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Presentation on theme: "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."— Presentation transcript:

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. LIPOPROTEIN MANAGEMENT IN ACS Improving Outcomes in Patients with Complex Lipid Disorders

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. The first 50 respondents to the follow-up survey will receive an Amazon gift card from CE Outcomes. Thank you. LIPOPROTEIN MANAGEMENT IN ACS Improving Outcomes in Patients with Complex Lipid Disorders

3

4 Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: XXXXXXXXX, MD, FAHA, FNLA Consultant: Roche, Abbott, Amarin, Daiichi-Sankyo, GlaxoSmithKline, Merck, Atherotech, Essentialis; Speaker: Abbott, Daiichi-Sankyo, GlaxoSmithKline, Merck; Researcher: Abbott, Merck XXXXXXXXX, MD, FACC, FAHA Nothing to disclose TO BE FILLED IN BY PRESENTING PHYSICIAN(S)

5 Steering Committee and Consultant Disclosures The Steering Committee and Curriculum Consultants reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Michael Davidson, MD: Speakers’ Bureau: Abbott, AstraZeneca, GlaxoSmithKline, Merck; Advisory Board/Consultant: Abbott, Aegerion, Amgen, AstraZeneca, Atherotech, Daiichi-Sankyo, DTC MD, Esperion, GlaxoSmithKline, iMD (Intelligent Medical Decisions), Kinemed, LipoScience, Merck, Novo Nordisk, Roche, Sanofi- Aventis, Synarc, Takeda, Vindico Medical Education; Grant Research: Abbott, Daiichi-Sankyo, GlaxoSmithKline, Merck, Roche ; Board of Directors/Equity: DTC MD, Omthera, Professional Evaluation Inc., Sonogene Peter P. Toth, MD, PhD: Speaker: Abbott, AstraZeneca, Merck, Takeda, GlaxoSmithKline, Boehringer-Ingelheim; Consultant: Abbott, AstraZeneca, Merck, Genentech, Genzyme; Advisory Board: Atherotek William E. Boden, MD, FACC, FAHA: Speaker: Gilead, Abbott, Sanofi-Aventis, Kowa Michael Miller, MD, FACC, FAHA: Nothing to Disclose

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 need for comprehensive lipid management in dyslipidemic patients who sustain an ACS Compare the relative effectiveness of existing treatments to raise HDL-C and reduce CVD risk Explain the rationale for developing novel agents to increase HDL-C Provide an overview of clinical trials evaluating efficacy and safety of emerging therapies to modulate HDL-C

8 Key Learning Messages Lowering LDL-C reduced CVD risk in patients with CAD There is much residual CVD risk even with intense statin therapy But half of ACS patients present with LDL-C of 100-120 mg/dL Low HDL-C is an independent CVD risk factor High HDL-C is antiatherogenic, antiinflammatory, antioxidant, antithrombotic Should HDL-C be a target of therapy to reduce CVD risk? Niacin and fibrates may increase HDL-C, but do not reduce CVD risk CETP inhibitors may increase HDL-C and reduce CVD risk Emerging CETP inhibitors are mechanistically diverse HDL consists of heterogeneous particles, not all of which are functional Functional HDL has high cholesterol efflux capacity High cholesterol efflux capacity is associated with antiatherogenic effect

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 LDL-C Plays a Role in Atherosclerosis *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  Non-HDL (atherogenic) – LDL – IDL – VLDL /VLDL remnants – Chylomicron remnants – Lp(a)

12 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. Cardiovascular Risk Increases with Increased Plasma Apo B Lipoproteins Blood Apo B lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response

13 CHD Event Rates in Secondary Prevention and ACS Statin 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, Even with Intense Statin Therapy

15 Reduction in Major Coronary Events in Major Statin Trials by Level of Patient Risk Secondary Primary *P <0.001; † P =0.0005; ‡ P <0.0001; § P =0.002 LaRosa J et al. JAMA. 1999;282:2340-2346; HPS Collaborative Group. Lancet. 2002;360:7-22; Sever PS et al. Lancet. 2003;361:1149-1158. -38* High Risk 4S 4444 -36% AF/ TexCAPS 6605 -27% LIPID 9014 -25% CARE 4159 -28% WOSCOPS 6595 -26% Trial N  LDL-C -25*-25 § -31* -27 ‡ HPS 20,536 -29% Risk Reduction, (%) ASCOT 10,305 -28% -36 † Major coronary events defined as: fatal or nonfatal myocardial infarction (MI), unstable angina, sudden cardiac death in AF/TexCAPS; nonfatal MI or coronary death in WOSCOPS, ASCOT, HPS, LIPID, CARE; coronary death, nonfatal MI, silent MI, resuscitated cardiac arrest in 4S.

16 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 CHD Events Occur in Patients Treated with Statins

17 Residual CVD Risk in Patients Treated with Intensive Statin Therapy Remains 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

18 Placebo 251 / 8901 Rosuvastatin 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 JUPITER Primary Trial Endpoint MI, Stroke, UA/Revascularization, CV Death

19 A Case of Residual CVD Risk Patient Profile: 58-year-old white male – Known CAD (preclinical) – BMI 27 – LDL-C 67 mg/dL – Triglycerides 300 mg/dL – HDL-C 32 mg/dL – Treadmill stress test : achieved target heart rate without angina/ischemia Medications – Statin, blood pressure medication, aspirin Does this patient require additional treatment? If so, what? Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.

20 Tim Russert : Residual CVD Risk April 2008 – Known CAD (preclinical) – BMI 27 – LDL-C 67 mg/dL; Triglycerides 300 mg/dL; HDL-C 32 mg/dL – Treadmill stress test: achieved target heart rate without angina/ ischemia June 2008 – AMI at work – Attempts to resuscitate fail Could this have been avoided? Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.

21 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 Mr. Russert: Age: 58 Gender: male Total cholesterol: 150mg/dL HDL cholesterol: 32 mg/dL Smoker: no Systolic BP: 120 On HBP meds: yes TEN YEAR RISK SCORE: 10%

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

23 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.

24 Lowering LDL-C Alone only Moderately Reduces CHD Risk Major statin trials consistently show an approximate 25%-40% risk reduction for cardiovascular events, regardless of baseline LDL-C levels 1,2 Despite on-therapy LDL-C <80 mg/dL, a significant number of ACS patients still have events 3,4 Even with aggressive LDL-C lowering, residual risk remains high for at least 2 years following an index event, since 2/3-3/4 of CHD events are not avoided 1 There is a great need for further improvement in cardiovascular risk reduction 5 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. 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 Circulating Lipoproteins Play a Major Role in Atherosclerosis ApoAI-containing lipoproteins 1  HDL (antiatherogenic) – α-HDL – Pre-β HDL *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 ApoAI HDL ApoB-containing lipoproteins 1  Non-HDL (atherogenic) – LDL – IDL – VLDL /VLDL remnants – Chylomicron remnants – Lp(a)

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 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

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

30 High HDL-C Levels Reduce CVD Risk High levels of HDL-C are Anti-atherogenic, Anti-inflammatory, Anti-oxidant, and Antithrombotic

31 Residual CVD Risk: TNT Study HDL-C Inversely Predictive of Risk Even at LDL-C <70 mg/dL Barter P et al. N Engl J Med. 2007;357:1301-1310. Each 1 mg/dL increase in HDL-C decreases the risk of major CV events by approximately 1.1%, in models created both at baseline and at 3 months. Q1Q2Q3Q4Q5 (<37) (37 to <42) (42 to <47) (47 to <55) (≥55) Hazard ratio (95% CI) vs Q1 Q20.85 (0.57 - 1.25) Q30.57 (0.36 - 0.88) Q40.55 (0.35 - 0.86) Q50.61 (0.38 - 0.97) 5-Yr Risk of Major Cardiovascular Events (%) 10 9 8 7 6 5 4 3 2 1 0 Quintile of HDL Cholesterol Level (mg/dl)

32 Potential Antiatherogenic Actions of HDL-C 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-C LDL-C HDL-C inhibits expression of endothelial cell adhesion molecules and MCP-1 MCP-1 HDL-C inhibits oxidation of LDL-C HDL-C promotes efflux of cholesterol from foam cells

33 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” However, there are more clinical data to justify HDL-C as a therapeutic target in 2011 than there were for LDL-C in 1998. Grundy SM et al. Circulation. 2004;110:227-239.

34 Weight Reduction − For every 3 kg (7 lb) of weight loss, HDL-C levels increase 1 mg/dL Smoking Cessation − HDL-C levels in smokers are 7%-20% lower than those in nonsmokers − HDL-C levels return to normal within 30-60 days after smoking cessation Exercise − Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by about 2.5 mg/dL Rössner S et al. Atherosclerosis. 1987;64:125-130. Wood PD et al. N Engl J Med. 1988;319:1173-1179. 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. Effects of Lifestyle Modifications on HDL-C Levels

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

36 Nicotinic acid↑15%–35% Fibrates↑ 10%–15% Estrogens↑ 10%–15% Statins↑ 5%–10% α-blockers↑ 10%–20% Alcohol↑ 10% Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174. Effects of Drugs on HDL-C Levels

37 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

38 Niacin and Fibrates May Increase HDL-C, but Do Not Consistently Reduce CVD Risk

39 FIELD: Fenofibrate in People with DM Primary Outcome: CHD Events (CHD Death + Nonfatal MI) HR = 0.89 95% CI = 0.75–1.05 P =0.16 Placebo Fenofibrate Although fenofibrate reduced triglycerides and LDL-C, there was virtually no increase shown in HDL FIELD Study investigators. Lancet. 2005;366:1849-1861.

40 OutcomeFenofibrate (n=2765), %/yPlacebo (n=2753), %/yHazard ratio (95% CI) Primary outcome2.242.410.92 (0.79–1.08) Primary outcome plus revascularization or hospitalization for CHF b 5.355.640.94 (0.85–1.05) Major coronary disease event2.582.790.92 (0.79–1.07) Nonfatal MI1.321.440.91 (0.74–1.12) Any stroke0.380.361.05 (0.71–1.56) Nonfatal stroke0.350.301.17 (0.76–1.78) Death from any cause1.471.610.91 (0.75–1.10) Death from CV causes0.720.830.86 (0.66–1.12) Fatal or nonfatal CHF0.901.090.82 (0.65–1.05) Primary and secondary outcomes a a. At a median of 4.7 yearsb. CHF=congestive heart failure The combination of fenofibrate and simvastatin failed to reduce the risk of fatal CV events, nonfatal MI, or nonfatal stroke ACCORD Lipid: Results Ginsberg H. Presented at: ACC 2010 Scientific Sessions.

41 AIM-HIGH On-treatment lipids – 3414 men and women with vascular disease and HDL ≤40, TG 150-400, LDL-C ≤180 if statin naïve, <160 if on statin Therapy – Simvastatin (40-80 mg) vs simvastatin (40 + niaspan 1500-2000 mg) 1° Endpoints – CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization

42 AIM-HIGH Terminated by Data Safety Monitoring Board: 36-month Follow-up On-treatment Lipids – HDL-C ↑ 20% / TG ↓ 25% – Baseline LDL-C: 71 mg/dL 1° Endpoints: Negative – 28 strokes (1.6%) on extended release niacin (ERN) – 12 strokes (0.7%) in control group – 9 of 28 strokes in ERN discontinued drug at least 2 months and up to 4 years before CVA Study’s Drug Safety and Monitoring Board recommended early termination, due to “futility” or lack of efficacy and the stroke signal Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm.

43 CETP Inhibitors Increase HDL-C and May Reduce Atherosclerosis

44 Role of CETP Inhibition in Atherosclerosis Human CETP deficiency is usually associated with marked ↑ in HDL-C CETP activity is inversely correlated with plasma HDL-C Decreasing CETP activity has consistently inhibited 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

45 Emerging CETP Inhibitors are Mechanistically Diverse

46 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

47 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%

48 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

49 Off-target Pharmacological Effects of Torcetrapib In patients receiving torcetrapib in the ILLUMINATE trial there was a significant: 1 – Increase in blood pressure:  5.4 mmHg in SBP in the torcetrapib arm  >15 mmHg in SBP at 12 months in 9.4% of the atorvastatin-only group and 19.5% of the torcetrapib group ( P <0.001) – Decrease in serum potassium – Increase in serum bicarbonate – Increase in serum sodium – Increase in serum aldosterone The adverse outcomes in the ILLUMINATE trial may have been the consequence of off-target actions of torcetrapib and 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.

50 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

51 Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP AgentDose (Mg/day)HDH-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.

52 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

53 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 (%)

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

55 Comparison of the Effect of CETP Agents on Serum HDL-C·AUC and Fecal Radioactivity Niesor EJ et al. J Lipid Res. 2010;51:3443-3454. * P < 0.01 # P < 0.01 Fecal [ 3 H] Total Sterols (% of Injection) HDL-CAUCFecal [ 3 H] total sterols ControlDalcetrapibTorcetrapib Anacetrapib 1500 1000 500 0 20 15 10 5 0 * * * # # HDL-C·AUC (mg/dL/day)

56 Dalcetrapib and Torcetrapib Differ in Mechanism by Which They Decrease CETP Activity 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. Therefore, no conclusion should be drawn based on these comparisons. Clinical development of torcetrapib was halted due to off-target adverse effects. dal HDL tor or ana CETP HDL Dalcetrapib binds to CETP, inducing a conformational change to CETP that hinders its further association to HDL 1 Dalcetrapib binds to CETP only 2 Torcetrapib or anacetrapib binding to CETP results in a high affinity complex of CETP inhibitor, HDL, and CETP 2,3

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

58 HDL 2a HDL 2b HDL 3c HDL 3b HDL 3a Particle size Apolipoprotein composition Particle shape Discoidal Spherical A-I HDLA-I/A-II HDL Lipid-poor ApoA-I E HDL HDL Can Be Subdivided into Various Subpopulations Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.

59 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. Extracellular spaceCell membrane FC ABCA1 Diffusion SR-B1 Diffusion SR-B1 ABCG1 Diffusion SR-B1 ABCG1 Lipid-poor ApoA-I Discoidal HDL Small spherical HDL Larger spherical HDL LCAT

60 Conclusions Residual CV risk remains problematic despite statin- mediated LDL-C reductionResidual CV risk remains problematic despite statin- mediated LDL-C reduction Low levels of HDL-C is an independent risk factor for CHD and meta-analyses and multivariate regression support the hypothesis that raising HDL-C reduces risk for CVDLow levels of HDL-C is an independent risk factor for CHD and meta-analyses and multivariate regression support the hypothesis that raising HDL-C reduces risk for CVD A variety of therapeutic approaches to elevate HDL-C are being tested prospectively in randomized trialsA variety of therapeutic approaches to elevate HDL-C are being tested prospectively in randomized trials HDL-C consists of heterogeneous particles, not all of which possess functional anti-atherogenic propertiesHDL-C consists of heterogeneous particles, not all of which possess functional anti-atherogenic properties CETP inhibitors are among the most important novel therapies for the elevation of functional HDLCETP inhibitors are among the most important novel therapies for the elevation of functional HDL

61 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. The first 50 respondents to the follow-up survey will receive an Amazon gift card from CE Outcomes. LIPOPROTEIN MANAGEMENT IN ACS Improving Outcomes in Patients with Complex Lipid Disorders


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