Lipid management in chronic kidney disease patients is controversial due to a lack of large randomized controlled trials. However, two pilot studies called UK-HARP I and II found that simvastatin alone or combined with ezetimibe lowered LDL and total cholesterol levels safely in CKD patients. This paved the way for the larger SHARP trial to determine if lipid-lowering agents can slow CKD progression and delay time to dialysis. Until results from SHARP are available, existing evidence suggests initiating statin therapy lowers risks of heart attack, death from heart disease, and need for heart procedures in CKD patients.

1. Lipid Management in Chronic Kidney Disease PatientsTejas Desai, MDECU Nephrology & HypertensionOffice: 252-744-2113Email: desait@ecu.eduVersion 1: 9/17/9

2. Historical ControversiesKnown that for every Δ -40 mg/dL of total cholesterol in patients with pre-existing CAD & without CKD per se, there is a Δ -25-30% risk of MI or CVA Most of these trials did not focus on CKD patientsSome have even excluded CKD patients from their investigations altogether Proceedings of the Royal College of Physicians 1999, Volume 29, pp. 10-15Lancet 2002, Volume 360, pp. 7-22NEJM 2000, Volume 343, pp. 317-326Diabetes Care 1993, Volume 16, pp. 434-444

3. Historical ControversiesSome have argued that lipid-lowering therapy in CKD and ESRD patients may be harmful if drug effects are not studied firstSome have argued that only 25% of deaths in CKD/ESRD patients are due to MI (75% due to congestive heart failure, arrhythmias, sudden cardiac death)Conditions that are not easily treated with lipid-lowering agents

4. Intuitively, it makes sense to treat CKD patients with Lipid-lowering agentsAll CKD/ESRD patients are at increased risk for vascular diseaseLipid-lowering agents, such as statins, have shown a benefit inhaltingthe progression of atherosclerotic vascular disease in non-CKD patientsWhy would we not see a similar beneficial effect in CKD/ESRD patients?SHARP Trial

5. SHARPStudy of Heart and Renal ProtectionA trial designed to look for any benefits of lipid-lowering agents in patients with CKD/ESRDPrefaced by 2 pilot studies to assess safety of statins in CKD patientsUK-HARP I and UK-HARP II

6. UK-HARP IGoalsAssess biochemical efficacy & safety of simvastatin 20 mg daily in CKD patients for 1 yearEstablish the feasibility of conducting a large-scale randomized control trial*Note: also assessed the safety of 100 mg of ASA daily in CKD patients for 1 yearAmerican Journal of Kidney Diseases, 2005, Volume 45, Issue 3.

7. UK-HARP IInclusion CriteriaAnyone > 18 years of ageCKD: Cr > 1.7 mg/dlHD or PD patientsPCP or Nephrologist found no compelling reason to start a statin or a contraindication to oneExclusion Criteria

8. If the MD felt statin therapy was required

9. h/o inflammatory muscle disorders, uremia recently, or liver diseaseAmerican Journal of Kidney Diseases, 2005, Volume 45, Issue 3.

10. UK-HARP I: American Journal of Kidney Diseases, 2005, Volume 45, Issue 3.

11. UK-HARP I: American Journal of Kidney Diseases, 2005, Volume 45, Issue 3.

12. Thus far…UK-HARP I20 mg/dsimvastatin leads to sustained decreases in LDL, total cholesterolNo major differences in side effectsUK-HARP II“a little more greedy”Can the addition of ezetimibe to 20 mg/dsimvastatin lead to even greater reductions in cholesterol in CKD patients?

13. UK-HARP IIInclusion & Exclusion criteria were the same as in UK-HARP IAmerican Journal of Kidney Diseases, 2006, Volume 47, Issue 3, pp. 385-95

14. UK-HARP II: American Journal of Kidney Diseases, 2006, Volume 47, Issue 3, pp. 385-95

15. UK-HARP II: American Journal of Kidney Diseases, 2006, Volume 47, Issue 3, pp. 385-95

16. Summary of UK-HARP I & II

17. SHARPAim is to study 3000 dialysis patients & 6000 CKD patientsAssess whether lipid-lowering agents can retard the progression of CKD and time to dialysisResults not available as of today

18. What evidence does exist as of today?GREACE Study: Treatment of dyslipidemias in patients with CADNot on statin: 5.2% decrease in CrClOn a statin: 4.9 – 12% increase in CrClPravastatin Pooling Project (PPP): Treatment of dyslipidemias in patients with CKD at risk for CADPravastatin decreased the risk for MI, surgical revascularization, or coronary death in moderate CKD patients (HR 0.77, p < 0.05)Meta-Analysis looking at statins and their effects on renal outcomesModest improvement in proteinuria (-0.37g/24h) & albuminuria (-0.02g/24h)Modest improvement in halting progression of kidney function (1.22 ml/min/yr slower than placebo) Journal of Clinical Pathology, 2004, Vol. 57, pp. 728-734Circulation, 2004, Vol. 10, pp. 1557-63JASN, 2006, Vol. 17, pp. 2006-2016

19. SummaryUK-HARP I & II have set the stage for a large, RCT to determine if statins +/- ezetimibe can retard kidney failureSHARP is the trial that we are awaiting for definitive guidanceUntil then, UK-HARP I & II, along with the previous studies, suggest that we should initiate statin therapy to at least lower the risk of CAD, coronary death, and need for surgical revascularization