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RIGINAL INVESTIGATIONSathogenesis and Treatment of Kidney Disease
Effects of Atorvastatin on Kidney Outcomes and Cardiovascular Diseasein Patients With Diabetes: An Analysis From the Collaborative
Atorvastatin Diabetes Study (CARDS)
Helen M. Colhoun, MD,1 D. John Betteridge, PhD,2 Paul N. Durrington, MD,3
Graham A. Hitman, MD,4 H. Andrew W. Neil, DSc,5 Shona J. Livingstone, MSc,1
Valentine Charlton-Menys, PhD,3 David A. DeMicco, PharmD,6 and John H. Fuller, FRCP,7 onbehalf of the CARDS Investigators
Background: We examined whether atorvastatin affects diabetic kidney disease and whether theeffect of atorvastatin on cardiovascular disease (CVD) varies by kidney status in patients with diabetes.
Study Design: The Collaborative Atorvastatin Diabetes Study (CARDS) randomized placebo-controlled trial.
Setting & Participants: Patients with type 2 diabetes and no prior CVD (n � 2,838).Intervention: Random allocation to atorvastatin, 10 mg/d, or placebo, with a median follow-up of 3.9 years.Outcomes: Estimated glomerular filtration rate (eGFR), albuminuria, CVD.Measurements: Baseline and follow-up GFRs were estimated by using the Modification of Diet in
Renal Disease Study equation. Urinary albumin-creatinine ratio was measured on spot urine samples.Results: At baseline, 34% of patients had an eGFR of 30 to 60 mL/min/1.73 m2. Atorvastatin treatment
was associated with a modest improvement in annual change in eGFR (net, 0.18 mL/min/1.73 m2/y; 95%confidence interval [CI], 0.04 to 0.32; P � 0.01) that was most apparent in those with albuminuria (netimprovement, 0.38 mL/min/1.73 m2/y; P � 0.03). At baseline, 21.5% of patients had albuminuria and anadditional 6.8% developed albuminuria during follow-up. Atorvastatin did not influence the incidence ofalbuminuria (hazard ratio, 1.49; 95% CI, 0.73 to 3.04; P � 0.3) or regression to normoalbuminuria (hazardratio, 1.19; 95% CI, 0.57 to 2.49; P � 0.6). In 970 patients with a moderately decreased eGFR of 30 to 60mL/min/1.73 m2, there was a 42% reduction in major CVD events with treatment, including a 61% reductionin stroke. This treatment effect was similar to the 37% (95% CI, 17 to 52; P � 0.001) reduction in CVDobserved in the study overall (P � 0.4 for the eGFR-treatment interaction).
Limitations: Low incidence rates of albuminuria and transition to more severe kidney status limitpower to detect treatment effects.
Conclusions: A modest beneficial effect of atorvastatin on eGFR, particularly in those with albuminuria,was observed. Atorvastatin did not influence albuminuria incidence. Atorvastatin was effective at decreasingCVD in those with and without a moderately decreased eGFR and achieved a high absolute benefit.Am J Kidney Dis 54:810-819. © 2009 by the National Kidney Foundation, Inc.
INDEX WORDS: Statin; diabetes; cardiovascular; eGFR; albuminuria.
trt
hether statin therapy prevents diabetickidney disease is unknown. Thus, we do
ot know whether the increasing use of statin
1From the University of Dundee, Dundee, Scotland; 2Univer-ity College London Hospital, London; 3Cardiovascular Re-earch Group, School of Clinical and Laboratory Sciences,ore Technology Facility, University of Manchester; 4Centre
or Diabetes and Metabolic Medicine, Barts and the Londonchool of Medicine and Dentistry, London; 5University ofxford, Oxford Centre for Diabetes, Endocrinology and Metab-lism, Oxford, UK; 6Pfizer, New York, NY; and 7EURODIAB,epartment of Epidemiology and Public Health, Royal Freend University of London Medical School, London, UK.
Received December 5, 2008. Accepted in revised formarch 27, 2009. Originally published online as doi: 10.1053/
.ajkd.2009.03.022 on June 22, 2009.
American Journal of Kidn10
herapy is likely to have a large impact on futureates of kidney complications. Few large statinrials of patients with diabetes to date have evalu-
A list of the CARDS Investigators appears at the end ofhis article.
Trial registration: ClinicalTrials.gov; study number:CT00327418.Address correspondence to Helen M. Colhoun, MD, Bio-
edical Research Institute, University of Dundee, Macken-ie Bldg, Kirsty Semple Way, Dundee, DD2 4BF Scotland,K. E-mail: [email protected]© 2009 by the National Kidney Foundation, Inc.0272-6386/09/5405-0006$36.00/0doi:10.1053/j.ajkd.2009.03.022
t
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ey Diseases, Vol 54, No 5 (November), 2009: pp 810-819
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Atorvastatin Effect and Kidney Status 811
ted effects on glomerular filtration rate (GFR)r urinary albumin excretion rate.1 A recent meta-nalysis of the effects of statins on these endoints in both general and diabetic populationsas inconclusive and contained data for only48 patients.2 Therefore, the first aim of thisrticle is to report the effect of atorvastatin onlbuminuria and estimated GFR (GFR) in one ofhe largest randomized trials (n � 2,838) oftatin therapy in people with diabetes; the Col-aborative Atorvastatin in Diabetes StudyCARDS). Of CARDS participants, slightly morehan one-third (34%) of participants had stage 3,e, moderate kidney damage (eGFR, 30 to 60L/min/1.73 m2), and slightly more than one-fth had albuminuria at baseline.The efficacy of statin therapy for preventing
ardiovascular disease (CVD) in patients withiabetes is now well established. In CARDS, wereviously reported that atorvastatin, 10 mg/d,ecreased major CVD outcomes by 37% in pa-ients with type 2 diabetes and no prior CVD,ith a mean low-density lipoprotein cholesterol
LDL-C) level decrease of 46 mg/dL and a meanriglyceride level decrease of 35 mg/dL.3 How-ver, whether statins are as effective in prevent-ng CVD in patients with diabetes who havempaired renal function has been called intouestion.4 In Die Deutsche Diabetes Dialysetudie (4-D), there was little evidence of benefitf atorvastatin therapy on CVD in patients withiabetes and end-stage renal disease.5 The Na-ional Kidney Foundation’s Kidney Disease Out-omes Quality Initiative (KDOQI) 2007 clinicalractice recommendations for diabetes andhronic kidney disease (CKD)6 drew attention tohe paucity of trial data for this question. Itoncluded that the evidence for benefit of statinsn CVD in patients with CKD stages 1 to 3eGFR, 30 to 90 mL/min/1.73 m2) was justmoderate.” Therefore, a second aim of thisrticle is to examine whether baseline kidneytatus influenced the effect of atorvastatin onVD in CARDS.
METHODS
tudyDesign andPatients
The detailed methods used in CARDS and main outcomesave been published previously.3 The study was undertakenn accordance with the Declaration of Helsinki and Guide-
ines on Good Clinical Practice. Patients were recruited from both primary and secondary care centers, and all centersbtained local ethical approval after approval from theulticenter research ethics committee. Recruitment was
etween November 1997 and June 2001. All patients gaveully informed written consent. In brief, 2,838 patients withype 2 diabetes and no previous CVD were randomly as-igned to receive either placebo or atorvastatin, 10 mg, onceaily. Allocation was double blinded. To be eligible forandomization, patients had to have diabetes and at least 1 ofhe following risk factors: (1) history of hypertension, (2)etinopathy (ie, any retinopathy, maculopathy, or prior pho-ocoagulation), (3) microalbuminuria or macroalbuminuria,r (4) current smoking. Patients were ineligible if they had aistory of myocardial infarction, angina, coronary vascularurgery, cerebrovascular accident, or severe peripheral vas-ular disease (defined as warranting surgery). Patients werexcluded if they had a plasma creatinine concentrationreater than 1.7 mg/dL or glycated hemoglobin (hemoglobin
1c) level greater than 12%. Mean serum LDL-C concentra-ion during baseline visits before randomization had to be60 mg/dL or less (�4.14 mmol/L), and serum triglycerides,00 mg/dL or less (�6.78 mmol/L). The primary end pointf the trial was major CVD events, and the trial had 90%ower to detect a decrease of at least one-third in the CVDvent rate with atorvastatin. The trial was terminated early inune 2003 on the recommendation of the data and safetyonitoring board because a highly significant effect onVD was apparent at the second interim analysis. Meaneriods of observation for the primary end point were 3.77ears (median, 4.0 years) in the atorvastatin group and 3.66ears (median, 3.9 years) in the placebo group.
aboratoryMethods
Spot urine samples were collected at 2 baseline visits andnnually thereafter for measurement of albumin-creatinineatio (ACR). Urinary creatinine level was determined byeans of the Jaffé method using a Roche Modular P ana-
yzer (Roche Diagnostics, Lewes, UK). Plasma creatinineas assayed by using a modified Jaffé procedure, with use ofbilirubin oxidant to eliminate interference from bilirubin,ith reagents from Synermed Europe Ltd (Burgess Hill,K). Within-assay coefficients of variation (CVs) for uri-ary and plasma creatinine were less than 2% and between-ssay CVs were less than 3% in each case. Urinary albuminas determined on samples stored for up to 3 days at 4°C bysing an immunoturbimetric method and the Beckman Arraynalyzer (Beckman Coulter UK Ltd, High Wycombe, UK).he within-assay CV for urinary albumin was 2.9% at 1.64g/dL, and the between-assay CV was 4.1% at 1.58 mg/dL.
ndPointDefinition
We estimated GFR by using the 4-variable Modificationf Diet in Renal Disease (MDRD) Study equation (notsotope-dilution mass spectrometry traceable).7 For analyseseported here, only ACR readings from urine samples con-rmed by means of dipstick not to be infected (ie, sampleas negative for leucocytes, nitrites and blood) were used.lbuminuria was defined as ACR of 22 mg/g or greater
�2.5 mg/mmol). A patient was defined as albuminuric at
aseline if all available (1 or 2) pretreatment ACR valueswvwt(mtpArfisnar
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Colhoun et al812
ere 22 mg/g or greater, normoalbuminuric if all availablealues were less than 22 mg/g, and indeterminate if thereere 2 readings in disagreement. Almost all (�85%) of
hose with albuminuria were in the microalbuminuric rangealbumin, 22 to 221 mg/g); thus, our analyses focused onicroalbuminuria and macroalbuminuria combined. In pa-
ients who were normoalbuminuric at baseline, incidentersistent albuminuria was defined as the occurrence of anCR of 22 mg/g or greater confirmed by a subsequent ACR
eading with the onset considered to occur at the time of therst reading for the purposes of survival analyses. Regres-ion to normoalbuminuria was defined as the onset oformoalbuminuria (ACR � 22 mg/g) in those albuminurict baseline. Regression had to be confirmed by a subsequenteading.
tatisticalMethods
All analyses were by intention to treat. By the time oftudy closure (June 2003), of those randomly assigned2,838), 143 were known to be dead, and of the 2,695emaining participants, 2,341 (87%) had a GFR estimateithin the final calendar year of follow up. Those without a
eading were evenly distributed by treatment allocation,ith 172 (49%) in the placebo group and 182 (51%) in the
torvastatin group. Because some participants entered therial at an earlier calendar date than others, duration ofollow-up varies among participants. Linear mixed modelsere used to estimate annual change in eGFR (as given by
he regression coefficient of follow-up time on eGFR) andhe effect of atorvastatin on this annual change (given by theegression coefficient for the interaction between atorvasta-in and time). A random intercept model was fitted withaseline eGFR as the first observation for each participant,articipant as a random effect, and fixed terms for age, sex,
Table 1. Baseline Characteristics by Ba
Placebo
eGFR � 60 mL/min/1.73 m2
eGFR � 60 mL/min/1.73 m2
o. of patients 922 488ge (y) 60.1 � 8.1 65.0 � 6.7omen 21.4 (197) 52.5 (256)hite 93.2 (859) 95.7 (467)
CR (mg/g) 9.39 (4.92-25.47) 9.45 (4.83-27.42) 9lbuminuric 21.2 (181) 22.0 (94)lasma creatinine (mg/dL) 1.11 (1.01-1.19) 1.28 (1.10-1.38) 1GFR (mL/min/1.73 m2) 69.9 � 7.1 54.1 � 5.4enin-angiotensin system
drug 40.9 (377) 48.8 (238)ow-density lipoprotein
cholesterol (mg/dL) 115 � 27 120 � 26otal cholesterol (mg/dL) 204 � 31 212 � 31igh-density lipoprotein
cholesterol (mg/dL) 54 � 13 56 � 13
Note: Values expressed as mean � SD or percentage (nuartiles). GFR was estimated by using the 4-variable Modor 130 placebo and 142 atorvastatin participants at base
L/s/1.73 m2, �0.1667; plasma creatinine in mg/dL toipoprotein cholesterol in mg/dL to mmol/L, �0.0259; ACR i
Abbreviations: ACR, albumin-creatinine ratio; eGFR, est
ollow-up time, and interaction of treatment with time. e
ccelerated failure time models assuming a Weibull distribu-ion with interval censoring were used to test for a treatmentffect of atorvastatin on incidence of albuminuria and regres-ion to normoalbuminuria, with and without adjustment foraseline ACR. To evaluate whether baseline eGFR influ-nced CVD outcomes and whether eGFR modified the effectf atorvastatin, we used Cox proportional hazard regressionnalysis and included eGFR dichotomized at greater and lesshan 60 mL/min/1.73 m2 as the major independent variablend tested for an eGFR-by-treatment interaction.
RESULTS
ffect of Atorvastatin onKidneyOutcomes
Baseline characteristics are listed in Table 1.verall, only 21.5% of the placebo and atorvasta-
in groups had albuminuria at baseline. Medianollow-up was 3.9 years. In each treatment group,6% of those randomly assigned were not assess-ble for change in ACR (4% were missing base-ine ACR data, 4% had no follow-up ACR data,nd in 8%, the urine sample dipstick test wasuggestive of infection). In those normoalbumin-ric at baseline, the incidence of albuminuriauring follow-up was low (6.8%). There was noignificant difference in albuminuria incidenceetween treatment groups, adjusting for baselineCR, age at baseline, and sex (Table 2). In those
lbuminuric at baseline, overall, 20% experi-
eGFR in Treatment and Control Groups
Atorvastatin
eboeGFR � 60 mL/
min/1.73 m2eGFR � 60 mL/
min/1.73 m2 All Atorvastatin
946 482 1,4288.0 59.7 � 8.4 65.0 � 6.7 61.5 � 8.353) 21.9 (207) 51.7 (249) 31.9 (456)26) 93.1 (881) 97.3 (469) 94.5 (1350)25.98) 9.65 (5.27-22.14) 11.06 (5.54-32.01) 10.07 (5.34-24.05)75) 19.7 (168) 25.0 (108) 21.5 (276)-1.24) 1.11 (1.00-1.20) 1.28 (1.10-1.37) 1.14 (1.03-1.26)10.3 69.8 � 7.5 53.5 � 5.3 64.3 � 10.3
15) 39.9 (377) 53.9 (260) 44.6 (637)
27 116 � 28 120 � 27 117 � 2831 205 � 32 210 � 32 207 � 32
13 53 � 11 56 � 14 54 � 12
), except for ACR, which is given as median (first and thirdn of Diet in Renal Disease Study equation. ACR is missingonversion factors for units: eGFR in mL/min/1.73 m2 to, �88.4; low-density lipoprotein, total, and high-densityto mg/mmol, �0.1131.glomerular filtration rate.
seline
All Plac
1,41061.8 �
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umberificatioline. C
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nced regression to persistent normoalbumin-
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Atorvastatin Effect and Kidney Status 813
ria, with no difference between treatment groupsTable 2).
Using the MDRD Study equation to estimateFR, 34.6% and 33.8% of those in the placebo
nd atorvastatin groups had an eGFR less than 60L/min/1.73 m2 at baseline, respectively (Table
). Essentially, those with eGFR less than 60L/min/1.73 m2 make up a group with a moder-
te decrease in kidney function (ie, stage 3 kid-ey disease as defined by the KDOQI) becausenly 1 person had an eGFR less than 30 mL/min/.73 m2 at baseline. During follow-up in allarticipants combined, the mean within-personhange per annum in eGFR was a 0.39-mL/min/.73 m2 improvement (95% confidence intervalCI], 0.32 to 0.46; P � 0.001). Overall, the effectf atorvastatin was a net improvement of 0.18L/min/1.73 m2 (95% CI, 0.04 to 0.32; P �
.01) in the annual rate of change in eGFR.owever, as listed in Table 3 and shown in Fig 1,
he annual change in eGFR decreased overall inhose with albuminuria, but improved overall inhose with normoalbuminuria (� �1.22; 95% CI,
1.39 to �1.05; P � 0.001 for the interactionetween albuminuria and time). Given this strongffect of albuminuria on eGFR, we present herehe effect of atorvastatin by albuminuria status.n those normoalbuminuric at baseline, the effectf atorvastatin was a nonsignificant increase innnual improvement by 0.13 mL/min/1.73 m2
95% CI, �0.02 to 0.3; P � 0.1). In thoselbuminuric at baseline, the effect of atorvastatin
Table 2. Progression an
evelopment of albuminuria by treatmentNormoalbuminuric at baselineDeveloped albuminuriaIncidence/100 patient-yearsHazard ratio* (atorvastatin:placebo), 1.49 (95% CI, 0.73-
egression to normoalbuminuria by treatmentAlbuminuric at baselineDeveloped normoalbuminuriaIncidence/100 patient-yearsHazard ratio* (atorvastatin:placebo), 1.19 (95% CI, 0.57-
Note: Of 2,566 study participants with a baseline ACRollow-up data. An additional 112 placebo and 116 atorvaseline and are excluded from the incident analyses. Baslbuminuric defined as ACR of 22 mg/g or greater. ConversAbbreviations: ACR, albumin-creatinine ratio; CI, confide*Hazard ratio for atorvastatin versus placebo adjusted fo
as to reduce the annual decrease by 0.38 mL/ 0
in/1.73 m2 (95% CI, 0.04 to 0.72; P � 0.03).hus, although there was no significant albumin-ria-by-treatment interaction (� � 0.26; 95% CI,0.09 to 0.60; P � 0.1), the modest treatment
ffect was most apparent in the albuminuricroup. Overall, the cumulative incidence of a5% decrease in GFR (at any time during follow-p) did not differ significantly between those inhe placebo group (4.8%) and those in the atorva-tatin group (4.7%; odds ratio, 0.98; 95% CI,.69 to 1.39; P � 0.9 adjusted for age, sex, andaseline eGFR). The effect of atorvastatin, 10g/d, on eGFR was independent of on-treatment
ystolic blood pressure, diastolic blood pressure,nd hemoglobin A1c level in models with thesencluded as time-dependent covariates.
Very few cases of acute renal failure wereeported during the study (4 in the placebo group,in the atorvastatin group; P � 0.2).
ffect of Atorvastatin onCVDOutcomesyBaseline eGFR
Those with eGFR less than 60 mL/min/1.732 at baseline were older and more likely to be
emale; therefore, effects on CVD are shownith adjustment for age and sex. On adjusting for
ge, sex, and treatment allocation, those withGFR less than 60 mL/min/1.73 m2 at baselinead similar rates of acute coronary events (haz-rd ratio [HR], 1.01; 95% CI, 0.69 to 1.50; P �.9), revascularizations (HR, 0.89; 95% CI, 0.65o 1.22; P � 0.5), and stroke (HR, 0.96; 95% CI,
ression of Albuminuria
Placebo Atorvastatin
827 83548 (5.8%) 65 (7.4%)
1.95 2.53P � 0.3
242 24447 (19.4%) 50 (20.5%)
7.10 7.48P � 0.6
ng, 99 placebo and 91 atorvastatin participants had noparticipants were of indeterminate albuminuric status atata shown are for those with at least 1 follow-up reading.tor: ACR in mg/g to mg/mmol, �0.1131.erval.ine ACR, age, and sex.
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Colhoun et al814
n the rate of first major CVD event by baselineGFR (HR, 0.89; 95% CI, 0.65 to 1.22; P � 0.5)ompared with those with eGFR greater than thisevel. Total mortality was not significantly differ-nt in those with compared with those withoutecreased eGFR (HR, 1.05; 95% CI, 0.73 to.50; P � 0.8).Table 4 lists the effects of allocation to atorva-
tatin on the primary end point, its components,nd total mortality by baseline eGFR category.torvastatin treatment was associated with simi-
ar relative risk reductions in the primary endoint of major CVD and its components in thoseith eGFR less and greater than 60 mL/min/1.732 (P � 0.25 for all eGFR-by-treatment interac-
ions). In those with decreased eGFR, the 42%ecrease in the primary end point of major CVDith atorvastatin was significant examined sepa-
ately (P � 0.03), with a point estimate of a 34%ecrease in coronary heart disease, 61% decreasen stroke, and 59% decrease in coronary revascu-arization.
Expressed in absolute terms, for every 1,000atients with an eGFR of 60 mL/min/1.73 m2 orreater treated for an average of 4 years, 36ajor first CVD events would be avoided and a
imilar number (38) would be avoided in thoseith eGFR less than 60 mL/min/1.73 m2. In
hose with decreased eGFR, the incidence rateor all major CVD events (ie, first and subse-uent events) was 33.7/1,000 patient-years atisk in those given placebo and 17.6/1,000 patient-ears at risk in those given atorvastatin, such that4 major CVD events would be avoided withvery 1,000 patients treated for 4 years.
Albuminuria at baseline was associated with aignificantly greater major CVD event rate (HR,.65; 95% CI, 1.23 to 2.22; P � 0.001, adjustedor age, sex, and treatment allocation). The effi-acy of atorvastatin in preventing CVD wasimilar in those with and without albuminuriaTable 5).
Average absolute decreases in LDL-C andotal cholesterol levels with atorvastatin wereery slightly, but significantly, greater in thoseith eGFR less than 60 mL/min/1.73 m2 (49 and6 mg/dL for LDL-C and total cholesterol, respec-ively) compared with those with eGFR greaterhis level (45 and 53 mg/dL; coefficient and P fornteraction, �4 mg/dL [95% CI, �7 to �1]; P �
0.006, and �3 mg/dL [95% CI, �6 to 0.04]; P �
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Atorvastatin Effect and Kidney Status 815
.05, respectively.) There was no difference inreatment effect on lipid levels by albuminurictatus.
DISCUSSION
In this analysis from CARDS, we find evi-ence of a modest beneficial effect of statinherapy on eGFR. This was most apparent inhose with albuminuria at baseline because over-ll, the remainder of the CARDS population hadn eGFR at baseline that was stable or improvinguring follow-up. This stability probably re-
Figure 1. Yearly meanithin-person change in esti-ated glomerular filtration rate
eGFR) by treatment group andaseline albuminuria. Net ef-ect of atorvastatin on eGFR inhose with normoalbuminuria:.13 mL/min/1.73 m2/y; P �.1; in those with albuminu-ia: 0.38 mL/min/1.73 m2/y; P �.03. Interaction between albu-inuria and atorvastatin: � �.26 (95% confidence interval,0.09 to 0.60; P � 0.1).
Table 4. Treatment Effect on Effica
End Point
% With Event (n/N)
Placebo Atorvastati
ajor cardiovascular diseaseeGFR � 60 mL/min/1.73 m2 9.22% (85/922) 6.13% (58/94eGFR � 60 mL/min/1.73 m2 8.61% (42/488) 5.19% (25/48All 9.01% (127/1410) 5.81% (83/1,4Treatment-eGFR interaction coefficient, �0.14 (95% CI, �0.74 to 0.46); P �
oronary heart diseaseeGFR � 60 mL/min/1.73 m2 5.42% (50/922) 3.49% (33/94eGFR � 60 mL/min/1.73 m2 5.53% (27/488) 3.73% (18/48All 5.46% (77/1,410) 3.57% (51/1,4Treatment-eGFR interaction coefficient, 0.02 (95% CI, �0.72 to 0.76); P � 0
trokeeGFR � 60 mL/min/1.73 m2 2.60% (24/922) 1.59% (15/94eGFR � 60 mL/min/1.73 m2 3.07% (15/488) 1.24% (6/482All 2.77% (39/1,410) 1.47% (21/1,4Treatment-eGFR interaction coefficient, �0.48 (95% CI, �1.62 to 0.67); P �
oronary revascularizationeGFR � 60 mL/min/1.73 m2 2.39% (22/922) 2.01% (19/94eGFR � 60 mL/min/1.73 m2 2.46% (12/488) 1.04% (5/482All 2.41% (34/1,410) 1.68% (24/1,4Treatment-eGFR interaction coefficient, 0.73 (95% CI, �0.48 to 1.94); P � 0eath from any causeeGFR � 60 mL/min/1.73 m2 5.64% (52/922) 3.59% (34/94eGFR � 60 mL/min/1.73 m2 6.15% (30/488) 5.60% (27/48All 5.82% (82/1,410) 4.27% (61/1,4Treatment-eGFR interaction coefficient, 0.29 (95% CI, �0.39 to 0.96); P � 0
Abbreviations: CI, confidence interval; eGFR, estimated*Unadjusted HR is for the univariate Cox regression mod
ncludes age and sex. P values are from likelihood ratio tests.
ected the high rate of angiotensin-convertingnzyme inhibitor and other antihypertensive drugse in the trial. As reported previously at base-ine, 67% of each treatment group was on treat-ent with blood pressure–lowering drugs, and
his increased to 84% and 83% at 4 years ofollow-up, respectively. The beneficial effect onGFR was modest and of uncertain long-termlinical significance, but it suggests that longererm statin use in albuminuric patients with dia-etes might have some clinically beneficial pre-entive effect on decrease in kidney function.
d Points by Baseline eGFR Status
HR (95% CI) forTreatment Effect P
Adjusted HR*(95% CI) P
0.65 (0.46-0.90) 0.01 0.65 (0.47-0.91) 0.010.58 (0.36-0.96) 0.03 0.57 (0.35-0.94) 0.020.63 (0.48-0.83) �0.001 0.63 (0.48-0.83) �0.001
0.63 (0.40-0.98) 0.04 0.64 (0.41-0.99) 0.040.66 (0.36-1.20) 0.2 0.65 (0.36-1.17) 0.20.64 (0.45-0.91) 0.01 0.64 (6.45-0.91) 0.01
0.60 (0.32-1.14) 0.1 0.62 (0.33-1.18) 0.30.39 (0.15-1.01) 0.04 0.38 (0.15-0.99) 0.040.52 (0.31-0.89) 0.01 0.53 (0.31-0.89) 0.02
0.83 (0.45-1.54) 0.6 0.84 (0.45-1.54) 0.60.41 (0.14-1.17) 0.08 0.40 (0.14-1.15) 0.070.69 (0.41-1.16) 0.2 0.68 (0.41-1.15) 0.2
0.63 (0.41-0.98) 0.04 0.65 (0.42-1.00) 0.050.89 (0.53-1.50) 0.7 0.86 (0.51-1.45) 0.60.73 (0.52-1.01) 0.06 0.73 (0.53-1.02) 0.06
ular filtration rate; HR, hazard ratio.treatment group as major factor. The adjusted model also
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Few large prospective clinical trials have re-orted statin effects on diabetic kidney out-omes. In the Heart Protection Study (HPS), inatients with type 2 diabetes, GFR estimated bysing the MDRD Study equation decreased by.4 mL/min/1.73 m2 less in those on simvastatinherapy during a mean 4.8 years of follow-up.8 Inhe Greek Atorvastatin and Coronary Heart Dis-ase Evaluation (GREACE) Study, atorvastatinreatment was associated with an improvementn creatinine clearance.9 In a combined analysiscross the West of Scotland Coronary Preventiontudy (WOSCOPS), Cholesterol and Recurrentvents (CARE), and Long-term Intervention withravastatin in Ischemic Disease (LIPID) trials,ravastatin was associated with a significant, butmall, 0.24-mL/min/1.73 m2/y net benefit inGFR,10 although the effect in the 1,334 diabeticarticipants was not reported separately. In thereating to New Targets (TNT) Study, there wasreater improvement in eGFR on 80 versus 10g of atorvastatin in both diabetic participants (a
et 2.1-mL/min/1.73 m2 greater improvement)nd all participants combined.11-13 A recent meta-nalysis by Strippoli et al2 included only 548atients (diabetic and nondiabetic combined) inhom creatinine clearance was evaluated as anutcome. They concluded that there was no sig-ificant effect of statin therapy on creatininelearance2; however, eGFR data from such largetudies as the HPS were not included. In thentihypertensive and Lipid Lowering Therapy
o Prevent Heart Attack Trial (ALLHAT), thereas no effect of pravastatin, 40 mg/d, on eGFR.14
n the recent Justification for the Use of Statins inrimary Prevention: An Intervention Trial Evalu-ting Rosuvastatin (JUPITER), there was a sur-
Table 5. Treatment Effect on Rate of Major Cardiov
Baseline Status
% With Event (n/N)
Placebo Ator
lbuminuric 13.8% (38/275) 8.7%ot known to be albuminuric 7.8% (89/1,135) 5.1%ll 9.01% (127/1,410) 5.81%reatment-albuminuria interaction coefficient, �0.10 (95%
Abbreviations: CI, confidence interval; HR, hazard ratio.*Unadjusted HR is for the univariate Cox regression mod
ncludes age and sex. P values are from likelihood ratio teaseline albuminuric status.
rising decrease of 6 mL/min/1.73 m2 in eGFR p
n both the placebo and active rosuvastatin treat-ent groups at 12 months; however, the net
reatment effect on within-person change wasot reported.15 Our data are consistent with aecent cohort analysis from the large Veteransntegrated Service Network database (VISN 16),hich concluded that recipients of statin therapyad a 13% decrease in the odds of developingidney dysfunction during 3 years of follow-p.16 Overall, a fairly consistent picture of veryodest beneficial effects on eGFR with statin
herapy is emerging. However, an important ca-eat is that we do not know whether changes inGFR in all these trials reflect a true permanentffect on kidney function or a transient effect onlasma creatinine level.We found no evidence of an effect on albumin-
ria itself, although the low baseline prevalencend on-study incidence rate of albuminuria in theARDS population limits the power to detect
reatment effects. A recent meta-analysis of statintudies that reported albuminuria outcomes wasominated by a single pravastatin study thathowed no benefit on albuminuria and includedery few diabetic participants.17,18 Another meta-nalysis that included 39,704 participants foundsignificant benefit for eGFR (1.22 mL/min/1.732/y lower in statin recipients than placebo) anddecrease in albuminuria; however, the analysisithin the diabetic patient subgroup showed no
ignificant effect.1 The lack of effects in thatnalysis and our study may partly reflect highackground rates of angiotensin-converting en-yme inhibition in patients with diabetes. Inontrast in the Fenofibrate Intervention and Eventowering in Diabetes (FIELD) Study,19 fenofi-rate therapy was associated with 2.6% more
r Disease Events by Baseline Albuminuria Status
HR (95% CI) forTreatment Effect P Adjusted HR* P
) 0.59 (0.36-0.99) 0.04 0.59 (0.35-0.98) 0.0452) 0.64 (0.46-0.89) 0.007 0.64 (0.46-0.89) �0.00128) 0.63 (0.48-0.83) 0.001 0.63 (0.48-0.83) �0.001.71 to 0.50); P � 0.7
treatment group as major factor. The adjusted model alsoe hundred thirty placebo and 142 participants are without
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vastatin
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Atorvastatin Effect and Kidney Status 817
ng albuminuria regression or lack of progres-ion. The incidence of albuminuria progressionn the placebo group in the FIELD trial of fenofi-rate therapy was almost double that in CARDSt 11%.
We found that patients with an eGFR of 30 to0 mL/min/1.73 m2 (ie, stage 3 CKD) experi-nced the same substantial decreases in CVDnd points with atorvastatin therapy as seen inhe trial overall. Treatment of 26 such patientsuring 4 years would prevent 1 first major CVDvent, and 38 events would be avoided for every,000 patients treated for 4 years. These data aremportant because the recent KDOQI clinicalractice guidelines and clinical practice recom-endations for diabetes and CKD label the evi-
ence that LDL-C–lowering therapy decreasesVD in patients with diabetes and CKD stages 1
o 3 as just “moderate.”6 Other data supportinghe efficacy of statin therapy for preventing CVDn the presence of kidney function impairmentnclude the Pravastatin Pooling Project (PPP),20
he TNT Study,13 and the Scandinavian Simvasta-in Survival Study (4-S).21 In contrast to theseeports, these CARDS data are specifically fromatients at lower absolute risk selected not toave a CVD history and, as such, provide evi-ence for an important population not yet re-orted separately in the literature. The Choles-erol Treatment Trialists (CTT) collaboration, tohich we have contributed, recently confirmed
he lack of an effect of baseline eGFR on CVDrevention across all the major statin trials inatients with diabetes.22
As in the PPP, we did not find a significantlyreater incidence of CVD in those with de-reased eGFR at baseline. In contrast, in the TNTtudy, in which the median duration of follow-upas longer (5 years), 17.4% of patients with typediabetes mellitus with CKD experienced a
ajor cardiovascular event versus 13.4% of pa-ients with type 2 diabetes mellitus with normalGFR (P � 0.049). The difference may indicatehat at these moderate degrees of kidney damage,s in CARDS, longer follow-up is needed beforeifferences in CVD risk become apparent. It alsos possible that greater background rates of use oflood pressure–lowering agents, including angio-ensin-converting enzyme inhibition, in diabeticohorts may ameliorate the increased risk associ-
ted with decreased eGFR. BSome of the concern about whether the effi-acy of statins is decreased in the presence ofidney disease comes from the 4-D trial. In thatrial of patients with diabetes on hemodialysisherapy, atorvastatin, 20 mg/d, was associatedith a nonsignificant 8% decrease in the primary
nd point of major CVD, reflecting 18% feweroronary events (P � 0.03), but 12% moretrokes (P � not significant). Some prominenceas given to an analysis in which fatal strokeas examined separately and found to be greater
n those on atorvastatin therapy. However, theotal stroke rate did not differ significantly withreatment.
Our finding that in these patients with diabetesith milder impairment in kidney function, ator-astatin, 10 mg, was associated with a 61%ecrease in stroke rate is important reassurance.hese data are in contrast with those for patientsith severe kidney disease in the recentURORA (A Study to Evaluate the Use ofosuvastatin in Subjects on Regular Hemodialy-
is: An Assessment of Survival and Cardiovascu-ar Events) trial.23 In that trial rosuvastatin therapyid not reduce major CVD events in patients onemodialysis, including patients with diabetes.nother lipid lowering trial in patients with
evere kidney disease, the Study of Heart andenal protection (SHARP), is ongoing.24
In summary, these data from CARDS provideeassurance that the use of statins in the majorityf patients with diabetes delivers substantial ma-rovascular benefits, even in those with modestmpairment in kidney function; is safe with re-ard to renal outcomes; and may even confer aenefit on eGFR.
ACKNOWLEDGEMENTSWe thank the patients who took part in this study, study
urses, and local investigators. The CARDS Clinical Cen-ers and Investigators are as follows. Aberdeen Royal: J.room; Studholme Medical Centre, Ashford: K. Tang, S.utt; The Surgery, Ayr: B. Lennox; Ayr Hospital: A. Collier;eehive Surgery, Bath: J. Hampton; Oldfield Surgery, Bath:.J. Harris; Pulteney Street Surgery, Bath: P.J. Tilley; Royalnited, Bath: J. Reckless; St Chad’s Surgery, Bath: E.J.iddowson; St James’ Surgery, Bath: I.M. Orpen; Belfastity: M. Fetherstone, J.R. Hayes; Royal Victoria, Belfast: R.cCance; Medical Centre, Chelmsley Wood, Birmingham:.M. Allin; Birmingham Heartlands: P. Dodson; Queenlizabeth, Birmingham: U. Martin; Synexus Limited, Bir-ingham: M. Salman; Bolton Diabetes Centre: J. Dean;
ottreaux Practice, Boscastle: G.D. Garrod, C. Jarvis; RoyalBBAbCrRgHPDJLMDHWECMEwGeIHSeHHoMMMLLCMPmDHSLlMOORPPHCRdTRSJCk
NGbKSStRMJMDTcERDCeKDlGCWtWh
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Colhoun et al818
ournemouth: D. Kerr; St Alban’s Medical Centre,ournemouth: I. Nelemans; Health Centre, Bradford onvon: J.S. Heffer; Frenchay, Bristol: V.J. Parfitt; Adden-rookes, Cambridge: M.J. Brown; Synexus Limited, Cardiff:. Godfrey, G.L. Newcombe; St Helier, Carshalton: J. Bar-
on; Aspire Research Limited, Chesterfield: M. Blagden;owden Surgery, Chippenham: R.M.C. Gaunt; Porch Sur-ery, Corsham: A. Cowie; Coventry & Warwickshire: E.illhouse; Bridge Medical Centre, Crawley: A.L. Cooper;ound Hill Surgery, Crawley: N.W. Jackson; Derby City: R.onnelly; Dewsbury District: T. Kemp, C. Rajeswaren; St
ames’, Dublin: J. Nolan; Dumfries & Galloway Royal: J.R.awrence; St Michael’s, Dun Laoghaire: M.J. McKenna;uirhead Medical Centre, Dundee: B. Kilgallon; Ninewells,undee: A.D. Morris, G.P. Leese; Hairmyres, East Kilbride:.N. Cohen, S.J. Benbow; Edinburgh Royal: J.D. Walker;estern General, Edinburgh: J.A. McKnight; St Margaret’s,
pping: G.B. Ambepitiya; Epsom District: C. Speirs; Healthentre, Falmouth: A. Seaman; River Practice, Fowey: A.iddleton; Frome Medical Practice: T.E. Cahill; Queen
lizabeth, Gateshead: J. Weaver, S.S. Razvi, A. Syed; Med-ay Maritime, Gillingham: I. Scobie; Gartnaval General,lasgow: M. Small; Glasgow Royal: K.R. Paterson; South-
rn General, Glasgow: S.J. Gallacher, L. Fraser; Victorianfirmary, Glasgow: C.M. Kesson; Harrogate District: P.ammond; Hartlepool General: J. MacLeod; St Thomasurgery, Haverfordwest: R.W.G. Thompson; Withybush Gen-ral, Haverfordwest: N. Jowett; Princess Royal, Haywardseath: T. Wheatley; Hemel Hempstead General: C. Johnston;etton le Hole Medical Centre: M. Baldasera; Hildenbor-ugh Medical Group: P. Goozee; Raigmore, Inverness: S.acRury; Townhead Surgery, Irvine: M.F. Doig, D.D.cKeith; Leicester General: R. Gregory, A.C. Burden, L.C.eakin; Synexus Limited, Liverpool: J. Robinson; Royal
iverpool & Broadgreen: J.P. Vora; St John’s at Howden,ivingstone: R.S. Gray; Charing Cross, London: M. Seed,. Leroux; Hammersmith, London: A. Dornhorst; Northiddlesex, London: H. Tindall; Royal Free, London: M.
ress; Symons Medical Centre, Maidenhead: R.C.F. Sy-ons; Hope, Manchester: R. Young; North Manchesteriabetes Centre: P. Wiles; Synexus Limited, Manchester:.S. Parry, D. Dev; Trafford General, Manchester: W.P.tephens; Giffords Primary Care Centre, Melksham: C.H.ennon; Newcastle General: S. Marshall; Friarage, Northal-
erton: R. Fisken; Queens Medical Centre, Nottingham: P.I.ansell; George Eliot, Nuneaton: V. Patel; Southport &rmskirk, Ormskirk: R.S. Oelbaum, J. Horsley; Royalldham: D. Bhatnagar; Churchill, Oxford: D. Matthews;oyal Alexandra, Paisley: J. Hinnie; Alverton Practice,enzance: J.F. Ryan; Cape Cornwall Surgery, St Just,enzance: A. Ellery; Knowle House Surgery, Plymouth: T.all, K. Gillespie; Woolwell Medical Centre, Plymouth:.P. Fletcher; Pontefract General: C. White, J. Howell;oyal Glamorgan, Pontypridd: M.D. Page; Queen Alexan-ra, Portsmouth: K.M. Shaw; Synexus Limited, Reading: M.homson, M. Horne, H. Shaw; Clinton Road Surgery,edruth: N.I.D.B. Gray; St Cross, Rugby: J.P. O’Hare; Theurgery, Ryde: E.J. Hughes; Brannel Surgery, St Austell:.R. Cecil; Salisbury District: N. O’Connell; Saltash Healthentre: R.C. Cook; Scunthorpe General: S. Beer; Carter-
nowle & Dore Medical Practice, Sheffield: B. King; sorwood Medical Centre, Sheffield: P. Hardy; Southeyreen Medical Centre, Sheffield: N.H. Patel; Royal Shrews-ury: A. MacLeod; Chiltern International Limited, Slough:.A. Gunawardena, M. MacMahon, P. Palmer; Brook Laneurgery, Southampton: T.M. Tayler; Royal South Hants,outhampton: B. Leatherdale; Queensway Surgery, Sou-
hend on Sea: D. Sills; Lister, Stevenage: L.J. Borthwick;oyal, Stirling: C.J.G. Kelly, S.B.M. Reith; Huthwaiteedical Centre, Sutton-in-Ashfield: E. Ulliott, P. Smith;
ohn Pease Diabetes Centre, Sutton-in-Ashfield: R. Lloyd-ostyn, K. Sands; Cwmfelin Medical Centre, Swansea: P.J.avies; St Helens Medical Centre, Swansea: P. Cummings;alybont Surgery, Swansea: P.A. Edwards, M. Ferry (de-eased), A.H. Jones; Jubilee Surgery, Titchfield: P.W.G.vans; Bradford Road Medical Centre, Trowbridge: S.C.W.owlands; Lovemead Group Practice, Trowbridge: M.J.B.uckworth; Treliske, Truro: S. Fleming; Grosvenor Medicalentre, Tunbridge Wells: G.J. Charlwood; Pinderfields Gen-ral, Wakefield: D. Nagi; The Avenue Surgery, Warminster:.R. Bullen; Watford General: M. Clements; Sandwellistrict General, West Bromwich: D.A. Robertson; East-
eigh Surgery, Westbury: R. Edwards; Weston-super-Mareeneral: C. Dayan; Queen Elizabeth II, Welwyn Gardenity: P. Winocour; Synexus Limited, Wigan: J. Fraser;ishaw General: I.A.D. O’Brien; New Cross, Wolverhamp-
on: B.M. Singh; Nottinghamshire Research Associates,orksop: J.A. Fulton, L. Millar, S. Warner; Maelor, Wrex-
am: J.N. Harvey; York District: P. Jennings, J. Thow.Support: This study was funded in part by the UK Depart-ent of Health and Diabetes UK. Additional information on
unding sources is listed in the financial disclosure.Financial Disclosure: This study was funded in part by
fizer Inc, which markets atorvastatin. Dr DeMicco is aalaried employee of Pfizer. Universities employing Drsurrington, Colhoun, Fuller, and Charlton-Menys and Msivingstone have received research grants from Pfizer. Drsetteridge, Colhoun, Hitman, Fuller, and Neil have received
ees for lectures and consultancy work from Pfizer. Drurrington has received lecture fees from Pfizer.
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