2. Historical Controversies Known 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 patients Some have even excluded CKD patients from their investigations altogether Proceedings of the Royal College of Physicians 1999, Volume 29, pp. 10-15 Lancet 2002, Volume 360, pp. 7-22 NEJM 2000, Volume 343, pp. 317-326 Diabetes Care 1993, Volume 16, pp. 434-444
3. Historical Controversies Some have argued that lipid-lowering therapy in CKD and ESRD patients may be harmful if drug effects are not studied first Some 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 agents All CKD/ESRD patients are at increased risk for vascular disease Lipid-lowering agents, such as statins, have shown a benefit inhaltingthe progression of atherosclerotic vascular disease in non-CKD patients Why would we not see a similar beneficial effect in CKD/ESRD patients? SHARP Trial
5. SHARP Study of Heart and Renal Protection A trial designed to look for any benefits of lipid-lowering agents in patients with CKD/ESRD Prefaced by 2 pilot studies to assess safety of statins in CKD patients UK-HARP I and UK-HARP II
6. UK-HARP I Goals Assess biochemical efficacy & safety of simvastatin 20 mg daily in CKD patients for 1 year Establish 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 year American Journal of Kidney Diseases, 2005, Volume 45, Issue 3.
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 I 20 mg/dsimvastatin leads to sustained decreases in LDL, total cholesterol No major differences in side effects UK-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 II Inclusion & Exclusion criteria were the same as in UK-HARP I American 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
17. SHARP Aim is to study 3000 dialysis patients & 6000 CKD patients Assess whether lipid-lowering agents can retard the progression of CKD and time to dialysis Results not available as of today
18. What evidence does exist as of today? GREACE Study: Treatment of dyslipidemias in patients with CAD Not on statin: 5.2% decrease in CrCl On a statin: 4.9 – 12% increase in CrCl Pravastatin Pooling Project (PPP): Treatment of dyslipidemias in patients with CKD at risk for CAD Pravastatin 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 outcomes Modest 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. 728-734 Circulation, 2004, Vol. 10, pp. 1557-63 JASN, 2006, Vol. 17, pp. 2006-2016
19. Summary UK-HARP I & II have set the stage for a large, RCT to determine if statins +/- ezetimibe can retard kidney failure SHARP is the trial that we are awaiting for definitive guidance Until 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
