University of Groningen Better prediction of drug response ...pensed study medication as determined...

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Better prediction of drug response in diabetic kidney diseaseIdzerda, Nienke

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https://doi.org/10.33612/diss.113117223

3Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin- treated patients; a post hoc analysis of the PLANET trials

NMA IdzerdaMJ PenaHH ParvingD de ZeeuwHJL Heerspink

Nephrology Dialysis Transplantation. 2018 Sep;1–8

Abstract

Background: Statins have shown multiple effects on different

renal risk factors such as lowering of total cholesterol (TC) and

lowering of proteinuria (UPCR). We assessed whether these effects

of statins vary between individuals, the extent of discordance of

treatment effects on both TC and UPCR within an individual,

and the association of responses in TC and UPCR with estimated

glomerular filtration rate (eGFR) decline.

Methods: The PLANET I and II trials examined effects of ator-

vastatin and rosuvastatin on proteinuria and renal function in pa-

tients with proteinuria. We post-hoc analyzed 471 therapy adherent

proteinuric patients from the two trials and assessed the individual

variability in UPCR and TC response from 0 to 14 weeks and

whether these responses were predictive of eGFR decline during

the subsequent 9 months of follow-up.

Results: UPCR and TC response varied between individuals:

mean UPCR response was −1.3% (5th–95th percentile −59.9,

141.8) and mean TC response was −93.9 mg/dL (−169.1, −26.9),

respectively. Out of 471 patients, 123 (26.1%) showed a response

in UPCR but not in TC, and 96 (20.4%) showed a response

in TC but not in UPCR. eGFR (mL/min/1.73m2) did not de-

crease significantly from baseline in both UPCR responders (0.4;

95%CI [−1.6, 0.9]; p = 0.54) and TC responders (0.3; [−1.8, 1.1];

p = 0.64), whereas UPCR and TC non-responders showed a signif-

icant decline in eGFR from baseline (1.8; [0.6, 3.0]; p = 0.004 and

1.7; [0.5, 2.9]; p = 0.007, respectively). A lack of response in both

parameters resulted in the fastest rate of eGFR decline (2.1; [0.5,

3.7]; p = 0.01). These findings were not different for rosuvastatin or

atorvastatin.

Conclusions: Statin-induced change in cholesterol and protein-

uria vary between individuals and do not run in parallel within

an individual. The initial fall in cholesterol and proteinuria is

independently associated with a reduction in eGFR decline. This

highlights the importance of both monitoring cholesterol and pro-

teinuria after initiating statin therapy.

41

3

Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin- treated patients; a post hoc analysis of the PLANET trials

Introduction

Although statins uniformly confer cardiovascular protection in diabetic

and non-diabetic patients[1, 2], their effects on slowing chronic kid-

ney disease (CKD) progression are inconsistent.[3] The SHARP trial

showed that treatment with simvastatin plus ezetimibe did not slow re-

nal disease progression in a large population of CKD patients during

4.8 years of follow up.[4] In the PLANET I and II trials, rosuvastatin

did not confer beneficial renal effects, whereas treatment with atorvas-

tatin reduced proteinuria and slowed renal function decline.[5] Of note,

in the PLANET trials, it seemed that the individual cholesterol and

proteinuria response to atorvastatin and rosuvastatin varied between pa-

tients. Whether individual responses in both proteinuria and cholesterol

are congruent within an individual is unknown. In other words, no stud-

ies have investigated whether a response in cholesterol is accompanied

by a response in proteinuria within an individual. It is not yet known

how this variability in response in proteinuria and cholesterol between

and within individual patients is associated with renal function decline.

We therefore performed a post-hoc analysis of the PLANET I trial

(Renal Effects of Atorvastatin and Rosuvastatin in Patients with Diabe-

tes who have Progressive Renal Disease) and the PLANET II trial (Pro-

spective Evaluation of Proteinuria and Renal Function in Non-diabetic

Patients With Progressive Renal Disease). First, we assessed the varia-

bility in cholesterol and proteinuria response between individual patients.

Second, we examined the extent of discordance in proteinuria and cho-

lesterol within individual patients, and subsequently determined whether

these responses were predictive of change in renal function.

Materials and methods

This post-hoc analysis includes the combined population of the PLANET

I and PLANET II trials. The PLANET I trial (NCT00296374) was a

randomized, double-blind, multicenter study in patients with type 1 or

type 2 diabetes and proteinuria (urine protein:creatinine ratio [UPCR]

500–5000 mg/g). The PLANET II trial (NCT00296400) was a simi-

lar study of patients with proteinuria but without diabetes. A total of

42

Chapter 3

545 patients were included in the intended-to-treat population of the

combined trials. The design of the study has been described previously.

[5] In brief, patients were randomly assigned to treatment with rosuvas-

tatin 10 mg, rosuvastatin 40 mg, or atorvastatin 80 mg and followed for

1 year. During an 8-week lead in period, patients were given dietary ad-

vice, underwent optimization of existing antihypertensive treatment, and

discontinued statin therapy (if applicable). Patients had to be receiving

treatment with angiotensin-converting enzyme inhibitors, angiotensin

receptor blockers, or both for at least 3 months before the first screening

visit. After randomization, patients collected first morning void urine

samples on 3 consecutive days prior to the randomization visit (week 0),

and then at 14, 26, 39, and 52 weeks for assessment of UPCR.

The trials were performed in accordance with the Declaration of Hel-

sinki and Good Clinical Practice guidelines. Ethics committees and in-

stitutional review boards approved the research protocol. All patients

gave written informed consent.

PatientsPatients aged 18 years or older and with low density lipoprotein

(LDL-C) concentrations of ≥ 90.1 mg/dL with type 1 or type 2 dia-

betes (PLANET I) or without diabetes (PLANET II) were enrolled.

The main exclusion criteria were glycated hemoglobin (HbA1c) levels

greater than 11%, statin intolerance, presence of familial hypercholes-

terolaemia or known type 3 hyperlipoproteinaemia, severe renal im-

pairment (estimated glomerular filtration rate [eGFR] < 40 mL/min per

1.73 m² 1 week before randomization), active liver disease, and use of

immunosuppressive drugs for treatment of proteinuria or renal disease

or both within 3 months of the first screening visit.

For this post-hoc study, data were analyzed from 471 patients who

adhered to study medication (defined as administration of > 80% of dis-

pensed study medication as determined by pill count), and had total

cholesterol (TC) and UPCR measurements available at baseline and at

14 weeks post-randomization.

MeasurementsSerum creatinine concentration was measured at the screening visit, ran-

domization visit, and then after 4, 8, 14, 26, 39, and 52 weeks follow-up.

43

3


eGFR was calculated with the modified Modification of Diet in Renal

Disease (MDRD) equation[6]. LDL cholesterol was calculated by the

Friedewald equation unless triglyceride concentration was more than

400 mg/dl, in which case a β-quantification measurement was used. All

laboratory analyses, including first morning void urine analysis, were

performed at central laboratories (Covance; Indianapolis, IN, USA, and

Geneva, Switzerland).

Statistical analysisWe assessed the change in UPCR and the change in TC from baseline

to week 14. UPCR change was calculated as the ratio of UPCR at week

14 divided by baseline on the log scale. Change in TC was calculated as

the difference between TC levels at week 14 and at baseline on the nat-

ural scale. We considered the treatment effects of the statins to be fully

present at week 14.

Patients were divided into subgroups according to their response

in UPCR and TC. A response in UPCR was defined as a decrease in

UPCR compared to baseline and a non-response in UPCR was de-

fined as an increase in UPCR, compared with baseline. A response in

TC was defined by a decline of ≥ 100 mg/dL, compared with baseline,

whereas a non-response in TC was defined by a decline of < 100 mg/dL,

compared with baseline. A response or a non-response in both UPCR

and TC were considered concordant responses, whereas a response in

one parameter and a non-response in the other was classified as a dis-

cordant response. In an additional analysis we considered finer catego-

ries of UPCR response (<−30%, −30% to 0%, 0 to 30% and > 30%

change) and TC response (<−125 mg/dL, −125 to −100 mg/dL, −100

to −75 mg/dL and >−75 mg/dL change). All categories were chosen

post hoc, with the aim of providing easily understandable thresholds

and approximately equal sample sizes in each subgroup. Similar catego-

ries of proteinuria responses were used in previous studies[7, 8].

Categorical variables are reported as frequencies and percentages.

Means and standard deviation (SD) were provided for variables with

a normal distribution. Means (calculated by 1-exp(geometric mean

change on log scale)* −100) and 95% confidence intervals or 5th to 95th

percentile are presented for UPCR change. Differences between groups

in continuous variables were tested with ANOVA with Bonferroni

44

Chapter 3

adjustments for multiple comparisons, or with Kruskall Wallis test with

Dunn’s test for multiple comparisons for non-normally distributed data.

Chi Square tests were used to test differences in categorical variables.

For this post-hoc study, we used a landmark approach and determined

the slope of eGFR change after the initial response to statin therapy was

established[9]. Since it is known that eGFR varies from day-to-day within

an individual[10], the mean eGFR of week 8 and week 14 was used as the

baseline value to calculate the “on treatment” eGFR slope to week 52.

A random effects mixed measures model was used to assess the rela-

tionship between the magnitude of TC and UPCR response and the “on

treatment” rate of subsequent eGFR change. In order to explore this re-

lationship, UPCR and TC response groups, stratified by responder and

non-responder groups, were entered in the model as a fixed effect. The

model also included visit as a fixed effect and response-strata by visit as

interaction term. The analysis was adjusted for age, sex, race, and base-

line eGFR, systolic and diastolic blood pressure, cholesterol, body mass

index, HbA1c and log transformed proteinuria. To allow generality for

the covariance structure, the variance-covariance structure was assumed

to be unstructured.

Two-sided p-values < 0.05 indicated statistical significance. Data were

analyzed with SAS version 9.3 (SAS Institute, Cary, NC) and R version

3.3.1 (The R Foundation for Statistical computing).

Results

Variability in cholesterol and proteinuria response between individualsUPCR response showed a large variability between patients in all treat-

ment groups combined: The mean UPCR response was −1.3% (5th–

95th percentile −59.9, 141.8) and the mean TC response −93.9 mg/dL

(−169.1, −26.9). In the atorvastatin group, mean UPCR response was

−9.9% (−58.9, 84.4) and mean TC response was −99.0 mg/dL (−168.8,

−36.5). In the rosuvastatin 10 mg/d group, mean UPCR response was

−4.2% (−62.5, 119.9) and mean TC response was −79.5 mg/dL (−156.5,

−32.1). In the rosuvastatin 40 mg/d group, mean UPCR and TC re-

sponse were +9.6% (−54.8, 167.8) and −98.1 mg/dL (−174.5, −14.5),

45

3


respectively. In the atorvastatin group, 57.3% of patients showed a re-

duction in UPCR and 49.1% showed a > 100 mg/dL reduction in TC.

In the low-dose and high-dose rosuvastatin group, a reduction in UPCR

was observed in 45.2% and 43.9% of patients, respectively, and 30.3%

and 48.0% showed a > 100 mg/dL reduction in TC, respectively. The

distribution of patients according to all pre-defined response categories

is illustrated in Figure 1.

Variability in proteinuria and cholesterol response within individualsThe number of patients with various response patterns in both TC and

UPCR is reported in Table 1. In 26.1% of patients, there was a reduc-

tion in UPCR but no response in TC (ΔTC>−100 mg/dL). Conversely,

20.4% of patients showed a >−100 mg/dL reduction in TC but not a

reduction in UPCR. Thus, 46.5% of patients showed a discordant re-

sponse in UPCR and TC. A similar discordance in response was observed

when atorvastatin and rosuvastatin groups were separately analyzed (Ta-

ble 1). As expected from the original article, the proportion with a lack

of response in both UPCR and TC was lowest with atorvastatin 80 mg.

Results remained similar when the analysis was performed for LDL-

cholesterol (LDL-C) and urinary albumin excretion (UACR) instead of

TC and UPCR (Supplementary tables 2 and 3). Results remained con-

sistent when TC was expressed as percentage change (Supplementary

table 4). When analyzed on a continuous scale, we observed no correla-

tion between UPCR and TC response in the combined treatment groups

(Pearson correlation r = 0.06, p = 0.23) and when they were analyzed sep-

arately (r = 0.10, p = 0.22; r = 0.06, p = 0.45; r = 0.02, p = 0.80) for rosu-

vastatin 10 mg, rosuvastatin 40 mg, and atorvastatin 80 mg, respectively;

Figure 1).

The baseline characteristics stratified for combined UPCR and TC

response are presented in Table 2. Both baseline UPCR and TC levels

were significantly different across response groups, with higher base-

line values in the responder population. The response groups differed

in statin treatment and body mass index (BMI). Statin-naïve patients

(N = 234) showed on average a larger reduction in total cholesterol

(−95.7 mg/dL, −108.1 mg/dL and 108.1 mg/dL for rosuvastatin 10 mg,

rosuvastatin 40 mg and atorvastatin 80 mg, respectively) in comparison

46

Chapter 3

with patients who used statins before enrolment into the trial (N = 237;

−73.8 mg/dL, −89.0 mg/dL and −88.7 mg/dL; Supplement table 6). The

variability in cholesterol response between patients as well as the dis-

cordance of cholesterol and proteinuria response did not differ between

these groups.

Figure 1. Correlation between UPCR change and TC change from baseline to week 14, represented for all treatment groups and per treatment group. Histograms: Distri-bution of patients according to UPCR change (left) and TC change (below) for rosu-vastatin 10 mg (green), rosuvastatin 40 mg (blue) and atorvastatin 80 mg (orange), re-spectively. Density is defined as the number of patients proportional to the intervals of UPCR and TC change. The percentage of patients according to pre-defined response groups within treatment groups are given above the histograms.

47

3


Association of short-term changes in UPCR and TC with changes in renal functionWe finally assessed whether changes in UPCR and TC were associated

with the slope of renal function decline. After multivariable adjustment,

Table 1. Distribution of patients according to change in proteinuria (UPCR) and change in total cholesterol (TC) from baseline to week 14 in all treatment groups (A) and stratified for treatment with rosuvastatin 10 mg (B), rosuvastatin 40 mg (C) and atorvastatin 80 mg (D).

A. Total analyzed population

ΔUPCR| ΔTC < −125 mg/dL −125 to −100 mg/dL

Total (%)

−100 to −75 mg/dL > −75 mg/dL Total

(%)<−30% 20 (4.2) 28 (5.9) 10.2 24 (5.1) 31 (6.6) 11.7−30% to 0% 30 (6.4) 28 (5.9) 12.3 27 (5.7) 41 (8.7) 14.4Total (%) 10.6 11.9 22.5 10.8 15.3 26.10% to 30% 24 (5.1) 22 (4.7) 9.8 33 (7.0) 30 (6.4) 13.4> 30% 28 (5.9) 22 (4.7) 10.6 31 (6.6) 52 (11.0) 17.6Total (%) 11.0 9.3 20.4 13.6 17.4 31.0

B. Rosuvastatin 10 mg

ΔUPCR| ΔTC <−125 mg/dL −125 to −100 mg/dL

Total (%)

−100 to −75 mg/dL >−75 mg/dL Total

(%)<−30% 7 (4.7) 8 (5.4) 10.1 8 (5.4) 13 (8.8) 14.2−30% to 0% 4 (2.7) 3 (2.0) 4.7 10 (6.8) 14 (9.5) 16.2Total (%) 7.4 7.4 14.9 12.2 18.2 30.40% to 30% 7 (4.7) 5 (3.4) 8.1 9 (6.1) 17 (11.5) 17.6> 30% 5 (3.4) 6 (4.1) 7.4 10 (6.8) 22 (14.9) 21.6Total (%) 8.1 7.4 15.5 12.8 26.4 39.2

C. Rosuvastatin 40 mg


Total (%)


(%)<−30% 5 (2.9) 12 (6.9) 9.8 6 (3.5) 7 (4.0) 7.5>−30% to 0% 16 (9.2) 10 (5.8) 15.0 8 (4.6) 12 (6.9) 11.6Total (%) 12.1 12.7 24.9 8.1 11.0 19.10% to 30% 7 (4.0) 10 (5.8) 9.8 13 (7.5) 7 (4.0) 11.6> 30% 15 (8.7) 10 (5.8) 14.5 15 (8.7) 20 (11.6) 20.2Total (%) 12.7 11.6 24.3 16.2 15.6 31.8

D. Atorvastatin 80 mg


Total (%)


(%)<−30% 8 (5.3) 8 (5.3) 10.6 10 (6.7) 11 (7.3) 14.0−30% to 0% 10 (6.7) 15 (10.0) 16.7 9 (6.0) 15 (10.0) 16.0Total (%) 12.0 15.3 27.3 12.7 17.3 30.00% to 30% 10 (6.7) 7 (4.7) 11.3 11 (7.3) 6 (4.0) 11.3> 30% 8 (5.3) 6 (4.0) 9.3 6 (4.0) 10 (6.7) 10.7Total (%) 12.0 8.7 20.7 11.3 10.7 22.0

Non-responders were further divided by > 30% increase in UPCR and a < 75 mg/dL de-crease in TC. Responders were divided by a > 30% decrease in UPCR and a > 125 mg/dL decrease in TC. Numbers are represented as frequency (%).

48

Chapter 3

Tab

le 2

. B

asel

ine

char

acte

rist

ics

of t

he in

tent

ion

to t

reat

pop

ulat

ion

stra

tifie

d by

gro

ups

of c

hang

e in

pro

tein

uria

and

cho

lest

erol

from

bas

elin

e to

wee

k 14

(N

= 5

04).

A n

egat

ive

conc

orda

nt r

espo

nse

is d

efine

d as

no

redu

ctio

n in

tota

l cho

lest

erol

(Δ

TC

> −

100

mg/

dL)

and

no r

educ

tion

in U

PC

R (

ΔU

PC

R

> 0

%).

A p

osit

ive

conc

orda

nt r

espo

nse

is d

efine

d by

a d

ecre

ase

in t

otal

cho

lest

erol

(Δ

TC

≤ −

100

mg/

dL)

and

a de

crea

se in

UP

CR

(Δ

UP

CR

≤ 0

%).

ΔT

C ≤

−10

0 m

g/dL

ΔU

PC

R ≤

0%

ΔT

C ≤

−10

0 m

g/dL

ΔU

PC

R >

0%

ΔT

C >

−10

0 m

g/dL

ΔU

PC

R ≤

0%

ΔT

C >

−10

0 m

g/dL

ΔU

PC

R >

0%

P-v

alue

Num

ber

of p

atie

nts

112

(22.

2)10

0 (1

9.8)

134

(26.

6)15

8 (3

1.3)

UP

CR

cha

nge*

−35

.6 [

−41

.1, −

29.7

]45

.2 [

36.7

, 54.

2]−

38.6

[−

43.9

, −32

.7]

52.3

[43

.4, 6

1.7]

< 0

.001

Cho

lest

erol

cha

nge#

−12

8.6

(26.

8)−

136.

9 (3

4.4)

−65

.2 (

28.1

)−

64.2

(27

.0)

< 0

.001

Age

(ye

ars)

54.7

(12

.6)

54.0

(11

.9)

53.1

(13

.5)

52.6

(13

.6)

0.59

2

Gen

der,

n (

%)

0.13

4

Wom

en35

(31

.2)

42 (

42.0

)37

(27

.6)

53 (

33.5

)

Men

77 (

68.8

)58

(58

.0)

97 (

72.4

)10

5 (6

6.5)

Rac

e, n

(%

)0.

625

Cau

casi

an10

2 (9

1.1)

87 (

87.0

)11

7 (8

7.3)

134

(84.

8)

Bla

ck4

(3.6

)8

(8.0

)5

(3.7

)9

(5.7

)

His

pani

c

4

(3.6

)4

(4.0

)9

(6.7

)8

(5.1

)

Oth

er2

(1.8

)1

(1.0

)3

(2.1

)6

(3.8

)

Dia

gnos

is o

f di

abet

es, n

(%

)71

(63

.4)

66 (

66.0

)74

(55

.2)

88 (

55.7

)0.

220

Sys

tolic

BP

(m

mH

g)13

7.4

(16.

1)13

4.5

(16.

7)13

6.3

(15.

4)13

2.4

(15.

9)0.

057

Dia

stol

ic B

P (

mm

Hg)

80.2

(9.

3)79

.8 (

9.5)

79.2

(10

.1)

80.3

(7.

9)0.

752

Bod

y m

ass

inde

x (k

g/m

²)31

.2 (

6.3)

32.5

(7.

8)29

.8 (

6.2)

30.0

(6.

3)0.

007

Hem

oglo

bin

(g/l)

142.

0 (1

5.5)

138.

7 (1

4.9)

139.

5 (1

8.1)

139.

1 (1

6.4)

0.44

4

HbA

1c (

%)

7.1

(1.5

)7.

1 (1

.6)

6.7

(1.5

)6.

7 (1

.5)

0.08

9

49

3


ΔT

C ≤

−10

0 m

g/dL

ΔU

PC

R ≤

0%

ΔT

C ≤

−10

0 m

g/dL

ΔU

PC

R >

0%

ΔT

C >

−10

0 m

g/dL

ΔU

PC

R ≤

0%

ΔT

C >

−10

0 m

g/dL

ΔU

PC

R >

0%

P-v

alue

Tot

al c

hole

ster

ol (

mg/

dL)

274.

4 (4

9.6)

301.

6 (6

0.0)

222.

8 (3

3.0)

230.

6 (4

3.6)

< 0

.001

HD

L c

hole

ster

ol (

mg/

dL)

50.0

(14

.2)

49.2

(14

.2)

49.3

(14

.4)

50.0

(16

.8)

0.95

8

LD

L c

hole

ster

ol (

mg/

dL)

171.

2 (4

3.0)

196.

9 (5

3.9)

137.

3 (2

7.9)

140.

7 (3

1.8)

< 0

.001

Tri

glyc

erid

es (

mg/

dL)

274.

3 (1

90.5

)27

3.1

(171

.3)

182.

7 (1

28.7

)19

6.8

(139

.2)

< 0

.001

Ser

um C

RP

(m

g/dL

)0.

5 (0

.5)

0.4

(0.4

)0.

5 (0

.7)

0.5

(0.9

)0.

180

eGF

R (

mL

/min

/1·7

3 m

²)†

71.6

(25

.0)

75.0

(33

.3)

73.2

(22

.3)

74.3

(29

.3)

0.79

9

UP

CR

(m

g/g)

1327

[11

88, 1

482]

1276

[11

33, 1

437]

1182

[10

71, 1

305]

1104

[10

07, 1

210]

0.05

8

Trea

tmen

t allo

catio

n, n

(%

)<

0.0

01

Ros

uvas

tati

n 10

mg

22 (

19.6

)23

(23

.0)

48 (

35.8

)66

(41

.8)

Ros

uvas

tati

n 40

mg

44 (

39.3

)46

(46

.0)

36 (

26.9

)57

(36

.1)

Ato

rvas

tati

n 80

mg

46 (

41.1

)31

(31

.0)

50 (

37.3

)35

(22

.2)

Num

eric

var

iabl

es a

re p

rese

nted

as

mea

n (S

D)

if n

orm

ally

dis

trib

uted

. UP

CR

is

pres

ente

d as

mea

n [9

5% C

I]. C

ateg

oric

al v

aria

bles

are

pre

sent

ed

as f

requ

ency

(%

). T

C, t

otal

cho

lest

erol

; BP,

blo

od p

ress

ure;

CR

P, C

-rea

ctiv

e pr

otei

n; H

DL

, hig

h de

nsit

y lip

opro

tein

; LD

L, l

ow d

ensi

ty li

popr

otei

n;

UP

CR

, uri

ne p

rote

in: u

rine

cre

atin

ine

rati

o; e

GF

R, e

stim

ated

glo

mer

ular

filt

rati

on r

ate.

* P

erce

ntag

e ch

ange

at

wee

k 14

as

com

pare

d to

bas

elin

e. #

A

bsol

ute

chan

ge a

t w

eek

14 a

s co

mpa

red

to b

asel

ine.

† C

alcu

late

d w

ith

the

Mod

ifica

tion

of

Die

t in

Ren

al D

isea

se s

tudy

equ

atio

n (M

DR

D).

50

Chapter 3

UPCR responders did not show a significant fall in eGFR (0.4; [−1.6,

0.9]; p = 0.54), whereas a significant decline in eGFR was observed in

patients who did not show a reduction in UPCR (1.8; 95%CI [0.6,

3.0]; p = 0.004; p vs non-responders 0.1; Figure 2A). Similarly, in TC

responders there was no evident change in eGFR (0.3; [−1.8, 1.1];

p = 0.64), whereas TC non-responders showed a significant eGFR de-

cline (1.7; [0.5, 2.9]; p = 0.007; p vs non-responders 0.2, figure 2B). Ad-

ditionally, the rate of eGFR decline in relation to the combined change

in UPCR and TC showed a stepwise increase in the rate of eGFR de-

cline across the combined response groups (Figure 2C). The combina-

tion of a lack of response in both UPCR and TC was associated with

the fastest rate of eGFR decline (2.1; [0.5, 3.7]; p = 0.01), whereas pa-

tients with a response in both parameters showed a stable renal function

(0.4; [−1.5, 2.2]; p = 0.70; p vs non-responders 0.05). Similar associa-

tions between treatment responses and renal outcome were observed in

the atorvastatin group as well as in both rosuvastatin groups.

Discussion

The PLANET trials showed that the proteinuria response to rosuvas-

tatin and atorvastatin differ despite a similar response in total choles-

terol on a population level.[5] In this post-hoc analysis we showed that

UPCR and TC response were not only variable between the statins, but

also highly variable between patients for both statins. In addition to

this between patient variability, we also observed that a reduction in

UPCR was not accompanied by a TC reduction in a substantial num-

ber of patients. Intriguingly, the individual responses in UPCR and TC

Figure 2. Change in eGFR from week 11 to week 52 according to UPCR change, TC change, and both UPCR and TC change from baseline to week 14. A: The left panel shows the mean change (95%CI) in UPCR from baseline to week 14 in patients with a reduction or an increase in UPCR, the right panel shows the mean eGFR change over time in both subgroups. B: The left panel shows the mean change (95%CI) in TC in patients with a reduction of more than 100 mg/dL or a reduction less than 100 mg/dL in TC, the right panel shows the eGFR change over time in both sub-groups. C: Least square means of eGFR change from week 11 to week 52 according to combined UPCR and TC change from baseline to week 14.

51

3


LS means

-6

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)

ΔTC ≤-100 mg/dlΔTC >-100 mg/dl

-0.3(-1.8, 1.1)

p=0.64

-1.7(-2.9, -0.5)p=0.007

-150

-100

-50

0

Mea

nch

oles

tero

l cha

nge

(mg/

dl)

-132.7(-137.0, -128.4)

-65.3(-68.5, -62.1)

B

ΔTC ≤-100 mg/dl ΔTC >-100 mg/dl

-50

0

50

Mea

nU

PCR

chan

ge (%

)-37.1

(-41.1, -32.8)

50.1(43.4, 57.1)

A

Δ UPCR≤0% Δ UPCR>0%

LS means

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)

Δ UPCR≤0%Δ UPCR>0% -1.8

(-3.0, -0.6)p=0.004

-0.4(-1.6, 0.8)

p=0.54

-4

-2

0

2

4

0.4(-1.5, 2.2)

p=0.70

-1.3(-3.4, 0.7)

p=0.21

-1.1(-2.8, 0.7)

p=0.22-2.1

(-3.7, -0.5)p=0.01

LS m

ean

eGFR

chan

ge (m

l/min

/1.7

3m²)

C

LS means

-6

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)


-0.3(-1.8, 1.1)

p=0.64

-1.7(-2.9, -0.5)p=0.007

-150

-100

-50

0

Mea

nch

oles

tero

l cha

nge

(mg/

dl)

-132.7(-137.0, -128.4)

-65.3(-68.5, -62.1)

B


-50

0

50

Mea

nU

PCR

chan

ge (%

)-37.1

(-41.1, -32.8)

50.1(43.4, 57.1)

A


LS means

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)


(-3.0, -0.6)p=0.004

-0.4(-1.6, 0.8)

p=0.54

-4

-2

0

2

4

0.4(-1.5, 2.2)

p=0.70

-1.3(-3.4, 0.7)

p=0.21

-1.1(-2.8, 0.7)

p=0.22-2.1

(-3.7, -0.5)p=0.01

LS m

ean

eGFR

chan

ge (m

l/min

/1.7

3m²)

C

LS means

-6

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)


-0.3(-1.8, 1.1)

p=0.64

-1.7(-2.9, -0.5)p=0.007

-150

-100

-50

0

Mea

nch

oles

tero

l cha

nge

(mg/

dl)

-132.7(-137.0, -128.4)

-65.3(-68.5, -62.1)

B


-50

0

50

Mea

nU

PCR

chan

ge (%

)

-37.1(-41.1, -32.8)

50.1(43.4, 57.1)

A


LS means

-4

-2

0

2

Time (weeks)

eGFR

chan

ge (m

l/min

/1.7

3m²)


(-3.0, -0.6)p=0.004

-0.4(-1.6, 0.8)

p=0.54

-4

-2

0

2

4

0.4(-1.5, 2.2)

p=0.70

-1.3(-3.4, 0.7)

p=0.21

-1.1(-2.8, 0.7)

p=0.22-2.1

(-3.7, -0.5)p=0.01

LS m

ean

eGFR

chan

ge (m

l/min

/1.7

3m²)

C

52

Chapter 3

correlated with individual renal function: a response in both UPCR and

TC resulted in a stable renal function, whereas non-responders in both

UPCR and TC showed the fastest rate of eGFR decline, independent

of the type of statin. These new findings indicate that reductions in both

UPCR and TC are predictors of eGFR changes during statin therapy in

diabetic and non-diabetic patients with proteinuria.

In the PLANET trials, treatment with rosuvastatin did not reduce

UPCR on a population level, whereas a significant reduction in UPCR

was observed in the atorvastatin group. Moreover, unlike atorvastatin

treated patients, patients in the rosuvastatin group showed an evident

decline in renal function. However, a substantial number of patients

in the rosuvastatin group did have a reduction in UPCR, which was

associated with less decline in renal function. This finding suggests that,

although rosuvastatin did not lower proteinuria at a population level, ro-

suvastatin may result in beneficial renal effects in a specific proportion

of patients. Thus, the faster eGFR decline with rosuvastatin is likely ex-

plained by the fact that many patients did not show a fall in proteinuria

and relatively more patients showed a considerable increase in UPCR,

compared with atorvastatin-treated patients. Hence, the reduction in

proteinuria may be used as an early marker to identify individuals who

are more likely to show a reduction in renal risk during atorvastatin or

rosuvastatin therapy.

The PLANET trials showed that differential proteinuria lowering

effects of the two statins were attained at similar cholesterol lowering

effects, suggesting that the proteinuria lowering effects are dissociated

from the lipid-lowering effects.[5] This post-hoc analysis supports these

results by demonstrating a lack of correlation between changes in TC

and UPCR. Interestingly, approximately 25% of patients either did not

show a reduction in UPCR but a response in TC or vice versa, a find-

ing that is consistent in both rosuvastatin and atorvastatin groups. The

underlying mechanisms of this discordance in response are unknown

but could be related to differences in drug disposition in different tis-

sues within an individual.[11, 12] Additionally, individual patient char-

acteristics such as inflammatory status could have influenced UPCR

response to a lesser or greater extent than TC response or vice versa. Of

note, the extent of discordance was comparable for the different statins

and were also observed when LDL cholesterol instead of TC response

53

3


was analyzed. It could be possible that a true correlation between UPCR

and TC response could not be detected due to random variability in uri-

nary protein excretion and lipid measurements. This is however unlikely

since we have previously shown that variation in albuminuria response

is reproducible upon re-exposure, suggesting that the individual albu-

minuria response is a true pharmacologic response and not a random

phenomenon.[13, 14]

This is not the first drug class for which it is shown that the response

in multiple renal risk markers within an individual is discordant. Pre-

vious studies already showed that a reduction in blood pressure dur-

ing renin-angiotensin-aldosterone-system (RAAS) inhibition was not

accompanied by a reduction in albuminuria in approximately 40% of

patients. In addition, sodium-glucose cotransporter-2 inhibitors also

exert multiple effects which can vary within an individual.[15]

Similar to the anti-proteinuric effects that were observed during treat-

ment with RAAS blockers[16, 17] and statins[18, 19], a reduction in

UPCR or TC induced by either rosuvastatin or atorvastatin was associ-

ated with less eGFR decline compared to a lack of response in either of

these parameters. This illustrates the importance of monitoring protein-

uria as well as cholesterol response in proteinuric patients after initia-

tion of statins. Further prospective clinical trials are obviously needed

to demonstrate whether specific targeting of proteinuria with statins will

improve renal outcomes.

A limitation of this study inherent to the design of the PLANET trials

and the post-hoc nature of this analysis is that there is no placebo ad-

justment. It is important to note that the PLANET trials were not pri-

marily aimed to investigate the dependence of renal outcome on various

levels of lipid-lowering and anti-proteinuric responses. The observed

responses could be the result of a regression to the mean phenomenon.

Therefore, the results can only be interpreted as hypothesis generating.

Furthermore, arbitrary thresholds of UPCR and TC were used to iden-

tify different response groups. However, similar categories of UPCR

response were used in previous studies.[7, 8] Moreover, stratification

of response groups by quartiles of TC and UPCR changes (absolute or

percentage) yielded similar results. Finally, our analysis did not include

hard clinical outcomes, and there was a relatively short follow-up pe-

riod to assess changes in eGFR.

54

Chapter 3

Previously we found that atorvastatin but not rosuvastatin reduced

proteinuria and slowed renal function decline. These population level

findings cannot be directly extrapolated to an individual patient level.

The current analysis shows that both in the rosuvastatin and the ator-

vastatin groups a substantial number of patients (more in the atorvas-

tatin group than in both rosuvastatin groups) can be identified with a

fall in proteinuria. Furthermore, proteinuria response to statin therapy

can be discordant from cholesterol response within an individual. Both

individual responses in proteinuria and cholesterol are independently

associated with a more stable eGFR, suggesting that changes in both

proteinuria and cholesterol should be individually monitored to identify

who will benefit from statin therapy.

Acknowledgments

The PLANET trials were sponsored by AstraZeneca. We thank all inves-

tigators, patients and support staff. We also like to thank the members

of the steering committee and the safety committee. The supplement

lists the steering committee, the safety committee and the investigators

of PLANET I and II.

References

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 ran-domised trials. Lancet 2010; 376: 1670–1681.

2. Taylor F, Huffman MD, Macedo AF et al. Statins for the primary pre-vention of cardiovascular disease. Cochrane Database Syst Rev 2013; (1):CD004816. doi: CD004816.

3. Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhib-itors (statins) for people with chronic

kidney disease not requiring dialy-sis. Cochrane Database Syst Rev 2014; (5):CD007784. doi: CD007784.

4. Haynes R, Lewis D, Emberson J et al. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol 2014; 25: 1825–1833.

5. de Zeeuw D, Anzalone DA, Cain VA et al. Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial. Lancet Diabetes Endocrinol 2015; 3: 181–190.

6. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate

55

3


glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Dis-ease Study Group. Ann Intern Med 1999; 130: 461–470.

7. Eijkelkamp WB, Zhang Z, Remuzzi G et al. Albuminuria is a target for reno-protective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analy-sis from the Reduction of Endpoints in NIDDM with the Angiotensin II An-tagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007; 18: 1540–1546.

8. Holtkamp FA, de Zeeuw D, de Graeff PA et al. Albuminuria and blood pres-sure, independent targets for cardi-oprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur Heart J 2011; 32: 1493–1499.

9. Dafni U. Landmark analysis at the 25-year landmark point. Circ Cardio-vasc Qual Outcomes 2011; 4: 363–371.

10. Toffaletti JG, McDonnell EH. Varia-tion of serum creatinine, cystatin C, and creatinine clearance tests in per-sons with normal renal function. Clin Chim Acta 2008; 395: 115–119.

11. Blanco-Colio LM, Tunon J, Mar-tin-Ventura JL et al. Anti-inflamma-tory and immunomodulatory effects of statins. Kidney Int 2003; 63: 12–23.

12. Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renal function. Am J Kidney Dis 2005; 45: 2–14.

13. Petrykiv SI, de Zeeuw D, Persson F et al. Variability in response to albu-minuria-lowering drugs: true or ran-dom? Br J Clin Pharmacol 2016.

14. Petrykiv SI, Laverman GD, Zeeuw D et al. The albuminuria lowering re-sponse to dapagliflozin is variable and reproducible between individual pa-tients. Diabetes Obes Metab 2017.

15. Petrykiv S, Sjostrom CD, Greasley PJ et al. Differential Effects of Dapagli-flozin on Cardiovascular Risk Factors

at Varying Degrees of Renal Function. Clin J Am Soc Nephrol 2017.

16. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in pa-tients with type 2 diabetes and ne-phropathy. N Engl J Med 2001; 345: 861–869.

17. Parving HH, Lehnert H, Broch-ner-Mortensen J et al. The effect of irbesartan on the development of di-abetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–878.

18. Tonolo G, Velussi M, Brocco E et al. Simvastatin maintains steady pat-terns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes. Kidney Int 2006; 70: 177–186.

19. Bianchi S, Bigazzi R, Caiazza A et al. A controlled, prospective study of the effects of atorvastatin on proteinu-ria and progression of kidney disease. Am J Kidney Dis 2003; 41: 565–570.

56

Chapter 3

Supplementary files

Supplementary Table 1. Baseline characteristics of the intention to treat population for patients with a decrease in proteinuria (ΔUPCR ≤ 0%) and no decrease in pro-teinuria (ΔUPCR ≤ 0%) and for patients with a robust response in cholesterol (ΔTC ≤ −100 mg/dL) and a suboptimal response in cholesterol (ΔTC > −100 mg/dL) from baseline to week 14 (N = 504).

ΔUPCR ≤ 0% ΔUPCR > 0% P-value ΔTC ≤ −100 mg/dL

ΔTC > −100 mg/dL P-value

Number of patients 229 (48.6) 242 (51.4) 202 (42.9) 269 (57.1)

UPCR change**

−37.1 [−41.1, −32.8]

50.1 [43.4, 57.1] < 0.001 −5.4

[−12.7, 2.6] 1.2 [−6.3, 9.3] 0.241

Cholesterol change# −95.1 (42) −93.4 (46) 0.679 −132.7 (31) −65.3 (27) < 0.001

Age (years) 53.7 (13) 53.6 (13) 0.954 54.3 (12) 53.1 (13) 0.356

Gender, n (%) 0.128 0.296

Women 69 (30.1) 90 (37.2) 74 (36.6) 85 (31.6)

Men 160 (69.9) 152 (62.8) 128 (63.4) 184 (68.4)

Race, n (%) 0.591 0.321

Caucasian 205 (89.5) 209 (86.4) 182 (90.1) 232 (86.2)

Black 9 (3.8) 17 (7.0) 12 (6.0) 14 (5.2)

Hispanic 11 (4.8) 10 (4.1) 6 (3.0) 15 (5.6)

Other 4 (1.7) 6 (2.5) 2 (1.0) 8 (3.1)

Diagnosis of di-abetes, n (%) 134 (58.5) 143 (59.1) 0.974 128 (36.6) 149 (55.4) 0.100

Systolic BP (mmHg) 136.9 (16) 133.3 (16) 0.014 136.2 (17) 134.2 (16) 0.188

Diastolic BP (mmHg) 79.8 (9.5) 80.2 (8.6) 0.706 80.2 (9.3) 79.9 (8.8) 0.727

Body mass in-dex (kg/m²) 30.4 (6.1) 31.2 (7.1) 0.225 31.7 (6.9) 30.1 (6.3) 0.01

Hemoglobin (g/L) 140.7 (17) 139.1 (16) 0.309 140.7 (15) 139.3 (18) 0.341

HbA1c (%) 6.9 (1.5) 6.9 (1.6) 0.973 7.0 (1.6) 6.7 (1.5) 0.032

Total choles-terol (mg/dL) 247.4 (49) 259.0 (62) 0.026 288.1 (57) 227.3 (40) < 0.001

HDL choles-terol (mg/dL) 50.0 (15) 49.6 (16) 0.83 49.8 (14) 49.8 (16) 0.996

LDL choles-terol (mg/dL) 152.9 (40) 163.1 (51) 0.017 183.6 (50) 139.0 (31) < 0.001

57

3


ΔUPCR ≤ 0% ΔUPCR > 0% P-value ΔTC ≤ −100 mg/dL

ΔTC > −100 mg/dL P-value

Triglycerides (mg/dL) 226.8 (170) 228.42 (158) 0.914 275.6 (184) 191.4 (137) < 0.001

Serum CRP (mg/dL) 0.5 (0.7) 0.5 (0.8) 0.434 0.4 (0.5) 0.5 (0.9) 0.056

eGFR (mL/min/1·73 m²)† 73.1 (24) 75.0 (31) 0.441 73.7 (29) 74.4 (27) 0.801

UPCR (mg/g) 1256 [1163, 1356]

1140 [1058, 1227] 0.073 1291

[1190, 1401]1127

[1051, 1208] 0.013

Treatment allo-cation, n (%) 0.034 0.001

Rosuvastatin 10 mg 67 (29.3) 81 (33.5) 45 (22.3) 103 (38.3)

Rosuvastatin 40 mg 76 (33.2) 97 (40.1) 85 (42.1) 88 (32.7)

Atorvastatin 80 mg 86 (37.6) 64 (26.4) 72 (35.6) 78 (29.0)

* In multivariate analysis, treatment allocation, systolic BP, diastolic BP, HDL cho-lesterol and baseline proteinuria were independently associated with proteinuria re-sponse. Treatment allocation, systolic BP, diastolic BP and baseline proteinuria were independently associated with cholesterol response.

Numeric variables are presented as mean (SD) if normally distributed. UPCR is pre-sented as mean [95% CI]. Categorical variables are presented as frequency (%). TC, total cholesterol; BP, blood pressure; CRP, C-reactive protein; HDL, high density li-poprotein; LDL, low density lipoprotein; UPCR, urine protein: urine creatinine ratio; eGFR, estimated glomerular filtration rate. ** Percentage change at week 14 as com-pared to baseline. # Absolute change at week 14 as compared to baseline. † Calcu-lated with the Modification of Diet in Renal Disease study equation (MDRD).

58

Chapter 3

Supplementary Table 2. Distribution of patients according to change in proteinuria (UPCR ) and change in low density lipoprotein cholesterol (LDL-C) from baseline to week 14; in all treatment groups (A) and stratified for treatment with rosuvastatin 10, rosuvastatin 40 mg, or atorvastatin 80 mg (B). Non-responders were further divided by a > 30% increase in UPCR and a < 50 mg/dl decrease in LDL-C. Responders were divided by a > 30% decrease in UPCR and a > 100 mg/dl decrease in LDL-C. Num-bers are represented as frequency (%).

A.

ΔUPCR | ΔLDL-C < −100 mg/dL

−100 to −75 mg/dL

Total (%)

−75 to −50 mg/dL > −50 mg/dL

Total (%)

<−30% 23 (4.9) 32 (6.9) 11.8 29 (6.2) 14 (3.0) 9.2−30% to 0% 27 (5.8) 44 (9.4) 15.2 35 (7.5) 20 (4.3) 11.8Total (%) 10.7 16.3 27.0 13.7 7.3 21.00% to 30% 26 (5.6) 33 (7.1) 12.7 35 (7.5) 15 (3.2) 10.7 > 30% 42 (9.0) 29 (6.2) 15.2 32 (6.9) 30 (6.4) 13.3Total (%) 14.6 13.3 27.9 14.4 9.7 24.0

B.Rosuvastatin 10 mg


−100 to −75 mg/dL

Total (%)

−75 to −50 mg/dL > −50 mg/dL

Total (%)

< −30% 7 (4.8) 7 (4.8) 9.5 13 (8.8) 8 (5.4) 14.3−30% to 0% 3 (2.0) 10 (6.8) 8.8 9 (6.1) 9 (6.1) 12.2Total (%) 6.8 11.6 18.4 15.0 11.6 26.50% to 30% 7 (4.8) 9 (6.1) 10.9 15 (10.2) 7 (4.8) 15.0> 30% 9 (6.1) 11 (7.5) 13.6 11 (7.5) 12 (8.2) 15.6Total (%) 10.8 13.6 24.5 17.7 12.9 30.6

Rosuvastatin 40 mg


−100 to −75 mg/dL

Total (%)

−75 to −50 mg/dL > −50 mg/dL

Total (%)

< −30% 10 (5.8) 10 (5.8) 11.6 8 (4.7) 1 (0.6) 5.2−30% to 0% 13 (7.6) 17 (9.9) 17.4 12 (7.0) 4 (2.3) 9.3Total (%) 13.4 15.7 29.1 11.6 2.9 14.50% to 30% 10 (5.8) 14 (8.1) 14.0 9 (5.2) 4 (2.3) 7.6> 30% 21 (12.2) 12 (7.0) 19.2 16 (9.3) 11 (6.4) 15.7Total (%) 18.0 15.1 33.1 14.5 8.7 23.3

Atorvastatin 80 mg


−100 to −75 mg/dL

Total (%)

−75 to −50 mg/dL > −50 mg/dL

Total (%)

< −30% 6 (4.1) 15 (10.2) 14.3 8 (5.4) 5 (3.4) 8.8−30% to 0% 11 (7.5) 17 (11.6) 19.0 14 (9.5) 7 (4.8) 14.3Total (%) 11.6 21.8 33.3 15.0 8.2 23.10% to 30% 9 (6.1) 10 (6.8) 13.0 11 (7.5) 4 (2.7) 10.2> 30% 12 (8.2) 6 (4.1) 12.2 5 (3.4) 7 (4.8) 8.2Total (%) 14.3 10.9 25.2 10.9 7.5 18.4

59

3


Supplementary Table 3. Distribution of patients according to change in albuminu-ria (UACR ) and change in total cholesterol (TC) from baseline to week 14; in all treatment groups (A) and stratified for treatment with rosuvastatin 10 mg, rosuvasta-tin 40 mg, or atorvastatin 80 mg (B). Non-responders were further divided by a > 30% increase in albuminuria and a < 75 mg/dl decrease in cholesterol. Responders were divided by a > 30% decrease in albuminuria and a > 125 mg/dl decrease in cholesterol. Numbers are represented as frequency (%).

A.

ΔUACR| ΔTC < −125 mg/dL−125 to

−100 mg/dLTotal (%)

−100 to −75 mg/dL > −75 mg/dL

Total (%)

< −30% 22 (4.7) 34 (7.2) 11.8 33 (7.0) 35 (7.4) 14.4−30% to 0% 31 (6.6) 20 (4.2) 10.8 28 (5.9) 44 (9.3) 15.2Total (%) 11.2 11.4 22.6 12.9 16.7 29.60% to 30% 21 (4.4) 26 (5.5) 9.9 24 (5.1) 25 (5.3) 10.4> 30% 28 (5.9) 20 (4.2) 10.1 30 (6.3) 52 (11.0) 17.3Total (%) 10.4 9.7 20.1 11.4 16.3 27.7


ΔUACR| ΔTC < −125 mg/dl−125 to

−100 mg/dlTotal (%)

−100 to −75 mg/dl > −75 mg/dl

Total (%)

< −30% 7 (4.7) 7 (4.7) 9.4 13 (8.7) 11 (7.4) 16.1−30% to 0% 5 (3.4) 4 (2.7) 6.0 10 (6.7) 19 (12.8) 19.5Total (%) 8.1 7.4 15.4 15.4 20.1 35.60% to 30% 5 (3.4) 5 (3.4) 6.7 4 (2.7) 13 (8.7) 11.4> 30% 6 (4.0) 6 (4.0) 8.1 10 (6.7) 24 (16.1) 22.8Total (%) 7.4 7.4 14.8 9.4 24.8 34.2

Rosuvastatin 40 mg

ΔUACR| ΔTC < −125 mg/dl−125 to

−100 mg/dlTotal (%)

−100 to −75 mg/dl > −75 mg/dl

Total (%)

< −30% 7 (4.0) 12 (6.9) 10.9 10 (5.7) 9 (5.2) 10.9−30% to 0% 14 (8.1) 9 (5.2) 13.2 8 (4.6) 14 (8.0) 12.6Total (%) 12.1 12.1 24.1 10.3 13.2 23.60% to 30% 8 (4.6) 12 (6.9) 11.5 11 (6.3) 5 (2.9) 9.2> 30% 14 (8.1) 9 (5.2) 13.2 13 (7.5) 19 (10.9) 18.4Total (%) 12.7 12.1 24.7 13.8 13.8 27.6

Atorvastatin 80 mg

ΔUACR| ΔTC < −125 mg/dL−125 to

−100 mg/dLTotal

(%)−100 to

−75 mg/dL > −75 mg/dLTotal

(%)< −30% 8 (5.3) 15 (10.0) 15.3 10 (6.7) 15 (10.0) 16.7−30% to 0% 12 (8.0) 7 (4.7) 12.7 10 (6.7) 11 (7.3) 14.0Total (%) 13.3 14.7 28.0 13.3 17.3 30.70% to 30% 8 (5.3) 9 (6.0) 11.3 9 (6.0) 7 (4.7) 10.7> 30% 8 (5.3) 5 (3.3) 8.7 7 (4.7) 9 (6.0) 10.7Total (%) 10.7 9.3 20.0 10.7 10.7 21.3

60

Chapter 3

Supplementary Table 4. Distribution of patients according to percentage change in proteinuria (UPCR ) and absolute change in total cholesterol (TC) from baseline to week 14; in all treatment groups (A) and stratified for treatment with rosuvastatin 10, rosuvastatin 40 mg, or atorvastatin 80 mg (B). Response groups are defined by quar-tiles of percentage change in UPCR and absolute change in TC, where the highest quartile represents the patients with the greatest response. Numbers are represented as frequency (%).

A.

ΔUPCR | ΔTC > Q3 Q3 – medianTotal (%) median – Q1 < Q1

Total (%)

> Q3 29 (6.2) 37 (7.9) 14.0 24 (5.1) 29 (6.2) 11.3

Q3 – median 33 (7.0) 29 (6.2) 13.2 31 (6.6) 25 (5.3) 11.9

Total (%) 13.2 14.0 27.2 11.6 11.5 23.1median – Q1 27 (5.7) 29 (6.2) 11.8 30 (6.4) 31 (6.6) 13.0

< Q1 30 (6.4) 23 (4.9) 11.3 33 (7.0) 31 (6.6) 13.6

Total (%) 12.1 11.0 23.1 13.4 13.2 26.5



Total (%)

> Q3 7 (4.7) 13 (8.8) 13.5 7 (4.7) 12 (8.1) 12.8Q3 – median 5 (3.4) 3 (2.0) 5.4 10 (6.8) 13 (8.8) 8.6Total (%) 8.1 10.8 18.9 11.5 16.9 28.4median – Q1 7 (4.7) 10 (6.8) 11.5 9 (6.1) 15 (10.1) 16.2< Q1 6 (4.1) 6 (4.1) 8.2 15 (10.1) 10 (6.8) 16.9Total (%) 8.8 10.8 19.6 16.2 16.9 33.1

Rosuvastatin 40 mg


Total (%)


Atorvastatin 80 mg


Total (%)


61

3


Supplementary Table 5. Distribution of patients according to percentage change in proteinuria (UPCR ) and percentage change in total cholesterol (TC) from baseline to week 14; in all treatment groups (A) and stratified for treatment with rosuvastatin 10, rosuvastatin 40 mg, or atorvastatin 80 mg (B). Response groups are defined by quar-tiles of percentage change in UPCR and TC, where the highest quartile represents the patients with the greatest response. Numbers are represented as frequency (%).

A.


Total (%)




Total (%)


Rosuvastatin 40 mg


Total (%)

> Q3 14 (8.1) 12 (6.9) 15.0 4 (2.3) 6 (3.5) 5.8

Q3 – median21

(12.1) 6 (3.5) 15.6 9 (5.2) 5 (2.9) 8.1Total (%) 20.2 10.4 30.6 7.5 6.4 13.9median – Q1 11 (6.4) 15 (8.7) 15.0 7 (4.0) 6 (3.5) 7.5< Q1 15 (8.7) 16 (9.2) 17.9 12 (6.9) 14 (8.1) 15.0Total (%) 15.0 17.9 32.9 10.9 11.6 22.5

Atorvastatin 80 mg


Total (%)


62

Chapter 3

Supplementary Table 6. Change in proteinuria (A) and cholesterol (B) from base-line to week 14, stratified for prior statin use. Results are given as mean [95%CI]. Change in proteinuria and cholesterol are presented as percentage change and abso-lute change in mg/dL, respectively.

A.

Statin naïve (n = 234) Prior statin use (n = 237)

P for difference

Rosuvastatin 10 mg −5.8 [−19.1, 5.9] 12.2 [−5.7, 27.0] 0.09Rosuvastatin 40 mg −12.7 [−26.0, −0.8] −4.3 [−19.8, 9.1] 0.34Atorvastatin 80 mg 6.3 [−4.6, 15.9] 13.9 [0.4, 25.6] 0.32

B.

Statin naïve (n = 234) Prior statin use (n = 237)

P for difference

Rosuvastatin 10 mg −95.7 [−105.8, −85.6] −73.8 [−82.2, −65.4] < 0.001Rosuvastatin 40 mg −108.1 [−118.1, −98.1] −89.0 [−97.9, −80.0] 0.01Atorvastatin 80 mg −108.1 [−118.8, −97.5] −88.7 [−97.4, −80.1] 0.007

University of Groningen Better prediction of drug response ...pensed study medication as determined...

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