Comprehensive Publication Review: Dyslipidemia, Chronic Kidney Disease and Cardiovascular Disease

Comprehensive Publication Review:

Dyslipidemia, Chronic Kidney Diseaseand 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


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


Lipid-lowering Therapy forRenal 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


Post-hoc Analyses of CKD Patients in Major Statin Trials

Trial Lipid-lowering Agent Findings

CARE Pravastatin• 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

HPS Simvastatin

VA-HIT Gemfibrozil

4S Simvastatin

AFCAPS/TexCAPS Lovastatin

TNT Atorvastatin


Prospective Studies of Lipid-lowering in Stage 4 CKD

Trial Lipid-lowering Agent Findings

4D Atorvastatin • Statin therapy had no effect on CVD morbidity, all-cause mortality or CV mortalityAURORA Rosuvastatin

ALERT Fluvastatin

• 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


Ongoing Studies ofLipid-lowering in CKD

SHARP LORD

Full study titleStudy of Heart and Renal Protection

Lipid lowering and Onset of Renal Disease

TreatmentsSimvastatin +

ezetimibe vs. placeboAtorvastatin vs. placebo

Primary outcome variable

CVD morbidityProgression of kidney

disease


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


Risk Reduction with Statins in Renal Dyslipidemia


100

GFR

50

Cardiovascularrisk reduction

by statins?

Renoprotectionby statins?

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


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 lipid-

lowering 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 pooling project

4491 patients with eGFR 30-60 mL/min

Pravastatin reduced risk of composite endpoint (time to MI, coronary death or revascularization;HR 0.77)

Suggested benefit in secondary prevention setting

Heart Protection Study

375 patients with serum creatinine1.25 – 2.28 mg/dL (women), 1.48 – 2.28 mg/dL (men)

Simvastatin reduced risk of first major vascular event (HR 0.70)

Supports benefit of treatment with statins in relatively mild CKD

ASCOT-LLA 6517 hypertensive adults with undefined "renal dysfunction"

Atorvastatin lowered the risk of nonfatal MI and fatal CHD (HR 0.61)

Further supports a role for statins in 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 (pre-dialysis, 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

HD: hemodialysis; IDL: intermediate-density lipoproteinAdapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.

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

DiabetesUremic 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

Alterations in Lipid Profiles in CKD


Generally Increased Levels Generally Decreased Levels

TriglyceridsLipoprotein(a)Apoprotein BVLDL-CIDL-C

Total cholesterolLDL-CHDL-CApoprotein A1

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)



• 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



• 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


CVD in CKD and Implications for Lipid-lowering 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


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

Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

100

90

80

70

60

50

40

30

20

10

0None Stage 1 – 2 Stage 3 – 4

%

CKD stage

28%

35%

24%

10%

3%

31%

32%

24%

9%

4%3%

30%

31%

26%

10%

ATC III cholesterolclassification

Very high, ≥190 mg/dL

High, 160-189 mg/dL

Borderline high, 130-159 mg/dL

Near optimal, 100-129 mg/dL

Optimal, <100 L

High Cholesterol: Prevalence, Awareness, Treatment and Control

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 ProgramAdult Treatment Panel III LDL cholesterol targets.2. National Cholesterol Education Program Adult Treatment Panel III, ≥40 mg/dL. Unadjusted.3. UnadjustedAdapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

No prior CVD Prior CVD

No CKDCKD

stages 1-2CKD

stages 3-4No CKD

CKD stages 1-2

CKD stages 3-4

High LDL-C prevalence1 32 46 81 90 84 83

High cholesterol

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

Odds Ratios for Control of High Cholesterol by CKD Stage: No History of CVD

*Significant interaction between history of CVD and CKD stageAdapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

0.2 2.61.40.6 5.0

Odds ratio (log scale)

CKDstage OR

3 – 4

1 – 2LLA use

0.84

0.90

3 – 4

1 – 2Control*

0.14

0.75

3 – 4

1 – 2Treatment*

0.39

0.89

3 – 4

1 – 2Awareness*

0.35

0.89

1 – 2

3 – 4

Highcholesterol*

1.25

5.03

Reference:non-CKD = 1

Odds Ratios for Control of High Cholesterolby CKD Stage: History of CVD

*Significant interaction between history of CVD and CKD stageAdapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

0.2 2.61.40.6 5.0Odds ratio (log scale)

3 – 4

1 – 2

3 – 4

1 – 2

3 – 4

1 – 2

3 – 4

1 – 2

3 – 4

1 – 2High cholesterol*

LLA use

Control*

Treatment*

Awareness*

Reference:non-CKD = 1

CKDstage OR

0.84

0.90

1.69

1.28

1.02

0.75

0.85

0.75

0.39

0.41

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


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


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


Stages of CKD*

* Kidney damage or GFR less than 60 mL/min/1.73 m2 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)


Stage DescriptionGFR,

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)

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


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


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


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


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


Recommendations forLDL Lowering in CKD

Stage of CKD Recommendations

Stages 1–3

• Statin therapy should be initiated according to existing lipid guidelines for the general population

• 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


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


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 albumin-

creatinine 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


Differences in Demographic Characteristics by Baseline eGFR (1 of 3)

TotalEstimated Mean GFR (mL/min/1.73m2)

p value≥ 90 60-89 15-59

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 <0.001

Prevalent CHD, % 7.6 4.1 10.9 38.4




p value≥90 60–89 15–59

Hypertension category, % <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 <0.001

Smoking status <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




p value≥90 60–89 15–59

Body mass index, kg/m2 26.5 26.2 27.1 27.6 <0.001

Physical activity, % <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


Adjusted Incidence Rates of CV Mortality, by Kidney Function


5

4

3

2

1

0>90 60–89 15–59

Normal

Microalbuminuria

Marcoalbuminuria

Estimated GFR(mL/minute/173 m2)

Ad

just

ed in

cid

ence

rat

e(p

er 1

00 p

erso

n-y

ears

)

Adjusted Incidence Rates of All-cause Mortality, by Kidney Function


10

8

6

4

2

0>90 60–89 15–59

Normal

Microalbuminuria

Macroalbuminuria

Estimated GFR(mL/minute/173 m2)

Ad

just

ed in

cid

ence

rat

e(p

er 1

00 p

erso

n-y

ears

)

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

.08

.06

.04

.02

0-60 -50 -40 -30 -20 -10 0 10 20 30 40

% annual change in eGFR between visit 1and visit 2

Den

sity

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


Adjusted Incidence Rates for CHD by Quartiles of % Annual Change in eGFR


25

20

15

10

5

0Q1 Q2 Q3 Q4

3-year change

9-year change

Ad

just

ed in

cid

ence

rat

e o

f C

HD

p

er 1

,000

per

son

-yea

rs

Quartiles of % annual change in eGFR

Adjusted Incidence Rates for All-cause Mortality by Quartiles of % Annual Change in eGFR


25

20

15

10

5

0Q1 Q2 Q3 Q4

3-year change

9-year change

Ad

just

ed in

cid

ence

rat

e o

f al

l-ca

use

mo

rtal

ity

per

1,0

00 p

erso

n-y

ears

Quartiles of % annual change in eGFR

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


Time to First Major CV Event Among Patients with CKD at Baseline

Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.

20

15

10

5

00 1 2 3 4 5 6

Patients with CKD at baselineAtorvastatin 10 mg

Atorvastatin 80 mg

HR=0.68 (95% CI 0.55, 0.84)P=0.0003, ARR=4.1%, NNT=24

Time (Years)No. of CKD patients at riskAtorva 10 mg 1505 1468 1422 1367 1310 687 0Atorva 80 mg 1602 1579 1539 1495 1450 701 0

% o

f p

atie

nts

wit

h m

ajo

r C

V e

ven

ts

Time to First Major CV Event Among Patients with no CKD at Baseline


20

15

10

5

00 1 2 3 4 5 6

Patients with normal eGFR at baselineAtorvastatin 10 mg

Atorvastatin 80 mg

HR=0.85 (95% CI 0.72, 1.00)P=0.049, ARR=1.4%, NNT=74

Time (Years)No. of CKD patients at riskAtorva 10 mg 3324 3263 3192 3114 3036 1557 0Atorva 80 mg 3225 3180 3113 3044 2963 1579 0

% o

f p

atie

nts

wit

h m

ajo

r C

V e

ven

ts

Primary and Secondary Event Rates in Patients with CKD and Patients with Normal eGFR


Any coronary eventAll Patients* 1078 (21.6%) 1326 (26.5%)Patients with CKD 356 (22.2%) 431 (28.6%)Patients with normal eGFR 676 (21.0%) 828 (24.9%) P=0.285

Major cardiovascular eventAll Patients* 434 (8.7%) 548 (10.9%)Patients with CKD 149 (9.3%) 202 (13.4%)Patients with normal eGFR 254 (7.9%) 307 (9.2%) P=0.113

Any cardiovascular eventAll Patients* 1405 (28.1%) 1677 (33.5%)Patients with CKD 489 (30.5%) 574 (38.1%)Patients with normal eGFR 857 (26.6%) 1027 (30.9%) P=0.225

Major coronary eventAll Patients* 334 (6.7%) 418 (8.3%)Patients with CKD 110 (6.9%) 157 (10.4%)Patients with normal eGFR 198 (6.1%) 226 (6.8%) P=0.040

Cerebrovascular eventAll Patients* 196 (3.9%) 250 (5.0%)Patients with CKD 74 (4.6%) 104 (6.9%)Patients with normal eGFR 111 (3.4%) 139 (4.2%) P=0.281CHF with hospitalizationAll Patients* 122 (2.4%) 164 (3.3%)Patients with CKD 49 (3.1%) 84 (5.6%)Patients with normal eGFR 71 (2.2%) 72 (2.2%) P=0.011Peripheral artery diseaseAll Patients* 275 (5.5%) 285 (5.6%)Patients with CKD 121 (7.6%) 112 (7.4%)Patients with normal eGFR 147 (4.6%) 160 (4.8%) P=0.629All-cause mortalityAll Patients* 284 (5.7%) 282 (5.6%)Patients with CKD 112 (7.0%) 113 (7.5%)Patients with normal eGFR 132 (4.1%) 124 (3.7%) P=0.401

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

Event rate80 mg

P-value forheterogeneity10 mg

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 high-risk 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


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


Mean Change in LDL-C


120

100

80

60

40

20

00 1 2 3 4 5

Rosuvastatin

No. at riskPlacebo 1372 1248 1005 719 543 298 70Rosuvastatin 1375 1243 994 719 553 315 61

Mea

n L

DL

-C (

mg

/dl)

Year

Placebo

Rosuvastatin vs. Placebo: Primary Composite Endpoint


No. at riskPlacebo 1384 1163 952 809 534 153Rosuvastatin 1390 1152 962 826 551 148

Cu

mu

lati

ve i

nci

de

nce

of

the

pri

ma

ry

end

po

int

(%)

Year

40

35

30

25

15

5

00 1 2 3 4 5

20

10

Rosuvastatin

Placebo

Hazard ratio, 0.96P=0.59

Rosuvastatin vs. Placebo: Components of the Primary Endpoint

Event

Rosuvastatin (n=1389)

Placebo (n=1384)

HR (95%CI)

p valueNo. of pts.

No. of events /

100 pt-yrs

No. of pts.

No. of events /

100 pt-yrs

CV death 324 7.2 324 7.31.00

(0.85-1.16)

0.97

Nonfatal MI

91 2.1 107 2.50.84

(0.64-1.11)

0.23

Nonfatal stroke

53 1.2 45 1.11.17

(0.79-1.75)

0.42


Rosuvastatin vs. Placebo: Adverse Events

Adverse events (AEs)

No. of patients (%)

p valueRosuvastatin

(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


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


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 Non-diabetic CKD Patients with Dyslipidemia

• Objective: To investigate whether co-administration 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

239,0

172,2

243,6

154,2

0

50

100

150

200

250

300

Before treatment After treatment

To

tal c

ho

les

tero

l (m

g/d

L)

Pitavastatin 2 mg

Pitavastatin 2 mg + ezetimibe 10 mg

Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].

Reduction in LDL-C with Pitavastatin ± Ezetimibe


162,6

97,9

167,9

82,2

0

20

40

60

80

100

120

140

160

180


LDL-

C (

mg/

dL)

Reduction in Serum ADMA Levels with Pitavastatin ± Ezetimibe


0,59

0,52

0,60

0,51

0,46

0,48

0,50

0,52

0,54

0,56

0,58

0,60

0,62


Pitavastatin 2 mg


Ser

um A

DM

A (

nmol

/mL)

Reduction in Proteinuria with Pitavastatin ± Ezetimibe


1508

1042

1512

786

0

200

400

600

800

1000

1200

1400

1600


Pitavastatin 2 mg


Pro

tein

uria

(m

g/d)

Discussion: Cholesterol-independent 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 cholesterol-independent manner

• Possible mechanisms of ezetimibe benefit on renal parameters:

– Anti-oxidative properties

– Direct effect on endothelial function


Ezetimibe in Non-diabetic CKD Patients with Dyslipidemia: Conclusions

• Co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients, partly via a cholesterol-independent manner

• Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering 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.


Changes in Total Cholesterol: Statin ± Ezetimibe in Kidney Transplant Patients

Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.

20

10

0

-10

-20

-300 3 6 9 12

Ezetimibe treated

Control

p=0.001

mg

/dL

Months

Changes in LDL-C: Statin ± Ezetimibe in Kidney Transplant Patients


0

-10

-20

-30

-400 3 6 9 12

Ezetimibe treated

Control

p=0.002

mg

/dL

Months

Changes in Creatinine Clearance: Statin ± Ezetimibe in Kidney Transplant Patients


7

65

432

10

-1

-2-3

-4-5-6

-12 -9 -6 -3 0 3 6 9 12

Ezetimibe treated

Control

Months

mg

/dL

p=0.025

(Cockcroft-Gault formula)

7

65

432

10

-1

-2-3

-4-5-6

-12 -9 -6 -3 0 3 6 9 12

Ezetimibe treated

Control

Months

mg

/dL

/1.7

3m

2

p=0.033

(MDRD equation)

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

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


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


Study of Heart and Renal Protection (SHARP)

Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.

Background: Rationale for the SHARP Study

Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.

• 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

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


Association Between Cholesterol and CV Mortality


100

10

1

< 4.

7

4.7

– 6.

2>

6.2

< 4.

7

4.7

– 6.

2>

6.2

Non-diabetic

Diabetic

General population

Total cholesterol, mmol/L

CV

mo

rtal

ity,

% p

er a

nn

um

100

10

1

< 2.

6

2.6

– 3.

8

3.9

– 5.

1

5.2

– 6.

3

6.4

– 7.

7

7.8

– 9.

0>

9.0

Hemodialysis patients

Total cholesterol, mmol/L

To

tal

mo

rta

lity

, %

per

an

nu

m

Causes of CV Mortality in CKD


~75%: Other causes (cardiacarrest, arrhythmia, heartfailure) Not as dependent on cholesterol reduction

~25%: Directly attributable to MI(potentially avoidablewith 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. andLandray 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 pre-dialysis, 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

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


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


Documents

Comprehensive Publication Review: Dyslipidemia, Chronic Kidney Disease and Cardiovascular Disease