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 CHD Risk Ratio Kannel WB, Am J Cardiol, 1983;52:9B-12B 4.0 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%)

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

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

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

12. Low HDL-C Increases Cardiovascular Disease Risk Even If LDL-C Levels Are Well-controlled: The Treating to New Targets Study 5-Year Risk of Major Cardiovascular Disease Events (%) HDL-C quintiles* (mg/dL) *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 Patients (n = 2661) with LDL-C <70 mg/dL on a Statin* † 37 to <4242 to <4742 to <55>55<37 0.850.570.550.61Hazard Ratio vs. Q1 ‡ Barter P, et al. N Engl J Med. 2007;357:1301-1310. +64%

13. Coronary Lesion Change with HDL- Raising Drug Treatment Using Niacin mm Mean change, minimum lesion diameter BECAIT LOCATDAISCLASFATSHATS

14. Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients (8341 men) Niacin Placebo P = 0.0012 100 90 80 70 60 50 40 30 20 10 0 2 4 6 8 12 14 16 Years of follow-up Survival (%) 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

22. Fibric acid derivatives (Fibrates) Increases HDL-C levels by 10-15% by PPAR-  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%

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

24. 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

28. Background: CETP inhibition HDL LDL / VLDL Liver Bile CE LDL-R FC FC LCAT CETP CECECECE SR-B1 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. Free Cholesterol (FC) in Extrahepatic tissues

29. 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

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

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

32. Safety of Anacetrapib in Patients with or at Risk for Coronary Heart Disease 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

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

34. Effects on LDL-C and HDL-C LDL-C Study Week BaselineWk 6Wk 12Wk 18Wk 24Wk 30Wk 46Wk 62Wk 76 LDL-C (mg/dL) (SE) 0 20 40 60 80 100 Anacetrapib Placebo Anacetrapib n =804771716687646604568540 Placebo n =803759741743735711691666 -39.8% (p<0.001) +138.1% (p<0.001)

35. 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

36. 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

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

38. 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

39. 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

40. ACAT Inhibitors rHDL Infusions A1 Milano Infusions A1 Peptide Mimetics A1 Up-regulators rHDL Infusions A1 Milano Infusions A1 Peptide Mimetics A1 Up-regulators Other Therapeutic Modalities

41. 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

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

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

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

46. p=0.002

47. 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

48. 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

49. Main Issues 1.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

50. Thank You