Disclosures / Conflicts of Interest Alfred K. Cheung, M.D.

1. Disclosures / Conflicts of InterestAlfred K. Cheung, M.D. None relevant to this topic

3. Lipid Control Is it really needed in the ESRD patient? ESRD: STATE OF THE ART AND CHARTING THE CHALLENGES FOR THE FUTURE April 23-26, 2009 Alfred K. Cheung, M.D.

4. Lipid Control Is it really needed in the ESRD patient? I don’t know

5. Unconventional Relationship with Clinical Outcomes in HD Patients • Blood pressure • Hemoglobin • Blood glucose

6. Is Dialysis World round or flat?

7. Serum Cholesterol and CHD Death Rate in MRFIT(N=361,662) Martin, Lancet 1986

8. Can LDL-C be too low?(Atorvastatin 80 mg in PROVE-IT with achieved LDL <100 mg/dl) Target 70-100 Wiviott , 2005

9. CAD Risk Reduction in 49 Randomized Trials Should be long enough for HD patients to benefit Law MR, 2003

10. Hemodialysis Patients N = 13,535 Relative Death Risk Total Cholesterol (mg/dL) Lowrie, 2002

11. Total cholesterol n = 206 213 130 85 43 65 52 29 Inflammation / Malnutrition Liu, CHOICE, 2004

12. Effect in Simvastatin on Total Mortality in Mild CKD Total Mortality eGFR < 75 eGFR ≥ 75 • 4S post-hoc analysis • 4444 patients with CHD • 2314 (52%) CKD eGFR < 75 eGFR ≥ 75 Major coronary events eGFR < 75 eGFR ≥ 75 CHD death or nonfatal MI eGFR < 75 eGFR ≥ 75 CABG or PTCA eGFR < 75 eGFR ≥ 75 Stroke 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Simvastatin Better Simvastatin Worse Chonchol AJKD, 2007

13. Die Deutsche Diabetes Dialyse Studie 4D Study: Effects of Statins on HD Patients Prospective, randomized double-blind study with type II DM Atorvastatin 20 mg QD Placebo 1255patients Placebo Wanner, NEJM. 2005;

14. 4D LDL-C Lowering by Atorvastatin in DM HD 140 120 Placebo 100 LDL cholesterol (mg/dL) 80 60 Atorvastatin 40 20 0 0 1 2 3 4 5 6 Years Wanner, 2005

15. 4D Primary composite end point (Cardiac death / MI / stroke) 60 • 2X fatal stroke (13 vs. 27 events, p=0.04) • 32% incardiac events 50 40 Cumulative incidence (%) 30 Placebo 20 Atorvastatin RR reduction = 8% (0.77-1.10) 10 0 4 0 1 2 3 5 5.5 years Years from Randomization Wanner, 2005

16. A study to evaluate the Use of Rosuvastatin in subjects on Regular hemodialysis: an Assessment of survival and CV events (AURORA) • 280 centers in 25 countries • 2,776 HD patients (age 50-80 yrs) ~40% history of CVD ~25% DM (vs. 4D) • Rosuvastatin (10 mg vs. placebo) • ACM and CV events Fellstrom, 2009

17. AURORA RESULTS Decrease in LDL-C by 46% No effect on primary outcome: CV death + MI + stroke

18. Study of Heart and Renal Protection • ~9,000 patients (~6000 CKD + ~3000 HD/PD) • No lipid criteria (statin not obviously indicated) • 19% DM (vs. 100% in 4D) • No prior MI or coronary revascularization • Simvastatin (20 mg) + ezetimibe (10 mg) • Results? • It is very difficult to prophesize, especially about the future

19. Why is lowering LDL-cholesterol ineffective in improving clinical outcomes in dialysis patients?

20. It is too late to treat !!

21. Hypothesis: Atherosclerosis is not a major problem in dialysis patients

22. LIPIDS Oxidative stress Inflammation Uremia Endothelial dysfunction Homocysteine CVD Abnormal glucose metabolism Fluid HTN Genetics Phosphorus Vascular calcification Too thin Vitamin D deficiency Too fat Too much ESA Vitamin K deficiency Too much blood Anemia

23. VLDLr torcetrapib Cholesterol ester transfer protein Lecitin cholesterol acyl-transferase

24. Dyslipidemia in Dialysis Patients • Hypertriglyceridemia • in lipoprotein remnants • Total TG ~265 mg/dL in 4D; ~155 mg/dL in AURORA • Low HDL and impaired anti-oxidant activity of HDL • Abnormal LDL • modified (oxidized, glycated, carbamylated) Not responsive to statins

25. Triglycerides and HDL-C are Independent CAD Risk Factors Hopkins , JACC, 2005

26. Fasting TG, HDL and Risk for CHDThe Helsinki Heart Study 67% reduction ns ns ns Manninen, Circulation, 1992.

27. LDL-cholesterol

28. Tentative Practice Guidelines for Dyslipidemia in HD Patients • Would not discontinue statins; consider initiating statin for LDL-C >130 mg/dL (reduce lovastatin dose by 50%) • For total TG >500 mg/dL • w-3 FA 3-4 gm QD • gemfibrozil 600 mg QD (beware of fenofibrate) • Niacin is a reasonable alternative • decrease TG • increase HDL-C • decrease small dense LDL

29. Conclusions in ESRD Patients • Serum total and LDL-cholesterol levels are not usually high • Despite lowering of LDL-cholesterol levels, there is no convincing evidence for benefits or harm associated with statin use • There are other dyslipidemia that may be more atherogenic in uremia (e.g., hypertriglyceridemia associated with retention of lipoprotein remnants; low HDL levels and activities as result of uremic modifications) • Future clinical research should concentrate on these other dyslipidemic states

30. Lipid Control Is it really needed in the ESRD patient? CANNOT SAY “YES” IN 2009 NOT total cholesterol or LDL-cholesterol

32. ADA/ACC 2008 Consensus Statement:Treatment Goals in Patients With Cardiometabolic Risk “In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C, especially if Apo B levels remain elevated,combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid…” Brunzell JD, et al. JACC 2008; 51:1512.

34. ADA and ACC Consensus StatementTreatment Recomendations • A statin is the initial drug of choice. • If LDL goal not reached consider adding: • ezetimibe • bile acid sequestrants (can raise TG) • niacin • Low HDL-C or elevated non-HDL-C, especially if apoB remains elevated: • combination therapy is recommended • niacin first choice Brunzell JD, et al. JACC 2008; 51:1512.

35. ADA and ACC Consensus StatementTreatment Recomendations • Fibrates have been shown to reduce CVD events in some studies but not total mortality • N-3 fatty acid therapy • CVD outcome data are lacking for hypertriglyceridemic patients • Clear reduction in CV risk in other studies • Severe hypertriglyceridemia : • fat restriction • fibrate • niacin • high-dose n-3 FA (4 g / day) Brunzell JD, et al. JACC 2008; 51:1512.

36. ADA and ACC Consensus StatementTreatment Recommendations: Niacin • Niacin decreased CVD in the Coronary Drug Project and total mortality in an extended follow up • Niacin in combination with bile-acid sequestrants or statin was associated with regression of atherosclerosis and CVD events in several studies • FATS, HATS, ARBITER 2, CLAS • In diabetes the use of low dose niacin (1500 mg/day) does not significantly increase A1C levels Brunzell JD, et al. JACC 2008; 51:1512.

37. Potential Mechanism of Statin Benefit in Kidney Disease • Inhibit mesangial proliferation • Inhibit induction of TGF- and increase in extracellular matrix • Inhibition of induction of MCP-1 • Decrease in inflammation and oxidative stress • Ameliorate podocyte damage • Hemodynamic effects on endothelial function and vasodilation • Ameliorate renal vascular disease Fried L, et al. Kidney Int. 2008;74:571-576.

38. Statins for Improving Renal Outcomes: Meta-analysis • 39,704 participants (27 studies) • 21 studies with data for eGFR and 20 for albuminuria or proteinuria • Change in mean differences for eGFR was significant: 1.22 ml/min per yr slower in statin recipients • Subgroup analysis: benefit of statin was significant in studies of participants with CVD but not in populations with diabetic or hypertensive kidney disease or glomerulonephritis • Reduction in albuminuria or proteinuria as a result of statin therapy was also significant: 0.58 Units of SD greater decrease in statin recipients Sandhu S, et al. JASN. 2006;17:2006-2016.

39. Meta-analysis: Lipid Reduction Shown to Reduce Albuminuria and Proteinuria -0.9 0.0 0.3 WMD Favors Statin Favors Placebo Douglas K, et al. Ann Intern Med. 2006;145:117-124.

40. Cumulative Incidence, % Year VA-HIT: Cumulative Incidence of CHD Death and Nonfatal MI Placebo Gemfibrozil Rubins HB, et al. N Engl J Med. 1999;341:410-418.

41. Statins decreases CV events in Patients with normal LDL-C • JUPITER • Comparative Atorvastatin Pleiotropic Effects • However, no effect in HD patients (11% decrease in CRP in AURORA, not ine 4D)

42. Rate of Change in MDRD-GFR in Pravastatin CKD Recipients Loss of Kidney Function Faster than Placebo Loss of Kidney Function Slower than Placebo N=690 (20.4%) GFR < 60, no proteinuria GFR < 60, proteinuria GFR < 50, no proteinuria GFR < 50, proteinuria GFR < 40, no proteinuria GFR < 40, proteinuria -2.5 -1.5 - 0.5 0.5 1.5 2.5 4.5 3.5 Rate of Kidney Function Loss mL/min/1.73m2 Tonelli M, et al. JASN. 2003;14:1605-1613.

43. Effect of Atorvastatin on Inflammation in Patients with Type 2 Diabetes Mellitus on Hemodialysis p=0.71 p=0.001 Krane V, et al. Kidney Int 2008.

44. Dosing Modifications for Lipid-Lowering Drugs in CKD Harper CR. J Am Coll Cardiol. 2008;51:2375-2384..

45. How Should We Treat Them? Harper CR. J Am Coll Cardiol. 2008;51:2375-2384.

46. Drug Interactions Agarwal R. Mayo Clin Proc. 2007;82:1381-1390.

47. How Should We Treat Them? Harper CR. J Am Coll Cardiol. 2008;51:2375-2384.

48. Apolipoprotein abnormalities in CRF • ↓ ApoA-1, ↓ ApoA-2 • ↓ ApoE • ↓ Apo CII/CIII ratio • ↑ ApoB • ↑ LP(a)

49. Triglycerides and TG-Rich LP Metabolism In CRF • ↑ plasma VLDL, ↓ VLDL and CM clearance, • ↑ plasma IDL and CM remnants • ↑ plasma triglyceride • ↓ adipose tissue triglyceride • TG-enrichment of LDL and HDL

50. Lipoprotein Lipase Deficiency (LPL) • ↓ LPL expression and activity in muscle, myocardium and fat tissue (CRF rats) (Vaziri, Liang, Kidney Int 50:1928-1935, 1996; Vaziri et al AJP 273:F929-930, 1997) • Contributing factors: ↑ PTH, ↓ physical activity, uremic endocrinopathies, ↓ ApoC II/C III ratio, ↑ pre-B HDL, ↓ HDL-2, chronic heparin use, ?uremic inhibitor(s) • Consequences: - deficient delipidation of VLDL and CM - ↓ fat tissue TG - ↑ plasma TG - lipid fuel availability to muscles