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Clinical Therapeutics/Volume 33, Number 6, 2011

Longitudinal Assessment of Estimated Glomerular FiltrationRate in Apparently Healthy Adults: A Post hoc Analysis fromthe JUPITER Study (Justification for the Use of Statins inPrevention: An Intervention Trial Evaluating Rosuvastatin)

Donald G. Vidt, MD1; Paul M. Ridker, MD, MPH2; John T. Monyak, PhD3;Martin J. Schreiber, MD1; and Michael D. Cressman, DO3

1Cleveland Clinic Foundation, Cleveland, Ohio; 2Brigham and Women’s Hospital, Harvard Medical3

School, Boston, Massachusetts; and AstraZeneca Pharmaceuticals LP, Wilmington, Delaware

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ABSTRACTBackground: Serum creatinine–based estimates of

glomerular filtration rate (eGFR) are frequently used toidentify patients with chronic kidney disease and assesscardiovascular risk both in clinical trials and in clinicalpractice. Although change in eGFR may be useful to as-sess change in renal function in patients with chronic kid-ney disease, the utility of serum creatinine–based eGFR isuncertain, particularly among individuals with normal oronly mildly impaired renal function.

Objective: The goal of this study was to examine therelationship between baseline serum creatinine andeGFR, as well as changes in these parameters, in appar-ently healthy adults in a post hoc analysis of data ob-tained in participants in the JUPITER study (Justificationfor the Use of Statins in Prevention: An Intervention TrialEvaluating Rosuvastatin).

Methods: JUPITER was a randomized study of rosu-vastatin 20 mg versus placebo in apparently healthyadults with high-sensitivity C-reactive protein levels �2.0

g/L, LDL-C �130 mg/dL, and serum creatinine �2.0g/dL. Changes from baseline in serum creatinine and

GFR, based on the Modification of Diet in Renal Dis-ase (MDRD) and Chronic Kidney Disease Epidemiol-gy Collaboration (CKD-EPI) equations, were assessedn the entire population and in subsets classified accord-ng to baseline eGFR status.

Results: Baseline characteristics of the 16,279 JUPI-ER study participants (mean age, 66 years; 62% men;2% white; and 58% with a history of hypertension)ho had both a baseline and �1 postbaseline serum cre-tinine measurement were similar to the entire popula-ion of 17,802 patients who entered the trial. The meange of the study population was 66 years, 62% were men,2% were white, and 58% had a history of hypertension.

ean (SD) serum creatinine increased from baseline by

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.08 (0.16) mg/dL and 0.09 (0.14) mg/dL in the rosuvas-atin and placebo groups, respectively (P � 0.001) at yearand by 0.09 (0.18) and 0.10 (0.16) mg/dL (P � 0.0045)t the final visit. Reductions in MDRD and CKD-EPIGFR were �0.5 mL/min/1.73 m2 greater with placebohan with rosuvastatin (P � 0.004) at year 1 and the finalisit. The magnitude of eGFR change was closely relatedo baseline eGFR, with greater reductions among subjectsith eGFR �60 mL/min/1.73 m2 in both the rosuvastatinnd placebo groups. Among those with an eGFR �90L/min/1.73 m2 , mean changes at year 1 and final visit

anged from –16 to –23 mL/min/1.73 m2 with MDRDand CKD-EPI, respectively; in contrast, mean changeswere �1 mL/min/1.73 m2 in subjects with eGFR �60

L/min/1.73 m2 .Conclusions: In JUPITER, reductions in MDRD or

KD-EPI eGFR levels were greater in study participantsith higher baseline eGFR levels but less in the rosuvas-

atin than in the placebo group. Future studies are re-uired to assess the reliability of serum creatinine–basedstimates of GFR to assess change in renal function, par-icularly among individuals with normal serum creatinineevels. ClinicalTrials.gov identifier: NCT00239681. (Clinher. 2011;33:717–725) © 2011 Elsevier HS Journals,

nc. All rights reserved.Key words: CKD-EPI equation, eGFR, MDRD

quation, serum creatinine.

INTRODUCTIONSerum creatinine is the most commonly used labora-tory measurement to assess renal function in clinical

Accepted for publication on May 3, 2011.doi:10.1016/j.clinthera.2011.05.0040149-2918/$ - see front matter

© 2011 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

practice because it reflects, albeit imperfectly, glomer-ular filtration rate (GFR). More accurate and preciseestimates of GFR can be obtained using equations thatcontrol for factors other than GFR that also affectserum creatinine. The most frequently used equationfor estimates of GFR (eGFR) is based on data obtainedfrom the Modification of Diet in Renal Disease(MDRD) study.1 This equation incorporates age, sex,nd race, in addition to serum creatinine levels. Moreecently, an eGFR equation was developed by thehronic Kidney Disease Epidemiology Collaboration

CKD-EPI) research group that included measure-ents of serum creatinine and GFR from apparentlyealthy individuals as well as from patients with CKD

n its validation data set.2

Although these equations unquestionably im-prove identification of patients with at least moder-ately impaired renal function when compared withserum creatinine alone, their utility in assessingchange in renal function over time is less clear, par-ticularly among individuals with normal or onlymildly impaired renal function (60 – 89 mL/min/1.73 m2).3 Changes in eGFR based on the MDRD

r CKD-EPI equations depend almost entirely onhanges in serum creatinine levels when assessedver a relatively short period of time (eg, �1 year)ecause gender and race are unchanged and the age-elated decline in renal function is small (�1 mL/in/1.73 m2 per year after the age of 30 years).4,5

For this reason, only a small change in eGFR duringa 1-year period would be expected among individu-als with normal renal function during a relativelybrief duration of follow-up. However, data obtainedfrom the previously reported JUPITER study (Justi-fication for the Use of Statins in Prevention: AnIntervention Trial Evaluating Rosuvastatin) wereassessed. The study determined the effects of rosuv-astatin 20 mg/d versus placebo on the risk of majorcardiovascular events among 17,802 apparently healthymen and women with LDL-C levels �130 mg/dL and

igh-sensitivity C-reactive protein (hsCRP) levels2.0 mg/L. A median MDRD eGFR was reported

hat was �7 mL/min/1.73 m2 lower when comparedith baseline after a 1-year follow-up of both rosu-astatin-treated study participants and those receiv-ng placebo.6 This magnitude of change was consid-

ered surprising when viewed within the context ofdata reported from other cardiovascular disease pre-

vention trials.7 For this reason, we performed an

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analysis of eGFR changes that were observed acrossthe range of baseline serum creatinine and eGFRlevels encountered in the JUPITER study population.Changes in eGFR were assessed using the MDRDand CKD-EPI equations among the entire group ofstudy participants and among subsets classified ac-cording to their baseline eGFR levels, using data ob-tained at year 1 and the final visit of the trial.

SUBJECTS AND METHODSJUPITER was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial conductedin 26 countries at 1315 sites designed to determine theeffects of rosuvastatin 20 mg/d on the risk of majorcardiovascular events among apparently healthy adultswith an elevated hsCRP but normal LDL-C level.6,8

The study was performed in accordance with ethicalprinciples that have origin in the Declaration of Hel-sinki9 and are consistent with International Confer-ence on Harmonisation/Good Clinical Practice.10 Sub-jects who consented to participate in the trial signed aconsent form that had been approved by an institu-tional review board or ethics committee. Financial sup-port for the trial was provided by AstraZeneca Phar-maceuticals LP, who collected trial data and monitoredstudy sites.

As previously described,8 study participants wereen aged �50 years and women aged �60 yearsith no pre-existing history of cardiovascular dis-

ase, LDL-C levels �130 mg/dL, and hsCRP �2.0mg/L. Subjects were excluded if they had serum cre-atinine levels �2.0 mg/dL. JUPITER was an event-driven trial designed to continue until a total of 520study participants experienced a confirmed majorcardiovascular event (cardiovascular death, stroke,myocardial infarction, unstable angina, or arterialrevascularization) unless early stopping criteria weremet at interim analyses. Criteria for stopping thetrial, which were based on the O’Brien-Flemingmethod and Lan-DeMets spending function, weremet at the second interim analysis and the trial wasclosed early due to clear evidence of a reduction inmajor cardiovascular events during rosuvastatintreatment. The median duration of follow-up was1.9 years, with a maximum follow-up of 5 years.6

Serum creatinine levels were obtained at baseline,after 1 year, and at the final visit of the JUPITER trial.Creatinine analyses were performed in JUPITER core

central laboratories using the Roche Modular Analyt-

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ics Chemistry System with Roche creatinine reagents(modified Jaffe’ reaction with rate blanking) (Roche

iagnostics, Township of Branchburg, New Jersey).ntra- and interassay %CVs were 4.1% and 3.9%, re-pectively. GFR was estimated based on the abbrevi-ted MDRD equation: [GFR (mL/min/1.73 m2) �86 � (serum creatinine in mg/dL)�1.154 � (age in

years)�0.203 � (0.742 if female) � (1.210 if black)1 tobe consistent with analyses of previously reportedeGFR data from trials of rosuvastatin treatment.11,12

The CKD-EPI eGFR equation used in the present anal-ysis was based on the published report by Levey et al2

in 2009 and also uses a 4-variable formula (serum cre-atinine in milligrams per deciliters, age in years, gen-der, and race) (Table I).

ANOVA comparisons for the changes from baselinein eGFR and serum creatinine were performed usingthe baseline value as a covariate.13 All statistical anal-ses were performed with SAS 8.2 (SAS Institute, Inc.,ary, North Carolina). Analyses were performed in

he entire group of study participants who had both aaseline and �1 follow-up serum creatinine measure-ent and in subsets of the population classified accord-

ng to their baseline eGFR level as either normal orncreased (eGFR �90 mL/min/1.73 m2), mildly re-uced (60–89 mL/min/1.73 m2), or moderately to se-erely decreased (eGFR �60 mL/min/1.73 m2). TheseGFR ranges are consistent with ranges used in theational Kidney Foundation’s staging of CKD.14 An

a priori level of statistical significance was set at

Table I. Chronic Kidney Disease Epidemiologic Col(GFR).

Race and SexSerum Creatinine

Level (mg/dL)

BlackFemale �0.7

�0.7Male �0.9

�0.9White or other

Female �0.7�0.7

Male �0.9�0.9

P � 0.05.

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RESULTSStudy Population

Baseline characteristics of the 16,279 JUPITERstudy participants (Table II) who had both a baselineand �1 postbaseline serum creatinine measurementwere similar to the entire population of 17,802 pa-tients who entered the trial.6 The mean age of thetudy population was 66 years, 62% were men, 72%ere white, and 58% had a history of hypertension.lthough subjects with diabetes were excluded from

he study, 31% of the study participants had a fast-ng glucose level �100 mg/dL. The study was termi-ated early based on the recommendation of an in-ependent data-monitoring board due to clearvidence of rosuvastatin’s efficacy in reducing theisk of major events. Baseline and 1-year follow-uperum creatinine and eGFR data were available for5,833 study participants (rosuvastatin, n � 7930;lacebo, n � 7903). The most frequent reason forhe absence of both baseline and 1-year follow-upata was closure of the trial before the 1-year fol-ow-up time point.

Serum Creatinine LevelsMean (SD) serum creatinine levels at baseline were

1.01 (0.19) mg/dL in both the rosuvastatin and placebogroups (Table II). Mean (SD) serum creatinine levelshad increased by 0.08 (0.16) mg/dL in the rosuvastatingroup and by 0.09 (0.14) mg/dL in the placebo group(between-group comparison, P � 0.001) at year 1 and

ation estimated glomerular filtration rate equation

Equation

� 166 � (serum creatinine/0.7)�0.329 � (0.993)Age

� 166 � (serum creatinine/0.7)�1.209 � (0.993)Age

� 163 � (serum creatinine/0.9)�0.411 � (0.993)Age

� 163 � (serum creatinine/0.9)�1.209 � (0.993)Age

� 144 � (serum creatinine/0.7)�0.329 � (0.993)Age

� 144 � (serum creatinine/0.7)�1.209 � (0.993)Age

� 141 � (serum creatinine/0.9)�0.411 � (0.993)Age

� 141 � (serum creatinine/0.9)�1.209 � (0.993)Age

labor

GFRGFRGFRGFR

GFRGFRGFRGFR

by 0.09 (0.18) mg/dL and 0.10 (0.16) mg/dL, respec-

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720

tively, at the final visit (between-group comparison,P � 0.0045) (Table III). The association of baselineerum creatinine with change in serum creatinine atear 1 is illustrated in Figure 1, which provides data forhe total population (placebo and rosuvastatin groupsombined) of JUPITER study participants; the differ-nce in mean serum creatinine change between the 2roups, although statistically significant, was small0.01 mg/dL). The 1-year data were used to eliminateny potential influence of variable duration of fol-ow-up among study participants with different base-ine serum creatinine levels. Serum creatinine levelsended to increase among study participants withower baseline values, particularly among study partic-pants with a baseline serum creatinine level �1.0 mg/L, in whom mean serum creatinine increases exceeded.1 mg/dL.

MDRD and CKD-EPI eGFRMean baseline MDRD and CKD-EPI eGFR were

�72 and �75 mL/min/1.73 m2 in both the rosuvasta-tin and placebo groups (Table II). Mean changes ineGFR ranged from –6.3 to –8.4 mL/min/1.73 m2 atyear 1 and the final visit in both the rosuvastatin andplacebo groups, based on either the MDRD or CKD-EPI equations (Table III). Mean reductions in MDRDand CKD-EPI eGFR were 0.5 to 0.6 mL/min/1.73 m2

greater in the placebo group compared with the rosu-vastatin group both at year 1 and the final visit (allcomparisons, P � 0.005).

Reductions in eGFR were greater among study partic-ipants with higher baseline eGFR values. Among studyparticipants with a baseline eGFR �90 mL/min/1.73 m2,

ean (SD) changes observed at year 1 were –19.6 (13.7)L/min/1.73 m2 in the rosuvastatin group and –20.2

13.5) mL/min/1.73 m2 in the placebo group based on theDRD equation (between-group comparison, P � 0.05)

nd –15.9 (10.6) mL/min/1.73 m2 in the rosuvastatingroup and –16.7 (10.5) mL/min/1.73 m2 in the placeboroup based on the CKD-EPI equation (Figure 2A). Thisifference was not statistically significant. Changes fromaseline to year 1 among study participants with a base-ine eGFR 60 to 89 mL/min/1.73 m2 were –5.8 (9.7) mL/in/1.73 m2 in the rosuvastatin group and –6.3 (9.4)L/min/1.73 m2 in the placebo group based on theDRD equation (between-group comparison, P �

.005); using the CKD-EPI equation, mean (SD) changes

Table II. Baseline characteristics of the JUPITERstudy population.

Rosuvastatin 20 mg(n � 8143)

Placebo(n � 8136)

Age at entry, mean(SD), y

66 (7.6) 66 (7.7)

Sex, no. (%)Male 5024 (61.7) 5056 (62.1)Female 3119 (38.3) 3080 (37.9)

Race, no. (%)White 5894 (72.4) 5844 (71.8)Non-white 2249 (27.6) 2292 (28.2)

Black 990 (12.2) 1011 (12.4)Asian 132 (1.6) 118 (1.5)Hispanic 965 (11.9) 1010 (12.4)Other 162 (2.0) 153 (1.9)

Hypertension, no. (%) 4677 (57.4) 4702 (57.8)Fasting glucose �100mg/dL, no. (%)

2532 (31.1) 2576 (31.7)

Dipstick urine protein,no. (%)*

None 6635 (81.5) 6658 (81.8)Trace or greater 1472 (18.1) 1449 (17.8)Not recorded 35 (0.4) 28 (0.3)

Serum creatinine, mg/dL†

Mean (SD) 1.01 (0.19) 1.01 (0.19)Median 1.00 1.00Interquartile range 0.9–1.1 0.9–1.1

eGFR, mL/min/1.73m2†

MDRDMean (SD) 75.4 (17.5) 75.4 (17.1)Median 73.6 73.6Interquartilerange

64.6–84.1 64.6–84.1

CKD-EPIMean (SD) 72.2 (15.7) 72.3 (15.7)Median 71.6 71.6Interquartilerange

61.3–82.6 61.2–82.6

JUPITER � Justification for the Use of Statins in Preven-tion: An Intervention Trial Evaluating Rosuvastatin;eGFR � estimated glomerular filtration rate; MDRD �Modification of Diet in Renal Disease; CKD-EPI �Chronic Kidney Disease Epidemiology Collaboration.*Data missing for one patient in each treatment group.†Data available for 15,833 study participants (rosuvasta-tin group, n � 7930; placebo group, n � 7903); to con-vert to ìmol/L, multiply by 88.

ere –6.2 (10.6) mL/min/1.73 m2 in the rosuvastatin

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group and –6.7 (9.7) mL/min/1.73 m2 in the placeboroup (between-group comparison, P � 0.05). In con-rast, among participants with a baseline eGFR �60 mL/in/1.73 m2, mean changes in eGFR were �1 mL/min/

1.73 m2 in both the rosuvastatin group and the placebo

Table III. Mean (SD) changes in serum creatinine lfiltration rate (eGFR) after 1 year and at fin

Rosuvastatin20 mg

Serum creatinineYear 1 (n � 15,833) 0.08 (0.16)Final visit† (n � 16,279) 0.09 (0.18)

MDRD eGFRYear 1 (n � 15,833) �7.1 (11.9)Final visit† (n � 16,279) �7.9 (13.5)

CKD-EPI eGFRYear 1 (n � 15,833) �6.3 (10.6)Final visit† (n � 16,279) �6.8 (12.2)

MDRD � Modification of Diet in Renal Disease; CKD-EPI �*Least-squares mean for placebo – rosuvastatin (95% CI).†Mean follow-up, 2.3 years.

0.30

0.25

0.20

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Figure 1. Mean (95% CI) changes from baseline incombined) according to baseline serum cre

June 2011

group using either the MDRD or CKD-EPI equations.None of the differences between treatments was statisti-cally significant. Findings were similar for change inMDRD or CKD-EPI eGFR from baseline to the final visit(Figure 2B).

(milligram per deciliter) and estimated glomerularit.

lacebo Difference* P

9 (0.14) 0.01 (0.003�0.012) 0.00100 (0.16) 0.01 (0.002�0.012) 0.0045

.7 (11.8) 0.5 (0.2�0.8) 0.0003

.4 (13.3) 0.6 (0.2�0.9) 0.0007

.9 (10.6) 0.5 (0.2�0.8) 0.0035

.4 (12.1) 0.6 (0.3�0.9) 0.0004

nic Kidney Disease Epidemiology Collaboration.

1.1 1.2 1.3 1.4 1.5 1.6 ≥1.7

2768 1635 755 355 172 100 109

atinine (mg/dL)

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Clinical Therapeutics

Association of Baseline Serum Creatinine witheGFR Change

The association of baseline serum creatinine levelswith change in eGFR at year 1 is illustrated in Figure 3,which provides data for the total population (placeboand rosuvastatin groups combined) of JUPITER studyparticipants. The 1-year data were used to eliminateany potential influence of variable duration of fol-

BaselineeGFREquationn

MDRD2819

CKD-EPI2352

MDRD10,150

CKD-EPI10,144

MDRD2864

CKD-EPI3337

BaselineeGFREquationn MDRD

2975CKD-EPI

2867MDRD10,150

CKD-EPI10,144

MDRD2975

CKD-EPI3642

≥90mL/min/1.73 m2

60–89mL/min/1.73 m2

<60mL/min/1.73 m2

≥90mL/min/1.73 m2

60–89mL/min/1.73 m2

<60mL/min/1.73 m2

10

5

0

–5

–10

–15

–20

–25

–30

–35

–40

Mea

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10

5

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–15

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–35

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PlaceboRosuvastatin

PlaceboRosuvastatin

*

*†

‡ ‡

A

B

Figure 2. Mean (SD) changes in estimated glomer-ular filtration rate (eGFR) (mL/min/1.73m2) after (A) 1 year and (B) at final visitaccording to baseline (eGFR). *P �0.05, †P � 0.005, ‡P � 0.001, changefrom baseline versus placebo.

low-up among study participants with different base-

722

line serum creatinine or eGFR levels. Mean changes ineGFR were �2 mL/min/1.73 m2 among study partici-ants with a baseline serum creatinine concentration1.1 mg/dL but were reduced compared with baseline

mong study participants with lower baseline levels.his was particularly true for study participants with aaseline serum creatinine level �1.0 mg/dL, in whomean reductions were �9 mL/min/1.73 m2 using either

the MDRD or CKD-EPI eGFR equation.

DISCUSSIONThe current post hoc analysis of data obtained in theJUPITER trial was prompted by the observation thateGFR, estimated by using the MDRD equation, was �7mL/min/1.73 m2 lower compared with baseline at the1-year follow-up time point among JUPITER study par-ticipants in both the placebo and rosuvastatin treatmentgroups.6 In the present analysis, we observed reductionsin MDRD or CKD-EPI eGFR that occurred in study par-ticipants with a baseline eGFR �60 mL/min/1.73 m2 butot in those with a baseline eGFR �60 mL/min/1.73 m2.

Among study participants with a baseline eGFR �90 mL/min/1.73 m2, mean reductions in the range of 20 mL/min/1.73 m2 for the MDRD and 16 mL/min/1.73 m2 for theCKD-EPI eGFR estimates were observed after a 1-yearperiod of follow-up. In contrast, mean changes in eGFRwere �1 mL/min/1.73 m2 among study participants with

baseline eGFR �60 mL/min/1.73 m2.A recognized limitation of the available information

from the JUPITER trial as it relates to renal function(ie, GFR) is that actual measurements of GFR using anoptimal marker, such as inulin, iothalamate, or io-hexol, were not obtained. Thus, we cannot exclude thepossibility that the reductions in eGFR observed inJUPITER study participants represented true reduc-tions in GFR. Although it is possible that inclusion ofsubjects with an elevated hsCRP level led to identifica-tion of a population with unrecognized progressive re-nal disease, this seems unlikely for several reasons.First, JUPITER study participants had a mean baselineserum creatinine level of 1.01 mg/dL and only 18%had dipstick-positive proteinuria (urine dipstick pro-tein that was trace or greater at baseline). Second, themagnitude of reduction in eGFR was similar at year 1and the final visit (which occurred after a mean fol-low-up period of 2.3 years). Finally, reductions ineGFR were only observed among study participantswith higher baseline eGFR levels and not those with a

baseline eGFR level �60 mL/min/1.73 m2.

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A much more likely explanation relates to the rela-tively large effects that small increases in serum creat-inine levels have on eGFR when baseline serum creat-inine levels are in the lower end of the normal range.For example, a 0.2-mg/dL increase in serum creatinineconcentration in a 65-year-old white man with a base-line serum creatinine concentration of 0.8 mg/dL re-sults in a reduction in MDRD eGFR from 97 to 75mL/min/1.73 m2, a decrease of 22 mL/min/1.73 m2. Inontrast, a 0.2-mg/dL increase in serum creatinine con-entration in a 65-year-old white man with a baselineerum creatinine of 1.5 mg/dL results in a reduction in

DRD from 47 to 41 mL/min/1.73 m2, a decrease of 6mL/min/1.73 m2. For this reason, reliable measure-

ents of serum creatinine are critical for GFR estima-ion.14 Calibration errors in the serum creatinine assaycross laboratories and over time have been found toave progressively larger effects among individualsith higher GFR levels.15 Although serum creatinine

levels from individual JUPITER study participantswere measured in the same clinical laboratory, assayswere performed at different times. Thus, we cannotexclude the possibility that variability in calibrationover time influenced the serum creatinine levels andeGFR values obtained in the JUPITER trial. Similarly,

10

0

–5

–10

–20

–30

–40≤0.6 0.7 0.8 0.9

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at

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Figure 3. Changes in Modification of Diet in Renal Diand Chronic Kidney Disease Epidemiology(rosuvastatin and placebo groups combine

we cannot exclude the possibility that changes in med-

June 2011

ications such as aspirin, NSAIDs, or drugs that altercreatinine metabolism without changing GFR hadsome impact on serum creatinine levels, particularlybecause some chemicals or drugs can influence serumcreatinine assays based on the conventional Jaffemethod.16,17 In JUPITER, 19.8% of study participantsreported use of �1 concomitant medication beforerandomization to receive rosuvastatin or placebo; as-pirin use at entry was also reported in 16.7% of studyparticipants.6 Use of �1 concomitant medication wasreported at some time during the randomized treat-ment phase of the trial in 99.4%, with no differencebetween the placebo and rosuvastatin groups.

The magnitude of reduction and SDs for change ineGFR was lower based on the CKD-EPI equation com-pared with the MDRD equation among study partici-pants who would be considered to have a normal orincreased GFR (�90 mL/min/1.73 m2).14 This could beiewed as evidence for an advantage of the CKD-EPIver the MDRD eGFR equation for use in assessinghange in renal function among subjects who do notave at least moderately impaired renal functioneGFR �60 mL/min/1.73 m2). However, data from the

current analysis suggest that comparisons of a singlebaseline and single follow-up GFR estimate using ei-

1.1 1.2 1.3 1.4 1.5 1.6 ≥1.7

2768 1635 755 355 172 100 109

atinine (mg/dL)

MDRDCKD-EPI

estimates of glomerular filtration rate (MDRD eGFR)boration (CKD-EPI) eGFR after 1 year of follow-up

cording to baseline serum creatinine levels.

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interpreted with caution when used to assess change inrenal function among individuals who have an eGFRthat is �60 mL/min/1.73 m2. This observation is con-istent with current recommendations for clinical lab-ratories to report numerical eGFR values only for

ndividuals with an eGFR level �60 mL/min/1.73 m2,a level that is reportedly associated with an increasedrisk of adverse renal and cardiovascular outcomes.18–22

We did observe a small but statistically significant netreduction in the decrease in eGFR in the rosuvastatingroup compared with the placebo group. This is consis-tent with data reported in other large cardiovascular dis-ease prevention trials using statins.7,23–25 Although it isot clear whether statins can reduce the progression ofhronic renal failure to end-stage renal disease, there isrowing evidence that statins are effective in reducingardiovascular risk in patients with impaired renal func-ion. In the JUPITER trial, there was approximately a0% greater risk of major cardiovascular events (cardio-ascular death, stroke, myocardial infarction, unstablengina, or arterial revascularization) among study partic-pants with a baseline MDRD eGFR �60 mL/min/1.73

2 compared with those with a baseline MDRD eGFR�60 mL/min/1.73 m2 (hazard ratio, 1.54; 95% CI, 1.23–.92; P � 0.0002).26 In addition, the rate of reported

renal adverse events was �50% higher among study par-ticipants in the placebo or rosuvastatin group with a base-line eGFR �60 mL/min/1.73 m2 when compared withstudy participants with a higher baseline eGFR. How-ever, there was a 45% reduction in the risk of majorcardiovascular events and a 44% reduction in total mor-tality, with no increase in reported renal adverse events inthe rosuvastatin group compared with the placebo groupamong study participants with a baseline MDRD eGFR�60 mL/min/1.73 m2. Thus, although the analysis ofdata included in this report raises questions about theutility of using eGFR to assess changes in renal functionamong individuals with normal or mildly impaired renalfunction, findings in JUPITER support the use of aneGFR �60 mL/min/1.73 m2 to identify patients with anincreased cardiovascular or renal risk.

CONCLUSIONSData from the JUPITER study suggest greater reductionsin MDRD or CKD-EPI eGFR among study participantswith higher baseline eGFR levels, but these reductionswere lower in magnitude in the rosuvastatin group thanin the placebo group. Future studies are required to assess

the reliability of serum creatinine–based estimates of

724

GFR to assess change in renal function, particularlyamong individuals with normal serum creatinine levels.

ACKNOWLEDGMENTSThis study was funded by AstraZeneca.

The authors thank Julia Breyer Lewis, MD (Universityof Utah School of Medicine), and Tom Greene, PhD(Vanderbilt University School of Medicine) for helpfuldiscussion during development of the manuscript. Edito-rial support was provided by Liz Anfield at Prime MedicaLtd. (Knutsford, Cheshire, United Kingdom) during thelater stages of manuscript development, funded by Astra-Zeneca. Responsibility for opinions, conclusions, and in-terpretation of the data lies with the authors.

Dr. Vidt has received grant support from AstraZenecaLP. Dr. Ridker has received grant support from Astra-Zeneca LP, Novartis AG, Merck & Co, Inc., Abbott Lab-oratories, F. Hoffmann-La Roche Ltd, and sanofi-aven-tis, and consulting fees or lecture fees or both fromAstraZeneca LP, Novartis AG, Merck & Co, Inc.,Merck–Schering-Plough Corporation, sanofi-aventis, IsisPharmaceuticals, Inc., Dade Behring, Inc., and VascularBiogenics Ltd. Dr. Ridker is also listed as a co-inventor onpatents held by Brigham and Women’s Hospital thatrelate to the use of inflammatory biomarkers incardiovascular disease and that are licensed to Dade Beh-ring, Inc. and AstraZeneca LP. Dr. Schreiber has receivedgrant support from Amgen Inc., Genzyme Corporation,and Novartis AG. Drs. Monyak and Cressman are em-ployees of AstraZene LP.

The authors have indicated that they have no otherconflicts of interest regarding the content of this article.

All authors contributed equally to the conduct ofthe study and creation of the manuscript.

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Address correspondence to: Michael D. Cressman, DO, AstraZeneca Phar-maceuticals LP, 1800 Concord Pike, Wilmington, DE 19850. E-mail:

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