1. New Advances in CV Risk Reduction in High Risk Patients A/Prof. Karam Kostner Mater Hospital and University of Queensland Brisbane, Australia

3. LL- Therapy LDL-C Lowering HDL-C Raising TG Lowering Statins Statins++++++++ Niacins Niacins+++++++++ Resins Resins+++0/- Fibrates Fibrates+/-+++++++ Ezetimibe Ezetimibe++++ n - 3 Ethyl Esters n - 3 Ethyl Esters0/-+++++ + = positive effect - = negative effect 0 = no effect

4. Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279 LaRosa JC et al. N Engl J Med 2005;352:1425-1435 Effect of Statins on CHD Events by LDL-C achieved: ‘ the lower the better ’ LDL- Cholesterol achieved, mmol/L CHD Event Rate (%) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx 0 5 10 15 20 25 30 1.01.62.12.63.13.64.14.7 6 Secondary Prevention Primary Prevention Rx - Statin therapy PRA – pravastatin ATV - atorvastatin 5.2 PROVE-IT - PRA PROVE-IT – ATV TNT – ATV10 TNT – ATV80 Cards - Rx Cards - Placebo HPS - Placebo HPS - Rx TNT Diab ATV 10 TNT Diab ATV 80

5. Persistent Lipid Abnormalities in Patients on Statins: DYSIS CHD or Risk Equivalent (n = 13,503) (70.3%) Two or More Risk Factors (n = 3,522) (18.3%) Zero or One Risk Factor (n = 2,171) (11.3%) LDL-C not at goal (%) 43.435.716.7 Non–HDL-C not at goal (%)* 71.156.835.8 Low HDL-C (%)35.933.61.4 Elevated triglycerides (%) 40.941.520.7 High triglycerides (%)** 67.470.269.5 Alexander W. American college of cardiology, 58th annual scientific session. P T. 2009;34(5):258-260

6. PROVE-IT: Residual CVS Events Risk Residual Risk pravastatin 40 mg LDL-C reduction 10% atorvastatin 80 mg LDL-C reduction 42% 16% reduction p=0.005 Cannon CP et al. N Engl J Med 2004; 350: 1495–1504

7. Approaches to Reduce Residual Risk Low Density Lipoprotein (LDL)  Low Density Lipoprotein (LDL)  Triglyceride  Triglyceride  High Density Lipoprotein (HDL)  High Density Lipoprotein (HDL)  ApoA-1  ApoA-1  Lp(a)  Lp(a)  Inflammation  Inflammation  BP, Smoking, Weight, Stress, Pollution BP, Smoking, Weight, Stress, Pollution

8. % CHD events O’Keefe, JACC 2004; 2142-6 What is the LDL-cholesterol level we should aim for? “in secondary prevention the event rate is predicted to approach zero at LDL of 30 mg/dl = 0.8 mmol/L” “in secondary prevention the event rate is predicted to approach zero at LDL of 30 mg/dl = 0.8 mmol/L” “in primary prevention the event rate is predicted to approach zero at LDL of 57 mg/dl = 1.5 mmol/L” “in primary prevention the event rate is predicted to approach zero at LDL of 57 mg/dl = 1.5 mmol/L” CARDS-S CARDS-P % CHD events IMPROVE-IT (Ezetimibe +Sim 40)

9. How low can we go? Cholesterol and TG can be reduced by 99% Kostner K et al. JCA. 2005 Oct;20(3):143-53.

10. THREE-STEP TITRATION 102030405060 % Reduction in LDL Cholesterol 0 -6% Statin 10 mg 20 mg 40 mg 80 mg -6% Effect of Statin Therapy on LDL-C Levels: “The Rule of 6” “The Rule of 6” for Statins

11. Ezetimibe: Efficacy LDL-CTriglycerideHDL-C * P < 0.05 vs placebo * * J Am Coll Cardiol 2000; 35(supp A):257A

12. Effect of ezetimibe coadministered with statins in heterozygous FH patients Piciotta L et al. Atherosclerosis 2006

13. Risk ratio & 95% CI EventPlaceboEze/simv (n=4620)(n=4650) Major coronary event213(4.6%)230(5.0%) Non-haemorrhagic stroke131(2.8%)174(3.8%) Any revascularization284(6.1%)352(7.6%) Major atherosclerotic event526(11.3%) 619 (13.4%)16.5% SE 5.4 reduction (p=0.0022) Other cardiac death162(3.5%)182(3.9%) Haemorrhaghic stroke45(1.0%)37(0.8%) Other major vascular events207(4.5%)218(4.7%)5.4% SE 9.4 reduction (p=0.57) Major vascular event701(15.1%)814(17.6%)15.3% SE 4.7 reduction (p=0.0012) 0.60.81.01.21.4 SHARP: Major Atherosclerotic Events Eze/simv better Placebo better

14. Risk Factor Components of the Atherogenic Lipid Profile Lp(a) HDL-C LDL-C Remnant Lipoproteins  Chylomicrons  VLDL Accelerated Atherosclerosis + Cardiovascular Disease Triglycerides TG-rich Lipoproteins  Fasting  Nonfasting

15. Treatment of elevated triglycerides 1) achieve LDL goal 2) low fat diets,weight red. and physical activity 3) fibrates, nicotinic acid 4) high dose fish oil 5) improve diabetic control

16. Reasons for Combination Therapy  To achieve LDL-C goal when monotherapy inadequate (elevated LDL-C)  To achieve Non- HDL-C or apoB, Lp(a) goal after LDL-C goal achieved (mixed HL)  To reduce Triglycerides in severe hypertriglyceridaemia (TG > 5 mmol/L)

17. Common Combination Therapies in Lipid Lowering “Safer” combinations Statins + BABRs for LDL-C lowering Statins + ezetemibe for LDL-C lowering Statins + niacin for LDL-C and TG lowering Statins + omega-3 ethyl esters for TG lowering Combinations that may require additional monitoring Statin + fibric acid for combined dyslipidemias Statin + fibric acid + niacin + for combined dyslipidemias

18. Ezetimibe/Simvastatin (VYTORIN) Significantly Reduces LDL-C Across the Dose Range Compared with ROSUVASTATIN 0 –50 –55 –45 –65 –60 a P<0.001; b P=0.001 vs rosuvastatin Adapted from Catapano AL et al Curr Med Res Opin. 2006;22:2041–2053. –54.8% b –52.3% 10/40 mg (n=477) 20 mg (n=478) –51.5% a –45.8% 10/20 mg (n=476) 10 mg (n=475) –61% a –56.7% 10/80 mg (n=474) 40 mg (n=475) Mean % change from baseline to week 6 Ezetimibe/simvastatin Rosuvastatin

19. SAFARI Trial: Combination Therapy with Simvastatin and Fenofibrate in Patients With Combined Hyperlipidemia Grundy SM et al Am J Cardiol 2005;95:462-468. *P<.001 versus simvastatin * * * * N=618

20. Steps to Minimize the Risk of Muscle Toxicity With Fibrate–Statin Combination Therapy  Use fenofibrate over gemfibrozil  Use low drug doses  Dose fibrate in AM and statin in PM  Caution in renal impairment  Watch for significant drug interactions  Teach patient to recognize muscle symptoms  Discontinue therapy with muscle symptoms and CK >10 upper limit of normal

21. Efficacy of Fixed-Dose Niacin ER/Simvastatin Combination Therapy SEACOAST I Simvastatin 20 mg (n = 90) Niacin ER/Simvastatin 1000/20 mg (n = 78) Niacin ER/Simvastatin 2000/20 mg (n = 40) Median % Change From Baseline a a Simvastatin 20 mg baseline *P<.01 versus simvastatin 20 mg; **P<.001 versus simvastatin 20 mg * ** * * Ballantyne C et al Am J Cardiol 2008;101:1428 Non–HDL-C HDL-C TG LDL-C Lp(a) 163.5 Median Baseline, mg/dL 156.3155.0119.0112.8115.0 42.5 42.8 43.0 194.5212.3196.512.010.017.0

22. Efficacy of Extended-Release Niacin Change from Baseline 2500 mg 3000 mg Goldberg A et al Am J Cardiol 2000;85:1100-1105. 2000 mg 1500 mg 1000 mg 500 mg HDL-C LDL-C Lp(a) TG –9% –14% –22% –21% –17% 29.5% 30% 26% 22% 15% 10% –28% –35% –44% –39% –11% –5% –26% –3% –12% –30% –24% –17%

23. Slide Source Lipids Online Slide Library www.lipidsonline.org Use of Niacin 1) High risk (post MI, ACS, DM) Addition to statin in patients with low HDL 2) Combined Hyperlipidemia (elevated TG and LDL) 3) Elevated Lp(a) Other Uses: Statin intolerant patients and FH Kostner, 2011

24. Most Patients on ER Niacin Therapy Do Not Reach Therapeutic 2g Dose Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™. Kamal-Bahl et al. Dosage and Titration Patterns of Extended Release Niacin in Clinical Practice. Abstract presented at AHA 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington, D.C., May, 2006. N=14,386 N=6,349 N=5,277 N=5,402 N=2,104

25. 0 20 40 60 80 100 Extreme (GFSS 10) Severe (GFSS 7-9) Moderate (GFSS 4-6) None/Mild (GFSS 0-3) PBO (n=66)ERN/LRPT (n=130) N-ER (n=134) 88% 12% 76% 14% 8.5% 1.5% 50% 26% 18% 6% Percent of Patients Maximum GFSS, Presented as Percent of Patients ERN/LRPT patients had significantly (p<0.001) less flushing vs. N-ER patients, as measured by maximum GFSS categorized as none/mild, moderate, severe, or extreme. Significantly fewer ERN/LRPT vs. N-ER patients had: –Moderate or greater flushing: 24% vs. 50% (p<0.001) –Severe or greater flushing: 10% vs. 24% (p=0.003) –Discontinuation due to flushing: 0.8% vs. 3.7% (p<0.001) Asia Flushing Study (PN 056): Results Debra Kush et al. Cardiology 2009;114:192–198

26. Summary of Adverse Experiences (AEs) Study Parameter ERN/LRPT N=2,548 ERN or NSP N=1,268 Simvastatin or Placebo N=931 n%n%n% Treatment-related clinical AE90135.4 c,d 50139.515616.8 Treatment-related serious clinical AE 80.3 e,f 10.11 Discontinued due to treatment-related clinical AE b 32812.920416.1283.0 Incidence of treatment-related a AEs was similar between ERN/LRPT and ERN or NSP a Determined by the investigator to be possibly, probably, or definitely treatment-related. b Some patients discontinued due to flushing without an associated AE report. c 95% CI for difference with ERN or NSP does not include 0. d 95% CI for difference with simvastatin or placebo does not include 0. e 95% CI for difference with ERN or NSP includes 0. f 95% CI for difference with simvastatin or placebo includes 0. The 2 primary reasons for discontinuation: Flushing symptoms: ERN/LRPT 7.2%; ERN or NSP 16.6% Clinical AEs: ERN/LRPT 9.7%; ERN or NSP 7.0% Paolini et al. Cardiol Clin. 2008;26:547–560.

27. Dose Range of Omega-3 Required To Reduce Triglycerides TG 1.8-5.0 mmol/L at baseline (after 8-week run-in) 4 capsules of Omacor ® to reduce triglycerides 27

28. Combination Omega-3 and Simvastatin (COMBOS) in Patients with HyperTG TG LDL-C HDL-C VLDL-C Omaacor 4 g/d + simvastatin 40 mg/d Placebo + simvastatin 40 mg/d Davidson MH et al. Clin Ther. 2007;29(7):1354-1367. *P <0.0001 between groups † P = 0.0232 between groups ‡ P = 0.0522 between groups Median Change From Baseline (%) 5 –5 –10 –15 –20 –25 –30 3.4* –6.3 –7.2 –1.2 –2.8 –29.5* 0.7 ‡ 0 –27.5* –4.2 † –1.9 Apo B Non-HDL-C –9.0* –2.2 Additional changes to baseline simvastatin therapy

29. Lp(a): Epidemiology, Pathophysiology and Therapeutic Considerations

30. Risk of Myocardial Infarction by Extreme Levels of Lipoprotein(a) in the General Population Kamstrup, P. R. et al. JAMA 2009;301:2331-2339

31. For any given RF, LP(a) augments risk..

32. ATHEROGENICITY of Lp(a): MECHANISMS

33. Treatment of elevated Lp(a) 1) achieve LDL goal 2) ACE in proteinuric patients 3) Nicotinic acid 4) LDL-apheresis 5) Anti Lp(a) antisense and other novel therapies

34. Aggressive LDL und Lp(a) Reduction in FH Patients Hoffmann U, Kostner K et al. Am J Cardiol. 2003 Feb 15;91(4):461-4

35. Efficacy of Extended-Release Niacin Change from Baseline 2500 mg 3000 mg Goldberg A et al. Am J Cardiol 2000;85:1100-1105. 2000 mg 1500 mg 1000 mg 500 mg HDL-C LDL-C Lp(a) TG –9% –14% –22% –21% –17% 29.5% 30% 26% 22% 15% 10% –28% –35% –44% –39% –11% –5% –26% –3% –12% –30% –24% –17%

36. Inverse Relationship between Bile Acids and Plasma Lp(a) 20 patients with obstructive cholestasis before and after surgery Bile acids are ligands for FXR

37. 0.2% cholic acid treatment reduces plasma apo(a) concentration in wt – mice but not in FXR-/- mice Plasma apo(a) levels were measured using DELFIA Single tg apo(a)-YAC Double tg apo(a)-YAC X FXR-/- I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin Invest.doi:10.1172/JCI45277;2011

38. i.p. injection of the FXR ligand GW4064 (30mg/kg body wt) (n=3) Quantifying hepatic apo(a) gene and protein expression 16hr-harvesting the tissues The selective FXR ligand GW4064 decreases apo(a) gene expression in YAC- apo(a) Tg mice (n=3) I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin Invest.doi:10.1172/JCI45277;2011

39. Selected Pipeline Therapies  Therapies to increase LDL particle clearance  Thyroid hormone analogue  Proprotein convertase subtilisin/kexin type 9 inhibitor  Squalene synthase inhibitors  Therapies to decrease LDL particle production  Microsomal triglyceride transfer protein (MTP) inhibitors  Apolippoprotein B antisense  Therapies to increase HDL  CETP Inhibitors Stein EA. Endocrinol Metab Clin North Am 2009;38:99-119. Davidson MH. Curr Atheroscler Rep 2008;11:67-70.

40. Apolipoprotein B-100 Antisense Oligonucleotide (ASO) Therapy: Mipomersen  Mipomersen: second generation ASO that inhibits apolipoprotein B-100 protein synthesis 1  Phase 2 studies 2,3 in patients on statins and other lipid- lowering agents showed mipomersen dose-dependently reduced:  Apo B  LDL-C  Non-HDL-C  Triglycerides (TGs) 1.Crooke R, et al. In: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton, Florida: CRC Press, 2007:601-639. 2.Kastelein JJ, et al. Circulation. 2006;114(16):1729-1735. 3.Stein EA. Endocrin Metab Clin N Am. 2009; 38:99-119. ‘ Shooting the Messenger ’

41. Results – LDL Cholesterol Raal FJ et al Lancet 2010;375:998-1006.  Mean LDL-C change from baseline to PET  Mipomersen: 11.4 mmol/L to 8.4 mmol/L (mean reduction 24.7%)  Placebo: 10.4 mmol/L to 10.1 mmol/L (mean reduction 3.3%)

42. Results – Lipoprotein (a) Raal FJ et al. Lancet 2010;375:998-1006.  Mean LDL-C change from baseline to PET  Mipomersen: 0.6 g/L to 0.4 g/L (mean reduction 31.1%)  Placebo: 0.7 mmol/L to 0.6 mmol/L (mean reduction 7.9%)

43. Proprotein Convertase Subtilisin/Kexin Type 9  Member of family of proteases that degrade LDL-Receptor  Mutations leading to loss of function are associated with lifelong low LDL-C levels and decreased risk of cardiovascular disease  Inhibitors of PCSK9 are in development Stein EA Endocrinol Metab Clin North Am 2009;38:99-119. Horton JD, Cohen JC, Hobbs HH J Lipid Res 2009; 50: S172-177

44. Cholesterol Ester Transfer Protein (CETP) Lipoprotein Binding Surface

45. Effects and Safety of Anacetrapib Bloomfield D et al Am Heart J 2009;157:352-60.e2 Cannon CP et al N Eng J Med 2010, November 17 on-line

46. Results: HDL-cholesterol Bloomfield D et al. Am Heart J 2009;157:352-60.e2

47. Results: LDL-cholesterol Bloomfield D et al Am Heart J 2009;157:352-60.e2

48. Results: Lp(a) Bloomfield D et al. Am Heart J 2009;157:352-60.e2

49. Conclusions  Extensive evidence suggests statins as initial therapy for dyslipidemia ( FH, DM, CHD), except in severe hyperTG  Consider adding second or third agent when LDL-C (ezetimibe) or non-HDL-C goal (niacin, fenofibrate) not achieved  For high risk patients with elevated TG and/or low HDL-C, consider adding a fibrate, niacin or n-3 acid ethyl esters to LDL-C lowering therapy  Combination therapy holds great promise for reducing residual CVD risk, especially with new agents in pipeline