Comprehensive Publication Review:
Dyslipidemia, Chronic Kidney Disease
and Cardiovascular Disease
Table of Contents
Author(s)
Publication
Slides
Attman P-O, et al
Curr Opin Lipidol 2009
3 – 14
Nogueira J, et al
Clin J Am Soc Nephrol 2007
15 – 24
Snyder JJ, et al
Am J Nephrol 2009
25 – 32
Levin A, et al
CMAJ 2008
33 – 46
Astor BC, et al
Am J Epidemiol 2008
47 – 56
Matsushita K, et al
Clin Epidemiol 2009
57 – 64
Shepherd J, et al
J Am Coll Cardiol 2008
65 – 71
Fellström B, et al
N Engl J Med 2009
72 – 78
Nakamura T, et al
Pharmacol Res 2009
79 – 86
Türk TR, et al
Nephrol Dial Transplant 2008
87 – 95
Baigent C, et al
Kidney Int Suppl 2003
96 – 105
Dyslipidemia of Kidney Disease
Attman PO, et al:
Curr Opin Lipidol 2009; 20(4):293-9.
Dyslipidemia of Kidney Disease
• Objective: To summarize current knowledge of the
pathophysiology of renal dyslipidemia and the
therapeutic options
• Topics covered:
–
–
–
–
Lipoprotein profile
Causes
Consequences
Therapy
Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Background on Dyslipidemia in
CKD
• With declining renal function, a complex series of
various metabolic changes and adaptations occur
• In advanced chronic kidney disease (CKD), the
lipid profile is characterized by the following:
– Markedly elevated triglycerides and triglyceride-rich
apoB-containing lipoproteins
– Decreased HDL-cholesterol (HDL-C)
– Minimal to no change in LDL-cholesterol (HDL-C)
• This profile has been linked to high incidence of
cardiovascular (CV) morbidity and mortality
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Consequences of Renal
Dyslipidemia
• Cardiovascular disease (CVD) is the main cause of
mortality during dialysis and after renal
transplantation
• The accelerated development of atherosclerosis
and CVD in progressive renal disease is well
documented
• The prevalence of CVD is also high in renal
patients in the early stages of CKD, long before the
time of initiating dialysis
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Lipid-lowering Therapy for
Renal Dyslipidemia
• Lipid-lowering intervention has the theoretical
potential to attenuate deleterious processes
associated with CKD:
– Accelerated atherosclerosis
– Progression of renal functional impairment
• However, to date, only a few studies have been
specifically designed to address these issues
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Post-hoc Analyses of CKD
Patients in Major Statin Trials
Trial
Lipid-lowering Agent Findings
CARE
Pravastatin
HPS
Simvastatin
VA-HIT
Gemfibrozil
4S
Simvastatin
AFCAPS/TexCAPS
TNT
Lovastatin
Atorvastatin
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
• Both statin and fibrate
treatment result in
reductions of LDL-C or
triglyceride levels or both
• Both statin and fibrate
treatment reduce the
relative risk of CHD and
overall CVD morbidity to
the same extent as in
patients with normal renal
function
Prospective Studies of Lipidlowering in Stage 4 CKD
Trial
Lipid-lowering Agent Findings
4D
Atorvastatin
AURORA
Rosuvastatin
ALERT
Fluvastatin
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
• Statin therapy had no
effect on CVD morbidity,
all-cause mortality or CV
mortality
• Subgroup analysis
suggested a reduction in
the incidence of
myocardial infarction (MI)
• Extended follow-up (mean
6.7 years) showed that
major CV events were
significantly reduced
Why Aren't Statins Powerfully
Effective in Stage 4 CKD?
• Statins are not very effective in reducing
triglyceride-rich apoB- and apoC-containing
lipoproteins
• This is the major lipoprotein abnormality of
advanced renal failure
• We should therefore not expect statins to
significantly attenuate renal dyslipidemia in
advanced CKD
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Ongoing Studies of
Lipid-lowering in CKD
Full study title
Treatments
Primary outcome
variable
SHARP
LORD
Study of Heart and
Renal Protection
Lipid lowering and Onset of
Renal Disease
Simvastatin +
ezetimibe vs. placebo
Atorvastatin vs. placebo
CVD morbidity
Progression of kidney
disease
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Attenuation of Progression of
Renal Disease?
• The TNT study (patients with coronary heart disease [CHD]
± CKD) suggested that high-dose atorvastatin seemed to
be beneficial, increasing eGFR by ~ 1 mL/min
• Meta-analyses based on small studies have suggested a
positive effect of statin treatment on the progression of CKD
• However:
– Post-hoc analyses of larger lipid-lowering intervention trials
have failed to show benefit or have been inconclusive
– Confounding effects of concomitant antihypertensive therapy
cannot be ruled out
• The impact of lipid-lowering therapy on progression of renal
disease remains to be established
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Risk Reduction with Statins in
Renal Dyslipidemia
Cardiovascular
risk reduction
by statins?
GFR
100
Renoprotection
by statins?
50
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
Dyslipidemia of Kidney Disease:
Conclusions
• Recent studies have shown important
pathophysiological links between an increase of
apoC-III-containing lipoproteins and the
inflammatory processes that ultimately can result in
accelerated vascular disease in CKD patients
• For stage 1–3 CKD patients, lipid-lowering
interventions should be beneficial
– Further research is required for definitive answers
• Statin treatment cannot reduce CVD in patients
with renal failure on hemodialysis
Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
The Unique Character of CVD in CKD
and Its Implications for Treatment with
Lipid-lowering Drugs
Nogueira J, et al:
Clin J Am Soc Nephrol 2007;
2(4):766-85.
CVD in CKD: Implications for
Lipid-lowering Treatment
• Background:
– There are very limited data to guide the use of lipidlowering drugs in CKD
– Data from trials in the general population may not be
generalizable to those with CKD
• Objectives:
– To review the data that are pertinent to the CKD
population
– To update recommendations for use of lipid-lowering
therapy in the CKD population
Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Evidence for Lipid-lowering Therapy in
CKD: Subgroup Analyses of Major Trials
Study
n
Results
Comments
Pravastatin
4491 patients with
pooling project eGFR 30-60
mL/min
Pravastatin reduced risk Suggested benefit in
of composite endpoint
secondary prevention
(time to MI, coronary
setting
death or
revascularization;
HR 0.77)
Heart
Protection
Study
375 patients with
serum creatinine
1.25 – 2.28 mg/dL
(women), 1.48 –
2.28 mg/dL (men)
Simvastatin reduced risk Supports benefit of
of first major vascular
treatment with statins
event (HR 0.70)
in relatively mild CKD
ASCOT-LLA
6517 hypertensive
adults with
undefined "renal
dysfunction"
Atorvastatin lowered the Further supports a
risk of nonfatal MI and
role for statins in
fatal CHD (HR 0.61)
relatively mild CKD
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Completed Prospective Trials of
Lipid-lowering Therapy in CKD
Study
n
Results
Comments
ALERT
2102 renal transplant
recipients
No significant risk reduction
for major adverse cardiac
events
Trial had insufficient
power to detect primary
endpoint difference
4-D
1255 hemodialysis
patients with type 2
diabetes
No significant risk reduction
in composite of cardiac
death, nonfatal MI, stroke
Perhaps a higher dose
of statin may have
produced benefit
PREVEND-IT
864 patients with
microalbuminuria,
creatinine clearance
> 60% of normal
No significant risk reduction
in CV mortality or
hospitalization for CV
morbidity
Study was unable to
show a benefit of statin
therapy early in the CKD
spectrum
UK-HARP-1*
448 patients with
later-stage CKD (predialysis, dialysis or
post-transplant)
Statins produced sustained
reduction in LDL with no
evidence of toxicity
Provides support for the
safety of statins in CKD
*Precursor to the larger SHARP study, currently ongoing.
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Potential Contributors to the
Development of CVD in Patients with CKD
Common to General
Population
Unique or Relatively Much More Important to the CD Population
Aging
Oxidative stress
Volume overload
High LDL-C
Inflammation
Anemia
Low HDL-C
Malnutrition
Rapid volume changes with HD
Hypertension
Vascular calcification
Rapid electrolyte changes in HD
Diabetes
Uremic cellular metabolic
derangements
Immunosuppressant drugs in
transplantation
Tobacco use
LDL oxidation
Endothelial dysfunction
Physical inactivity
Hypertriglyceridemia
Altered nitric oxide balance
Familial/inherited
predisposition
High IDL-C
Advanced glycation end products
Postmenopausal
hormone changes
Left ventricular hypertrophy
Coagulation abnormalities
Hyperhomocysteinemia
Sleep disturbances
Hyperuricemia
Sympathetic overactivity
Carnitine deficiency
Cardiac microvessel disease
Leptin
Arrhythmic sudden death
Recurrent intradialytic hypotension
HD: hemodialysis; IDL: intermediate-density lipoprotein
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Alterations in Lipid Profiles
in CKD
Generally Increased Levels
Generally Decreased Levels
Triglycerids
Lipoprotein(a)
Apoprotein B
VLDL-C
IDL-C
Total cholesterol
LDL-C
HDL-C
Apoprotein A1
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Updated Recommendations for
Lipid-lowering Therapy in CKD
• It is advisable to aggressively treat individuals who
have an eGFR of 30 to 60 mL/min/1.73 m2 and
have known CHD and probably those without
known coronary disease
– On the basis of the findings from the Pravastatin
Pooling Project
• It is reasonable to apply the currently accepted and
footnoted guidelines (NCEP ATP-III) schema for
treatment on the basis of LDL-C levels and LDL-C
goals to those who have not yet reached end-stage
renal disease (ESRD)
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Updated Recommendations for
Lipid-lowering Therapy in CKD
• It may be advisable to treat those with high risk for
atherosclerotic cardiac events regardless of initial
LDL level to achieve a marked (at least 30 to 40%)
reduction in LDL
• A lower goal LDL of 70 mg/dL may be a
reasonable therapeutic option in patients with CKD
• The increase in mortality in hemodialysis patients
at lower cholesterol levels demands caution within
this population
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
Updated Recommendations for
Lipid-lowering Therapy in CKD
• It is reasonable but not mandatory to consider a
reduced GFR, proteinuria, and perhaps
microalbuminuria to be a “CHD-risk equivalent”
• Routine treatment of hemodialysis patients with
diabetes may not be warranted
• Ezetimibe is a reasonable choice for a second-line
lipid-lowering therapy in the CKD population and
probably in kidney transplant recipients
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
CVD in CKD and Implications for Lipidlowering Treatment: Conclusions
• As the severity and duration of uremia increase,
the epidemiology, pathophysiology and response
to treatment of CVD changes gradually from what
is experienced in the general population to what is
unique to the uremic milieu
– It becomes much less clear whether lipid-lowering
agents are of benefit as CKD advances, especially
in dialysis patients
• There is great potential for benefit of statins and
other lipid-lowering agents in this population, but
the need for further study is urgent
Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
KDOQI Hypertension, Dyslipidemia, and
Diabetes Care Guidelines and Current
Care Patterns in the United States CKD
Population: National Health and
Nutrition Examination Survey 1999-2004
Snyder JJ, et al:
Am J Nephrol 2009; 30(1):44-54.
Hypertension, Dyslipidemia and
Diabetes Care in CKD
• Objective: To assess current CKD population
health and adherence to recommendations in the
United States
• Subjects: 14,213 patients with CKD, aged ≥20
years
– From the National Health and Nutrition Examination
Survey 1999-2004
• Assessments: Rates of hypertension and
dyslipidemia management and diabetes control,
stratified by CKD status and prior history of CVD
Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
Background
• The US National Kidney Foundation published a
series of guidelines in the 2000s
– Aim was to slow CKD progression and reduce
morbidity and mortality
• CKD patients are more than 6 times more likely to
die from CVD than to reach ESRD
• Understanding of adherence to guidelines for CVD
risk factors is crucial to evaluating overall health of
these patients
Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
Measured LDL-C Levels,
by Stage of CKD
%
100
90
80
70
3%
10%
24%
3%
10%
26%
4%
9%
24%
35%
31%
32%
40
20
0
Borderline high,
130-159 mg/dL
Near optimal,
100-129 mg/dL
30
10
Very high,
≥190 mg/dL
High,
160-189 mg/dL
60
50
ATC III cholesterol
classification
28%
30%
31%
None
Stage 1 – 2
Stage 3 – 4
CKD stage
Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
Optimal,
<100 L
High Cholesterol: Prevalence,
Awareness, Treatment and Control
No prior CVD
No CKD
High LDL-C
prevalence1
Prior CVD
CKD
CKD
stages 1-2 stages 3-4
No CKD
CKD
CKD
stages 1-2 stages 3-4
32
46
81
90
84
83
Unaware
38
40
53
35
37
33
Aware, untreated
10
9
10
9
8
4
Aware, treated, not
controlled
21
26
10
35
37
37
Aware, treated,
controlled
31
26
11
21
18
26
Within HDL target
range2
81
76
81
69
73
76
Lipid-lowering agent
use3
20
21
22
41
48
55
High cholesterol
Values are %. CKD = Chronic kidney disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.
1 Taking lipid-lowering agents, dieting, or not meeting National Cholesterol Education Program
Adult Treatment Panel III LDL cholesterol targets.
2. National Cholesterol Education Program Adult Treatment Panel III, ≥40 mg/dL. Unadjusted.
3. Unadjusted
Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
Odds Ratios for Control of High Cholesterol by
CKD Stage: No History of CVD
Reference:
non-CKD = 1
High
cholesterol*
Awareness*
Treatment*
Control*
LLA use
0.2
0.6
1.4
2.6
Odds ratio (log scale)
*Significant interaction between history of CVD and CKD stage
Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
5.0
CKD
stage
OR
1–2
1.25
3–4
5.03
1–2
0.89
3–4
0.35
1–2
0.89
3–4
0.39
1–2
0.75
3–4
0.14
1–2
0.90
3–4
0.84
Odds Ratios for Control of High Cholesterol
by CKD Stage: History of CVD
Reference:
non-CKD = 1
High cholesterol*
Awareness*
Treatment*
Control*
LLA use
0.2
0.6
1.4
2.6
Odds ratio (log scale)
*Significant interaction between history of CVD and CKD stage
Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
5.0
CKD
stage
OR
1–2
0.41
3–4
0.39
1–2
0.75
3–4
0.85
1–2
0.75
3–4
1.02
1–2
1.28
3–4
1.69
1–2
0.90
3–4
0.84
Dyslipidemia in CKD:
Conclusions
• The U.S. National Kidney Foundation has identified many
target areas for preventative care in the CKD population
– Identifying risk factors such as dyslipidemia could improve
morbidity and mortality
• In later stage CKD, those with reported CVD history were
more likely to be aware of, treated for, and in control of high
cholesterol than those without CVD
• Participants with CKD stages 1–2 were less likely to have
controlled cholesterol if they had reported CVD history
– This represents a care gap for earlier-stage patients
– Further research is warranted to investigate these differences
• There are many opportunities for improvement in the
management of patients with CKD
Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.
Guidelines
for the Management of CKD
Levin A, et al:
CMAJ 2008; 179(11):1154-62.
Review of Canadian Guidelines for
the Management of CKD
• Objective: To outline evidence-based
recommendations from the Canadian Society of
Nephrology guidelines on aspects of management
of CKD
• Topics covered:
– Targets for various abnormalities
– Strategies for treatment
– Frequency of follow-up
• Focus: For the purposes of this document, the
focus is on CV abnormalities, specifically
dyslipidemia
Levin A, et al: CMAJ 2008; 179(11):1154-62.
A Few Notes About the Canadian
Guidelines for the Management of CKD
• The recommendations are meant for pre-dialysis
patients only
• The target audience includes both general
practitioners and specialists
• The guidelines are part of a comprehensive
national strategy management
• The recommendations are aligned with guidelines
of other national societies (e.g., Canadian Diabetes
Association, Canadian Hypertension Education
Program and Canadian Cardiovascular Society)
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Definition of CKD
• The presence of kidney damage for a period
greater than 3 months
• Abnormal kidney function is noted if:
– Estimated / measured GFR <60 mL/min/1.73 m2
– Estimated / measured GFR >60 mL/min/1.73 m2,
accompanied by:
• Abnormalities of urine sediment; or
• Abnormal results of imaging tests; or
• If the patient has had a kidney biopsy with
documented abnormalities
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
CKD and CVD
• CKD is estimated to affect between 1.9 million and
2.3 million Canadians
– This is a major public health problem
• CKD often coexists with CVD and diabetes
– CKD is recognized as a risk factor for all-cause
mortality and CVD
– Most patients with CKD will die of events related to
CVD before ESRD develops
– An important focus of care for patients with CKD
includes management of CVD risk factors
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Stages of CKD*
Stage
Description
GFR,
mL/min/1.73 m2
1
Kidney damage† with normal or increased GFR
≥90
2
Kidney damage† with mild decreased GFR
60–89
3
Moderately decreased GFR
30–59
4
Severely decreased GFR
15–29
5
Kidney failure
<15 (or dialysis)
* Kidney damage or GFR less than 60 mL/min/1.73 m 2 for 3 or more months.
† Pathologic abnormalities or markers of damage, including persistent proteinuria, abnormalities in urine sediment
(persistent presence of erythrocytes, erythrocyte casts, leukocytes or leukocyte casts) or abnormal results in imaging
studies (evidence of scarring or small kidneys on ultrasound or bilateral cystic changes consistent with polycystic
kidney disease)
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Canadian CKD Guidelines:
Shared Care Is Recommended
• The guidelines were developed to facilitate shared
care of patients with CKD by GPs and specialists
(including internists, endocrinologists, cardiologists
and nephrologists)
• Most cases of nonprogressive CKD can be
managed in primary care without referral to a
nephrologist
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Scenarios in Which Referral to a
Nephrologist Should Be Considered
• Acute kidney failure
• Persistent eGFR <30 mL/min/1.73 m2
• Progressive decline of kidney function
• Ratio of urine protein to creatinine >100 mg/mmol
(about 900 mg/24 h)
• Urine albumin to creatinine ratio >60 mg/mmol
(about 500 mg/24 h)
• Inability to achieve treatment targets
• Rapid changes in kidney function
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Recommendations for Screening for
Dyslipidemia in CKD
• A fasting lipid profile (total cholesterol, LDL-C,
HDL-C and triglyceride) should be measured in
adults with stage 1–3 CKD
• A fasting lipid profile should be measured in adults
with stage 4 CKD only if the results would influence
the decision to initiate or alter lipid-modifying
treatment
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Canadian CKD Guidelines: Recognition of
Common Comorbidities and Risk Factors
• Groups at particular risk of developing CKD:
–
–
–
–
CVD
Diabetes
Specific ethnicities
Family history of CKD
• There is a high prevalence of dyslipidemia at every
stage of CKD
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Recommendations for
Monitoring Dyslipidemia in CKD
• Lipid profiles should be measured after an
overnight fast (ideally ≥12 h duration)
• Total cholesterol, LDL-C, HDL-C and triglycerides
should be measured
• Fasting lipid profiles should be measured no
sooner than 6 weeks after initiation or change in
pharmacologic therapy
• Thereafter, lipid profiles should be monitored every
6–12 months if the results could influence
subsequent therapeutic decisions
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Recommendations for
LDL Lowering in CKD
Stage of CKD
Recommendations
• Statin therapy should be initiated according to existing
lipid guidelines for the general population
Stages 1–3
• Clinicians should consider titrating the dose of statin
according to lipid guidelines for the general population
Stage 4
• Clinicians should consider initiating statin therapy for
patients with stage 4 CKD and titrating the dose to
achieve an LDL-C level <2.0 mmol/L and a ratio of total
cholesterol to HDL-C <4.0
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Recommendations for Monitoring
for Adverse Effects of Medication
• Serial monitoring of creatinine kinase and alanine
aminotransferase:
– Not required for asymptomatic patients with CKD taking a
low to moderate dose of statin (≤20 mg/d of simvastatin
or atorvastatin, or an equivalent dose of another statin)
– Should be measured every 3 months for patients with
stage 4 CKD who are taking a moderate to high dose of
statin (≥40 mg/d of simvastatin or atorvastatin, or an
equivalent dose of another statin)
• A statin and fibrate should not be coadministered to
patients with stage 4 CKD because of the risk of
rhabdomyolysis
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
Guidelines for the Management of
CKD: Conclusions
• The complexity of CKD clearly requires a better
understanding of the absolute and relative value of
identifying and treating the myriad clinical and laboratory
abnormalities
• It is critical that we better define the importance of these
conditions for each stage of CKD
• We must ensure that patients with CKD and any other risk
factor for CVD receive aggressive treatment, and that a
sense of therapeutic nihilism does not overcome our
judgment and clinical care
• The lack of evidence should encourage us to advocate for
the design of and enrolment into randomized control trials
that answer questions relevant to this population
Levin A, et al: CMAJ 2008; 179(11):1154-62.
GFR, Albuminuria and Risk of
Cardiovascular and All-cause
Mortality in the US Population
Astor BC, et al:
Am J Epidemiol 2008; 167(10):1226-34
GFR, Albuminuria and the Risk of CV and
All-cause Mortality in the US Population
• Objective: To evaluate the separate and
combined effects of decreased GFR and
albuminuria on CV and all-cause mortality
• Subjects: 14,586 adults from NHANES III
• Methodology:
– GFR was estimated from standardized serum
creatinine levels
– Albuminuria was defined by the urinary albumincreatinine ratio
– Incidence rate ratios for mortality were adjusted for
major CVD risk factors and C-reactive protein (CRP)
Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
GFR, Albuminuria and the Risk of CV and
All-cause Mortality: Background
• Patients with CKD are much more likely to die of CVD
than to experience kidney failure
• Experts have recommended using CKD in CV-risk
stratification and treatment guidelines
• Defining and staging kidney disease relies on
combining information on kidney damage and
decreased renal filtration
– Most prospective studies examine one or the other, but
not both
• The risk associated with varying levels of albuminuria
by level of kidney function has not been quantified in
large cohort studies
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
GFR, Proteinuria and CV Risk
• Lower GFR predicts CV events and mortality in:
– Patients with existing CVD
– Patients at high risk of CVD
– The general population
• Leakage of protein in the urine (proteinuria or
albuminuria) is a sensitive indicator of:
– Early kidney damage (especially in diabetes)
– GFR decline
– Higher risk of CVD and mortality
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Differences in Demographic
Characteristics by Baseline eGFR (1 of 3)
Total
Estimated Mean GFR (mL/min/1.73m2)
≥ 90
60-89
15-59
p value
Mean age, yrs
44.2
38.5
52.8
70.4
< 0.001
Female sex, %
52.1
51.4
52.5
60.7
< 0.001
Race / ethnicity, %
< 0.001
Non-Hispanic White
76.0
70.6
86.1
86.5
Non-Hispanic Black
11.1
13.6
6.2
8.3
Mexican-American
5.2
6.8
2.3
1.3
Other
7.7
9.0
5.4
4.9
Diabetes, %
4.8
3.4
6.2
15.8
Prevalent CHD, %
7.6
4.1
10.9
38.4
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
<0.001
Differences in Demographic
Characteristics by Baseline eGFR (2 of 3)
Total
Estimated Mean GFR (mL/min/1.73m2)
≥90
60–89
15–59
Hypertension category, %
p value
<0.001
Optimal
47.1
54.4
36.1
13.3
Prehypertension
34.9
33.6
37.9
32.0
Stage 1 hypertension
13.4
9.6
18.9
33.3
Stage 2 hypertension
4.6
2.4
7.1
21.4
Use of antihypertensive
medication, %
12.7
6.8
17.9
52.3
Smoking status
<0.001
<0.001
Never smoker
45.7
45.3
46.5
44.6
Former smoker
25.8
21.3
33.3
41.6
Current smoker
28.5
33.4
20.2
13.9
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Differences in Demographic
Characteristics by Baseline eGFR (3 of 3)
Total
Body mass index, kg/m2
26.5
Estimated Mean GFR (mL/min/1.73m2)
≥90
60–89
15–59
26.2
27.1
27.6
Physical activity, %
p value
<0.001
<0.001
Inactive
25.1
25.7
22.6
34.4
Moderately active
53.6
51.4
57.6
58.1
Active
21.3
22.9
19.8
7.5
LDL-C level (mg/dL)
123.5
118.4
131.6
144.1
0.003
HDL-C level (mg/dL)
50.8
51.0
50.5
48.9
0.005
Triglyceride level (mg/dL)
145.9
139.1
153.9
194.6
<0.001
C-reactive protein level
0.002
<0.22 mg/dL
71.5
73.7
69.6
51.6
0.22–0.99 mg/dL
21.1
19.6
22.8
31.7
≥1.0 mg/dL
7.4
6.7
7.6
16.7
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Adjusted Incidence Rates of CV
Mortality, by Kidney Function
5
Adjusted incidence rate
(per 100 person-years)
Normal
4
Microalbuminuria
Marcoalbuminuria
3
2
1
0
>90
60–89
Estimated GFR
(mL/minute/173 m2)
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
15–59
Adjusted Incidence Rates of Allcause Mortality, by Kidney Function
10
Adjusted incidence rate
(per 100 person-years)
Normal
8
Microalbuminuria
Macroalbuminuria
6
4
2
0
>90
60–89
Estimated GFR
(mL/minute/173 m2)
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
15–59
GFR, Albuminuria and the Risk of CV and
All-cause Mortality: Conclusions
• Lower eGFR and higher urinary ACR independently predict
CV and all-cause mortality
– The presence of both abnormalities confers even greater risk
– Elevated risks remained strong after adjustment for potential
confounders
– Similar results were seen among persons with and without
diabetes
• These data support the use of CKD in risk stratification and
treatment guidelines
• The reasons for the increased risk of CVD in CKD are not
fully understood
– Persons with CKD have a higher prevalence of several CVD
risk factors, including dyslipidemia
Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Change in eGFR Associates
with CHD and mortality
Matsushita K, et al:
J Am Soc Nephrol 2009;
20(12):2617-24.
Background:
Rationale for the Study
• There are many studies documenting an
independent association between baseline kidney
function and future CV events
• Little is known about the impact of sequential
changes in kidney function on future CV risk
• There is some evidence that suggests that:
– Deterioration in kidney function is associated with
CVD
– Change in kidney function may be a better CV risk
marker than baseline kidney function
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Impact of Changes in eGFR
Over Time on CHD and Mortality
• Objective: To investigate whether changes in
eGFR associated with risk for CHD and all-cause
mortality
• Subjects: 13,029 participants of the
Atherosclerosis Risk in Communities (ARIC) Study
• Methodology:
– The investigator examined the impact of both
intermediate (3-year) and long-term (9-year)
changes in eGFR
– Results were also analyzed after adjustment for
covariates
Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Annual Change in eGFR from
Baseline to Year 3
.10
Density
.08
.06
.04
.02
0
-60
-50
-40
-30
-20
-10
0
10
20
30
% annual change in eGFR between visit 1and visit 2
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
40
Characteristics of Patients with
Largest Declines in eGFR
• Participants with the largest declines in eGFR:
– Were more likely to be women
– Were more likely to be black
– Had higher average systolic BP but lower LDL-C
and higher HDL-C than patients with more stable
eGFR
– Had the highest mean baseline eGFR
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Adjusted Incidence Rates for CHD by
Quartiles of % Annual Change in eGFR
Adjusted incidence rate of CHD
per 1,000 person-years
25
20
15
10
3-year change
5
9-year change
0
Q1
Q2
Q3
Quartiles of % annual change in eGFR
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Q4
Adjusted Incidence Rates for All-cause Mortality
by Quartiles of % Annual Change in eGFR
Adjusted incidence rate of all-cause
mortality per 1,000 person-years
25
20
15
10
3-year change
5
9-year change
0
Q1
Q2
Q3
Quartiles of % annual change in eGFR
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Q4
Impact of Changes in eGFR Over Time on
CHD and Mortality: Conclusions
• A steeper than average decline in eGFR (i.e., >5%/year) was
associated with a higher risk for all-cause mortality independent of
eGFR and other known risk factors at baseline or follow-up
– This was more relevant for individuals with mildly or moderately
reduced eGFR (30 to 89 mL/min per 1.73m2)
• The results after adjustment for covariates suggests the observed
effect is independent of the deterioration in traditional risk factors
• There may be clinical value in sequential eGFR data, often
measured in routine care, even among individuals with mildly
reduced eGFR
• The causative mechanisms by which impaired kidney function
contributes to CHD and other causes of mortality are not fully
elucidated
Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
Intensive Lipid Lowering with
Atorvastatin in Patients with CHD
and CKD: the TNT Study
Shepherd J, et al:
J Am Coll Cardiol 2008;
51(15):1448-54.
Intensive Statin Therapy in Patients with
CHD and CKD (TNT Sub-analysis)
• Objective: To investigate the effects of intensive lipid
lowering with atorvastatin in patients with CHD, with
and without pre-existing CKD
• Subjects: 10,001 patients with established CHD
– Including 3107 patients with mild-to-moderate CKD
– Post-hoc subanalysis of the TNT study
• Methodology:
– Subjects were randomized to double-blind therapy with
atorvastatin 80 mg/day or 10 mg/day
– Patients with CKD were identified at baseline by eGFR
(Modification of Diet in Renal Disease [MDRD] equation) <60
mL/min/1.73 m2
– Primary efficacy outcome: Time to first major CV event
Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Observations About Baseline
Characteristics
• Patients with CKD were older, and there were
more women and fewer smokers than among
patients with normal eGFR
• Pre-existing CV morbidity at baseline was
generally greater in patients with CKD than in
patients with normal eGFR
• There were no imbalances in baseline
characteristics by randomized treatment
assignment
Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Time to First Major CV Event Among
Patients with CKD at Baseline
20
% of patients with major CV events
Patients with CKD at baseline
Atorvastatin 10 mg
Atorvastatin 80 mg
15
HR=0.68 (95% CI 0.55, 0.84)
P=0.0003, ARR=4.1%, NNT=24
10
5
0
0
No. of CKD patients at risk
Atorva 10 mg 1505
Atorva 80 mg 1602
1
2
3
Time (Years)
4
5
6
1468
1579
1422
1539
1367
1495
1310
1450
687
701
0
0
Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Time to First Major CV Event Among
Patients with no CKD at Baseline
20
% of patients with major CV events
Patients with normal eGFR at baseline
Atorvastatin 10 mg
Atorvastatin 80 mg
15
HR=0.85 (95% CI 0.72, 1.00)
P=0.049, ARR=1.4%, NNT=74
10
5
0
0
No. of CKD patients at risk
Atorva 10 mg 3324
Atorva 80 mg 3225
1
2
3
Time (Years)
4
5
6
3263
3180
3192
3113
3114
3044
3036
2963
1557
1579
0
0
Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Primary and Secondary Event Rates in Patients
with CKD and Patients with Normal eGFR
P-value for
heterogeneity
Event rate
80 mg
10 mg
Major cardiovascular event
All Patients*
Patients with CKD
Patients with normal eGFR
434 (8.7%)
149 (9.3%)
254 (7.9%)
548 (10.9%)
202 (13.4%)
307 (9.2%)
P=0.113
1405 (28.1%)
489 (30.5%)
857 (26.6%)
1677 (33.5%)
574 (38.1%)
1027 (30.9%)
P=0.225
334 (6.7%)
110 (6.9%)
198 (6.1%)
418 (8.3%)
157 (10.4%)
226 (6.8%)
P=0.040
1078 (21.6%)
356 (22.2%)
676 (21.0%)
1326 (26.5%)
431 (28.6%)
828 (24.9%)
P=0.285
196 (3.9%)
74 (4.6%)
111 (3.4%)
250 (5.0%)
104 (6.9%)
139 (4.2%)
P=0.281
122 (2.4%)
49 (3.1%)
71 (2.2%)
164 (3.3%)
84 (5.6%)
72 (2.2%)
P=0.011
275 (5.5%)
121 (7.6%)
147 (4.6%)
285 (5.6%)
112 (7.4%)
160 (4.8%)
P=0.629
284 (5.7%)
112 (7.0%)
132 (4.1%)
282 (5.6%)
113 (7.5%)
124 (3.7%)
P=0.401
Any cardiovascular event
All Patients*
Patients with CKD
Patients with normal eGFR
Major coronary event
All Patients*
Patients with CKD
Patients with normal eGFR
Any coronary event
All Patients*
Patients with CKD
Patients with normal eGFR
Cerebrovascular event
All Patients*
Patients with CKD
Patients with normal eGFR
CHF with hospitalization
All Patients*
Patients with CKD
Patients with normal eGFR
Peripheral artery disease
All Patients*
Patients with CKD
Patients with normal eGFR
All-cause mortality
All Patients*
Patients with CKD
Patients with normal eGFR
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Hazard ratio (95% CI)
Atorvastatin 80 mg better
Atorvastatin 10 mg better
Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Intensive Statin Therapy in Patients
with CHD and CKD : Conclusions
• This post-hoc analysis of the TNT study extends the
CV benefit of aggressively lowering LDL-C to a highrisk patient population with mild-to-moderate CKD and
stable CHD
• Patients with CHD and mild-to-moderate CKD may
differ from those with more advanced renal failure or
ESRD
• These data support the use of high-dose statin therapy
to achieve lower target LDL-C levels for optimal
prevention of CV events in high-risk patient groups
• CKD should not preclude use of a statin
Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
Rosuvastatin and CV Events in
Patients Undergoing
Hemodialysis
Fellström BC, et al:
N Engl J Med 2009; 360(14):1395-407.
Rosuvastatin and CV Events in Patients
Undergoing Hemodialysis (The AURORA Study)
• Objective: To determine whether statins reduce
the incidence of CV events in patients undergoing
hemodialysis
• Subjects: 2776 patients, 50 to 80 years of age,
undergoing maintenance hemodialysis
• Methodology:
– Subjects were randomly assigned to receive
rosuvastatin 10 mg daily or placebo
– Combined primary end point: CV death, nonfatal MI
or nonfatal stroke
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Mean Change in LDL-C
120
Placebo
100
Mean LDL-C (mg/dl)
80
60
Rosuvastatin
40
20
0
0
No. at risk
Placebo
1372
Rosuvastatin 1375
1
2
3
4
5
543
553
298
315
70
61
Year
1248
1243
1005
994
719
719
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Rosuvastatin vs. Placebo:
Primary Composite Endpoint
Cumulative incidence of the primary
end point (%)
40
35
Placebo
30
Rosuvastatin
25
20
15
Hazard ratio, 0.96
P=0.59
10
5
0
0
No. at risk
Placebo
1384
Rosuvastatin 1390
1
2
3
4
5
809
826
534
551
153
148
Year
1163
1152
952
962
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Rosuvastatin vs. Placebo:
Components of the Primary Endpoint
Rosuvastatin
(n=1389)
Event
CV death
Nonfatal
MI
Nonfatal
stroke
No. of
pts.
324
91
53
No. of
events /
100 pt-yrs
7.2
2.1
1.2
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Placebo (n=1384)
No. of
pts.
324
107
45
HR
(95%CI)
p value
7.3
1.00
(0.851.16)
0.97
2.5
0.84
(0.641.11)
0.23
1.1
1.17
(0.791.75)
0.42
No. of
events /
100 pt-yrs
Rosuvastatin vs. Placebo:
Adverse Events
No. of patients (%)
Adverse events (AEs)
p value
Rosuvastatin
(n=1389)
Placebo
(n=1384)
Any AE
1338 (96.3)
1332 (96.7)
0.56
Any serious AE
1140 (82.1)
1159 (84.1)
0.80
Serious AE requiring permanent
discontinuation of study drug
438 (31.5
442 (32.1)
0.78
AE leading to death
640 (46.1)
662 (48.0)
0.49
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Rosuvastatin and CV Events in Patients
Undergoing Hemodialysis: Conclusions
• In patients undergoing hemodialysis, the initiation
of treatment with rosuvastatin:
– Lowered the LDL-C level
– Lowered the concentration of hsCRP
– Had no significant effect on the composite primary
end point of death from CV causes, nonfatal MI or
nonfatal stroke
• The trial did not meet its primary endpoint
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
Co-administration of Ezetimibe
Enhances Proteinuria-lowering Effects
of Pitavastatin in CKD Patients Partly
Via a Cholesterol-independent Manner
Nakamura T, et al:
Pharmacol Res 2009 Aug 8.
[Epub ahead of print].
Renoprotection with Ezetimibe in Nondiabetic CKD Patients with Dyslipidemia
• Objective: To investigate whether coadministration of ezetimibe with pitavastatin could
augment renoprotective properties of pitavastatin
• Subjects: 20 non-diabetic patients with stage 1 or
2 CKD and dyslipidemia
• Methodology:
– Patients were randomly assigned to either 2 mg
pitavastatin once or 2 mg pitavastatin + 10 mg
ezetimibe once daily
– Assessments: Effects of therapy on plasma lipids
and on proteinuria
Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
Reduction in Total Cholesterol
with Pitavastatin ± Ezetimibe
Total cholesterol (mg/dL)
300
250
Pitavastatin 2 mg
243,6
Pitavastatin 2 mg +
ezetimibe 10 mg
239,0
200
172,2
150
154,2
100
50
0
Before treatment
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
After treatment
Reduction in LDL-C with
Pitavastatin ± Ezetimibe
180
167,9
160
162,6
LDL-C (mg/dL)
140
120
97,9
100
80
82,2
60
40
20
0
Before treatment
After treatment
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
Reduction in Serum ADMA Levels
with Pitavastatin ± Ezetimibe
0,62
Pitavastatin 2 mg
0,60
Serum ADMA (nmol/mL)
0,60
0,58
Pitavastatin 2 mg +
ezetimibe 10 mg
0,59
0,56
0,54
0,52
0,52
0,51
0,50
0,48
0,46
Before treatment
After treatment
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
Reduction in Proteinuria with
Pitavastatin ± Ezetimibe
1600
Proteinuria (mg/d)
1400
1512
1508
Pitavastatin 2 mg
Pitavastatin 2 mg +
ezetimibe 10 mg
1200
1042
1000
800
786
600
400
200
0
Before treatment
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
After treatment
Discussion: Cholesterolindependent Effects of Ezetimibe
• These findings support previous studies, which
found that:
– Ezetimibe decreased serum ADMA levels and
improved renal damage in non-diabetic stage 1 – 2
CKD patients with dyslipidemia in a cholesterolindependent manner
• Possible mechanisms of ezetimibe benefit on renal
parameters:
– Anti-oxidative properties
– Direct effect on endothelial function
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
Ezetimibe in Non-diabetic CKD Patients
with Dyslipidemia: Conclusions
• Co-administration of ezetimibe enhanced
proteinuria-lowering effects of pitavastatin in nondiabetic CKD patients, partly via a cholesterolindependent manner
• Ezetimibe may have pleiotropic actions that could
contribute to renoprotective properties of this lipidlowering agent
Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
Ezetimibe Treatment in
Hypercholesterolemic Kidney
Transplant Patients is Safe and Effective
and Reduces the Decline of Renal
Allograft Function: a Pilot Study
Türk TR, et al:
Nephrol Dial Transplant 2008; 23(1):369-73.
Ezetimibe in Hypercholesterolemic
Kidney Transplant Patients: Background
• Ezetimibe has shown efficacy in the treatment of
hypercholesterolemia in renal transplant patients
• This is the first study investigating the effect of
ezetimibe on renal function in kidney transplant
recipients
Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Ezetimibe in Hypercholesterolemic
Kidney Transplant Patients
• Objective: To prospectively investigate the effect of
ezetimibe on renal function in kidney transplant
recipients
• Subjects: 56 patients with statin-resistant
hypercholesterolemia (total cholesterol >200 mg/dL)
after renal transplantation
• Methodology:
– Study patients received additional ezetimibe therapy
(10 mg/day) for 12 months (n=56)
– A group receiving statin therapy (n=28) alone served as
controls
– Investigators assessed changes in total cholesterol and LDL-C
concentrations, as well as in creatinine clearance.
Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Changes in Total Cholesterol: Statin ±
Ezetimibe in Kidney Transplant Patients
20
10
mg/dL
Control
0
Ezetimibe treated
-10
p=0.001
-20
-30
0
3
6
9
Months
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
12
Changes in LDL-C: Statin ± Ezetimibe in
Kidney Transplant Patients
0
-10
mg/dL
Control
Ezetimibe treated
-20
-30
p=0.002
-40
0
3
6
9
Months
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
12
Changes in Creatinine Clearance: Statin
± Ezetimibe in Kidney Transplant
Patients
7
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-12
(MDRD equation)
Control
Ezetimibe treated
p=0.025
-9
-6
-3
0
3
6
9
12
mg/dL/1.73m2
mg/dL
(Cockcroft-Gault formula)
7
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-12
Months
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Control
Ezetimibe treated
p=0.033
-9
-6
-3
0
Months
3
6
9
12
Multivariate Analysis for Change
in Creatinine Clearance
Dependent Variable:
Delta Creatinine Clearance
Cockcroft-Gault
MDRD
Treatment group
0.0187
0.0195
Tacrolimus
0.1261
0.0958
Cyclosporine
0.6763
0.2722
Acute rejection
0.0773
0.2147
Donor age
0.5287
0.2071
HLA mismatches
0.0874
0.0922
Months after transplantation
0.6818
0.8832
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Other Observations with Ezetimibe
in Kidney Transplant Patients
• The investigators reported that:
– Ezetimibe therapy was “nearly without side effects”
in this population
– Ezetimibe’s positive effects on endothelial function
may be an explanation for the drug’s positive effects
on renal function
• Previous studies have indicated a direct positive
effect of ezetimibe on endothelial function
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Ezetimibe in Hypercholesterolemic
Kidney Transplant Patients: Conclusions
• Ezetimibe treatment in renal transplant patients was effective in
lowering LDL-C and total cholesterol and is nearly without side
effects
• There was also a better preservation of renal function after 12
months of additional treatment with ezetimibe compared with the
control group continuing high-dose statin therapy
– Previous reports show benefits of statin therapy in renal transplant
patients but not always a better preservation of renal function
– The cholesterol-lowering effect of ezetimibe is one possible
explanation for its positive effect on renal function
– Benefit of ezetimibe on endothelial function may also play a role
• Further studies with renal function as primary endpoint are
required to investigate the influence of ezetimibe on kidney
transplants
Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
Study of Heart and Renal
Protection (SHARP)
Baigent C, et al:
Kidney Int Suppl 2003; (84):S207-10.
Background: Rationale for the
SHARP Study
• Patients with established CKD are at high risk of CV
events; the benefits of cholesterol-lowering therapy
might be expected to be substantial in this population
– There is evidence, however, that the benefits in the
general population may not translate to patients with
CKD
– Safety is not well established in CKD
• Patients with CKD have generally been excluded from
previous lipid-lowering trials
• There is an important need for reliable direct evidence
for cholesterol-lowering therapy in CKD
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
What Do We Know About the
Impact of LDL-lowering in CKD?
• LDL may not play as large a role in mediating CV
risk in CKD as it does in the general population
– Investigators have reported a negative association
between blood total cholesterol and mortality in CKD
– Only ~1/4 of cardiac mortality in CKD is directly
attributable to MI (dependent on LDL); the other
causes (cardiac arrest, arrhythmia, heart failure) are
less dependent on LDL
– The long-term safety of LDL lowering in CKD
remains unclear
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
Association Between
Cholesterol and CV Mortality
General population
100
Diabetic
10
Non-diabetic
Total mortality, % per annum
CV mortality, % per annum
100
Hemodialysis patients
10
1
1
Total cholesterol, mmol/L
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
Total cholesterol, mmol/L
Causes of CV Mortality in CKD
~25%:
Directly attributable to MI
(potentially avoidable
with cholesterol reduction)
~75%:
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
Other causes (cardiac
arrest, arrhythmia, heart
failure)
Not as dependent on
cholesterol reduction
Pilot Study of Lipid Lowering in
Patients with CKD: UK-HARP I
• Objective: To test the efficacy and safety of
simvastatin and aspirin in CKD
• Subjects: 448 patients with CKD (242 predialysis, 73
on dialysis, 133 with functioning transplant)
• Interventions: Patients randomized in a 2x2 factorial
design to simvastatin vs. placebo and aspirin vs.
placebo for 1 year
• Simvastatin results:
– Simvastatin 20 mg reduced LDL-C by 26% vs. placebo
– Simvastatin was not associated with excess risk of elevated
liver transaminases or serious myopathy vs. placebo
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10 and
Baigent C, et al: Am J Kidney Dis 2005 45(3):473-84.
Pilot Study of Lipid Lowering in
Patients with CKD: UK-HARP II
• Objective: To compare the efficacy and safety of
simvastatin and simvastatin + ezetimibe in CKD
• Subjects: 203 patients with CKD (152 predialysis, 33
on peritoneal dialysis, 18 on hemodialysis)
• Interventions: Patients randomized to simvastatin 20
mg + ezetimibe 10 mg or simvastatin 20 mg + placebo
for 6 months
• Results:
– Simvastatin + ezetimibe decreased LDL-C by an additional
21% vs. simvastatin alone
– There were no serious adverse events caused by study
treatments
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10. and
Landray M, et al: Am J Kidney Dis 2006; 47(3):385-95.
The Study of Heart and Renal
Protection (SHARP)
• Objectives: To assess the effects of lowering
cholesterol on major vascular events and on the rate of
progression to ESRD among patients with CKD
• Subjects: ~9,000 patients with CKD (6,000 predialysis, 3,000 on dialysis)
• Interventions: Simvastatin / ezetimibe combination
vs. placebo
• Assessments:
– Effect of LDL lowering on time to first vascular event (primary)
– Effect of treatment on progression to ESRD
– Effect of treatment on various mortality and morbidity endpoint
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
Rationale for the Treatment
Agents in SHARP
• Patients with CKD generally have average (or
below-average) LDL-C levels
– They may require a regimen that can produce a
substantial proportional reduction to produce a
worthwhile reduction in events
– Use of higher doses of statins may increase the risk
of muscle toxicity
– Ezetimibe is a well-tolerated agent that has
demonstrated additional LDL-lowering efficacy when
added to statin therapy
– The regimen chosen for SHARP was, therefore,
simvastatin + ezetimibe
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
SHARP: Conclusions
• There is currently a lack of evidence supporting an
association between dyslipidemia and increased
CVD in patients with CKD
• It remains unclear what proportion of cardiac
disease in CKD is atherosclerotic and, hence,
potentially modifiable with cholesterol-lowering
therapy
• In the coming years, SHARP and other studies in
patients with renal disease should help to answer
these outstanding questions
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.