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Comparison of the Efficacy and Safety Profile of Morning Administration of Controlled-release Simvastatin Versus Evening Administration of Immediate-release Simvastatin in Chronic Kidney Disease Patients With Dyslipidemia
Clinical Therapeutics/Volume 36, Number 8, 2014
Comparison of the Efficacy and Safety Profile of Morning Administration of Controlled-release Simvastatin Versus Evening 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 1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Korea University Medical College, Seoul, Republic of Korea; 3Division of 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; 5Department 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 2
ABSTRACT Purpose: Evening administration of the conventional immediate-release (IR) formulation of simvastatin is recommended because of its short half-life (1.9 hours). In a healthy population, morning administration of a controlled-release (CR) formulation of simvastatin was shown to have equivalent lipidlowering efficacy and a safety profile similar to that of 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 patients with CKD and dyslipidemia to 1 of 2 drug administration groups: morning administration of CR simvastatin 20 mg (test group) and evening administration 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 significant (P ¼ 0.858). The 95% CI
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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). Treatmentrelated adverse events were similar in both groups (10 events in the test group vs 8 events in the control group, P ¼ 0.691). Implications: The efficacy of morning administration of CR simvastatin was noninferior to evening administration of IR simvastatin in patients with CKD. Furthermore, the safety profile analysis showed no significant 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. Published by 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/).
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Y.J. Yi et al. Key words: chronic kidney disease, controlledrelease preparations, drug administration schedule, dyslipidemia, simvastatin.
INTRODUCTION 3-Hydroxy 3-methylglutaryl coenzyme A (HMGCoA) 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 beneficial for the primary1 and secondary2–4 prevention of cardiovascular disease, such as coronary atherosclerosis. Statin therapy is of particular benefit 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 Outcome Quality Initiative guidelines for dyslipidemia6 recommend that lipid-lowering therapy, along with therapeutic lifestyle modification, 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 mortality was significantly decreased without increasing treatment-related adverse effects.7,8 Despite the beneficial effects of statin therapy, patients with chronic diseases who are taking medications 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 efficacy of morning and evening administration of simvastatin, there was significantly lower reduction in LDL-C levels when simvastatin was given in the morning.14 However, taking simvastatin 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 efficacy *
Trademark: Simvast CR tablets, Hanmi Pharmaceutical Co, Ltd, Seoul, Republic of Korea.
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and a similar safety profile within the study population 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 efficacy of CR simvastatin administered in the morning was noninferior to that of IR simvastatin administered 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.
METHODS The present study was a prospective, randomized, double-dummy, double-blind,, multicenter Phase IV trial that evaluated the efficacy and safety profile of morning administration of CR simvastatin tablets compared with evening administration of IR simvastatin 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 was performed in accordance with the Declaration of Helsinki and its amendments.
Patients The 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: Zocors tablet, Merck & Co, Inc, Whitehouse Station, New Jersey.
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Clinical Therapeutics 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 and deep venous thrombosis in the past 6 months, active peptic ulcer disease, gastrointestinal disease that might influence 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 derivatives, omega-3 fatty acid formulations, fibric acids, peroxisome proliferatoractivated receptor γ agents, and bile acid sequestrants.
Screening and Treatment Period At 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 modification, 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 simvastatin (test group) and IR simvastatin (control group). We used a fixed-allocation (1:1) block-randomization method. 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 20mg 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 color and shape as the corresponding drugs so that patients and physicians could not differentiate them (doubleblinding). 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 evaluation. At 8 weeks (visit 4), the patients were evaluated for drug compliance, efficacy, and safety profile
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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 final (efficacy) laboratory tests at visit 4.
Efficacy and Safety Profile Assessment LDL-C, HDL-C, total cholesterol (TC), and TG levels in 12-hour fasting blood samples were determined 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 profile assessment, vital signs and laboratory parameters were monitored, including hemoglobin level; hematocrit, white blood cell, and platelet counts; transaminase, γ-glutamyl transferase, serum creatinine, blood glucose, and creatine kinase levels; urinalysis; and ECG.
Statistical Analysis The aim of the study was to conduct a noninferiority 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 at 80% 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 final sample size of 61 patients in each group. The equation for sample size determination was as follows: n ¼ 2ðZα þ Zβ Þ2 σ 2 ððμT μC Þ dÞ2 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 efficacy testing at week 8. The safety profile analysis was based on the safety set, which was defined as the group of patients who had taken at least 1 tablet of the study drug.
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Y.J. Yi et al. 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 efficacy evaluation blood test after 8 weeks of medication. Forty-five patients in the test group and 47 in the control group completed the study (Figure 1).
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 efficacy of CR simvastatin was considered to be noninferior. To assess the significance 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 variables that followed a normal distribution were presented 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 defined as statistically significant. All statistical analyses were performed using SPSS 19.0 (SPSS Inc, an IBM company, Chicago, Illinois).
Of 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 receptor blockers, β-blockers, calcium channel blockers, and loop and thiazide diuretics), and baseline laboratory test results (TC, TG, LDL-C, HDL-C, and creatinine levels), there were no statistically significant differences between the test and control groups (Table I).
RESULTS
Changes in the Lipid Profile
A total of 122 patients were randomly assigned to either the test (n = 62) or control (n = 60) group. On
Both the morning dose of CR simvastatin and evening dose of IR simvastatin significantly lowered
Baseline Characteristics
Screening : Patients with dyslipidemia and CKD (n = 168) 34 were in exclusion criteria
12 rejected TLC
122 subjects randomized 1 refused after randomization
3 failed to perform efficacy test
118 patients at week 0 : ITT population
59 received morning administration
59 received evening administration
of CR simvastatin
of IR simvastatin
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
45 completed study
47 completed study PP popualtion (N=92)
Figure 1. Flow chart of the study. CKD ¼ chronic kidney disease; CR ¼ controlled-release; IR ¼ immediaterelease; ITT ¼ intention-to-treat; PP ¼ per-protocol; TLC ¼ therapeutic lifestyle change.
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Table I. Baseline characteristics of the intention-to-treatment population in the trial. Characteristic Age, y, mean (SD) Sex, male, no. (%) Weight, kg, mean (SD) CKD stage, no. (%) 3 4 5 Alcohol consumption, no. (%) None Present Underlying disease, no. (%) Hypertension Diabetes mellitus Ischemic heart disease Stroke Previous statin use, no. (%) Medication, no. (%) Aspirin ACEi/ARB β-Blocker Calcium channel blocker Loop diuretics Thiazide Baseline laboratory tests, mg/dL, mean (SD) Total cholesterol LDL-C HDL-C Triglycerides Creatinine
Test Group (n ¼ 59)
Control Group (n ¼ 59)
Total (N ¼ 118)
56.9 (10.5) 28 (47.5) 64.3 (11.1)
57.0 (12.1) 29 (55.1) 63.7 (10.4)
57.0 (11.3) 57 (48.3) 64.0 (10.8)
43 (72.9) 15 (25.4) 1 (1.7)
40 (67.8) 18 (30.5) 1 (1.7)
83 (70.3) 33 (28.0) 2 (1.7)
47 (80.7) 12 (20.3)
43 (72.9) 16 (27.1)
90 (76.3) 28 (23.7)
52 24 3 4 9
(88.1) (40.7) (5.1) (6.8) (15.2)
54 18 1 2 9
(91.5) (30.5) (1.7) (3.4) (15.2)
106 42 4 6 18
(89.8) (35.6) (3.4) (5.0) (15.2)
0.542 0.249 0.618 0.579 1.000
20 52 18 33 10 10
(33.9) (88.1) (30.5) (59.9) (16.9) (16.9)
16 52 15 24 9 6
(27.1) (88.1) (25.4) (40.7) (15.3) (10.1)
36 104 33 57 19 16
(30.5) (88.1) (28.0) (48.3) (16.1) (13.5)
0.424 1.000 0.538 0.097 0.802 0.282
228.7 143.9 46.9 190.3 2.0
(36.8) (28.1) (14.5) (73.0) (0.9)
220.0 137.0 48.8 167.6 2.0
(36.4) (28.4) (13.5) (70.7) (0.8)
224.4 140.5 47.8 178.9 2.0
(36.8) (28.3) (14.0) (72.5) (0.8)
0.199 0.186 0.464 0.090 0.816
P 0.978 0.853 0.764 0.827
0.387
ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CKD ¼ chronic kidney disease.
blood levels of LDL-C, TC, and TG. Levels of HDL-C significantly increased in both groups. A betweengroup analysis of HDL-C level after treatment revealed a significantly 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
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difference in the percentage of change in LDL-C level between the test and control groups was (–6.0% to 5.0%), which did not meet the predefined noninferiority margin (–6.5%) in a 1-tailed significance test (Figure 2).
Adverse Events One 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
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Y.J. Yi et al.
40
TC
LDL-C
TG
HDL-C –10.2 ± –4.5 ± 20.7% 11.4%
% change
20
0
–20
DISCUSSION
–40
–60
the chronological order of administration, a response of discontinuation or redosing, and other significant 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 and nausea developed during the trial. There was no difference between the 2 groups in the incidence of treatmentrelated adverse events (P ¼ 0.691, by the χ2 test).
–24.3 ± –26.5 ± 12.5% 12.0% –10.6 ± –12.4 ± 35.1% 33.2%
–35.1 ± –35.6 ± 15.7% 14.6%
Control group
Test group
Figure 2. Percentage of change in lipid parameters after treatment. TC ¼ total cholesterol; TG ¼ triglycerides.
similar in both groups. In terms of a causal relationship, the adverse events were classified into 5 categories: definitely related, probably related, possibly related, uncertainly related, and not related to treatment. Each category was further defined according to
The present study was designed as a double-blind, prospective, randomized clinical trial with an active comparator. It compared the efficacy and safety profile of morning administration of a CR simvastatin formulation with those of IR simvastatin in patients with underlying CKD. The difference in the percentage of change in LDL-C level did not meet the predefined noninferiority margin. This finding suggests that CR simvastatin has an efficacy similar to that of IR simvastatin. In the Scandinavian Simvastatin 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 efficacy. There were also no significant differences in the incidence of treatment-related adverse events.
Table II. Profiles and differences of fasting lipids at baseline and 8 weeks after treatment. Test Group (n ¼ 59) Baseline Total cholesterol, 228.7 (36.8) mg/dL Change, %* Triglycerides, 190.3 (73.0) mg/dL Change, %* LDL-C, mg/dL 143.9 (28.1) Change, %* HDL-C, mg/dL 46.9 (14.5) Change, %*
Control Group (n ¼ 59)
8 Weeks After P (Within Treatment Group)
Baseline
8 Weeks After P (Within Treatment Group)
P (Between Groups After Treatment)
172.3 (35.1)
o0.001
220.0 (36.4)
160.6 (31.9)
o0.001
0.587
−24.3 (12.5) 159.8 (65.9)
o0.001 o0.001
167.6 (70.7)
−26.5 (12.0) 136.6 (61.6)
o0.001 o0.001
0.317 0.963
−10.6 92.8 −35.1 51.0 10.2
0.023 o0.001 o0.001 0.001 o0.001
−12.4 87.5 −35.6 50.7 4.5
0.001 o0.001 o0.001 0.011 0.003
0.575 0.722 0.858 0.012 0.064
(35.1) (25.7) (15.7) (15.6) (20.7)
137.0 (28.4) 48.8 (13.5)
(33.2) (23.2) (14.6) (14.3) (11.4)
Values shown are mean (SD). * Percentage of change from baseline to end of treatment phase.
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Table III. Treatment-related adverse events among the study participants. Test Group (n ¼ 62*) Gastrointestinal disorders Nausea Abdominal pain Diarrhea Musculoskeletal disorders Myalgia Central nervous system disorders Headache Dizziness Urinary system disorders Albuminuria Other disorders Edema Total events
Control Group (n ¼ 59)
Total (N ¼ 121*)
2 (3.2) 0 (0) 1 (1.6)
2 (3.4) 3 (5.1) 0 (0)
4 (3.3) 3 (2.5) 1 (0.8)
1 (1.6)
2 (3.4)
3 (2.5)
2 (3.2) 1 (1.6)
0 (0) 0 (0)
2 (1.7) 1 (0.8)
2 (3.2)
0 (0)
2 (1.7)
1 (1.6) 10 (16.1)
1 (1.7) 8 (13.6)†
2 (1.7) 18 (14.9)†
P
0.691
Values shown are number (%). * Three patients who took the test drug at least once but did not undergo efficacy laboratory tests were also included in the safety analysis. † One patient in the control group experienced both edema and nausea during medication.
With regard to the secondary end points, the HDLC 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 beneficial in terms of HDL-C than its immediate release. Dyslipidemia is one of the most important management 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 vicious cycle.23,24 A meta-analysis of randomized, controlled trials reported that lipid lowering preserved the glomerular filtration rate and reduced proteinuria in patients with renal disease.25 Although 2 large-scale clinical trials in patients with CKD have reported conflicting 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
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cardiovascular events in patients with CKD.8 Such evidence suggests that statin treatment could be justified for predialysis in patients with CKD. Simvastatin is an established HMG-CoA reductase inhibitor that has been studied in 2 large-scale outcome trials, the Heart Protection Study and the 4S.2,13 These 2 landmark studies showed that simvastatin treatment reduced coronary heart disease and allcause mortality as their primary outcome, and confirmed the long-term safety profile. The half-life of the active metabolite of conventional 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 more pronounced with evening versus morning administration.14,29,30 According to these results, it is recommended 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 schedule more complex and might compromise patient compliance.10,11 The present study showed that the
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Y.J. Yi et al. therapeutic efficacy of morning administration of CR simvastatin is equivalent to that of evening administration 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 flatulence. 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 definition of myopathy in the literature is broad, ranging from mild muscular pain to severe rhabdomyolysis. 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 efficacy 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.
CONCLUSIONS For patients with CKD, morning administration of CR simvastatin and evening administration of IR simvastatin didn't show statistically significant differences in safety profile or efficacy. Morning administration of CR simvastatin may simplify the administration schedule and improve the compliance of patients with CKD who are taking multiple medications.
ACKNOWLEDGMENTS This study was funded by Hanmi Pharmaceutical Company Ltd., Seoul, Republic of Korea.
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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 Hwang participated in the patient recruitment, implementation of the study, safety monitoring and manuscript overviewing.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Disorders Identification Test. Arch Intern Med. 1998;158:1789–1795. Bradley KA, Bush KR, McDonell MB, Malone T, Fihn SD, Project ACQI. Screening for problem drinking. J Gen Intern Med. 1998;13:379–389. doi: 10.1046/j.1525-1497.1998.00118.x. Products CfPM. Guideline on the choice of the non-inferiority margin. London (UK): European Medicines Agency (EMEA); 2005. Sbarouni E, Flevari P, Kroupis C, Kyriakides ZS, Koniavitou K, Kremastinos DT. The effects of raloxifene and simvastatin on plasma lipids and endothelium. Cardiovasc Drugs Ther. 2003;17:319–323. Jang SB, Lee YJ, Lim LA, et al. Pharmacokinetic comparison of controlled-release and immediaterelease oral formulations of simvastatin in healthy Korean subjects: A randomized, open-label, parallel-group, single-and multiple-dose study. Clin Ther. 2010;32:206–216. Kaysen GA. Lipid and lipoprotein metabolism in chronic kidney disease. J Ren Nutr. 2009;19:73–77. Tsimihodimos V, Dounousi E, Siamopoulos KC. Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment. Am J Nephrol. 2008;28:958–973. Moorhead JF, Chan MK, El-Nahas M, Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet. 1982;2:1309–1311. Gyebi L, Soltani Z, Reisin E. Lipid nephrotoxicity: new concept for an old disease. Curr Hypertens Rep. 2012; 14:177–181.
25. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a metaanalysis. Kidney Int. 2001;59:260–269. 26. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181–2192. 27. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395–1407. 28. Vickers S, Duncan C, Chen I-W, Rosegay A, Duggan D. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos. 1990;18:138–145. 29. Lund TM, Torsvik H, Falch D, Christophersen B, Skardal R, Gullestad L. Effect of morning versus evening intake of simvastatin on the serum cholesterol level in patients with coronary artery disease. Am J Cardiol. 2002;90:784–786. 30. Wallace A, Chinn D, Rubin G. Taking simvastatin in the morning compared with in the evening: randomised controlled trial. BMJ. 2003;327:788. 31. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co, Inc. (1993). 32. Boccuzzi SJ, Bocanegra TS, Walker JF, et al. Long-term safety and efficacy profile of simvastatin. Am J Cardiol. 1991;68:1127–1131. 33. Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther. 2006;28:26–35.
Address correspondence to: Kook-Hwan Oh, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehakro, Chongno-Gu, Seoul, 110-744, Seoul, Republic of Korea. E-mail: khoh@ snu.ac.kr
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Comparison of the Efficacy and Safety Profile of Morning Administration of Controlled-release Simvastatin Versus Evening 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 1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Korea University Medical College, Seoul, Republic of Korea; 3Division of 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; 5Department 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 2
ABSTRACT Purpose: Evening administration of the conventional immediate-release (IR) formulation of simvastatin is recommended because of its short half-life (1.9 hours). In a healthy population, morning administration of a controlled-release (CR) formulation of simvastatin was shown to have equivalent lipidlowering efficacy and a safety profile similar to that of 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 patients with CKD and dyslipidemia to 1 of 2 drug administration groups: morning administration of CR simvastatin 20 mg (test group) and evening administration 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 significant (P ¼ 0.858). The 95% CI
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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). Treatmentrelated adverse events were similar in both groups (10 events in the test group vs 8 events in the control group, P ¼ 0.691). Implications: The efficacy of morning administration of CR simvastatin was noninferior to evening administration of IR simvastatin in patients with CKD. Furthermore, the safety profile analysis showed no significant 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. Published by 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/).
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Y.J. Yi et al. Key words: chronic kidney disease, controlledrelease preparations, drug administration schedule, dyslipidemia, simvastatin.
INTRODUCTION 3-Hydroxy 3-methylglutaryl coenzyme A (HMGCoA) 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 beneficial for the primary1 and secondary2–4 prevention of cardiovascular disease, such as coronary atherosclerosis. Statin therapy is of particular benefit 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 Outcome Quality Initiative guidelines for dyslipidemia6 recommend that lipid-lowering therapy, along with therapeutic lifestyle modification, 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 mortality was significantly decreased without increasing treatment-related adverse effects.7,8 Despite the beneficial effects of statin therapy, patients with chronic diseases who are taking medications 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 efficacy of morning and evening administration of simvastatin, there was significantly lower reduction in LDL-C levels when simvastatin was given in the morning.14 However, taking simvastatin 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 efficacy *
Trademark: Simvast CR tablets, Hanmi Pharmaceutical Co, Ltd, Seoul, Republic of Korea.
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and a similar safety profile within the study population 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 efficacy of CR simvastatin administered in the morning was noninferior to that of IR simvastatin administered 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.
METHODS The present study was a prospective, randomized, double-dummy, double-blind,, multicenter Phase IV trial that evaluated the efficacy and safety profile of morning administration of CR simvastatin tablets compared with evening administration of IR simvastatin 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 was performed in accordance with the Declaration of Helsinki and its amendments.
Patients The 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: Zocors tablet, Merck & Co, Inc, Whitehouse Station, New Jersey.
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Clinical Therapeutics 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 and deep venous thrombosis in the past 6 months, active peptic ulcer disease, gastrointestinal disease that might influence 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 derivatives, omega-3 fatty acid formulations, fibric acids, peroxisome proliferatoractivated receptor γ agents, and bile acid sequestrants.
Screening and Treatment Period At 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 modification, 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 simvastatin (test group) and IR simvastatin (control group). We used a fixed-allocation (1:1) block-randomization method. 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 20mg 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 color and shape as the corresponding drugs so that patients and physicians could not differentiate them (doubleblinding). 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 evaluation. At 8 weeks (visit 4), the patients were evaluated for drug compliance, efficacy, and safety profile
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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 final (efficacy) laboratory tests at visit 4.
Efficacy and Safety Profile Assessment LDL-C, HDL-C, total cholesterol (TC), and TG levels in 12-hour fasting blood samples were determined 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 profile assessment, vital signs and laboratory parameters were monitored, including hemoglobin level; hematocrit, white blood cell, and platelet counts; transaminase, γ-glutamyl transferase, serum creatinine, blood glucose, and creatine kinase levels; urinalysis; and ECG.
Statistical Analysis The aim of the study was to conduct a noninferiority 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 at 80% 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 final sample size of 61 patients in each group. The equation for sample size determination was as follows: n ¼ 2ðZα þ Zβ Þ2 σ 2 ððμT μC Þ dÞ2 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 efficacy testing at week 8. The safety profile analysis was based on the safety set, which was defined as the group of patients who had taken at least 1 tablet of the study drug.
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Y.J. Yi et al. 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 efficacy evaluation blood test after 8 weeks of medication. Forty-five patients in the test group and 47 in the control group completed the study (Figure 1).
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 efficacy of CR simvastatin was considered to be noninferior. To assess the significance 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 variables that followed a normal distribution were presented 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 defined as statistically significant. All statistical analyses were performed using SPSS 19.0 (SPSS Inc, an IBM company, Chicago, Illinois).
Of 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 receptor blockers, β-blockers, calcium channel blockers, and loop and thiazide diuretics), and baseline laboratory test results (TC, TG, LDL-C, HDL-C, and creatinine levels), there were no statistically significant differences between the test and control groups (Table I).
RESULTS
Changes in the Lipid Profile
A total of 122 patients were randomly assigned to either the test (n = 62) or control (n = 60) group. On
Both the morning dose of CR simvastatin and evening dose of IR simvastatin significantly lowered
Baseline Characteristics
Screening : Patients with dyslipidemia and CKD (n = 168) 34 were in exclusion criteria
12 rejected TLC
122 subjects randomized 1 refused after randomization
3 failed to perform efficacy test
118 patients at week 0 : ITT population
59 received morning administration
59 received evening administration
of CR simvastatin
of IR simvastatin
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
45 completed study
47 completed study PP popualtion (N=92)
Figure 1. Flow chart of the study. CKD ¼ chronic kidney disease; CR ¼ controlled-release; IR ¼ immediaterelease; ITT ¼ intention-to-treat; PP ¼ per-protocol; TLC ¼ therapeutic lifestyle change.
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Table I. Baseline characteristics of the intention-to-treatment population in the trial. Characteristic Age, y, mean (SD) Sex, male, no. (%) Weight, kg, mean (SD) CKD stage, no. (%) 3 4 5 Alcohol consumption, no. (%) None Present Underlying disease, no. (%) Hypertension Diabetes mellitus Ischemic heart disease Stroke Previous statin use, no. (%) Medication, no. (%) Aspirin ACEi/ARB β-Blocker Calcium channel blocker Loop diuretics Thiazide Baseline laboratory tests, mg/dL, mean (SD) Total cholesterol LDL-C HDL-C Triglycerides Creatinine
Test Group (n ¼ 59)
Control Group (n ¼ 59)
Total (N ¼ 118)
56.9 (10.5) 28 (47.5) 64.3 (11.1)
57.0 (12.1) 29 (55.1) 63.7 (10.4)
57.0 (11.3) 57 (48.3) 64.0 (10.8)
43 (72.9) 15 (25.4) 1 (1.7)
40 (67.8) 18 (30.5) 1 (1.7)
83 (70.3) 33 (28.0) 2 (1.7)
47 (80.7) 12 (20.3)
43 (72.9) 16 (27.1)
90 (76.3) 28 (23.7)
52 24 3 4 9
(88.1) (40.7) (5.1) (6.8) (15.2)
54 18 1 2 9
(91.5) (30.5) (1.7) (3.4) (15.2)
106 42 4 6 18
(89.8) (35.6) (3.4) (5.0) (15.2)
0.542 0.249 0.618 0.579 1.000
20 52 18 33 10 10
(33.9) (88.1) (30.5) (59.9) (16.9) (16.9)
16 52 15 24 9 6
(27.1) (88.1) (25.4) (40.7) (15.3) (10.1)
36 104 33 57 19 16
(30.5) (88.1) (28.0) (48.3) (16.1) (13.5)
0.424 1.000 0.538 0.097 0.802 0.282
228.7 143.9 46.9 190.3 2.0
(36.8) (28.1) (14.5) (73.0) (0.9)
220.0 137.0 48.8 167.6 2.0
(36.4) (28.4) (13.5) (70.7) (0.8)
224.4 140.5 47.8 178.9 2.0
(36.8) (28.3) (14.0) (72.5) (0.8)
0.199 0.186 0.464 0.090 0.816
P 0.978 0.853 0.764 0.827
0.387
ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CKD ¼ chronic kidney disease.
blood levels of LDL-C, TC, and TG. Levels of HDL-C significantly increased in both groups. A betweengroup analysis of HDL-C level after treatment revealed a significantly 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
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difference in the percentage of change in LDL-C level between the test and control groups was (–6.0% to 5.0%), which did not meet the predefined noninferiority margin (–6.5%) in a 1-tailed significance test (Figure 2).
Adverse Events One 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
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Y.J. Yi et al.
40
TC
LDL-C
TG
HDL-C –10.2 ± –4.5 ± 20.7% 11.4%
% change
20
0
–20
DISCUSSION
–40
–60
the chronological order of administration, a response of discontinuation or redosing, and other significant 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 and nausea developed during the trial. There was no difference between the 2 groups in the incidence of treatmentrelated adverse events (P ¼ 0.691, by the χ2 test).
–24.3 ± –26.5 ± 12.5% 12.0% –10.6 ± –12.4 ± 35.1% 33.2%
–35.1 ± –35.6 ± 15.7% 14.6%
Control group
Test group
Figure 2. Percentage of change in lipid parameters after treatment. TC ¼ total cholesterol; TG ¼ triglycerides.
similar in both groups. In terms of a causal relationship, the adverse events were classified into 5 categories: definitely related, probably related, possibly related, uncertainly related, and not related to treatment. Each category was further defined according to
The present study was designed as a double-blind, prospective, randomized clinical trial with an active comparator. It compared the efficacy and safety profile of morning administration of a CR simvastatin formulation with those of IR simvastatin in patients with underlying CKD. The difference in the percentage of change in LDL-C level did not meet the predefined noninferiority margin. This finding suggests that CR simvastatin has an efficacy similar to that of IR simvastatin. In the Scandinavian Simvastatin 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 efficacy. There were also no significant differences in the incidence of treatment-related adverse events.
Table II. Profiles and differences of fasting lipids at baseline and 8 weeks after treatment. Test Group (n ¼ 59) Baseline Total cholesterol, 228.7 (36.8) mg/dL Change, %* Triglycerides, 190.3 (73.0) mg/dL Change, %* LDL-C, mg/dL 143.9 (28.1) Change, %* HDL-C, mg/dL 46.9 (14.5) Change, %*
Control Group (n ¼ 59)
8 Weeks After P (Within Treatment Group)
Baseline
8 Weeks After P (Within Treatment Group)
P (Between Groups After Treatment)
172.3 (35.1)
o0.001
220.0 (36.4)
160.6 (31.9)
o0.001
0.587
−24.3 (12.5) 159.8 (65.9)
o0.001 o0.001
167.6 (70.7)
−26.5 (12.0) 136.6 (61.6)
o0.001 o0.001
0.317 0.963
−10.6 92.8 −35.1 51.0 10.2
0.023 o0.001 o0.001 0.001 o0.001
−12.4 87.5 −35.6 50.7 4.5
0.001 o0.001 o0.001 0.011 0.003
0.575 0.722 0.858 0.012 0.064
(35.1) (25.7) (15.7) (15.6) (20.7)
137.0 (28.4) 48.8 (13.5)
(33.2) (23.2) (14.6) (14.3) (11.4)
Values shown are mean (SD). * Percentage of change from baseline to end of treatment phase.
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Clinical Therapeutics
Table III. Treatment-related adverse events among the study participants. Test Group (n ¼ 62*) Gastrointestinal disorders Nausea Abdominal pain Diarrhea Musculoskeletal disorders Myalgia Central nervous system disorders Headache Dizziness Urinary system disorders Albuminuria Other disorders Edema Total events
Control Group (n ¼ 59)
Total (N ¼ 121*)
2 (3.2) 0 (0) 1 (1.6)
2 (3.4) 3 (5.1) 0 (0)
4 (3.3) 3 (2.5) 1 (0.8)
1 (1.6)
2 (3.4)
3 (2.5)
2 (3.2) 1 (1.6)
0 (0) 0 (0)
2 (1.7) 1 (0.8)
2 (3.2)
0 (0)
2 (1.7)
1 (1.6) 10 (16.1)
1 (1.7) 8 (13.6)†
2 (1.7) 18 (14.9)†
P
0.691
Values shown are number (%). * Three patients who took the test drug at least once but did not undergo efficacy laboratory tests were also included in the safety analysis. † One patient in the control group experienced both edema and nausea during medication.
With regard to the secondary end points, the HDLC 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 beneficial in terms of HDL-C than its immediate release. Dyslipidemia is one of the most important management 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 vicious cycle.23,24 A meta-analysis of randomized, controlled trials reported that lipid lowering preserved the glomerular filtration rate and reduced proteinuria in patients with renal disease.25 Although 2 large-scale clinical trials in patients with CKD have reported conflicting 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
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cardiovascular events in patients with CKD.8 Such evidence suggests that statin treatment could be justified for predialysis in patients with CKD. Simvastatin is an established HMG-CoA reductase inhibitor that has been studied in 2 large-scale outcome trials, the Heart Protection Study and the 4S.2,13 These 2 landmark studies showed that simvastatin treatment reduced coronary heart disease and allcause mortality as their primary outcome, and confirmed the long-term safety profile. The half-life of the active metabolite of conventional 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 more pronounced with evening versus morning administration.14,29,30 According to these results, it is recommended 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 schedule more complex and might compromise patient compliance.10,11 The present study showed that the
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Y.J. Yi et al. therapeutic efficacy of morning administration of CR simvastatin is equivalent to that of evening administration 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 flatulence. 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 definition of myopathy in the literature is broad, ranging from mild muscular pain to severe rhabdomyolysis. 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 efficacy 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.
CONCLUSIONS For patients with CKD, morning administration of CR simvastatin and evening administration of IR simvastatin didn't show statistically significant differences in safety profile or efficacy. Morning administration of CR simvastatin may simplify the administration schedule and improve the compliance of patients with CKD who are taking multiple medications.
ACKNOWLEDGMENTS This study was funded by Hanmi Pharmaceutical Company Ltd., Seoul, Republic of Korea.
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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 Hwang participated in the patient recruitment, implementation of the study, safety monitoring and manuscript overviewing.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Address correspondence to: Kook-Hwan Oh, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehakro, Chongno-Gu, Seoul, 110-744, Seoul, Republic of Korea. E-mail: khoh@ snu.ac.kr
Volume 36 Number 8