1. Chronic kidney disease (CKD) is associated with a significantly higher risk of cardiovascular disease (CVD) mortality. CVD is the leading cause of death in CKD patients. 2. Lipid abnormalities are common in CKD and contribute to increased CVD risk. Statins are generally safe and effective for lowering lipid levels in CKD, and may help slow CKD progression as well as reduce proteinuria. 3. Other lipid lowering agents like fibrates and omega-3 fatty acids may benefit CKD patients, especially those with high triglyceride levels, but require monitoring for side effects. New drugs continue to be studied to provide more comprehensive cardioprotection for those with CKD.

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.

37. See you inSee you in
2323--24 December 201024 December 2010