CKD Dengan Dislipidemia

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Clinical Therapeutics/Volume 36, Number 8, 2014

Comparison of the Ef cacy and Safety Prole of MorningAdministration of Controlled-release Simvastatin VersusEvening Administration of Immediate-release Simvastatin

in Chronic Kidney Disease Patients With Dyslipidemia Yong Jin Yi, MD1; Hyo Jin Kim, MD1; Sang Kyung Jo, MD2; Sung Gyun Kim, MD3; Young Rim Song, MD3; Wookyung Chung, MD4; Kum Hyun Han, MD5;Chang Hwa Lee, MD6; Young-Hwan Hwang, MD7; and Kook-Hwan Oh, MD, PhD1

1Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Internal Medicine, Korea University Medical College, Seoul, Republic of Korea; 3Divisionof Nephrology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang,Republic of Korea; 4Department of Internal Medicine, Gachon University of Medicine and Science,

Incheon, Republic of Korea;

5

Department of Internal Medicine, Inje University Ilsan Paik Hospital, Ilsan,Republic of Korea; 6Department of Internal Medicine, Hanyang University, Seoul, Republic of Korea; and 7 Department of Internal Medicine, Eulji General Hospital, Eulji University, Seoul, Republic of Korea

ABSTRACT

Purpose: Evening administration of the conven-

tional immediate-release (IR) formulation of simvas-

tatin is recommended because of its short half-life (1.9

hours). In a healthy population, morning administra-

tion of a controlled-release (CR) formulation of

simvastatin was shown to have equivalent lipid-

lowering ef cacy and a safety prole similar to thatof evening doses of IR simvastatin. The present study

aimed to verify noninferiority and to compare the

safety of morning administration of CR simvastatin

with that of evening administration of IR simvastatin

in patients with chronic kidney disease (CKD) who

have dyslipidemia.

Methods: The present study was a prospective,

multicenter, double-blind, Phase IV trial with an

active comparator. We randomly assigned 122 pa-

tients with CKD and dyslipidemia to 1 of 2 drug

administration groups: morning administration of CRsimvastatin 20 mg (test group) and evening admin-

istration of IR simvastatin 20 mg (control group).

After 8 weeks, the treatment outcomes and adverse

effects of the 2 treatments were compared.

Findings: The mean (SD) percentage of change in

serum LDL-C at the end of treatment was –35.1%

(15.7%) for the test group and –35.6% (14.6%) for

the control group. The difference between the 2

groups was not signicant (P ¼ 0.858). The 95% CI

of the difference in the percentage of change of LDL-C

between the test and control groups was –6.0 to 5.0.

There was no difference in the percentage of change of

total cholesterol (–24.3% [12.5%] vs –26.5%

[12.0%], P ¼ 0.317), triglyceride (–10.6% [35.1%]

vs –12.4% [33.2%], P ¼ 0.575) and HDL-C (10.2%

[20.7%] vs 4.5% [11.4%], P ¼ 0.064). Treatment-

related adverse events were similar in both groups (10events in the test group vs 8 events in the control

group, P ¼ 0.691).

Implications: The ef cacy of morning administra-

tion of CR simvastatin was noninferior to evening

administration of IR simvastatin in patients with

CKD. Furthermore, the safety prole analysis showed

no signicant difference between the 2 treatments.

Morning administration of CR simvastatin is expected

to increase patient compliance and therefore better

control of dyslipidemia in CKD patients. (Clin Ther.

2014;36:1182–

1190) & 2014 The Authors. Publishedby Elsevier HS Journals, Inc.

Accepted for publication June 2, 2014.

http://dx.doi.org/10.1016/j.clinthera.2014.06.005

0149-2918/$ - see front matter

& 2014 The Authors. Published by Elsevier HS Journals, Inc. This is an

open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1182 Volume 36 Number 8

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Key words: chronic kidney disease, controlled-

release preparations, drug administration schedule,

dyslipidemia, simvastatin.

INTRODUCTION3-Hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are

a highly potent group of agents that reduce serum

LDL-C levels. Previous clinical trials have reported

that statin therapy is benecial for the primary1 and

secondary2–4 prevention of cardiovascular disease,

such as coronary atherosclerosis. Statin therapy is of

particular benet to dyslipidemia patients with

chronic kidney disease (CKD), which is associated

with a high incidence and increased severity of

cardiovascular disease.5 The Kidney Disease Out-

come Quality Initiative guidelines for dyslipidemia6

recommend that lipid-lowering therapy, along with

therapeutic lifestyle modication, should be initiated

for CKD patients with LDL-C levels above 100 mg/

dL. According to the latest meta-analysis of statin

therapy in CKD, all-cause and cardiovascular mortal-

ity was signicantly decreased without increasing

treatment-related adverse effects.7,8

Despite the benecial effects of statin therapy,

patients with chronic diseases who are taking medi-

cations in multiple doses are frequently noncompliant

in taking their medication.9–11 There is a diurnal

variation of plasma LDL-C levels, with the lowest

levels detected in the morning and the highest levels

peaked in the evening.12 Simvastatin is an established

HMG-CoA reductase inhibitor that has been clinically

evaluated in thousands of cases.2,13 In some trials

comparing the ef cacy of morning and evening ad-

ministration of simvastatin, there was signicantly

lower reduction in LDL-C levels when simvastatin

was given in the morning.14 However, taking simvas-

tatin in the evening may increase the complexity of the

dosing regimen, in turn, reducing patient compliance.9

Recently, a controlled-release (CR) simvastatin

formulation was released (Simvast CR tablet*); it

has a longer half-life (11.4 hours) than that of the

conventional immediate-release (IR) formulation (1.9

hours). In a Phase III trial of CR simvastatin, the

formulation was reported to have equivalent ef cacy

and a similar safety prole within the study popula-

tion as those of IR simvastatin.15 We designed a Phase

IV, postmarketing trial of CR simvastatin in CKD

patients. The purposes of the present study were

twofold: (1) to verify in CKD patients whether the

ef cacy of CR simvastatin administered in the

morning was noninferior to that of IR simvastatinadministered in the evening and (2) to assess whether

a regular dose regimen of CR simvastatin was safe

compared with that of IR simvastatin in CKD

patients.

METHODSThe present study was a prospective, randomized,

double-dummy, double-blind,, multicenter Phase IV

trial that evaluated the ef cacy and safety prole of

morning administration of CR simvastatin tablets

compared with evening administration of IR simvas-

tatin tablets (Zocor tablet†) in CKD patients. The

participants were recruited from the following

hospitals in South Korea: Seoul National University

Hospital, Gachon University Gil Medical Center,

Seoul Eulji General Hospital, Hallym University

Sacred Heart Hospital, Inje University Ilsan Paik

Hospital, Hanyang University Seoul Hospital, and

Korea University Anam Hospital. Before entering the

study, all patients provided written informed consent.

The institutional review boards of each hospital

approved the study design, and the study wasperformed in accordance with the Declaration of

Helsinki and its amendments.

PatientsThe study was conducted from December 2010 to

May 2012. Patients, 20 to 75 years of age, with CKD

stage 3, 4, or 5 (predialysis) were enrolled if their

serum LDL-C levels were between 100 and 220 mg/dL

and their serum triglyceride (TG) levels were o400

mg/dL. The reasons for exclusion of patients were as

follows: previous hypersensitivity to components of

any HMG-CoA reductase inhibitor, drug abuse and

alcohol consumption of least 14 standard units per

week,16,17 impaired liver function (serum aspartate

aminotransferase or alanine aminotransferase level of

42 times the upper limit of normal), uncontrolled

diabetes (HgA1c level of 49.0%), uncontrolled

* Trademark: Simvast CR tablet s, Hanmi Pharmaceutical Co,Ltd, Seoul, Republic of Korea.

† Trademark: Zocor s tablet, Merck & Co, Inc, WhitehouseStation, New Jersey.

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hypertension (systolic blood pressure 4160 mm Hg

or diastolic 4100 mm Hg at screening), congestive

heart failure with symptoms of New York Heart

Association Functional Class III or IV symptoms,

unstable angina, myocardial infarction, history of

percutaneous coronary intervention or bypass surgery,

cerebral infarction or transient ischemic accident anddeep venous thrombosis in the past 6 months, active

peptic ulcer disease, gastrointestinal disease that might

inuence the absorption of the test drug, current

therapy with an immunosuppressant, and malignancy.

The following drugs were prohibited during the entire

study period: other

HMG-CoA reductase inhibitors, nicotinic acid de-

rivatives, omega-3 fatty acid

formulations, bric acids, peroxisome proliferator-

activated receptor γ agents, and bile acid sequestrants.

Screening and Treatment PeriodAt visit 1, all screened patients were instructed to

discontinue lipid-lowering medication during the

screening period and to initiate therapeutic lifestyle

changes (TLCs), including diet modication, for 4

weeks. Participants’ serum lipid levels were reassessed

after 4 weeks of TLCs (visit 2). At visit 2, patients who

met the above LDL-C and TG criteria were randomly

assigned to 2 drug administration groups: CR simvas-

tatin (test group) and IR simvastatin (control group).

We used a xed-allocation (1:1) block-randomizationmethod. The size of each block was 4 patients. The

study referral institutions completed the random

assignment of patients. All clinicians and patients

remained blinded until the end of the study.

During 8 weeks of treatment, patients in the test

group took a CR formulation of simvastatin as a 20-

mg tablet in the morning and a placebo of IR

simvastatin in the evening. Conversely, patients in the

control group took a placebo of CR simvastatin in

the morning and an IR simvastatin 20-mg tablet in the

evening. Each placebo was prepared in the same colorand shape as the corresponding drugs so that patients

and physicians could not differentiate them (double-

blinding). Four weeks after randomization (visit 3), the

participants were contacted by telephone to check for

any adverse events or concomitant medications. If any

adverse events were reported, the participants were

asked to return to the outpatient clinic for an evalua-

tion. At 8 weeks (visit 4), the patients were evaluated

for drug compliance, ef cacy, and safety prole

pertaining to the treatment. Patients who dropped out

after randomization (1 subject in the test group and 2

in the control group) were also encouraged to visit for

the nal (ef cacy) laboratory tests at visit 4.

Efficacy and Safety Profile Assessment LDL-C, HDL-C, total cholesterol (TC), and TGlevels in 12-hour fasting blood samples were deter-

mined at week 0 (baseline) and week 8 (Wako Pure

Chemical Industries Ltd, Osaka, Japan). The primary

end point of the study was the percentage of change in

LDL-C levels over the 8 weeks of treatment. The

secondary end points were the percentage of change in

TC, HDL-C, and TG levels. For the safety prole

assessment, vital signs and laboratory parameters

were monitored, including hemoglobin level; hema-

tocrit, white blood cell, and platelet counts; trans-aminase, γ-glutamyl transferase, serum creatinine,

blood glucose, and creatine kinase levels; urinalysis;

and ECG.

Statistical AnalysisThe aim of the study was to conduct a noninfer-

iority comparison between a morning dose of CR

simvastatin and an evening dose of IR simvastatin.18

The margin of difference for noninferiority was

regarded as o–6.5%, according to previous

studies.19,20

When setting the statistical power at80% and the α value at 0.05, the calculated number

of enrolled patients required was 52 in each group. An

assumed a dropout rate of 15% gave a nal sample

size of 61 patients in each group. The equation for

sample size determination was as follows:

n ¼ 2ðZα þ Z β Þ2σ 2

ðð μT μC Þ d Þ2

Zα = the limit value of α error (0.05) in normal

distribution, Zβ = the limit value of β error (0.20) in

normal distribution, d = noninferiority margin (6.5%),and σ ¼ SD.

The primary and secondary end-point analyses

were based on the intention-to-treat (ITT) population,

which included any enrolled patients who took at least

1 dose of the medication and underwent ef cacy

testing at week 8. The safety prole analysis was

based on the safety set, which was dened as the

group of patients who had taken at least 1 tablet of

the study drug.

Clinical Therapeutics




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To compare the percentage of change in LDL-C

levels, the primary end point, the Student t test was

performed to calculate the 95% CI of the percentage

of difference between the test and control groups. If

the 95% CI did not exceed the set point of the

noninferiority margin (–6.5%), the ef cacy of CR

simvastatin was considered to be noninferior. Toassess the signicance of the change in LDL-C, TC,

HDL-C, and TG levels before and after treatment, the

paired t test (to compare within groups) and Student t

test (to compare between groups) were used. In an

analysis of participant demography, continuous vari-

ables that followed a normal distribution were pre-

sented as mean (SD) and were analyzed using the

Student t test; categorical values were represented by

number and percentage and were analyzed by the χ2

or Fisher exact test. P o 0.05 was dened as statisti-

cally signicant. All statistical analyses were performedusing SPSS 19.0 (SPSS Inc, an IBM company, Chicago,

Illinois).

RESULTSA total of 122 patients were randomly assigned to

either the test (n = 62) or control (n = 60) group. On

completion, 118 patients (59 for each group) were

included in the ITT population, after exclusion of 1

subject in the control group who refused to participate

immediately after enrollment without taking the study

drug and 3 in the test group who failed to undergo the

ef cacy evaluation blood test after 8 weeks of medi-

cation. Forty-ve patients in the test group and 47 inthe control group completed the study (Figure 1).

Baseline CharacteristicsOf the 118 patients assigned to treatment, 92

completed the 8-week trial. With regard to age, sex,

weight, CKD stage, alcohol consumption, underlying

disease, previous medication (including statins, aspirin,

angiotensin-converting enzyme inhibitors/angiotensin re-

ceptor blockers, β-blockers, calcium channel blockers,

and loop and thiazide diuretics), and baseline laboratory

test results (TC, TG, LDL-C, HDL-C, and creatininelevels), there were no statistically signicant differences

between the test and control groups (Table I).

Changes in the Lipid ProfileBoth the morning dose of CR simvastatin and

evening dose of IR simvastatin signicantly lowered

Screening : Patients with dyslipidemia and CKD (n = 168)

12 rejected TLC

122 subjects randomized

118 patients at week 0 : ITT population

Discontinued administration : 1

Drug compliance < 75% : 4 Violate prohibited drug : 7

Others : 2

Discontinued administration : 2

Drug compliance < 75% : 4 Violate prohibited drug : 5

Others : 1

At week 8

PP popualtion (N=92)

45 completed study 47 completed study

59 received morning administration

of CR simvastatin

59 received evening administration

of IR simvastatin

1 refused after randomization

3 failed to perform efficacy test

34 were in exclusion criteria

Figure 1. Flow chart of the study. CKD ¼ chronic kidney disease; CR ¼ controlled-release; IR ¼ immediate-release; ITT ¼ intention-to-treat; PP ¼ per-protocol; TLC ¼ therapeutic lifestyle change.

Y.J. Yi et al.

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blood levels of LDL-C, TC, and TG. Levels of HDL-Csignicantly increased in both groups. A between-

group analysis of HDL-C level after treatment re-

vealed a signicantly higher HDL-C level in the test

group than in the control group (P ¼ 0.012). There

were no between-group differences in LDL-C, TC, or

TG level after treatment (Table II).

Patient LDL-C levels decreased by 35.1% (SD

15.7%) in the test group and by 35.6% (SD 14.6%)

in the control group (P ¼ 0.858). The 95% CI of the

difference in the percentage of change in LDL-C levelbetween the test and control groups was (–6.0% to

5.0%), which did not meet the predened noninferiority

margin (–6.5%) in a 1-tailed signicance test (Figure 2).

Adverse EventsOne patient in the test group discontinued the study

because of a side effect (dizziness) of the test drug. The

medication was well tolerated by all other participants.

The number and incidence of total adverse events were

Table I. Baseline characteristics of the intention-to-treatment population in the trial.

Characteristic

Test Group

(n ¼ 59)

Control Group

(n ¼ 59)

Total

(N ¼ 118) P

Age, y, mean (SD) 56.9 (10.5) 57.0 (12.1) 57.0 (11.3) 0.978

Sex, male, no. (%) 28 (47.5) 29 (55.1) 57 (48.3) 0.853 Weight, kg, mean (SD) 64.3 (11.1) 63.7 (10.4) 64.0 (10.8) 0.764

CKD stage, no. (%) 0.827

3 43 (72.9) 40 (67.8) 83 (70.3)

4 15 (25.4) 18 (30.5) 33 (28.0)

5 1 (1.7) 1 (1.7) 2 (1.7)

Alcohol consumption, no. (%) 0.387

None 47 (80.7) 43 (72.9) 90 (76.3)

Present 12 (20.3) 16 (27.1) 28 (23.7)

Underlying disease, no. (%)

Hypertension 52 (88.1) 54 (91.5) 106 (89.8) 0.542

Diabetes mellitus 24 (40.7) 18 (30.5) 42 (35.6) 0.249Ischemic heart disease 3 (5.1) 1 (1.7) 4 (3.4) 0.618

Stroke 4 (6.8) 2 (3.4) 6 (5.0) 0.579

Previous statin use, no. (%) 9 (15.2) 9 (15.2) 18 (15.2) 1.000

Medication, no. (%)

Aspirin 20 (33.9) 16 (27.1) 36 (30.5) 0.424

ACEi/ARB 52 (88.1) 52 (88.1) 104 (88.1) 1.000

β-Blocker 18 (30.5) 15 (25.4) 33 (28.0) 0.538

Calcium channel blocker 33 (59.9) 24 (40.7) 57 (48.3) 0.097

Loop diuretics 10 (16.9) 9 (15.3) 19 (16.1) 0.802

Thiazide 10 (16.9) 6 (10.1) 16 (13.5) 0.282

Baseline laboratory tests, mg/dL, mean (SD) Total cholesterol 228.7 (36.8) 220.0 (36.4) 224.4 (36.8) 0.199

LDL-C 143.9 (28.1) 137.0 (28.4) 140.5 (28.3) 0.186

HDL-C 46.9 (14.5) 48.8 (13.5) 47.8 (14.0) 0.464

Triglycerides 190.3 (73.0) 167.6 (70.7) 178.9 (72.5) 0.090

Creatinine 2.0 (0.9) 2.0 (0.8) 2.0 (0.8) 0.816

ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CKD ¼ chronic kidney disease.





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similar in both groups. In terms of a causal relation-

ship, the adverse events were classied into 5 catego-

ries: denitely related, probably related, possibly

related, uncertainly related, and not related to treat-

ment. Each category was further dened according to

the chronological order of administration, a response

of discontinuation or redosing, and other signicant

causes of the adverse events.

Treatment-related adverse events are shown in Table

III. In total, 10 patients in the test group and 8 in the

control group reported treatment-related adverse events.

In 1 patient in the control group both edema andnausea developed during the trial. There was no differ-

ence between the 2 groups in the incidence of treatment-

related adverse events (P ¼ 0.691, by the χ2 test).

DISCUSSIONThe present study was designed as a double-blind,

prospective, randomized clinical trial with an active

comparator. It compared the ef cacy and safety

prole of morning administration of a CR simvastatin

formulation with those of IR simvastatin in patients

with underlying CKD. The difference in the percent-age of change in LDL-C level did not meet the

predened noninferiority margin. This nding sug-

gests that CR simvastatin has an ef cacy similar to

that of IR simvastatin. In the Scandinavian Simvasta-

tin Survival Study (4S),2 simvastatin doses of 20 to 40

mg/d lowered the LDL-C level by 35%, which was

similar to results seen in the present study of IR

simvastatin ef cacy. There were also no signicant

differences in the incidence of treatment-related ad-

verse events.

LDL-C40

20

0

–20 % c

h a n g e

–40

–60

Test group

–35.1 ±15.7%

–35.6 ±14.6%

Control group

TC TG HDL-C

–24.3 ±12.5%

–26.5 ±12.0%

–10.6 ±35.1%

–12.4 ±33.2%

–10.2 ±20.7%

–4.5 ±11.4%

Figure 2. Percentage of change in lipid para-meters after treatment. TC ¼ totalcholesterol; TG ¼ triglycerides.

Table II. Profiles and differences of fasting lipids at baseline and 8 weeks after treatment.

Test Group (n ¼ 59) Control Group (n ¼ 59)P (Between

Groups After

Treatment)Baseline

8 Weeks After

Treatment

P (Within

Group) Baseline

8 Weeks After

Treatment

P (Within

Group)

Total cholesterol,

mg/dL

228.7 (36.8) 172.3 (35.1) o0.001 220.0 (36.4) 160.6 (31.9) o0.001 0.587

Change, %* −24.3 (12.5) o0.001 −26.5 (12.0) o0.001 0.317

Triglycerides,mg/dL

190.3 (73.0) 159.8 (65.9) o0.001 167.6 (70.7) 136.6 (61.6) o0.001 0.963

Change, %* −10.6 (35.1) 0.023 −12.4 (33.2) 0.001 0.575LDL-C, mg/dL 143.9 (28.1) 92.8 (25.7) o0.001 137.0 (28.4) 87.5 (23.2) o0.001 0.722

Change, %* −35.1 (15.7) o0.001 −35.6 (14.6) o0.001 0.858HDL-C, mg/dL 46.9 (14.5) 51.0 (15.6) 0.001 48.8 (13.5) 50.7 (14.3) 0.011 0.012

Change, %* 10.2 (20.7) o0.001 4.5 (11.4) 0.003 0.064

Values shown are mean (SD).*Percentage of change from baseline to end of treatment phase.

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With regard to the secondary end points, the HDL-

C level after treatment was higher in the test group

than in the control group. However, the increment of HDL-C after treatment was only marginally greater in

the test group. It remains to be investigated in a future

study whether slow controlled release of simvastatin is

more benecial in terms of HDL-C than its immediate

release.

Dyslipidemia is one of the most important manage-

ment issues for patients with CKD. It is known that an

abnormality of plasma lipoprotein metabolism in

kidney disease causes dyslipidemia,21,22 and it is also

suggested that lipid toxicity causes glomerular and

tubulointerstitial injury, thereby generating a viciouscycle.23,24 A meta-analysis of randomized, controlled

trials reported that lipid lowering preserved the

glomerular ltration rate and reduced proteinuria in

patients with renal disease.25

Although 2 large-scale clinical trials in patients

with CKD have reported conicting results for the

effects of statin therapy on cardiovascular outcomes

and all-cause mortality,26,27 1 recent meta-analysis

reported that statin therapy reduces the risk of major

cardiovascular events in patients with CKD.8 Such

evidence suggests that statin treatment could be

justied for predialysis in patients with CKD.Simvastatin is an established HMG-CoA reductase

inhibitor that has been studied in 2 large-scale out-

come trials, the Heart Protection Study and the 4S.2,13

These 2 landmark studies showed that simvastatin

treatment reduced coronary heart disease and all-

cause mortality as their primary outcome, and con-

rmed the long-term safety prole.

The half-life of the active metabolite of conven-

tional IR simvastatin is 1.9 hours.28 A few studies on

the administration time of IR simvastatin have

reported that lowering of serum LDL-C levels is morepronounced with evening versus morning administra-

tion.14,29,30 According to these results, it is recom-

mended to take IR simvastatin in the evening.31

However, given that CKD patients are likely to take

multiple medications such as aspirin, antihypertensive

drugs, diuretics, and phosphate binders, evening

administration could render the medication sche-

dule more complex and might compromise patient

compliance.10,11 The present study showed that the

Table III. Treatment-related adverse events among the study participants.

Test Group

(n ¼ 62*)

Control Group

(n ¼ 59)

Total

(N ¼ 121*) P

Gastrointestinal disorders

Nausea 2 (3.2) 2 (3.4) 4 (3.3)Abdominal pain 0 (0) 3 (5.1) 3 (2.5)

Diarrhea 1 (1.6) 0 (0) 1 (0.8)

Musculoskeletal disorders

Myalgia 1 (1.6) 2 (3.4) 3 (2.5)

Central nervous system disorders

Headache 2 (3.2) 0 (0) 2 (1.7)

Dizziness 1 (1.6) 0 (0) 1 (0.8)

Urinary system disorders

Albuminuria 2 (3.2) 0 (0) 2 (1.7)

Other disorders

Edema 1 (1.6) 1 (1.7) 2 (1.7) Total events 10 (16.1) 8 (13.6)† 18 (14.9)† 0.691

Values shown are number (%).* Three patients who took the test drug at least once but did not undergo ef cacy laboratory tests were also included in thesafety analysis.†One patient in the control group experienced both edema and nausea during medication.




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therapeutic ef cacy of morning administration of CR

simvastatin is equivalent to that of evening adminis-

tration of IR simvastatin in terms of lowering LDL-C,

TC, and TG levels. Therefore, morning administration

of CR simvastatin could simplify the dosing schedule

and improve the compliance of patients with CKD

who are taking multiple medications.According to a previous study,32 common adverse

effects of simvastatin include gastrointestinal symptoms

such as constipation, abdominal pain, and atulence. In

the present study, there was no difference in the

frequency of gastrointestinal side effects between the

test and control groups. Myopathy is a common

adverse effect of HMG-CoA reductase inhibitors. The

denition of myopathy in the literature is broad,

ranging from mild muscular pain to severe rhabdo-

myolysis. In a previous study,32 myopathy leading to

the discontinuation of simvastatin developed in 0.08%of patients. It is also known that the frequency of severe

biochemical abnormalities (serum creatine kinase level

410 times the upper normal level) is very low.33 In this

study, overall, there were 3 cases of myalgia (2.5%)

related to statin administration, and no difference was

reported in the frequency of myalgia between the 2

groups. Only 1 patient (0.8%) in the test group

exhibited an increase in creatine kinase 410 times the

upper limit of normal at the end of treatment, which

returned to a normal level after completing treatment.

The present study has the following limitations: (1)The ITT population was smaller than we expected.

This was due to a higher dropout rate and several

patients who failed to undergo the ef cacy test at the

end of treatment. (2) Dietary compliance of both

groups was assumed to be equivalent because both

groups were equally given TLC during the screening

and follow-up periods.

CONCLUSIONSFor patients with CKD, morning administration of CR

simvastatin and evening administration of IR simvas-tatin didn't show statistically signicant differences in

safety prole or ef cacy. Morning administration of

CR simvastatin may simplify the administration sched-

ule and improve the compliance of patients with CKD

who are taking multiple medications.

ACKNOWLEDGMENTSThis study was funded by Hanmi Pharmaceutical

Company Ltd., Seoul, Republic of Korea.

Dr. Yi participated in the implementation of the

study, data collection and analysis and manuscript

preparation. Dr. H.J. Kim contributed to the data

collection and analysis. Dr. Oh had a substantial

contribution to the design of the study, data analysis

and manuscript preparation and overviewing. Drs. Jo,

S.G. Kim, Song, Chung, Han, Lee and Hwangparticipated in the patient recruitment, implementa-

tion of the study, safety monitoring and manuscript

overviewing.

CONFLICTS OF INTEREST The authors have indicated that they have no conicts

of interest regarding the content of this article.

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snu.ac.kr


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