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HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC TOOL OR JUST A PASSING FANCY?

HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC TOOL OR JUST A PASSING FANCY?. GARY A. LOPEZ, M.D. Disclosures. None. Atherosclerotic Heart Disease. Continues to be the foremost cause of mortality in the Western world and is rapidly becoming so in the developing nations

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HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC TOOL OR JUST A PASSING FANCY?

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  1. HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC TOOL OR JUST A PASSING FANCY? GARY A. LOPEZ, M.D.

  2. Disclosures None

  3. Atherosclerotic Heart Disease • Continues to be the foremost cause of mortality in the Western world and is rapidly becoming so in the developing nations • Low-density lipoprotein (LDL) reduction using statins have been established to reduce the number of recurrent cardiovascular events and has been the main contributor of CHD reduction • Residual events still occur despite statin treatment

  4. Coronary Heart Disease according to HDL-C Levels: The Framingham Heart Study 4.0 CHD Risk Ratio 2.0 1.0 • For every 1 mg/dl decrease in HDL, there is a corresponding 2% increased risk • of CHD in men and 3% for women (overall average = 2.5%) Kannel WB, Am J Cardiol, 1983;52:9B-12B

  5. (22 studies;90,000 patients)

  6. Properties of HDL Function • Reverse cholesterol transport (RCT) • LDL antioxidation • Endothelial protection • Antiplatelet activity • Anticoagulation Mechanism • Cholesterol efflux through ABCA1, ABCG1, ABCG4 • Activation of LCAT • Inhibition of adhesion molecule expression, prevention of monocyte chemotaxis, nitric oxide synthase stimulation • Protection against endothelial injury • Inhibition of factors Va and VIIa

  7. HDL Functionality and Reverse Cholesterol Transport CE CETP TG PPAR ACAT ACAT LCAT

  8. Treatment: Non-pharmacologic • Aerobic exercise • Diet • Weight loss • Tobacco cessation • Alcohol • ALL MODESTLY INCREASE HDL-C

  9. Statins • LDL-C reduction causing decrease in atherosclerosis progression and cardiovascular events • Increases HDL-C levels by 5-15% (ave. = 9%) • HDL-C effects relatively smaller compared to LDL-C • Promotes formation of more favorable HDL subfraction profile by creating more cholesterol-rich HDL particles thru reduction of cholesterol transfer from HDL

  10. CTT Meta Analysis 70% 69% 76% 76% 84% 76% 76% 44% Percent Residual Cardiovascular Risk

  11. Low HDL-C is a Predictor of Coronary Events in Statin-Treated Patients Statin Placebo 4S LIPID CARE HPS 35 30 25 20 Coronary Events (%) 15 10 5 0 HDL-C (mg/dl) mmol/L mg/dl  1.35 52  0.99 38  1.0 >39  1.0 <39  1.26 44  0.75 33  1.1 42 < 0.9 35 Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.

  12. Low HDL-C Increases Cardiovascular Disease Risk Even If LDL-C Levels Are Well-controlled: The Treating to New Targets Study Patients (n = 2661) with LDL-C <70 mg/dL on a Statin*† +64% 5-Year Risk of Major Cardiovascular Disease Events (%) HDL-C quintiles* (mg/dL) <37 37 to <42 42 to <47 42 to <55 >55 Hazard Ratio vs. Q1‡ 0.85 0.57 0.55 0.61 *On-treatment level (3 months statin therapy) †Mean low-density lipoprotein cholesterol (LDL-C) level = 58 mg/dL; mean triglyceride (TG) level = 126 mg/dL ‡P=.03 for differences among quintiles of HDL-C Barter P, et al. N Engl J Med. 2007;357:1301-1310.

  13. Coronary Lesion Change with HDL-Raising Drug Treatment Using Niacin Mean change, minimum lesion diameter mm BECAIT LOCAT DAIS CLAS FATS HATS

  14. Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients (8341 men) 100 90 80 70 Niacin 60 Survival (%) 50 Placebo 40 30 P = 0.0012 20 10 16 14 12 10 6 8 4 0 2 Years of follow-up Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

  15. Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH Trial) • Patients: 3,414 M/F with vascular disease and HDL-C <40 and 50 mg/dL, respectively; TG 150–400; and LDL-C <180 mg/dL, 3–5-year follow-up • Centers: 91 centers (~36 patients per center) in US and Canada (20%) • Therapy: Simvastatin vs. Simvastatin + Extended-release niacin (1500-2000mg) • Primary Endpoint: Coronary heart disease death, myocardial infarction, stroke, or high-risk acute coronary syndrome hospitalization

  16. AIM-HIGH Trial: CHD Death, MI, Stroke, High-Risk ACS Hospitalization

  17. Boden WE et al, New Eng J Med, 2011; 365:2255-67

  18. Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH Trial) • Trial stopped 18 mos. early 5/25/11 by Data Monitoring Board • Niacin failed to reduce CV events in 36 mos. • Ischemic strokes higher in Niacin arm (1.6% vs. 0.7%) • Primary endpoint around 16% CV events reduction in both arms – less frequent than the expected 25% • LDL averaged below 70 in both arms at 3 years • 25% increase in HDL and 29% trig reduction in Niacin arm

  19. Issues Regarding AIM-HIGH • Placebo group received 50 mg Niacin and had modest 10% increase in HDL-C • High-risk patients such as those recently hospitalized for ACS were excluded • Few women (15%) and minorities (8%) enrolled

  20. Fibric acid derivatives (Fibrates) • Increases HDL-C levels by 10-15% by PPAR-a activation, causing up-regulation of ABCA1 and hepatic HDL synthesis • Main effect is to lower triglycerides by 25-45% and lower LDL-C by 10-20%

  21. Jun M et al, Lancet ,2010; 375: 1875-84

  22. Thiazolidinediones • Insulin-sensitizers (Pioglitazone,Rosiglitazone) • FDA-approved for treatment of diabetes • Noted to modestly increase HDL levels (2.7-4.6 mg/dl) • Rosiglitazone pulled out from market; Pioglitazone has side effect issues • With current data, generally not used primarily for HDL modification

  23. Background: CETP inhibition X inhibition Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig. LDL / VLDL LDL-R CE SR-B1 Liver CETP FC CE HDL LCAT Free Cholesterol (FC) in Extrahepatic tissues Bile FC

  24. The Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events(ILLUMINATE Trial) • 15,067 patients with history of CV disease or Type 2 DM receiving atorvastatin • Randomly assigned to torcetrapib or placebo • Over 1 year, Torcetrapib group had : - 72.1% increase in HDL-C - 24.9% decrease in LDL-C - 9% decrease in triglycerides

  25. ILLUMINATE Trial HR 1.25 P=0.001 HR 1.54 P=0.006 5.0 % 1.2 (Primary endpoint) NEJM 2007; 357:2109-22

  26. Dalcetrapib : dal-OUTCOMES Trial Primary Endpoint: Time to first occurrence Of CHD death, nonfatal AMI, unstable angina requiring hospitalization,resuscitated cardiac arrest or atherosclerotic stroke • May 7,2012: Trial stopped despite no safety signals due to “a lack in • clinically meaningful efficacy” in the results.

  27. Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD, Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD, DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons, MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip Barter, MD, PhD, for the DEFINE Investigators Safety of Anacetrapib in Patients with or at Risk for Coronary Heart Disease

  28. DEFINE TrialCardiovascular Death, MI, Unstable Angina or Stroke(after 24 weeks / 1623 patients) % Cannon CP, et al. N Engl J Med 2010;363:2406-2415

  29. HDL-C Anacetrapib Anacetrapib 100 120 Placebo Placebo 100 80 80 60 HDL-C (mg/dL) (SE) 60 40 40 20 20 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 0 Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 Study Week Effects on LDL-C and HDL-C LDL-C -39.8% (p<0.001) +138.1% (p<0.001) LDL-C (mg/dL) (SE) Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666 Study Week

  30. 30,000 patients with occlusive arterial disease in North America, Europe and Asia • Background LDL-lowering with Atorvastatin • Randomized to Anacetrapib 100 mg vs placebo • Scheduled follow-up in 4 years • Primary outcome: coronary death, myocardial infarction or coronary revascularization

  31. Lipid-Modulating Effects of Evacetrapib, a Novel CETP Inhibitor, Administered as Monotherapy or in Combination with the Most-Commonly Used Statins SJ Nicholls, HB Brewer, JJP Kastelein,KA Krueger, MD Wang, K Wolski , E McErlean, SE Nissen Presented at AHA Scientific Sessions, Orlando, Nov, 2011

  32. Percent Change HDL-C: Evacetrapib 100 mg Combined with Statin Therapy P<0.001 P,0.001 P<0.001 86.6 94 79.9 % 7.3 5.5 1.4

  33. Evacetrapib: Conclusions • Evacetrapib monotherapy produced a dose-dependent increase in HDL-C up to 128.8% and decrease in LDL-C up to 35.9% • Evacetrapib was well-tolerated with no adverse blood pressure or mineralocorticoid effects • The impact of evacetrapib on cardiovascular events remains to be determined

  34. Summary of CETP Inhibition Trials • The state of CETP inhibition remains strong with ongoing studies testing the hypothesis that raising HDL through CETP inhibition will be beneficial for RCT and modulation of cardiovascular disease

  35. Other Therapeutic Modalities rHDL Infusions A1 Milano Infusions A1 Peptide Mimetics A1 Up-regulators ACATInhibitors

  36. Association of an HDL-C Genetic Variant (LIPG Ans396Ser) With Myocardial Infarction in 116,320 Participants From 20 Studies (PROCARDIS Consortium) Voight BF et al, Lancet,17 May, 2012

  37. Large HDL particle size has the most favourable CHD risk profile Arsenault BJ et al, Epic-Norfolk Prospective Population Study, Atherosclerosis, Sept,2009

  38. Dysfunctional HDL • HDL transformed into a pro-inflammatory and pro-oxidative state • Inflammation plays a central role in creating dysfunctional HDL and disrupting RCT

  39. Cholesterol within Macrophage Foam Cells Is Cholesterol Efflux Capacity More Reliable Instead of HDL Quantity?

  40. p=0.002

  41. Conclusion • There is overwhelming evidence that high levels of HDL-C is associated with lower risk of coronary HD • HDL-C has evolved as one of the risk factor to predict risk of incident Coronary HD • Lifestyle interventions are safe but only modestly increase HDL-C • Best treatment currently are the niacin derivatives particularly for atherogenic dyslipidemia and metabolic syndrome with high cardiometabolic risk

  42. Conclusion (2) • Newer agents such as CETP inhibitors hold much promise. • Other possible points to target include: -efflux or cycling of HDL instead of HDL level -raising specific HDL subclasses instead of HDL itself

  43. Main Issues • Could we accept HDL as a significant risk factor in the progression of Atherosclerotic Vascular Disease? YES 2. Is HDL a reliable therapeutic target in Atherosclerotic Vascular Disease? NO 3. Can we completely disregard HDL in monitoring lipids and simply label it as a passing fancy? NO

  44. Thank You

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