Disclosures / Conflicts of Interest Alfred K. Cheung, M.D.

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Disclosures / Conflicts of InterestAlfred K.
Cheung, M.D.

• None relevant to this topic

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(No Transcript)
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Lipid Control Is it really needed in the ESRD
patient?

• ESRD STATE OF THE ART AND CHARTING THE
  CHALLENGES FOR THE FUTURE
• April 23-26, 2009
• Alfred K. Cheung, M.D.

4
Lipid Control Is it really needed in the ESRD
patient?

• I dont know

5
Unconventional Relationship with Clinical
Outcomes in HD Patients

• Blood pressure
• Hemoglobin
• Blood glucose

6
Is Dialysis World round or flat?
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Serum Cholesterol and CHD Death Rate in MRFIT
(N361,662)
Martin, Lancet 1986
8
Can LDL-C be too low?(Atorvastatin 80 mg in
PROVE-IT with achieved LDL lt100 mg/dl)
Target 70-100
Wiviott , 2005
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CAD Risk Reduction in 49 Randomized Trials
Should be long enough for HD patients to benefit
Law MR, 2003
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Hemodialysis Patients
N 13,535
Relative Death Risk
Total Cholesterol (mg/dL)
Lowrie, 2002
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Liu, CHOICE, 2004
12
Effect in Simvastatin on Total Mortality in Mild
CKD
Total Mortality
eGFR lt 75 eGFR 75

• 4S post-hoc analysis
• 4444 patients with CHD
• 2314 (52) CKD

eGFR lt 75 eGFR 75
Major coronary events
eGFR lt 75 eGFR 75
CHD death or nonfatal MI
eGFR lt 75 eGFR 75
CABG or PTCA
eGFR lt 75 eGFR 75
Stroke
0 0.5 1.0 1.5
2.0 2.5 3.0 3.5
Simvastatin Better
Simvastatin Worse
Chonchol AJKD, 2007
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Die Deutsche Diabetes Dialyse Studie 4D Study
Effects of Statins on HD Patients
Prospective, randomized double-blind study with
type II DM
Atorvastatin 20 mg QD Placebo
1255patients
Placebo
Wanner, NEJM. 2005
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4D
LDL-C Lowering by Atorvastatin in DM HD
140
120
Placebo
100
LDL cholesterol (mg/dL)
80
60
Atorvastatin
40
20
0
4
0
1
2
3
5
6
Years
Wanner, 2005
15
Primary composite end point (Cardiac death / MI /
stroke)
4D
60

• 2X fatal stroke (13 vs. 27 events, p0.04)
• 32 in cardiac events

50
40
Cumulative incidence ()
30
Placebo
20
Atorvastatin
RR reduction 8 (0.77-1.10)
10
0
1
2
3
4
5
0
5.5 years
Years from Randomization
Wanner, 2005
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A study to evaluate the Use of Rosuvastatin in
subjects on Regular hemodialysis an Assessment
of survival and CV events (AURORA)

• 280 centers in 25 countries
• 2,776 HD patients (age 50-80 yrs)
• 40 history of CVD
• 25 DM (vs. 4D)
• Rosuvastatin (10 mg vs. placebo)
• ACM and CV events

Fellstrom, 2009
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AURORA RESULTS
Decrease in LDL-C by 46
No effect on primary outcome CV death MI
stroke
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Study of Heart and Renal Protection

• 9,000 patients (6000 CKD 3000 HD/PD)
• No lipid criteria (statin not obviously
  indicated)
• 19 DM (vs. 100 in 4D)
• No prior MI or coronary revascularization
• Simvastatin (20 mg) ezetimibe (10 mg)
• Results?
• It is very difficult to prophesize, especially
  about the future

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Why is lowering LDL-cholesterol ineffective in
improving clinical outcomes in dialysis patients?
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It is too late to treat !!
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Hypothesis

• Atherosclerosis is not a major problem in
  dialysis patients

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Oxidative stress
Inflammation
Uremia
CVD
Fluid HTN
Genetics
Phosphorus Vascular calcification
Too thin
Vitamin D deficiency
Too fat
Too much ESA
Vitamin K deficiency
Too much blood
Anemia
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VLDLr
torcetrapib
Cholesterol ester transfer protein
Lecitin cholesterol acyl-transferase
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Dyslipidemia in Dialysis Patients

• Hypertriglyceridemia
• in lipoprotein remnants
• Total TG 265 mg/dL in 4D 155 mg/dL in AURORA
• Low HDL and impaired anti-oxidant activity of HDL
• Abnormal LDL
• modified (oxidized, glycated, carbamylated)

Not responsive to statins
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Triglycerides and HDL-C are Independent CAD Risk
Factors
Hopkins , JACC, 2005
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MI or Sudden Death in Bezafibrate Infarction
Prevention (BIP)
N3,090 TGlt300 mg/dL HDL-Clt45 mg/dL, LDLlt180
mg/dL
TG lt 200 mg/dL
TG gt 200 mg/dL
Rate
Rate
0 1 2 3
4 5 6 Time
(Years)
0 1 2 3
4 5 6 Time
(Years)
Circ. 2000
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Fasting TG, HDL and Risk for CHDThe Helsinki
Heart Study
67 reduction
ns
ns
ns
Manninen, Circulation, 1992.
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LDL-cholesterol
29
Tentative Practice Guidelines for Dyslipidemia
in HD Patients

• Would not discontinue statins consider
  initiating statin for LDL-C gt130 mg/dL (reduce
  lovastatin dose by 50)
• For total TG gt500 mg/dL
• w-3 FA 3-4 gm QD
• gemfibrozil 600 mg QD (beware of fenofibrate)
• Niacin is a reasonable alternative
• decrease TG
• increase HDL-C
• decrease small dense LDL

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Conclusions in ESRD Patients

• Serum total and LDL-cholesterol levels are not
  usually high
• Despite lowering of LDL-cholesterol levels, there
  is no convincing evidence for benefits or harm
  associated with statin use
• There are other dyslipidemia that may be more
  atherogenic in uremia (e.g., hypertriglyceridemia
  associated with retention of lipoprotein
  remnants low HDL levels and activities as result
  of uremic modifications)
• Future clinical research should concentrate on
  these other dyslipidemic states

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Lipid Control Is it really needed in the ESRD
patient?

• CANNOT SAY YES IN 2009
• NOT total cholesterol or LDL-cholesterol

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ADA/ACC 2008 Consensus StatementTreatment Goals
in Patients With Cardiometabolic Risk
Goals
LDL-C NonHDL-C Apo B
Highest-Risk Patients Known CVD Diabetes plus 1 additional major CVD risk factor lt70 mg/dL lt100 mg/dL lt80 mg/dL
High-Risk Patients 2 major CVD risk factors, no diabetes or known CVD but Diabetes but no other major CVD risk factors lt100 mg/dL lt130 mg/dL lt90 mg/dL
In individuals on statin therapy who continue to
have low HDL-C or elevated nonHDL-C, especially
if Apo B levels remain elevated, combination
therapy is recommended. The preferred agent to
use in combination with a statin is nicotinic
acid
Brunzell JD, et al. JACC 2008 511512.
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ADA and ACC Consensus StatementTreatment
Recomendations

• A statin is the initial drug of choice.
• If LDL goal not reached consider adding
• ezetimibe
• bile acid sequestrants (can raise TG)
• niacin
• Low HDL-C or elevated non-HDL-C, especially if
  apoB remains elevated
• combination therapy is recommended
• niacin first choice

Brunzell JD, et al. JACC 2008 511512.
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ADA and ACC Consensus StatementTreatment
Recomendations

• Fibrates have been shown to reduce CVD events in
  some studies but not total mortality
• N-3 fatty acid therapy
• CVD outcome data are lacking for
  hypertriglyceridemic patients
• Clear reduction in CV risk in other studies
• Severe hypertriglyceridemia
• fat restriction
• fibrate
• niacin
• high-dose n-3 FA (4 g / day)

Brunzell JD, et al. JACC 2008 511512.
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ADA and ACC Consensus StatementTreatment
Recommendations Niacin

• Niacin decreased CVD in the Coronary Drug Project
  and total mortality in an extended follow up
• Niacin in combination with bile-acid sequestrants
  or statin was associated with regression of
  atherosclerosis and CVD events in several studies
• FATS, HATS, ARBITER 2, CLAS
• In diabetes the use of low dose niacin (1500
  mg/day) does not significantly increase A1C
  levels

Brunzell JD, et al. JACC 2008 511512.
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Potential Mechanism of Statin Benefit in Kidney
Disease

• Inhibit mesangial proliferation
• Inhibit induction of TGF-? and increase in
  extracellular matrix
• Inhibition of induction of MCP-1
• Decrease in inflammation and oxidative stress
• Ameliorate podocyte damage
• Hemodynamic effects on endothelial function and
  vasodilation
• Ameliorate renal vascular disease

Fried L, et al. Kidney Int. 200874571-576.
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Statins for Improving Renal Outcomes
Meta-analysis

• 39,704 participants (27 studies)
• 21 studies with data for eGFR and 20 for
  albuminuria or proteinuria
• Change in mean differences for eGFR was
  significant 1.22 ml/min per yr slower in statin
  recipients
• Subgroup analysis benefit of statin was
  significant in studies of participants with CVD
  but not in populations with diabetic or
  hypertensive kidney disease or glomerulonephritis
  
• Reduction in albuminuria or proteinuria as a
  result of statin therapy was also significant
  0.58 Units of SD
  greater decrease in statin recipients

Sandhu S, et al. JASN. 2006172006-2016.
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Meta-analysis Lipid Reduction Shown to Reduce
Albuminuria and Proteinuria
Study, Year Statin Sample Size, n Effect (95 CI),
Excretion lt30 mg/d
Asselbergs et al., 2004 Pravastatin 864 12 (-1 to 25)
Dalla Nora et al., 2003 Atorvastatin 25 -70 (-171 to 31)
Fried et al., 2001 Simvastatin 39 -5 (-90 to 81)
Subtotal of WMD 2 (-32 to -35)

Excretion, 30-299 mg/d
Buemi et al., 2000 Fluvastatin 21 -73 (-136 to -10)
Lintott et al., 1995 Fluvastatin 42 -81 (-217 to 55)
Nakamura et al., 2001 Cerivastatin 60 -61 (-106 to -16)
Nielsen et al., 1993 Simvastatin 18 -44 (-113 to 25)
Tonolo et al., 1997 Simvastatin 20 -50 (-93 to -7)
Zhang et al., 1995 Pravastatin 20 -8 (-61 to 45)
Subtotal of WMD -48 (-71 to -25)

Excretion ?300 mg/d
Hommei et al., 1992 Simvastatin 21 -5 (-137 to 128)
Lam et al., 1995 Lovastatin 36 -32 (-102 to 38)
Lee et al., 2002 Pravastatin 66 -47 (-64 to -29)
Lee et al., 2005 Pravastatin 82 -62 (-79 to -45)
Nakamura et al., 2002 Cerivastatin 40 -67 (-87 to -48)
Thomas et al., 1993 Simvastatin 30 20 (-28 to 67)
Subtotal of WMD -47 (-67 to -26)
0.3
0.0
-0.9
WMD
Favors Statin
Favors Placebo
Douglas K, et al. Ann Intern Med.
2006145117-124.
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VA-HIT Cumulative Incidence of CHD Death and
Nonfatal MI
Placebo
Gemfibrozil
Rubins HB, et al. N Engl J Med. 1999341410-418.
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Statins decreases CV events in Patients with
normal LDL-C

• JUPITER
• Comparative Atorvastatin Pleiotropic Effects
• However, no effect in HD patients (11 decrease
  in CRP in AURORA, not ine 4D)

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Rate of Change in MDRD-GFR in Pravastatin CKD
Recipients
Loss of Kidney Function Faster than Placebo
Loss of Kidney Function Slower than Placebo
N690 (20.4)
GFR lt 60, no proteinuria
GFR lt 60, proteinuria
GFR lt 50, no proteinuria
GFR lt 50, proteinuria
GFR lt 40, no proteinuria
GFR lt 40, proteinuria
2.5
1.5
0.5
- 0.5
-1.5
4.5
-2.5
3.5
Rate of Kidney Function Loss
mL/min/1.73m2
Tonelli M, et al. JASN. 2003141605-1613.
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Effect of Atorvastatin on Inflammation in
Patients with Type 2 Diabetes Mellitus on
Hemodialysis
p0.71
p0.001
Krane V, et al. Kidney Int 2008.
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Dosing Modifications for Lipid-Lowering Drugs in
CKD
Agent GFR 60-90ml/min/1.73m2 GFR 15-59 ml/min/1.73m2 GFR lt15ml/min/1.73m2 Notes
Statins
Atorvastatin No No No
Fluvastatin No Not defined Not defined ? dose to one-half at GFR lt30 ml/min/1.73 m2
Lovastatin No ? to 50 ? to 50 ? dose to one-half at GFR lt30 ml/min/1.73 m2
Pravastatin No No No Start at 10 mg/day for GFR lt60 ml/min/1.73 m2
Rosuvastatin No 5-10 mg 5-10 mg Start at 5 mg/day for GFR lt30 ml/min/1.73 m2, max dose 10 mg/day
Simvastatin No No 5 mg Start at 5 mg if GFR lt 10 ml/min/1.73 m2
Nonstatins
Nicotinic acid No No ? to 50 34 kidney excretion
Cholestyramine No No No Not absorbed
Colesevelam No No No Not absorbed
Ezetimibe No No No
Fenofibrate ? to 50 ? to 25 Avoid May ? serum creatinine
Gemfibrozil No No No NLA recommends a dose of 600 mg/day for GFR 15-59 ml/min/1.73m2
Omega-3 FAs No No No
Harper CR. J Am Coll Cardiol. 2008512375-2384..
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How Should We Treat Them?
Lipid Disorder Lipid Disorder Therapeutic Option Therapeutic Option
Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2) Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2) Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2)
Elevated LDL-C 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia (not at non-HDL goal) 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal
Very high triglycerides (triglyceride ?500 mg/dl) 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day
CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2) CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2) CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2)
Elevated LDL-C Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal
Very high triglycerides Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day
Harper CR. J Am Coll Cardiol. 2008512375-2384.
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Drug Interactions
Statin Metabolic pathway Drug interactions
Atorvastatin CYP450 3A4 CYA, digoxin, fibric acid, niacin, erythromycin, antifungals
Fluvastatin CYP450 2C9 Omeprazole, phenytoin, ranitidine, rifampicin
Pravastatin Minimally metabolized Gemfibrozil
Rosuvastatin CYP450 2C9 (not extensively metabolized) CYA, gemfibrozil
Simvastatin CYP450 3A4 Amiodarone, CYA, gemfibrozil, antifungals, erythromycin, HIV protease inhibitors, verapamil
Agarwal R. Mayo Clin Proc. 2007821381-1390.
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How Should We Treat Them?
Lipid Disorder Lipid Disorder Therapeutic Option Therapeutic Option
Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2) Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2) Moderate to severe CKD, stages 3 to 4 (GFR 15-59 ml/min/1.73 m2)
Elevated LDL-C 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal 1. Atorvastatin, add ezetimibe if not at LDL-C goal 2. Fluvastatin, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia (not at non-HDL goal) 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal 1. Atorvastatin ofrfluvastatin ezetimibe 2. Fluvastatin gemfibrozil 600 mg/day ezetimibe if not at non HDL goal 3. Statin omega 3 fatty acids, add ezetimibe if not at non-HDL goal 4. Statin fenofibrate 48 mg/day, add ezetimibe if not at non-HDL goal
Very high triglycerides (triglyceride ?500 mg/dl) 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day 1. Gemfibrozil 600 mg/day 2. Omega-3 fatty acids 3-4 g/day 3. Fenofibrate 48 mg/day
CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2) CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2) CKD stage 5 (hemodialysis or GFR lt15 ml/min/1.73 m2)
Elevated LDL-C Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal Atorvastatin (10-80 mg/day) or fluvastatin 40 mg/day, add ezetimibe if not at LDL-C goal
Mixed dyslipidemia Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal Atorvastatin or fluvastatin 40 mg/day, add ezetimibe 10 mg/day or omega-3 fatty acids 3-4 g/day if not at non-HDL goal
Very high triglycerides Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day Omega-3 fatty acids 3-4 g/day or gemfibrozil 600 mg/day
Harper CR. J Am Coll Cardiol. 2008512375-2384.
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Apolipoprotein abnormalities in CRF

• ? ApoA-1, ? ApoA-2
• ? ApoE
• ? Apo CII/CIII ratio
• ? ApoB
• ? LP(a)

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Triglycerides and TG-Rich LP Metabolism In CRF

• ? plasma VLDL, ? VLDL and CM clearance,
• ? plasma IDL and CM remnants
• ? plasma triglyceride
• ? adipose tissue triglyceride
• TG-enrichment of LDL and HDL

51
Lipoprotein Lipase Deficiency (LPL)

• ? LPL expression and activity in muscle,
  myocardium and fat tissue (CRF rats)
• (Vaziri, Liang, Kidney Int 501928-1935,
  1996 Vaziri et al AJP 273F929-930, 1997)
• Contributing factors ? PTH, ? physical activity,
  uremic endocrinopathies, ? ApoC II/C III ratio,
• ? pre-B HDL, ? HDL-2, chronic heparin use,
  ?uremic inhibitor(s)
• Consequences
• - deficient delipidation of VLDL and CM
• - ? fat tissue TG
• - ? plasma TG
• - lipid fuel availability to muscles

52
VLDL Receptor Deficiency

• ? VLDLr mRNA and protein in skeletal muscle and
  fat tissue in CRF rats
• (Vaziri, Liang, Kidney Int 51913-919, 1997)
• CRF-induced VLDLr deficiency is unrelated to
• ? PTH
  
• (Liang, Oveisi, Vaziri, Kidney Int 53
  626-630, 1998)
• Consequences
• - ? VLDL clearance
• - ? plasma VLDL

53
Hepatic Lipase Deficiency in CKD

• ? Hepatic lipase mRN and activity in CRF rats
• (Klin et al, JCI 972167-2173, 1996 Sato,
  Liang, Vaziri, KI 641780-1786, 2003)
• Deficiency linked to 2 hyperparathyroidism
• (Klin et al)
• Consequences
• - ? IDL (? IDL? LDL conversion),
• - ? LDL-TG,
• - ? HDL-TG

54
Downregulation of LDL Receptor-Related Protein
(LRP) in CKD

• ? Hepatic LRP mRNA and protein abundance in CRF
  rats
• (Kim C, Vaziri ND. Kidney Int 671028-1032,
  2003)
• Consequences
• - ? Clearance and ? plasma chylomicron remnants
• (prolonged Post-prandial
  hyperlipidemia)

55
HDL- Metabolism in CRF

• ? HDL-3 maturation to HDL-2
• ? Pre-Beta HDL
• ? HDL-cholesterol
• ? HDL triglyceride
• Impaired HDL function

56
1-Apo A-I and Apo A-II In CRF

• ? Plasma ApoA-I and -II in CRF humans and animals
  
• ? Hepatic Apo A-I gene expression in CRF rats
• (Vaziri, Ding, Liang NDT 141462-1466, 1999)
• Consequence
• - ? plasma HDL

57
3- Lecithin Cholesterol Acyltransferase(LCAT)

• -Made by liver, secreted in plasma LCAT
  --Catalyzes extra-cellular
• A- Hydrolysis of sn-2 Fatty acid in
  phospholipids (phospholipase-2)
• B- Esterification of free cholesterol
• (acyltransferase activity)

58
Anti-atherogenic Actions of HDL

• A- Reverse cholesterol - lipid transport
• B- Antioxidant/anti-inflammatory actions
• a. ApoA-I mediated extraction of oxidized
  phospholipids from lipoproteins and cell
  membrane
• b. LCAT-mediated hydrolysis of proinflammatory
  oxidized phospholipids (AA at sn-2)
• c. Prevention of LDL oxidation and destruction
  of oxidized phospholipids by paraoxonase-1 GPX
• d. Inactivation of PAF and PAF-like
  phospholipids by PAF acetyl hydrolase
  (anti-inflammatory / anti-thrombotic)

59
Conclusions (2/3)

• These abnormalities are compounded by concomitant
  proteinuria (or ? PD) which can raise plasma chol
  by up-regulating HMG-CoA reductase lowering
  LDLr.
• Dysregulation of lipid metabolism and
  inflammation work in concert to promote
  atherosclerosis.
• Atherosclerosis in ESRD is primarily driven by
  inflammation which tends to lower plasma chol.
• Consequently, therapeutic strategies should be
  directed at amelioration of oxidative stress
  inflammation HDL and TG metabolism (as opposed
  to chol-lowering Rx).

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Hypertriglyceridemia in ESRD
VLDL
IDL
TG
LPL
FFA
LPL
CM remnant
CM
TG
Decreased LPL activity and VLDL receptor
therefore retain remnant particles, which are
putatively highly atherogenic
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Dyslipidemia in ESRD
Parameter Hemodialysis
Total cholesterol ??
LDL cholesterol ??
HDL cholesterol ?
Non-HDL cholesterol ??
TG ?
Lp(a) ?
ApoA-I ?
ApoA-IV ?
ApoB ??
Kwan BC, et al. J Am Soc Nephrol.
2007181246-1261.
62
Fasting Triglycerides and Incident CVD Risk
Meta-Analysis of Prospective Studies
Austin , Am J Cardiol 1998
63
Remnant-like lipoproteins activate endothelial
cells

• RLP isolated from postprandial plasma of patients
  with high RLP (gt75th percentile).
• RLP and other fractions incubated with confluent
  HUVEC
• ICAM-1, VCAM-1, tissue factor mRNA and on cell
  surface all increased similarly.
• Plasma sICAM-1 and sVCAM-1 higher in these
  patients.
• Possibly mediated by increased NF-?B,
  intracellular oxidation.

Doi H, et al. Circulation 2000 102670
p lt0.05 vs control p lt0.005 vs control
64
The Fenofibrate Intervention and Event Lowering
in Diabetes Trial

• N 9.795 type II DM
• No clear indication for lipid-lowering drugs
• Baseline LDL-C 119 mg/dL TG 154 mg/dL
• Fenofibrate 200 mg QD
• Subgroup TG gt200 mg/dL HR 0.77 (p0.01)
• Subgroup TG gt200 mg/dL low HDL-C HR 0.73
  (p0.005)

Unadj. Adjusted for statin
Lancet , 2005. Diabetic Care, 2009
65
Potential Caveats of AURORA

• Exclude patients on statins (who might need
  statins)
• Low event rates (selection bias against patients
  who needed statins)
• Age 50-80 yrs

66
SPACE (Secondary Prevention with Antioxidants of
CVD in ESRD)

• 196 HD patients with CVD
• Vitamin E (800 IU/d) vs. placebo
• Median F/U 1.4 yrs
• 1 endpoint Composite of MI / unstable angina /
  ischemic stroke / PVD
• Vitamin E arm
• RR 0.46 0.27-0.78 p0.014 for 1 endpoint
• No difference in mortality or individual CVD

Boaz, Lancet, 2000
67
JUPITER
Ridker P, Lancet, 2009
68
N-Acetylcysteine (NAC) in Hemodialysis

• 134 HD patients (including DM CVD)
• NAC 600 mg BID vs. placebo
• Median F/U 14.5 (124) months
• 1 endpoint Composite of CVD death / MI /
  coronary revascularization / ischemic stroke /
  PVD surgery
• RESULTS
• 28 of NAC vs. 47 of placebo reached 1 endpoint
  (RR 0.60 0.38-0.95 p0.03)
• No difference in total mortality

Tepel, Circ, 2003