DOI: 10.31662/jmaj.2021-0212
https://www.jmaj.jp/

Original Research Article

Effect of Pemafibrate on Serum Creatinine in Patients with Chronic Kidney
DiseaseEnyu Imai1),2),3), and Atsuhiro Imai4)
Abstract:
Introduction: Fibrates are recommended not to be used for the treatment of hypertriglyceridemia in patients with chronic
kidney disease (CKD) based on clinical practice guidelines. The major reason for the negative suggestion is the elevation ofserum creatinine and rhabdomyolysis by fibrates. This may cause clinical inertia for the treatment of hypertriglyceridemia
using fibrate in patients with CKD, who are associated with an increasing risk of cardiovascular disease.
Methods: We retrospectively studied the change of serum creatinine via the treatment of pemafibrate.
Results: A total of 39 patients with CKD were treated with 0.2 mg of pemafibrate. Serum triglyceride was decreased in 23
fibrate-naïve patients from 380 [308, 455] mg/dL to 180 [152, 215] mg/dL via treatment with pemafibrate (p = 0.00003).
Serum creatinine and eGFR were not changed from 1.22 ± 0.29 mg/dL to 1.21 ± 0.28 mg/dL (p = 0.70) and from 45.7 ±10.9 mL/min/1.73 m2 to 46.2 ± 12.0 mL/min/1.73 m2 (p = 0.67) via treatment with pemafibrate, respectively. In 16 patients, with a change of treatment from fenofibrate or bezafibrate to pemafibrate, serum creatinine was significantly decreased from 1.32 ± 0.36 mg/dL to 1.17 ± 0.24 mg/dL (p = 0.003). eGFR was significantly increased from 45.2 ± 9.9
mL/min/1.73 m2 to 50.1 ± 8.6 mL/min/1.73 m2 (p = 0.001).
Conclusions: These results suggest that treatment with pemafibrate does not affect the serum creatinine level and is suitable for use in patients with CKD for the treatment of hypertriglyceridemia.
Key Words:
creatinine, renal function, fibrates, pemafibrate, CKD

Introduction

Patients with CKD frequently have mixed dyslipidemia andrequire treatment with both statins and fibrates. Co-administration of fibrates with statins increases the risk of rhabdomyolysis (7), particularly in CKD (11). Guidelines for treatmentof lipid abnormality in CKD do not recommend using fibrates for the treatment of hypertriglyceridemia (12), (13).
More than 20 mmol/L of TG concentration potentiallycauses acute pancreatitis (14) and is subjected to treatment with
TGs lowering drugs. In real-world clinical practice, administration of fibrates to patients with CKD is limited to greatly
elevated concentrations of TGs for prophylactic treatment of
acute pancreatitis.
Increasing serum creatinine concentration has been reported by the administration of fenofibrate or bezafibrate(10), (15)
. By contrast, pemafibrate is reported to not affect the serum concentration of creatinine (16), (17). Nevertheless, thesestudies did not focus on renal function in patients with CKD.
We retrospectively studied the change of serum creatinine

Mild-to-moderately raised triglyceride (TG) concentration(2-10 mmol/L) at non-fasting conditions causes atherosclerosis but not at a greatly elevated concentration of TGs (>50mmol/L) (1). Mild-to-moderately raised TG concentration isreported to be a risk factor for cardiovascular diseases (1), (2).
Chronic kidney disease (CKD) is at a milieu of increasing TGs
where apo CIII is increasing and lipoprotein is suppressed.
Hypertriglyceridemia is associated with 15%-38% of patientswith CKD (3), (4), (5). CKD is a strong risk factor for cardiovascular disease (6), and hypertriglyceridemia associated with CKD
may be a cause of the high prevalence of cardiovascular diseases in this population.
Hypertriglyceridemia associated with CKD, however, istended to clinical inertia because the administration of fibrates
sometimes causes rhabdomyolysis (7), (8) and potentially deteriorates renal function, particularly, in patients with CKD (9), (10).

Nakayamadera Imai Clinic, Takarazuka, Japan. 2) Department of Nephrology, Fujita Medical University, Toyoake, Japan. 3) Department of Nephrology andRheumatology, Aichi Medical University, Nagakute, Japan. 4) Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
Corresponding author: Enyu Imai, ads12069@nifty.com
JMA J. 2022;5(3):328-333
Received: December 15, 2021 / Accepted: March 3, 2022 / Advance Publication: June 17, 2022 / Published: July 15, 2022
Copyright © Japan Medical Association

1)

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concentration after the administration of pemafibrate in patients with eGFR 20-60 mL/min/1.73 m2. Additionally, weinvestigate the change of serum concentration of creatinine via
treatment with pemafibrate in patients treated with fenofibrate or bezafibrate.

= 13) or from 200 to 400 mg of bezafibrate (n = 3) and 23 patients were naïve for fibrate. Seventeen patients were treatedwith statins.
TG was decreased in fibrate-naïve patients from 380 [308,455] mg/dL to 180 [152, 215] mg/dL by treatment with pemafibrate (p = 0.00003) (Figure 1). HDL cholesterol was significantly increased from 45.0 ± 8.0 mg/dL to 56.1 ± 9.8
mg/dL (p < 0.0001). Serum creatinine and eGFR were notchanged from 1.22 ± 0.29 mg/dL to 1.21 ± 0.28 mg/dL (p =0.70) and from 45.7 ± 10.9 mL/min/1.73 m2 to 46.2 ± 12.0
+11.8 mL/min/1.73 m2 (p = 0.67) via treatment with pemafibrate, respectively (Figure 1).
In patients, with a change of treatment from fenofibrateor bezafibrate to pemafibrate, TG and HDL cholesterol were
not changed from 202 [170, 304] mg/dL to 198 [157, 233]
mg/dL (p = 0.10) and from 45 + 11mg/dL to 48 + 12 mg/dL(p = 0.079), respectively (Figure 2 and Table 2). Serum creatinine was significantly decreased from 1.32 ± 0.36 mg/dL to
1.17 ± 0.24 mg/dL (p = 0.003). eGFR was significantly increased from 45.2 ± 9.9 mL/min/1.73 m2 to 50.1 ± 8.6
mL/min/1.73 m2 (p = 0.001) (Figure 2).
ALT and γ-GTP were significantly decreased after treatment with pemafibrate (Table 2). AST, blood pressure, andurinary protein/creatinine ratio were not changed via thetreatment of pemafibrate (Figure 3). No patient had rhabdomyolysis during the study period.

Materials and Methods
Study design
We conducted a retrospective observational study. Nakayamadera Imai Clinic treated approximately 1600 patients amonth, and 95% of them had chronic non-communicable diseases, mainly diabetes and CKD. In the clinic, patients whose
triglyceridemia was higher than 300 mg/dL or higher than 200
mg/dL with metabolic syndrome were treated with fibrates,
according to Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (NCEP-ATP
III)(18). One hundred and four patients with hypertriglyceridemia were treated with pemafibrate between June 2019 and
May 2021. Among them, we enrolled 39 patients with CKD
defined by GFR 20-60 mL/min/1.73 m2. We extracted clinicallaboratory data from medical records. The clinical laboratory
data were collected before and 2-3 months after treatment
with pemafibrate, which included serum creatinine, TG, totalcholesterol, HDL cholesterol, LDL cholesterol, AST, ALT, γGTP, blood pressure, and urinary protein concentration.
These data were measured at the usual clinic visit in a nonfasting condition.
This study was approved by the ethics committee of Japan
Medical Association (R3-03). Since this study is retrospective,
we used the opt-out approach and the requirement for written
informed consent was waived. This study was conducted according to the principles of the Declaration of Helsinki.

Discussion
In the present study, serum creatinine concentration was notchanged by the administration of pemafibrate in patients witheGFR 20-60 mL/min/1.73 m2 as consistent with previous
studies including patients with normal renal function and
CKD. In patients treated with fenofibrate or bezafibrate, serum creatinine concentration was decreased by 0.15 mg/dL after shifting to pemafibrate. Similarly, eGFR was increased byapproximately 10% from mean eGFR 45 mL/min/1.73 m2.
In a Japanese evidence-based clinical practice guideline for
CKD 2018 (13) as well as in KDIGO clinical practice guideline
for lipid management 2013 (12), treatment of hypertriglyceridemia with fibrates is not recommended. As a basis, these guidelines cited a large observational study that found that prescriptions for fibrate significantly increased sCr levels, as well as therisk of hospitalization and nephrologist consultation (10). These
guidelines only suggest the change of lifestyle such as dietarymodification, weight reduction, increased physical activity, reducing alcohol intake, and treatment of hyperglycemia (ifpresent). Additionally, fibrates may cause rhabdomyolysis, inparticular, in the CKD population. Not only general practitioners but also nephrologists hesitate to use fibrates, although
they are aware of the potential benefit of lipid-lowering therapy with fibrates for preventing the incidence and recurrence of
CVD events. In meta-analyses, fibrates significantly reduced
the risk of cardiovascular death, non-fatal myocardial infarc-

Endpoints
The primary endpoint was the change of serum creatinine before and after the treatment of pemafibrate. We observed thechange of serum creatinine separately in patients treated withor without fenofibrate or bezafibrate.
Statistical analysis
The data are expressed in mean ± SD or median (interquartile
range). The changes in clinical laboratory data were analyzed
using paired t-test or Mann-Whitney U test; p < 0.05 indicatesstatistical significance. All analyses were performed using R
4.0.3.

Results
A total of 39 patients with CKD were treated with 0.2 mg ofpemafibrate. Table 1 shows the clinical characteristics of thepatients at baseline. Among them, 16 patients treated with pemafibrate were switched from 80 to 100 mg of fenofibrate (n329DOI: 10.31662/jmaj.2021-0212
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Table 1. Baseline Characteristics of CKD Patients Treated with Pemafibrate (n = 39).
All

Fibrate naïve

Treated with fibrates

p values(n = 39)(n = 23)(n = 16)Age (y.o.)

65 ± 1067 ± 963 ± 12

0.19

Male (n(%))

31 (79.5)

17 (73.9)

14 (87.5)

0.432

CKD Stage 3a (n(%))

19 (48.7)

11 (47.8)

8 (50.0)

1.0

CKD Stage 3b (n(%))

17 (43.6)

10 (43.4)

7 (43.8)

1.0

CKD stage 4 (n(%))

3 (7.7)2 (8.7)1 (6.3)

1.0

Diabetes Mellitus (n(%))

14 (36.9)

6 (26.1)

8 (50.0)

0.23

Hypertension (n(%))

35 (89.7)

20 (87.0)

15 (93,7)

0.88

CVD (n(%))

5 (12.8)

3 (13.0)

2 (12.5)

1.0

Body weight (kg)74.7 ± 13.2

74.3 ± 11.7

75.2 ± 15.5

0.84

BMI (kg/m )27.0 ± 4.0

27.2 ± 4.0

26.6 ± 4.2

0.67

Systolic blood pressure (mmHg)

131 ± 14.8

131 ± 14.5

132 ± 15.7

0.89

Serum creatinine (mg/dL)

1.26 ± 0.32

1.22 ± 0.29

1.32 ± 0.36

0.36

eGFR (mL/min/1.73 m )45.5 + 10.4

45.7 + 10.9

45.2 + 9.9

0.87

2

2

Triglyceride (mg/dL)

322 [206, 438]

380 [308, 455]

202 [170, 304]

0.001

Total cholesterol (mg/dL)

200 + 37.6

206 + 42.1

191 + 29.6

0.24

LDL-cholesterol (mg/dL)

107.4 + 26.7

106.1 + 28.9

109.2 + 24.1

0.73

HDL-cholesterol (mg/dL)

45.0 + 9.3

45.0 + 8.0

45.0 + 11.2

1.0

Treatment with bezafibrate (n(%))

3 (18.8)

Treatment with fenofibrate (n(%))

13 (81.2)

Treatment with statins (n(%))

17 (43.6)

10 (43.4)

7 (43.8)

LDL cholesterol: low-density lipoprotein cholesterol; HDL cholesterol: high-density lipoprotein cholesteroltion, and non-fatal stroke, in primary and secondary prevention (19), (20). We think that there is a clinical inertia in the treatment of hypertriglyceridemia in CKD. Pemafibrate, which
does not affect the serum creatinine concentration in patientswith CKD, may break through the inertia. A lower incident
rate of drug reaction of pemafibrate with statin than that offenofibrate (16) could encourage physicians to treat hypertriglyceridemia in CKD.
The present study is a retrospective observational study.
We cannot elucidate the cause of increasing serum creatinine
via treatment with fenofibrate or bezafibrate but not via treatment with pemafibrate. Nevertheless, in the literature of previous studies, it is apparent that the glomerular filtration rate
was not decreased by fibrates. Ansquer and colleagues (15) carefully demonstrated that fibrates did not reduce the inulin
clearance in patients with normal renal function. By contrast,
creatinine clearance was decreased by 10% (15), suggesting increasing creatinine synthesis and/or reduction of excretion ofcreatinine from the proximal tubule. Cystatin C, which is degraded in the proximal tubule, is also increased by treatment
with fenofibrate (16). This may support that fenofibrate attenuates proximal tubule function transiently since serum creatinine and cystatin C returned to the baseline level after discon-tinuance. Increasing urinary creatinine excretion was observedin the study (15), which may also cause an increasing level of serum creatinine.
Non-fasting hypertriglyceridemia is associated with myocardial infarction, stroke, and all-cause death (1). CKD is astrong risk factor for cardiovascular diseases (6). SHARP
study (21) showed that reduction of LDL cholesterol resulted ina 17% reduction of cardiovascular diseases. Nevertheless, 10%of the participants of the SHARP study developed CVD in 5
years of follow-up. Hence, reduction of LDL cholesterol alone
is not sufficient for secondary prevention of CVD. This may
suggest that the remaining hypertriglyceridemia may play animportant role in the high incidence of CVD after treatment
for LDL cholesterol. In a meta-analysis, lowering of hypertriglyceridemia showed a reduction of CVD in patients withCKD (10).
In a meta-analysis, the administration of fibrates was reported to reduce proteinuria (10). Treatment with pemafibrate
also showed a reduction of albuminuria in IgA patients (22). In
the present study, a reduction of proteinuria was not observed. However, it is hard to conclude since our study is a
short duration of treatment and the number of patients was
small. Further study is required.
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Figure 1. Change of triglyceride, serum creatinine, and eGFR in fibrate-naïve patients with CKD.
Fibrates-naïve patients with hypertriglyceridemia were treated with pemafibrate. Baseline and 2-3 months after treatment withpemafibrate, blood sampling was performed in non-fasting condition at clinic visit. Data are shown in mean ± SD or the median[25%, 75%].

Figure 2. Change of triglyceride, serum creatinine, and eGFR in patients with CKD treated with 200-400 mg of bezafibrate or
80-100 mg of fenofibrate.
Fibrate-treated patients with hypertriglyceridemia were shifted to pemafibrate. Baseline and 2-3 months after treatment with pemafibrate, blood sampling was performed in non-fasting condition at clinic visit. Data are shown in mean ± SD or the median[25%, 75%].

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Table 2. Effect of Pemafibrate Treatment on Liver Enzyme and Lipid.
Baseline

After treatment

p values

AST (U/L)

23.5 [20.0, 33.5]

26.5 [21.0, 31.0]

0.94

ALT (U/L)

24.5 [18.3, 47.0]

25.5 [15.5, 36.3]

0.006

g-GTP (U/L)

43.0 [25.0, 73.5]

25.5 [22.0, 53.3]

0.00001

Total cholesterol (mg/dL)

199.6 ± 37.6

192.1 ± 25.9

0.17

LDL-cholesterol (mg/dL)

107.4 ± 26.7

108.4 ± 20.0

0.82

HDL-cholesterol (mg/dL)

45.0 ± 9.3

52.7 ± 11.3

<0.00001

Triglyceride (mg/dL)

322 [206, 438]

188 [151, 232]

<0.00001

AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GTP: γ-glutamyl transferase; LDL cholesterol: low-density lipoprotein cholesterol;
HDL-cholesterol: high-density lipoprotein cholesterol

Figure 3. Change of urinary protein/creatinine ratio and systolic blood pressure.
Urinary protein/creatinine ratio was measured at baseline and after treatment with pemafibrate in patients with proteinuria (n =9). Systolic blood pressure was shown at baseline and after treatment (n = 38). Data were shown in mean ± SD or the median[25%, 75%].

Reduction of ALT and γ-GTP levels by pemafibrate waspreviously reported in patients with CKD (17), as well as inthose without CKD (16).
The limitations of our study are as follows. This is a retrospective observational study conducted in a single center. We
draw data from medical records during clinical practice. Cystatin C is not available for a marker of renal function in general practice because we cannot measure it in less than 3 months
under practice according to national insurance.

mL/min/1.73 m 2. In patients treated with fenofibrate or bezafibrate, serum creatinine concentration was decreased by 0.15
mg/dL after the switch to pemafibrate. Similarly, eGFR was
increased by approximately 10% from mean eGFR 45
mL/min/1.73 m2. Pemafibrate significantly decreased serum
TGs equivalent to fenofibrate or bezafibrate in patients with
CKD. These results suggest that pemafibrate is suitable for use
in patients with CKD for the treatment of hypertriglyceridemia. To investigate the impact of pemafibrate on primary andsecondary prevention of cardiovascular diseases in patientswith CKD, further study is warranted.

Conclusion
Serum creatinine concentration was not changed via the administration of pemafibrate in patients with eGFR 20-60
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Article Information

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Conflicts of Interest

Enyu Imai received honorarium from Boehringer Ingelheim,
Daiichi Sankyo, Lilly, Novo, and Bayer; Enyu Imai received research fundings from Tanabe Mitsubishi, Boehringer Ingelheim, Kissei, Kyowa Kirin, Daiichi Sankyo, and AstraZeneca.
Author Contributions

Enyu Imai has responsibility regarding all of the study.
Atsuhiro Imai conducted statistics of this study.
Approval by Institutional Review Board (IRB)

This study was approved by the ethics committee of Japan
Medical Association (R3-03).

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