comprehensive publication review: dyslipidemia, chronic kidney disease and cardiovascular disease
TRANSCRIPT
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
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 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
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• 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
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
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
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
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 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
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
Adapted from Attman PO, et al: Curr Opin Lipidol 2009; 20(4):293-9.
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
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 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
Adapted from Nogueira J, et al: Clin J Am Soc Nephrol 2007; 2(4):766-85.
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)
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 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
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
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
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*
* 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)
Adapted from Levin A, et al: CMAJ 2008; 179(11):1154-62.
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
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 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
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 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
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
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
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Differences in Demographic Characteristics by Baseline eGFR (2 of 3)
TotalEstimated Mean GFR (mL/min/1.73m2)
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
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Differences in Demographic Characteristics by Baseline eGFR (3 of 3)
TotalEstimated Mean GFR (mL/min/1.73m2)
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
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
Adjusted Incidence Rates of CV Mortality, by Kidney Function
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
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
Adapted from Astor BC, et al: Am J Epidemiol 2008; 167(10):1226-34.
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
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
.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
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
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
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
Adapted from Matsushita K, et al: J Am Soc Nephrol 2009; 20(12):2617-24.
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
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
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
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 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
Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.
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
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
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
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
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
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
Fellström BC, et al: N Engl J Med 2009; 360(14):1395-407.
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
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 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
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
162,6
97,9
167,9
82,2
0
20
40
60
80
100
120
140
160
180
Before treatment After treatment
LDL-
C (
mg/
dL)
Reduction in Serum ADMA Levels with Pitavastatin ± Ezetimibe
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
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
Before treatment After treatment
Pitavastatin 2 mg
Pitavastatin 2 mg + ezetimibe 10 mg
Ser
um A
DM
A (
nmol
/mL)
Reduction in Proteinuria with Pitavastatin ± Ezetimibe
Adapted from Nakamura T, et al: Pharmacol Res 2009 Aug 8. [Epub ahead of print].
1508
1042
1512
786
0
200
400
600
800
1000
1200
1400
1600
Before treatment After treatment
Pitavastatin 2 mg
Pitavastatin 2 mg + ezetimibe 10 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
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 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.
Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
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
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
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
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
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
Adapted from Türk TR, et al: Nephrol Dial Transplant 2008; 23(1):369-73.
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
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
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
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
Association Between Cholesterol and CV Mortality
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
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
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
~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)
Adapted from Baigent C, et al: Kidney Int Suppl 2003; (84):S207-10.
• 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
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.