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Lipid lowering therapy in CKD

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my lecture in lipid day ESC 11-nov-2010 …

my lecture in lipid day ESC 11-nov-2010
the updates about the use of lipid lowering therapy in CKD

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  • 1. Lipid lowering therapyLipid lowering therapy inin Chronic kidney diseaseChronic kidney disease AhmedAhmed TahaTaha M.ScM.Sc. Cardiology. Cardiology ZagazigZagazig UniversityUniversity www.cardiozag.comwww.cardiozag.com
  • 2. Is there is relationshipIs there is relationship betweenbetween CKD & CVD?CKD & CVD?.. •• CVD is the most common cause ofCVD is the most common cause of death in CKD Patientsdeath in CKD Patients.. Causes of Death in CKD Patients USRDS 2004 annual report ATP III, NCEP ATP III, NCEP CKD is considered >20% risk for CVD CKD is considered >20% risk for CVD
  • 3. The MoreThe More…… The MoreThe More…….. Hillege (PREVEND) population2002 Go (Kaiser) population2004 J circ 2002, J NEGM 2004
  • 4. RF deteriorationRF deterioration…….... •• Rapid changes inRapid changes in eGFReGFR is associated with higher risk and mortalityis associated with higher risk and mortality even after adjusting for covariates includingeven after adjusting for covariates including baslinebasline eGFReGFR.. A J soc kid,2009:Matsushita et al.,pages2617–2624
  • 5. Definition of CKDDefinition of CKD criteriacriteria Cockcroft-Gault formula : =(140-age)wt/72*cr.serum Women *0.85 MDRD: modified diet in renal disease : = 186 x [Pcr]-1.154 x [age]-0.203 x [0.742 if female] x [1.212 if AfAm] NKF KDOQI GUIDELINES 2002 < 15 or dialysis< 15 or dialysisKidney FailureKidney Failure55 1515--2929SevereSevere  GFRGFR44 3030--5959ModerateModerate  GFRGFR33 6060--8989MildMild  GFRGFR22 > 90> 90Kidney damage withKidney damage with normal ornormal or  GFRGFR 11 GFRGFR (mL/min/1.73m2)(mL/min/1.73m2) DescriptionDescriptionStageStage
  • 6. PathophysiologyPathophysiology of CVD in CKDof CVD in CKD J. Bras. Nefrol. São Paulo Jan./Mar. 2010 MIA syndrome
  • 7. Changes in lipid profile in CKDChanges in lipid profile in CKD Seliger SL et al. Kidney Int 2002;61:297-304.
  • 8. Lipid lowering therapyLipid lowering therapy HMGHMG CoACoA reductasereductase InhibitorsInhibitors ((statinsstatins))
  • 9. Effect ofEffect of statinsstatins in CKDin CKD Kerstin A. et al., Nephrol Dial Transplant (2010) RME-Megalin? prenylated GTP?
  • 10. 4D trial4D trial Wanner C et al. N Engl J Med. 2005;353:238-48.
  • 11. 4D study: primary endpoint4D study: primary endpoint Wanner C et al. N Engl J Med. 2005;353:238-48. KaplanKaplan--Meier estimate of time to first major CV eventMeier estimate of time to first major CV event Duration <3.5 y
  • 12. AURORA: primary endpointAURORA: primary endpoint KaplanKaplan--Meier estimate of time to first major CV eventMeier estimate of time to first major CV event Fellström BC et al. N Engl J Med 2009; 360: 1395–1407
  • 13. AURORA TrialAURORA Trial Primary and secondary endpointsPrimary and secondary endpoints Fellström BC et al. N Engl J Med 2009; 360: 1395–1407
  • 14. PostPost--hoc analysis of JUPITERhoc analysis of JUPITER trialtrial Ridker et al.,J. Am. Coll. Cardiol.2010 P=0.0001LDL>130mg/dl High hs-CRP CKD
  • 15. TNT (Treating to New Targets) studyTNT (Treating to New Targets) study CKD subCKD sub--studystudy Risk ReductionRisk Reduction --32% CKD32% CKD --15% normal15% normal eGFReGFR J Am CollCardiol.2008
  • 16. Strippoli G F M et al. BMJ 2008;336:645-651©2008 by British Medical Journal Publishing Group HoldassHoldass HH et al.(2007)et al.(2007) StrippoliStrippoli et al.(2008)et al.(2008) MetaMeta--analysisanalysis All cuase mortaility Non-significant (-17%;p=0.18) Combined incidence death Non-fatal MI High significant (-41%;p=0.007)
  • 17. 2009 Canadian Lipid2009 Canadian Lipid GuidelinesGuidelines •• StatinsStatins may not reduce risk inmay not reduce risk in hemodialysishemodialysis patients (AURORA,patients (AURORA, 4D trials): no effect on CVD.4D trials): no effect on CVD. •• We suggest that pts with CKD beWe suggest that pts with CKD be treated with thetreated with the lowest doselowest dose ofof statinstatin that reduces the LDLthat reduces the LDL--C to <C to < 2.62.6 mmolmmol/L/L”” IIb A K/DOQIK/DOQI GUIDELINESGUIDELINES IIa B
  • 18. ((PeroxisomePeroxisome proliferatorproliferator--activatedactivated receptorreceptor--alphaalpha)) PPARPPARαα transcriptiontranscription factorfactor ligandligand (( FibratesFibrates )) VAVA--HIT TrialHIT Trial ((Veterans' Affairs HighVeterans' Affairs High--DensityDensity Lipoprotein InterventionLipoprotein Intervention))
  • 19. VAVA--HIT: postHIT: post--hoc analysishoc analysis subgroup of 1,000 men with asubgroup of 1,000 men with a creatininecreatinine clearance <75ml/min (mild toclearance <75ml/min (mild to moderate CKD)moderate CKD) Incidence of death from CHD and nonfatal MI 1.200mg/day RRR 27% P=0.02 Tonelli M. et al., Kidney Int 2004;66:1123-1130 NKF guidelines: gemfibrozil is the fibrate of choice in patients with CKD
  • 20. OmegaOmega--3 Fatty Acids3 Fatty Acids The OPACH StudyThe OPACH Study ((OmegaOmega--3 Fatty Acids as Secondary Prevention Against3 Fatty Acids as Secondary Prevention Against Cardiovascular Events in Patients Who UndergoCardiovascular Events in Patients Who Undergo ChronicChronic HemodialysisHemodialysis)) A randomized, doubleA randomized, double--blind, placeboblind, placebo--controlled intervention trial compared thecontrolled intervention trial compared the effect of neffect of n--3 PUFA and a control treatment as secondary prevention of3 PUFA and a control treatment as secondary prevention of cardiovascular events in HD patients.cardiovascular events in HD patients.
  • 21. Copyright ©2006 American Society of Nephrology Svensson, M. et al. Clin J Am Soc Nephrol 2006;1:780-786 OPACH studyOPACH study
  • 22. Copyright ©2006 American Society of Nephrology Svensson, M. et al. Clin J Am Soc Nephrol 2006;1:780-786 OPACH studyOPACH study
  • 23. EzetimibeEzetimibe
  • 24. EzetimibeEzetimibe P<0.01 Ezetimibe is an option for patients who have not achieved NCEP/ ATP III LDL-C goals on statin monotherapy.
  • 25. SHARP trialSHARP trial •• 3,0003,000 hemodialysishemodialysis patients randomized topatients randomized to simvastatinsimvastatin 20mg/day or20mg/day or simvastatinsimvastatin 20mg/day plus20mg/day plus ezetimibeezetimibe.. •• The evaluation of the efficacy will no longer focus on the primaThe evaluation of the efficacy will no longer focus on the primaryry end point of major vascular events but instead will emphasize thend point of major vascular events but instead will emphasize thee effect on major atherosclerotic events, defined as the combinatieffect on major atherosclerotic events, defined as the combinationon of coronary death, MI, ischemic stroke, or any revascularizationof coronary death, MI, ischemic stroke, or any revascularization procedure (procedure (septsept 2010).2010). •• the results will be presented at the latethe results will be presented at the late--breaking clinical trialsbreaking clinical trials session at the American Society of Nephrology in Denver onsession at the American Society of Nephrology in Denver on Saturday 20th November 2010Saturday 20th November 2010
  • 26. NonNon--traditional lipidtraditional lipid lowering therapylowering therapy
  • 27. •• ionion--exchanging resin free of calcium andexchanging resin free of calcium and aluminiumaluminium that binds phosphate in the gutthat binds phosphate in the gut without increasing the calcium load.without increasing the calcium load. •• ItIt’’s found to have LDLs found to have LDL--lowering effect (bilelowering effect (bile--acidacid binding) without increase in TG.binding) without increase in TG. •• It hasIt has pleiotropicpleiotropic effect andeffect and uremicuremic toxintoxin clearance.clearance. •• But metBut met--analysis shows no better results thananalysis shows no better results than other Phother Ph--binders in all cause mortality andbinders in all cause mortality and primary endpoints.primary endpoints. Saudi J Kidney Dis Transpl 2008
  • 28. MetaMeta--analysisanalysis sevelamersevelamer vs calcium-based phosphate binders Tonelli M et al. Nephrol. Dial. Transplant. 2007;22:2856- 2866© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
  • 29. Non traditional Lipid loweringNon traditional Lipid lowering therapytherapy ACEIACEI Steno Type 2 StudySteno Type 2 Study ARBsARBs RENAAL TrialRENAAL Trial
  • 30. GUIDELINESGUIDELINES RECOMMENDATIONSRECOMMENDATIONS
  • 31. Practical guidelines approach inPractical guidelines approach in treatingtreating dyslipidemiadyslipidemia in CKDin CKD (ATP III) Guidelines(ATP III) Guidelines American Journal of Kidney Diseases,2003
  • 32. Proposed Treatment Algorithm for LipidProposed Treatment Algorithm for Lipid Management in Patients With CKDManagement in Patients With CKD ((Stage 3 to 5)Stage 3 to 5) OmegaOmega--3 fatty acids 33 fatty acids 3––4 g/day or4 g/day or gemfibrozilgemfibrozil 600mg/day600mg/dayVery high triglyceridesVery high triglycerides AtorvastatinAtorvastatin oror fluvastatinfluvastatin 40mg/day, add40mg/day, add ezetimibeezetimibe 10mg/day or omega10mg/day or omega--33 fatty acids 3fatty acids 3––4 g/day if not at non4 g/day if not at non--HDL goalHDL goal MixedMixed dyslipidemiadyslipidemia AtorvastatinAtorvastatin (10(10––80mg/day) or80mg/day) or fluvastatinfluvastatin 40mg/day, add40mg/day, add ezetimibeezetimibe if not atif not at LDLLDL--C goalC goal Elevated LDLElevated LDL--CC CKD stage 5 (CKD stage 5 (hemodialysishemodialysis or GFR <15ml/min/1.73mor GFR <15ml/min/1.73m22 )) 1.1. GemfibrozilGemfibrozil 600mg/day600mg/day 2.2. OmegaOmega--3 fatty acids 33 fatty acids 3––4 g/day4 g/day 3.3. FenofibrateFenofibrate 48mg/day48mg/day Very high triglyceridesVery high triglycerides (triglyceride(triglyceride ≥≥500mg/dl)500mg/dl) 1.1. AtorvastatinAtorvastatin oror fluvastatinfluvastatin ++ ezetimibeezetimibe 2.2. FluvastatinFluvastatin ++ gemfibrozilgemfibrozil 600mg/day +600mg/day + ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal 3.3. StatinStatin + omega+ omega--3 fatty acids, add3 fatty acids, add ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal 4.4. StatinStatin ++ fenofibratefenofibrate 48mg/day, add48mg/day, add ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal MixedMixed dyslipidemiadyslipidemia* (not at* (not at nonnon--HDLHDL†† goal)goal) 1.1. AtorvastatinAtorvastatin, add, add ezetimibeezetimibe if not at LDLif not at LDL--C goalC goal 2.2. FluvastatinFluvastatin, add, add ezetimibeezetimibe if not at LDLif not at LDL--C goalC goal Elevated LDLElevated LDL--CC Moderate to severe CKD, stages 3 to 4 (GFR 15Moderate to severe CKD, stages 3 to 4 (GFR 15––59ml/min/1.73m59ml/min/1.73m22 )) Therapeutic OptionTherapeutic OptionLipid DisorderLipid Disorder
  • 33. Lipid lowering therapy dose adjustedLipid lowering therapy dose adjusted for reduced GFR(ml/min/1.73 mfor reduced GFR(ml/min/1.73 m22 ))
  • 34. •• Patients at all stages of CKD have a significantlyPatients at all stages of CKD have a significantly elevated risk of allelevated risk of all--cause and CV mortality.cause and CV mortality. •• CKD may impart a CV risk equivalent toCKD may impart a CV risk equivalent to diabetes.diabetes. •• A decrease in CV events and CV mortality foundA decrease in CV events and CV mortality found inin predialysispredialysis (CKD stage3(CKD stage3--4)pts treated with4)pts treated with statinsstatins.. •• StatinsStatins may slow the rate of decline in renal fnmay slow the rate of decline in renal fn and reduceand reduce proteinuriaproteinuria •• Safe side effect profiles withSafe side effect profiles with statinsstatins with CKD.with CKD.
  • 35. •• FibratesFibrates may be used in CKD especially withmay be used in CKD especially with high TG levels, but with precautions of sidehigh TG levels, but with precautions of side effects (effects (RhabdomyolysisRhabdomyolysis).). •• GemfibrozilGemfibrozil is recommended by NFK.is recommended by NFK. •• New era of drugs likeNew era of drugs like sevelamersevelamer may providemay provide CKD pts. With moreCKD pts. With more proectionproection, but still need, but still need more large randomized trial to prove it.more large randomized trial to prove it.
  • 36. See you inSee you in 2323--24 December 201024 December 2010

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