1. Welcome! Please take a moment to complete the short Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. CVD RISK REDUCTION AND LIPID MANAGEMENT State of the Science in HDL Therapy

2. When filling out your evaluation form, please include your email address. When filling out your evaluation form, please include your email address. Those participants who do will be invited by CE Outcomes, LLC within 5-6 weeks to participate in a short, follow-up survey to identify and address future educational needs. Respondents to the follow-up survey are eligible for an Amazon gift card from CE Outcomes. Thank you. CVD RISK REDUCTION AND LIPID MANAGEMENT State of the Science in HDL Therapy

4. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S)

5. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Robert S. Rosenson, MD, FACC, FACP, FAHA, FNLA : Advisory Board: Abbott, Amgen, AstraZeneca, LipoScience Inc., Sanofi-Aventis; Stock Holdings: LipoScience Inc. Michael Miller, MD, FACC, FAHA : Consultant: Amarin, Abbott, Roche; Research: Abbott, Merck, Roche; Speaker: Merck Eliot A. Brinton, MD, FAHA, FNLA : Consultant: Abbott, Amarin, Daiichi-Sankyo, Essentialis, GlaxoSmithKline, Merck, Roche; Speaker: Abbott, Amarin, Daiichi-Sankyo, GlaxoSmithKline, Merck; Researcher: Abbott, Amarin, Merck; Scientific Advisory Board: Atherotech

6. Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Barry Watkins, PhD; Bradley Pine; Blair St. Amand; Jay Katz; Dana Simpler, MD: Nothing to Disclose

7. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Examine the extent of residual CVD risk that continues to burden dyslipidemic ACS patients despite intensive statin treatment Compare the relative effectiveness of existing treatments to raise HDL and reduce CVD risk Explain the rationale for developing CETP modulators and inhibitors to increase HDL and reduce CVD risk Discuss how the modulation of complex cholesterol metabolism could have an impact on atherogenesis and improve clinical outcomes

8. Key Learning Messages Residual CVD Risk in High-Risk Dyslipidemic Patients –Lowering LDL-C reduces CVD risk in ACS patients and in general, but –There is residual CVD risk even with LDL-C controlled on statins Relative Prognostic Value of LDL-C and HDL-C for CVD Event Risk –LDL-C is usually not elevated at time of ACS (average LDL-C ~100 mg/dL) –HDL-C is usually low at time of ACS (average < 40 mg/dL) –Low HDL-C is a strong CVD risk factor independent of LDL-C and non-HDL-C Growing Appreciation of the Complexities of HDL Metabolism –HDL particles are heterogeneous in composition and functionality –Cholesterol efflux by HDL may reflect its antiatherogenic effect Rationale for Targeting HDL-C in High-Risk Patients –The many potential antiatherogenic effects of HDL may be clinically important –Raising low HDL-C may increase HDL benefits and may be a potential target of therapy Current and Emerging Therapeutic Options to Increase HDL Levels –Niacin increases HDL-C and may reduce CVD risk, but data are inconclusive –CETP inhibitors increase HDL-C and might reduce CVD risk

9. Attributable Declines in CHD Deaths Between 1980 and 2000 47% Net 44% TherapiesLifestyle/RFs Attributable reduction in CHD deaths (%) Ford ES et al. N Engl J Med. 2007;356:2389-2398. Unexplained ↑TG,↓HDL-C Target Population

10. Lowering LDL-C Reduces CVD Risk in Patients with CAD

11. Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention Tabas I et al. Circulation. 2007;116:1832-1844. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551-561. Hoshiga M et al. Circ Res. 1995;77:1129-1135. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536-1540. Merrilees MJ et al. J Vasc Res. 1993;30:293-302. Nakata A et al. Circulation. 1996;94:2778-2786. Steinberg D et al. N Engl J Med. 1989;320:915-924. High Plasma Apo B Lipoprotein Levels Promote Atherogenesis Blood Apo B lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response

12. The Apo B-containing ( non-HDL ) Lipoprotein Family: All Atherogenic *ApoB is a component of all lipoprotein particles currently considered atherogenic 2 Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a) 1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3:491-502. 2. Grundy SM. Circulation. 2002;106:2526-2529. 3. Kunitake ST et al. J Lipid Res. 1992;33:1807-1816. Images available at: http://www.mc.vanderbilt.edu/lens/article/?id=186&pg=999. Accessed January 2010. Adapted with permission. ApoB* LDL ApoB-containing lipoproteins 1 – LDL—most common/most important – IDL – VLDL /VLDL remnants – Chylomicron remnants – Lp(a)

13. CHD Events Are Reduced Proportional to LDL-C Lowering w/ Statins: ACS &Other 2 o Prevention Trials Updated from O’Keefe J et al. J Am Coll Cardiol. 2004;43:2142-46. y = 0.1629x · 4.6776 R² = 0.9029 P <0.0001 LDL Cholesterol (mg/dL) CHD Events (%) PROVE-IT-PR PROVE-IT-AT CARE-S LIPID-S HPS-S 4S-S HPS-P CARE-P LIPID-P 4S-P 0 5 10 15 20 25 30 507090110130150170190210 TNT 80 TNT 10A2Z 80 A2Z 20 IDEAL S20/40 IDEAL A80

14. There is Much Residual CVD Risk with Statins, Even with Intensive Therapy

15. Residual CVD Risk in Statin vs Placebo 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 N4444415920 536659566059014 -35%-28%-29%-26%-25% SecondaryHigh RiskPrimary Patients Experiencing Major CHD Events, % 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 Placebo Statin 19.4 12.3 10.2 8.7 5.5 6.8 28.0 15.9 13.2 11.8 7.9 10.9 Many CHD Events Still Occur in Statin-Treated Patients 25-40% CVD Reduction Leaves High Residual Risk P = 0.003 P <0.001 P = 0.003 P = 0.0001 P <0.001

16. Residual CVD Risk with Intensive Statin Therapy Less, but Still Unacceptably High Patients Experiencing Major CVD Events, % PROVE IT-TIMI 22 2 IDEAL 3 TNT 4 n LDL-C* mg/dL 1 Superko HR. Br J Cardiol. 2006;13:131-136. 2 Cannon CP et al. N Engl J Med. 2004;350:1495-1504. 3 Pedersen TR et al. JAMA. 2005;294:2437-2445. 4 LaRosa JC et al. N Engl J Med. 2005;352:1425-1435. 4162888810,001 95 *Mean or median LDL-C after treatment 621048110177 Statistically significant, but clinically inadequate CVD reduction 1 Standard statin therapy Intensive high-dose statin therapy

17. Placebo 251 / 8901 Rosuvastatin 20 mg/d 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174 High Residual CVD Risk Remains Even with High-dose Rosuvastatin (JUPITER) Primary trial endpoint: MI, Stroke, UA/ Revascularization, CV Death Ridker PM. N Engl J Med. 2008;359:2195-2207.

18. A Case of Residual CVD Risk on Statin Therapy Patient Profile: 57-year-old white male (w/ stressful job) –Known CAD (preclinical) –BMI 27 kg/m 2 –LDL-C 67 mg/dL –Triglycerides 300 mg/dL –HDL-C 32 mg/dL –Treadmill ECG : achieved target heart rate w/o angina/ischemia Medications – Statin, blood pressure medication, aspirin Does this patient require additional treatment? If so, what ?

19. A Case of Residual CVD Risk July 2010—clinic visit –Known CAD (preclinical) –BMI 27 kg/m 2 –Statin compliant –LDL-C 67 mg/dL; Triglycerides 300 mg/dL; HDL-C 32 mg/dL –Treadmill ECG: achieved target heart rate w/o angina/ ischemia September 2010— sudden death –AMI and collapse at work –Attempts to resuscitate fail How could this have been avoided?

20. Annual CHD Event Rate Based on the Framingham Risk Score Braunwald E. J Am Coll Cardiol. 2006;47(8 Suppl):C101-C103. Wood D et al. Eur Heart J. 1998;19:A12-A19. FRAMINGHAM RISK FACTORS Case Age: 57 years Gender: male Total cholesterol: 150mg/dL HDL cholesterol: 32 mg/dL Smoker: no Systolic BP: 120 mm Hg On HBP meds: yes TEN YEAR RISK SCORE: 10%

21. CAD Hospitalization and Temporal Trends In Lipid Levels from 2000-2006 (Mean) Sachdeva A et al. Am Heart J. 2009;157:111-117.e2. LDL-C HDL-C Triglycerides

22. Lifetime Risk for CVD Increases With Greater Risk Factor Burden Lifetime Risk for CVD, % All Optimal ≥1 Not Optimal≥1 Elevated1 Major ≥2 Major Women Men 8 5 27 36 39 46 39 50 69 Risk Factor Burden at Age 50 (Estimated Risk by Age 95) 0 10 20 30 40 50 60 70 80 Lifetime burden stratified for risk factor burden years among Framingham Heart Study participants free of CVD at 50 years. Optimal risk factors defined as total cholesterol <180 mg/dL, BP <120/<80 mmHg, nonsmoker, and nondiabetic. Nonoptimal risk factors are defined as total cholesterol 180–199 mg/dL, systolic BP 120–139 mmHg, diastolic BP 80–89 mmHg, nonsmoker, and nondiabetic. Elevated risk factors are defined as total cholesterol 200–239 mg/dL, systolic BP 140–159 mmHg, diastolic BP 90–99 mmHg, nonsmoker, and nondiabetic. Major risk factors are defined as total cholesterol ≥240 mg/dL, systolic BP ≥160 mmHg, diastolic BP ≥100 mmHg, smoker, and diabetic. CVD = cardiovascular disease; BP = blood pressure. Lloyd-Jones DM et al. Circulation. 2006;113:791-798.

23. ≥2 major risk factors 1 major risk factor ≥ 1 elevated risk factor ≥1 risk factor not optimal all risk factors optimal Data were derived from 17 studies in a pooled cohort Berry JD et al. N Engl J Med. 2012;366:321-329. 0 60708090 0 10 20 30 40 Lifetime Risk (%) Attained Age (yr) Lifetime Risk of Death from CVD Among Black Men and White Men at 55 Years of Age 55657585

24. Lowering LDL-C Alone only Moderately Reduces CHD Risk Statins decrease CVD 25%-45% but leave 55-75% events not prevented 1,2 Despite on-Rx LDL-C <70-80 mg/dL, many ACS and other 2 o prevention patients still have CVD events 3,4,5 and these are related to low HDL-C 5 There is a great need for further improvement in cardiovascular risk reduction beyond statins 6 1. LaRosa J et al. JAMA. 1999;282:2340-2346. 2. HPS Collaborative Group. Lancet. 2002;360:7-22. 3. Cannon CP et al. N Engl J Med. 2004;350:1495-1504. 4. de Lemos JA et al. JAMA. 2004;292:1307-1316. 5. Barter P, et al. New Engl J Med. 2007;357:1301-1310. 6. Assmann G, Gotto AM Jr. Circulation. 2004;109(suppl III):8-14. CHD = coronary heart disease

25. Low HDL-C is an Independent CVD Risk Factor

26. CHD Risk According to HDL-C Levels The Framingham Heart Study Kannel WB. Am J Cardiol 1983;52:9B-12B. Copyright ©1983, with permission from Excerpta Medica Inc. 4.0 3.0 2.0 1.0 25 45 65 HDL-C (mg/dL) CHD risk ratio 2.0 1.0 0 4.0

27. Framingham Heart Study Low HDL-C Predicts CHD Independent of LDL-C Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a. HDL-C mg/dL CAD Risk After 4 Years* LDL-C, mg/dL 85 65 45 25 100160220 0 1 2 3 *Men aged 50-70 years HDL-C is inversely correlated with CAD risk Correlation is independent of LDL-C

28. HDL-C Quintiles, a mg/dL 5-Year Risk of Major CVD Events, % Low HDL-C Predicts Residual CVD Risk After Optimal Statin Rx: TNT Study LDL-C ≤70 mg/dL on Statin a,b (Treating to New Targets (TNT) Study) a On-treatment level (3 months statin therapy); n = 2661 b Mean LDL-C, 58 mg/dL; mean TG, 126 mg/dL * P =.03 for differences among quintiles of HDL-C Barter P et al. New Engl J Med. 2007;357:1301-1310. Q1 <37 Q2 37 to <42 Q3 42 to <47 Q5 ≥55 Q4 47 to <55 Hazard Ratio Versus Q1* 0.850.570.550.61 Case: HDL-C 32; LDL-C 67 on statin

29. Early and Late Mortality Post-DES Low HDL-C vs High HDL-C at Baseline Wolfram RM et al. Am J Cardiol. 2006;98:711-717. High HDL-C Low HDL-C

30. HDL Consists of Heterogeneous Particles, but Their Clinical Relevance Remains to Be Established

31. Separation of HDL by Physical Properties Ultracentrifugation – density –Isopycnic – preparative –Density Gradient – Vertical automated profile (VAP) Gradient gel electrophoresis (GGE) – size Rocket immunoelectrophoresis – apolipoprotein content Nuclear magnetic resonance (NMR) – terminal methyl 2-D gel electrophoresis – size and charge (shape) Ion mobility – charge (shape) and mass Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ. Clin Chem. 2011;57(3):392-410.

32. HDL 2a HDL 2b HDL 3c HDL 3b HDL 3a HDL Particle Size/Electrophoretic Mobility Apolipoprotein Content Particle Shape Particle Shape Discoidal Spherical A-I HDL A-I/A-II HDL Lipid-poor apoA-I HDL Subpopulations +other apos: A-IV, C, D, E, etc. +non-apo proteins: inflam, thromb, etc. --------------------------Alpha-migrating------------------------- --Pre-beta-migrating-- GlobularDiscoidal Globular Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.

33. Potential Antiatherogenic Actions of HDL MCP-1 = monocyte chemoattractant protein-1 Adapted from Barter PJ et al. Circ Res. 2004;95:764-772. Monocyte Macrophage Foam cell Vessel Lumen Endothelium Intima Cytokines Adhesion molecule Oxidized LDL LDL HDL inhibits expression of endothelial cell adhesion molecules and MCP-1 MCP-1 HDL inhibits oxidation of LDL-C HDL promotes efflux of cholesterol from foam cells

34. Processes Promoting Efflux of Cholesterol from Cells to HDL Particles Adapted from Barter P, Rye KA. High density lipoprotein cholesterol: the new target. A handbook for clinicians. 3 rd ed. Birmingham, UK: Sherbourne Gibbs, 2007:31. Rosen R et al. Circulation. 2012. Extracellular spaceCell membrane FC ABCA1 Diffusion SR-B1 Diffusion SR-B1 ABCG1 Diffusion SR-B1 ABCG1 Discoidal HDL Small spherical HDL Larger spherical HDL LCAT Cholesterol deficient, phospholipid depleted apo A-1

35. Proposed Term Very Large HDL (HDL-VL) Large HDL-V (HDL-L) Medium HDL (HDL-M) Small HDL (HDL-S) Very Small HDL (VS-HDL) Density range, g/mL1.063-1.0871.088-1.1101.110-1.1291.129-1.1541.154-1.21 Size range, nm12.9-9.79.7-8.88.8-8.28.2-7.87.8-7.2 Density gradient ultracentrifugation HDL2bHDL2aHDL3aHDL3bHDL3c Density range, g/mL1.063-1.0871.088-1.1101.110-1.1291.129-1.1541.154-1.170 Gradient gel electrophoresis HDL2bHDL2aHDL3aHDL3bHDL3c Size range, nm12.9-9.79.7-8.88.8-8.28.2-7.87.8-7.2 2D gel electrophoresisAlpha-1Alpha-2Alpha-3Alpha-4Preβ-1 HDL Size range, nm11.2-10.89.4-9.08.5-7.57.5-7.06.0-5.0 NMRLarge HDL-PMedium HDL-PSmall HDL-P Size range, nm 12.9-9.79.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2 Ion mobilityHDL2bHDL2a + 3 Size range, nm14.5-10.510.5-7.65 Classification of HDL by Physical Properties Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ. Clin Chem. 2011;57(3):392-410.

36. Functional and Compositional Assessment of HDL Cholesterol efflux Antioxidant activity Anti-inflammatory activity Proteomics/lipidomics Note: these are research tools w/o known clinical relevance of application Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ. Clin Chem. 2011;57(3):392-410.

37. HDL-C Risk Factor vs Risk Marker? Low HDL-C predicts high CVD Risk High HDL-C predicts anti-atherogenic effects: –Anti-inflammatory –Antioxidant –Antithrombotic –Pro-endothelial But clinical trials have not yet proven that: –HDL is a causal factor vs biomarker of risk, or –Raising HDL-C reduces CVD risk

38. Should High-density Lipoprotein Be a Target of Therapy ? ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. Circulation. 2004;110:227-239) Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib have increased doubts as to the value of raising HDL-C Recent clinical trial data from next generation investigational CETP inhibitors has refueled hope that this approach may increase HDL-C and improve clinical outcomes

39. Smoking Cessation −HDL-C levels are 7-20% lower in smokers, but return to normal 1-2 months after smoking cessation Whole Food Plant Based Diet Weight Reduction −For every 3 kg (7 lb) of weight loss, HDL-C levels increase about 1 mg/dL (~2-4% increase) Exercise −Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by about 2.5 mg/dL (~5-10% increase) Rössner S et al. Atherosclerosis. 1987;64:125-130. Wood PD et al. N Engl J Med. 1988;319:1173-1179. Ornish D et al. JAMA. 1998;280:2001-2007. Lifestyle Modifications to Raise HDL-C Levels Cullen P et al. Eur Heart J. 1998;19:1632-1641. Kokkinos PF et al. Arch Intern Med. 1995;155:415-420. Kodama S et al. Arch Intern Med. 2007;167:999-1008.

40. Reducing CAD Risk in Patients with Dyslipidemia Established LDL-C HDL-CTriglycerides Lp(a) Oxidized LDL Small dense LDL Homocysteine CRP Coagulability Reasonable Evidence Not Established

41. Available Agents for HDL-C Raising AgentHDL-C ↑ Primary Use Nicotinic acid15-35% HDL ↑ Fibrates 5-20% TG ↓ Statins 5-15% LDL ↓ Prescription Om-3* 2-10% TG ↓ Bile-acid resins* 2-5% LDL ↓ Ezetimibe* 1-3% LDL ↓ Pioglitazone* 5-20% Glucose ↓ Estrogens* 10-25% Hot flashes  -blockers* 10-20% BPH Alcohol* 5-15% Social, etc. *Lacking FDA-approved indication for HDL-raising. Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174. Insull W et al. Mayo Clin Proc. 2001;76:971-982. McKenney JM et al. Pharmacother. 2007;27:715-728.

42. Risk Reduction for CHD Events As a Function of Changes in TC, LDL-C, and HDL-C *4S, CARE, LIPID, WOSCOPS **HELSINKI, VA-HIT,AFCAPS/TexCAPS PERCENT CHD EVENT CHANGE RATE

43. Niacin Increases HDL-C, but May Not Consistently Reduce CVD Risk

44. CV Surgery Niacin Reduces CVD Events Coronary Drug Project Coronary Drug Project. JAMA. 1975;231:360-381. Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255. Subjects: men with prior MI Treatment arms, 5 lipid meds: –IR Niacin, 1 g TID (n=1119) estrogen (2 arms), dextrothyroxine, clofibrate –Niacin lipid effects: TC  10%, TG  27% (HDL-C not meas.) Results (6 yrs, end-study): benefit only seen in Niacin arm (  MI 27%, no  1 o endpoint=total mortality) Post-study f/u 15 yrs: 4% absolute  total mortality (NNT = 25) Event Rate (%) Nonfatal MI/CHD Death Nonfatal MI Stroke/ TIA Placebo Niacin – 14 – 27 – 26 – 47

45. Niacin Reduces CVD Pre-AIM-HIGH Trials Many of these trials were tests of drug combinations that included niacin. Bruckert E et al. Atherosclerosis. 2010;210:353-361. stat sig 27%↓

46. AIM-HIGH—Design Purpose: “[A] rigorous test of the HDL hypothesis…” Subjects: N=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-400) [median (range)] Randomized Therapy –Extended-release niacin (1500-2000 mg hs) vs –“Placebo” (immediate-release niacin 100-150 mg hs) Open-label titration/addition (keep LDL-C in 40-80 mg/dL) –Simvastatin 5-80 mg/d –Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg) AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267. AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.

47. Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579. AIM-HIGH—Results HDL-C at Baseline and Follow-up

48. 1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579. AIM-HIGH—Results Primary Outcome

49. AIM-HIGH Early Termination Lipids –Baseline: LDL-C 71 mg/dL w/ prior stain Rx (94% of subjects) –On Rx: HDL-C ↑ 25% ERN vs ↑ 10% “placebo” (<2/3 of projected) Data, Safety and Monitoring Board chose early termination –Due to futility (likely lack of efficacy) - 1° Endpoint HR 1.05 –Early concern about possible increased stroke rate signal Potential explanations for lack of observed efficacy: –“Placebo” arm received IR niacin, ↑ statin dose & ↑ ezetimibe (poor test of HDL hypothesis w/ just 15% net ↑ HDL-C) –Early study termination (VA HIT also negative at 3 y) –Sl lower than expected event rate (but still >5%/yr) –High prior statin use (94%, 40%>5y), prior niacin use (20%) Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm. Brinton EA. J Clin Lipi. 2011.www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm Rosenson RS. Curr Athero Rep. 2012 (in press).

50. CVD Events per Study AIM-HIGH is Small Relative to Earlier and Later Niacin Clinical Trials *At publication 11/15/11. **Estimated. Results due in ~1 year. Bruckert E et al. Athero. 2010;210:353-361. 3515 556* ~2300** ~1/7 ~4 x

51. Study Treatment n/N Control n/N Peto OR 95% Cl Peto OR 95% Cl ARBITER-6-HALTS2/1879/1760.25 (0.08, 0.84) Guyton JR et al1/6761/2720.35 (0.02, 7.56) AFREGS0/711/720.14 (0.00, 6.92) ARBITER-22/872/800.92 (0.13, 6.65) HATS1/385/380.24 (0.05, 1.26) UCSF_SCOR0/481/490.14 (0.00, 6.96) STOCKHOLM72/279100/2760.61 (0.43, 0.88) CLAS1/945/940.25 (0.05, 1.29) CDP287/1119839/27890.81 (0.69, 0.94) Total Test for heterogeneity: P = 0.24, I 2 = 23.0% Test for overall effect: P < 0.0001 0.75 (0.65, 0.86) Subtotal excluding CDP0.53 (0.38, 0.73) 0.1 0.2 0.5 1 2 5 10 Log scale Meta-Analysis: Effects of Nicotinic Acid Major Coronary Events Many of these trials were tests of drug combinations that included niacin Bruckert E et al. Atherosclerosis. 2010;210:353-361.

52. StudyN Treatment Mean (SD) N Control Mean SD WMD (fixed) 95% Cl WMD (fixed) 95% Cl ARBITER-6-HALTS97-12 (36)111-1 (31)-12 (-21, -2) Thoenes M et al30-5 (11)159 (12)-14 (-21, -7) ARBITER-27814 (104)7144 (100)-30 (-63, -3) CLAS39-12 (20)3912 (20) -25 (-34, -16) Total Test for heterogeneity: P = 0.13, I 2 = 47.4% Test for overall effect: P < 0.0001 -17 (-22, -12) Meta-Analysis: Effects of Nicotinic Acid Carotid Intima Media Thickness -100 -50 0 50 100 Annual change, μm/y E. Bruckert et al, Atherosclerosis 210 (2010) 353-361

53. CETP Inhibitors/Modulators Increase HDL-C and May Reduce Atherosclerosis

54. Role of CETP in Atherosclerosis Human CETP deficiency –↑ in HDL-C (codominant) –↓CVD Reducing CETP activity →↓ atherosclerosis in animal models Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167. Contacos C et al. Atherosclerosis. 1998;141:87-98. Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28: 148-154. LIVERPERIPHERAL TISSUE CE TG Bile Foam cells RCT HDL ABC-A1 VLDL LDL PLASMA LDL-R ABC-G1 Free cholesterol CETP Athero- sclerosis LDL

55. Development of CETP Inhibitors/Modulators

56. Barter et al. N Engl J Med. 2007;357:2109-2122. http://www.ama-assn.org/ama1/pub/upload/mm/365/dalcetrapib.doc. http://www.ama-assn.org/ama1/pub/upload/mm/365/torcetrapib.doc. Qiu et al. Nat Struct Mol Biol. 2007;14:106-112. http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf. CETP Inhibitors and Modulators CETP Evacetrapib

57. Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP AgentDose (Mg/day)HDL-C (%)LDL-C (%)TG (%) Torcetrapib6061-24-9 Anacetrapib100138-40-7 Evacetrapib500129-36-11 Dalcetrapib60031-2-3 Adapted from Cannon C et al. JAMA. 2011;306:2153-2155. Nicholls SJ et al. JAMA. 2011;306:2099-2109.

58. Torcetrapib “Beneficial” Effects on Lipoproteins Is the toxicity of torcetrapib related to the mechanism or the molecule? Placebo60 mg90 mg120 mg Barter PJ et al. N Engl J Med. 2007;357:2109-2122. HDL-C LDL-C +42% +49% +55% -20% -18% -1% +1%

59. Is the toxicity of torcetrapib related to the mechanism or the molecule? Atorvastatin only Torcetrapib plus atorvastatin 0 90 180 270 360 450 540 630 720 810 Days After Randomization Patients Without Event (%) 100 98 96 94 92 90 0 Barter PJ et al. N Engl J Med. 2007;357:2109-2122. Torcetrapib: BUT Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality HR = 1.25 P = 0.0001

60. Torcetrapib Caused Off-target Hyperaldosteronism Torcetrapib arm of ILLUMINATE trial showed significant: 1 –↑ Systolic B lood Pressure:  Mean ↑ 5.4 mmHg  >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, p<0.001) –↓ serum potassium –↑ serum bicarbonate –↑ serum sodium –↑ serum aldosterone Inverse relationship of CVD and on-Rx-HDL-C preserved Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of torcetrapib, not related to CETP inhibition 1,2 1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122. 2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.

61. Analysis of the Off-target Characteristics of Investigational CETP Inhibitors/Modulators CharacteristicTorcetrapibAnacetrapibDalcetrapibEvacetrapib Clinical evidence of increased BPYes 1 No 2 No 3 No 7 Preclinical evidence of increased aldosterone production* Yes 3 No 4 No 3 No 8 Preclinical evidence of aldosterone synthase (CYP11B2) mRNA induction* Yes 3 ?No 3 ? Preclinical evidence of RAAS- associated gene induction* Yes 5 ?No 5 ? L-type Ca 2+ channel activation*Yes 6 ?No 6 ? 1. Barter et al. N Engl J Med. 2007;357:2109-2122. 2. Masson D. Curr Opin Invest Drugs. 2009;10:980-987. 3. Stein et al. Am J Cardiol. 2009;104:82-91. 4. Forrest et al. Br J Pharmacol. 2008;154:1465-1473. 5. Stroes et al. Br J Pharmacol. 2009;158:1763-1770. 6. Clerc et al. J Hypertens. 2010: in press. 7. Nicholls et al. JAMA 2011;306:2099-2109 8. Cao et al. J Lipid Research. 2011;52:2169-2176

62. Anacetrapib Effects on LDL-C and HDL-C HDL-C Baseline 612182430466276 HDL-C (mg/dL) (SE) 0 20 40 60 80 100 120 Anacetrapib Placebo Anacetrapib n = 776757718687647607572543 Placebo n = 766761741744736711691666 LDL-C Study Week Baseline 612182430466276 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) Cannon CP et al. N Engl J Med. 2010;363:2406-2415. Study Week

63. Dalcetrapib Phase IIb Trial HDL-C Increase at Week 12 placebo n = 73 dalcetrapib 300 mg n = 75 NOTE: Dalcetrapib 600 mg is the dose used in phase III Stein EA. Am J Cardiol. 2009;104:82-91. * * *P <0.0001 vs placebo * dalcetrapib 600 mg n = 67 dalcetrapib 900 mg n = 72 Change From Baseline (%)

64. Dalcetrapib (JTT-705) Attenuates Atherosclerosis in Rabbits Okamoto H et al. Nature. 2000;406:203-207.

65. Dalcetrapib and Torcetrapib Appear to Differ in Mechanism of CETP Inhibition 1 Okamoto H et al. Nature. 2000;406:203-207. 2 Niesor EJ et al. Atherosclerosis. 2008;199:231. 3 Clark RW et al. J Lipid Res. 2006;47:537-552. NB: The clinical relevance of these differences is unknown ; these compounds have not been studied in head-to-head clinical trials. dal HDL tor or ana CETP HDL Dalcetrapib binds to CETP, inducing a conformational change to CETP that hinders association to HDL 1 Dalcetrapib binds to CETP only 2 Torcetrapib binding to CETP is an irreversible high affinity complex of CETP inhibitor, HDL, and CETP 2,3

66. “ The dal-OUTCOMES trial evaluated the efficacy and safety profile of dalcetrapib when added to existing standard of care in patients with stable coronary heart disease following an acute coronary syndrome. Following the results of the second interim analysis of the dalcetrapib dal-OUTCOMES Phase III trial the Independent Data and Safety Monitoring Committee (DSMC) has recommended stopping the trial due to a lack of clinically meaningful efficacy. No safety signals relating to the dal-OUTCOMES trial were reported from the DSMC. As a result, Roche has decided to terminate the dal-OUTCOMES trial, as well as all other on-going studies in the dal-HEART program, including dal-PLAQUE 2 and dal-OUTCOMES 2. Additional information will be provided in due course as data become available. Excerpt from letter to dal-OUTCOMES Investigators from Roche. Termination of Dalcetrapib Clinical Trial 7/7/2012 ”

67. Conclusions Residual CV risk remains problematic despite statin-mediated LDL-C reductionResidual CV risk remains problematic despite statin-mediated LDL-C reduction Low HDL-C is an independent risk factor for CHDLow HDL-C is an independent risk factor for CHD Most clinical trial and observational data suggest that raising HDL-C may reduce CVDMost clinical trial and observational data suggest that raising HDL-C may reduce CVD HDL particles are very heterogeneous in composition and function, not all HDL may be anti-atherogenicHDL particles are very heterogeneous in composition and function, not all HDL may be anti-atherogenic Many new HDL-C raising treatments are in developmentMany new HDL-C raising treatments are in development CETP inhibitors greatly raise HDL-C levels, but their effect on HDL function and clinical outcomes remains in questionCETP inhibitors greatly raise HDL-C levels, but their effect on HDL function and clinical outcomes remains in question

68. Revisiting the HDL Hypothesis Where to Next? Residual CVD risk exists despite intense statin monotherapy Low HDL-C predicts high CVD risk; high HDL-C is protective Existing HDL raising therapies have inconsistent effects Investigational drugs to raise HDL-C and reduce CVD risk –CETP inhibitors –PPAR agonists, APO A1 agonists, delipidating agents, etc. But clinical trials have not yet proven that: –HDL is a causal factor vs biomarker of risk –Raising HDL-C reduces CVD risk

69. Thank you for joining us today! Don’t forget to fill out your evaluation form for CME credit. Please include your email address. Don’t forget to fill out your evaluation form for CME credit. Please include your email address. Those participants who do will be invited by CE Outcomes, LLC within 5-6 weeks to participate in a short, follow-up survey to identify and address future educational needs. Respondents to the follow-up survey are eligible for an Amazon gift card from CE Outcomes. CVD RISK REDUCTION AND LIPID MANAGEMENT State of the Science in HDL Therapy