Lipid lowering therapyLipid lowering therapyinin

Chronic kidney diseaseChronic kidney disease

Ahmed Ahmed TahaTahaM.ScM.Sc. Cardiology. Cardiology

ZagazigZagazig UniversityUniversity

www.cardiozag.comwww.cardiozag.com

Is there is relationshipIs there is relationshipbetweenbetween

CKD & CVD?CKD & CVD?..

•• CVD is the most common cause ofCVD is the most common cause ofdeath 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

The MoreThe More…… The MoreThe More……..

Hillege (PREVEND) population2002 Go (Kaiser) population2004

J circ 2002, J NEGM 2004

RF deteriorationRF deterioration……....

•• Rapid changes in Rapid changes in eGFReGFR is associated with higher risk and mortality is associated with higher risk and mortality even after adjusting for covariates including even after adjusting for covariates including baslinebasline eGFReGFR..

A J soc kid,2009:Matsushita et al.,pages2617–2624

Definition of CKDDefinition of CKDcriteriacriteria

Cockcroft-Gault formula : =(140-age)wt/72*cr.serum Women *0.85MDRD: 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 dialysis Kidney FailureKidney Failure55

1515--2929Severe Severe GFRGFR44

3030--5959Moderate Moderate GFRGFR33

6060--8989Mild Mild GFRGFR22

> 90> 90Kidney damage with Kidney damage with normal or normal or GFRGFR

11

GFRGFR(mL/min/1.73m2)(mL/min/1.73m2)

DescriptionDescriptionStageStage

PathophysiologyPathophysiology of CVD in CKDof CVD in CKD

J. Bras. Nefrol. São Paulo Jan./Mar. 2010

MIA syndrome

Changes in lipid profile in CKDChanges in lipid profile in CKD

Seliger SL et al. Kidney Int 2002;61:297-304.

Lipid lowering therapyLipid lowering therapy

HMGHMG CoACoA reductasereductase InhibitorsInhibitors((statinsstatins))

Effect ofEffect of statinsstatins in CKDin CKD

Kerstin A. et al., Nephrol Dial Transplant (2010)

RME-Megalin?prenylated GTP?

4D trial4D trial

Wanner C et al. N Engl J Med. 2005;353:238-48.

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

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

AURORA TrialAURORA TrialPrimary and secondary endpointsPrimary and secondary endpoints

Fellström BC et al. N Engl J Med 2009; 360: 1395–1407

PostPost--hoc analysis of JUPITERhoc analysis of JUPITERtrialtrial

Ridker et al.,J. Am. Coll. Cardiol.2010

P=0.0001LDL>130mg/dlHigh hs-CRP

CKD

TNT (Treating to New Targets) study TNT (Treating to New Targets) study CKD subCKD sub--studystudy

Risk ReductionRisk Reduction

--32% CKD32% CKD

--15% normal 15% normal eGFReGFR

J Am CollCardiol.2008

Strippoli G F M et al. BMJ 2008;336:645-651©2008 by British Medical Journal Publishing Group

HoldassHoldass H H et al.(2007) et al.(2007) StrippoliStrippoli et al.(2008)et al.(2008)MetaMeta--analysisanalysis

All cuase mortailityNon-significant (-17%;p=0.18)

Combined incidence deathNon-fatal MI

High significant(-41%;p=0.007)

2009 Canadian Lipid2009 Canadian LipidGuidelinesGuidelines

•• StatinsStatins may not reduce risk in may 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 be We suggest that pts with CKD be treated with the treated with the lowest doselowest dose of of statinstatin that reduces the LDLthat reduces the LDL--C to < C to < 2.6 2.6 mmolmmol/L/L””

IIbA

K/DOQIK/DOQIGUIDELINESGUIDELINES

IIaB

((PeroxisomePeroxisome proliferatorproliferator--activated activated receptorreceptor--alphaalpha) ) PPARPPARαα transcription transcription

factor factor ligandligand( ( FibratesFibrates ))

VAVA--HIT TrialHIT Trial((Veterans' Affairs HighVeterans' Affairs High--Density Density

Lipoprotein InterventionLipoprotein Intervention))

VAVA--HIT: postHIT: post--hoc analysishoc analysis

subgroup of 1,000 men with a subgroup of 1,000 men with a creatininecreatinine clearance <75ml/min (mild to clearance <75ml/min (mild to moderate CKD)moderate CKD)

Incidence of death from CHD and nonfatal MI

1.200mg/day

RRR27%

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

OmegaOmega--3 Fatty Acids3 Fatty Acids

The OPACH StudyThe OPACH Study((OmegaOmega--3 Fatty Acids as Secondary Prevention Against 3 Fatty Acids as Secondary Prevention Against

Cardiovascular Events in Patients Who Undergo Cardiovascular Events in Patients Who Undergo Chronic Chronic HemodialysisHemodialysis))

A randomized, doubleA randomized, double--blind, placeboblind, placebo--controlled intervention trial compared the controlled intervention trial compared the effect of neffect of n--3 PUFA and a control treatment as secondary prevention of 3 PUFA and a control treatment as secondary prevention of

cardiovascular events in HD patients. cardiovascular events in HD patients.

Copyright ©2006 American Society of Nephrology Svensson, M. et al. Clin J Am Soc Nephrol 2006;1:780-786

OPACH studyOPACH study

Copyright ©2006 American Society of Nephrology Svensson, M. et al. Clin J Am Soc Nephrol 2006;1:780-786

OPACH studyOPACH study

EzetimibeEzetimibe

EzetimibeEzetimibe

P<0.01

Ezetimibe is an option for patients who have not achieved NCEP/ ATP III LDL-C goals on statin monotherapy.

SHARP trialSHARP trial•• 3,000 3,000 hemodialysishemodialysis patients randomized to patients randomized to simvastatinsimvastatin 20mg/day or 20mg/day or

simvastatinsimvastatin 20mg/day plus 20mg/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 primary ry end point of major vascular events but instead will emphasize thend point of major vascular events but instead will emphasize the e effect on major atherosclerotic events, defined as the combinatieffect on major atherosclerotic events, defined as the combination on of coronary death, MI, ischemic stroke, or any revascularizationof coronary death, MI, ischemic stroke, or any revascularizationprocedure (procedure (septsept 2010).2010).

•• the results will be presented at the latethe results will be presented at the late--breaking clinical trials breaking clinical trials session at the American Society of Nephrology in Denver on session at the American Society of Nephrology in Denver on Saturday 20th November 2010Saturday 20th November 2010

NonNon--traditional lipidtraditional lipidlowering therapylowering therapy

•• ionion--exchanging resin free of calcium and exchanging resin free of calcium and aluminiumaluminium that binds phosphate in the gut that 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--acid acid binding) without increase in TG.binding) without increase in TG.

•• It has It has pleiotropicpleiotropic effect and effect and uremicuremic toxin toxin clearance.clearance.

•• But metBut met--analysis shows no better results than analysis shows no better results than other Phother Ph--binders in all cause mortality and binders in all cause mortality and primary endpoints.primary endpoints.

Saudi J Kidney Dis Transpl 2008

MetaMeta--analysisanalysissevelamer sevelamer 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

Non traditional Lipid loweringNon traditional Lipid loweringtherapytherapy

ACEIACEISteno Type 2 StudySteno Type 2 Study

ARBsARBsRENAAL TrialRENAAL Trial

GUIDELINESGUIDELINESRECOMMENDATIONSRECOMMENDATIONS

Practical guidelines approach in Practical guidelines approach in treating treating dyslipidemiadyslipidemia in CKDin CKD

(ATP III) Guidelines(ATP III) Guidelines

American Journal of Kidney Diseases,2003

Proposed Treatment Algorithm for Lipid Proposed Treatment Algorithm for Lipid Management in Patients With CKD Management in Patients With CKD ((Stage 3 to 5)Stage 3 to 5)

OmegaOmega--3 fatty acids 33 fatty acids 3––4 g/day or 4 g/day or gemfibrozilgemfibrozil 600mg/day600mg/dayVery high triglyceridesVery high triglycerides

AtorvastatinAtorvastatin or or fluvastatinfluvastatin 40mg/day, add 40mg/day, add ezetimibeezetimibe 10mg/day or omega10mg/day or omega--3 3 fatty acids 3fatty acids 3––4 g/day if not at non4 g/day if not at non--HDL goalHDL goal

Mixed Mixed dyslipidemiadyslipidemia

AtorvastatinAtorvastatin (10(10––80mg/day) or 80mg/day) or fluvastatinfluvastatin 40mg/day, add 40mg/day, add ezetimibeezetimibe if not at if 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/day2.2. OmegaOmega--3 fatty acids 33 fatty acids 3––4 g/day4 g/day3.3. FenofibrateFenofibrate 48mg/day48mg/day

Very high triglycerides Very high triglycerides (triglyceride (triglyceride ≥≥500mg/dl)500mg/dl)

1.1. AtorvastatinAtorvastatin or or fluvastatinfluvastatin + + ezetimibeezetimibe2.2. FluvastatinFluvastatin + + gemfibrozilgemfibrozil 600mg/day + 600mg/day + ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal3.3. StatinStatin + omega+ omega--3 fatty acids, add 3 fatty acids, add ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal4.4. StatinStatin + + fenofibratefenofibrate 48mg/day, add 48mg/day, add ezetimibeezetimibe if not at nonif not at non--HDL goalHDL goal

Mixed Mixed dyslipidemiadyslipidemia* (not at * (not at nonnon--HDLHDL†† goal)goal)

1.1. AtorvastatinAtorvastatin, add , add ezetimibeezetimibe if not at LDLif not at LDL--C goalC goal2.2. 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 Option Therapeutic Option Lipid DisorderLipid Disorder

Lipid lowering therapy dose adjusted Lipid lowering therapy dose adjusted for reduced GFR(ml/min/1.73 mfor reduced GFR(ml/min/1.73 m22 ))

•• Patients at all stages of CKD have a significantly Patients 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 to CKD may impart a CV risk equivalent to diabetes.diabetes.

•• A decrease in CV events and CV mortality found A decrease in CV events and CV mortality found in in predialysispredialysis (CKD stage3(CKD stage3--4)pts treated with 4)pts treated with statinsstatins..

•• StatinsStatins may slow the rate of decline in renal fn may slow the rate of decline in renal fn and reduce and reduce proteinuriaproteinuria

•• Safe side effect profiles with Safe side effect profiles with statinsstatins with CKD.with CKD.

•• FibratesFibrates may be used in CKD especially with may be used in CKD especially with high TG levels, but with precautions of side high TG levels, but with precautions of side effects (effects (RhabdomyolysisRhabdomyolysis).).

•• GemfibrozilGemfibrozil is recommended by NFK.is recommended by NFK.•• New era of drugs like New era of drugs like sevelamersevelamer may provide may provide

CKD pts. With more CKD pts. With more proectionproection, but still need , but still need more large randomized trial to prove it.more large randomized trial to prove it.

See you inSee you in

2323--24 December 201024 December 2010