 81 101 77 26.3 13.7 10.9 12.0 22.4 8.7 Patients Experiencing Major CVD Events, %
  8. 8. Statin/ Fibrate Combination Therapy: Pharmacokinetic Interactions Backman JT, et al. Clin Pharmacol Ther . 2002;72:685-691. Abbott Laboratories. Data on file; 2005. Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-1287. Martin PD, et al. Clin Ther . 2003;25:459-471. Bergman AJ, et al. J Clin Pharmacol . 2004;44:1054-1062. Backman JT, et al. Clin Pharmacol Ther. 2005;78:154-67. TriCor [PI]. Abbott Laboratories;2004. Kyrklund C, et al. Clin Pharmacol Ther . 2001;69:340-345. Pan W-J, et al. J Clin Pharmacol . 2000;40:316-323. Backman JT, et al. Clin Pharmacol Ther . 2000;68:122-129 . Gemfibrozil Fenofibrate Atorvastatin  in C max by 2.7-fold No effect Simvastatin  in C max by 2-fold No effect Pravastatin  in C max by 2-fold No effect Rosuvastatin  in C max by 2-fold No effect Fluvastatin No effect No effect Lovastatin  in C max by 2.8-fold No effect Cerivastatin  in C max by 2-3 – fold No effect
  9. 9. <ul><li>New agent : ABT-335 is being studies in combination with simvastatin and with atorvastatin. Study results at ACC 08 - good efficacy and safety in lowering TG and raising HDL </li></ul><ul><li>Good safety data for extended-release niacin plus statins but some adherence/dose titration issues </li></ul><ul><li>In patients with high/very high TG, and poorly controlled diabetes, fenofibrate or fenofibrate plus omega-3 fatty acids may be better choice </li></ul><ul><li>Other benefits of fenofibrate on small vessels disease </li></ul><ul><li>SEACOAST data: niacin raises HDL independent of TG level </li></ul><ul><li>Fenofibrate requires TG to be high to raise HDL </li></ul><ul><li>Generally, men tolerate niacin better than women </li></ul>
  10. 10. <ul><li>AIM HIGH: Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes 1 </li></ul><ul><li>ER niacin plus simvastatin vs simvastatin alone at comparable levels of on-treatment LDL-C </li></ul><ul><li>n = 3,300 </li></ul><ul><li>Completion Q3, 2010 </li></ul><ul><li>HPS2-THRIVE: A Randomized Trial of the Long-Term Clinical Effects of Raising HDL Cholesterol With Extended Release Niacin/Laropiprant 2 </li></ul><ul><li>Participants have established CVD and receive LDL lowering therapy (40 mg of simvastatin or 10/40 mg ezetimibe/simvastatin) </li></ul><ul><li>Laropiprant - selective prostaglandin D2 receptor-1 (DP1) antagonist -reduces frequency and intensity of niacin-induced flushing </li></ul><ul><li>n = 20,000 </li></ul><ul><li>Completion Q4, 2011 </li></ul>1. http://clinicaltrials.gov/ct/show/NCT00120289 2. http://www.controlled-trials.com/ISRCTN29503772
  11. 11. <ul><li>ACCORD: Action to Control Cardiovascular Risk in Diabetes </li></ul><ul><li>Clinical benefit of adding fenofibrate to patients receiving simvastatin therapy </li></ul><ul><li>n = 5,900 Completion Q3, 2009 </li></ul><ul><li>FIRST: The effects of Fenofibrate on cIMT in patients with Residual risk on Statin Therapy 1 </li></ul><ul><li>Safety and efficacy study of ABT-335 in combination with atorvastatin </li></ul><ul><li>Uses carotid intima media thickness as surrogate end point </li></ul><ul><li>Recruiting </li></ul><ul><li>ARBITER-2: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2 </li></ul><ul><li>ER niacin added to lipid-lowering therapy in patients with known CHD and low HDL-C levels </li></ul><ul><li>Mean CIMT increased significantly in those not treated with niacin, while no significant increase in CIMT was found in the niacin-treated patients. </li></ul>1. http://clinicaltrials.gov/ct2/show/NCT00616772 2. Taylor et al. Circulation 110 (2004), pp. 3512–3517
  12. 12. Summary <ul><li>Residual risk remains when LDL is low, but TG remains high, HDL is low </li></ul><ul><li>Diet and exercise are foundation to therapy </li></ul><ul><li>Aspirin therapy, blood pressure and diabetes control </li></ul><ul><li>Need to correct metabolic &quot;derangement&quot; to improve patient outcomes - less progression of disease, fewer CV events </li></ul><ul><li>Combination therapy control all abnormal lipids to achieve LDL < 70 ; TG < 150 and HDL > 40 - don’t see events </li></ul>