Efficacy and Safety of Prolonged Treatment with Pemafibrate plus an HMG-CoA Reductase Inhibitor in Japanese Patients with Type 2 Diabetes Mellitus

Abstract

It has been suggested that caution should be exercised when using HMG-CoA reductase inhibitor (statin) in combination with a drug of the fibrate family because of the potentially elevated risk of development of hepatic function impairment and myopathy. We conducted this present study to evaluate the efficacy and safety of treatment with a statin plus pemafibrate (a new fibrate) versus treatment with pemafibrate alone in Japanese patients with type 2 diabetes mellitus.

In this study, a total of 23 Japanese patients with type 2 diabetes mellitus were divided into two groups: a group that received pemafibrate alone and a group that received pemafibrate+a statin for a period of 3 years, respectively. Blood levels of lipids and hepatic and renal function parameters were measured before and one and three years after the start of treatment.

The pemafibrate-alone group showed reduction of the blood lipid levels, but no adverse changes of the hepatic or renal function parameters were observed. Similarly, the combined pemafibrate+statin treatment group also showed lowering of the blood lipid levels without any adverse changes of the parameters.

Improvement of the blood lipid profile was observed in patients who received prolonged treatment with pemafibrate. Similarly, improvement of the blood lipid profile without any adverse changes of the hepatic or renal function parameters was also observed in patients who received prolonged combined pemafibrate+statin treatment. Thus, our findings confirm the safety and efficacy of pemafibrate administered either alone or in combination with a statin.

 

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Keywords

pemafibrate - statin - combined treatment - type 2 diabetes mellitus

Introduction

Pemafibrate is a drug of the fibrate family developed in Japan for the treatment of hyperlipidemia and was launched in the market in 2018. Until date, however, few reports of the efficacy and safety of prolonged treatment with this drug in patients with type 2 diabetes mellitus have been published. Diabetes mellitus is a major risk factor for atherosclerosis [1]. Patients with type 2 diabetes mellitus often show abnormal lipid metabolism, which is a well-known risk factor for atherosclerosis [2]. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), known to lower the serum cholesterol levels, have been used in the treatment of diabetes mellitus patients with accompanying hypercholesterolemia, while drugs of the fibrate family, known to lower serum triglyceride levels, have been used in the treatment of diabetes mellitus patients with accompanying hypertriglyceridemia. Combined use of a statin plus a drug of the fibrate family (combined fibrate+statin treatment) may be expected to be effective in diabetes mellitus patients with both hypercholesterolemia and hypertriglyceridemia, but it has been suggested that combined use of these two drugs could possibly elevate the risk of development of hepatic function impairment and myopathy, and requires caution [3]. Under such circumstances, we undertook the present study to evaluate the efficacy and safety of prolonged combined pemafibrate+statin treatment versus prolonged pemafibrate-alone treatment.

 

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Materials and Methods

Patients studied

This study was conducted in compliance with the ethical standards of the responsible institution for studies in human subjects as well as with Declaration of Helsinki.

Informed consent for participation in the study was obtained from each of the Japanese study participants with type 2 diabetes mellitus after they received an explanation about the study objectives by the attending physician. The protocol for this study was approved by the Ethics Committee of the Medical Corporation Odakai (IRB approval number 2023-01). This clinical study was officially registered as an open-label study in the UMIN registry (ID: UMIN000038160).

A total of 23 outpatients (16 males and 7 females) were registered in this study. The subjects were divided into two groups: a group that received pemafibrate alone (pemafibrate-alone group, n=10) and a group that received combined treatment with a statin+pemafibrate (combined P+S treatment group, n=13).

 

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Dosing method

Each patient received two doses of pemafibrate (Kowa Pharmaceutical Company Ltd. Tokyo, Japan) per day at 0.2 mg/dose for 3 years.

Patients of the combined P+S treatment group received a statin in addition, either rosuvastatin (n=4, Astra Zeneca, Osaka) or pitavastatin (n=9, Kowa Pharmaceutical Company Ltd., Tokyo, Japan). The dose of rosuvastatin was 2.5 mg/dose (administered once daily) and that of pitavastatin was 0.1 mg/dose (administered twice daily).

 

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Measurement of the blood levels of lipids, hepatic function parameters, renal function parameters, serum creatine kinase (CK) levels, hemoglobin A1c (HbA1c), and other biochemical parameters

Blood examinations were conducted before, and 1 and 3 years after the start of pemafibrate treatment. Serum was separated from the blood specimens and stored frozen at –80°C until the measurements. Measurements of the serum levels of lipids, HbA1c, glucose, creatinine, creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GTP), alkaline phosphatase (ALP), and uric acid were performed at the Handa Medical Association Health Center (Aichi, Japan), using an Auto-analyzer (JCA-BM8000 series, JAOL, Tokyo, Japan). Serum HbA1c was measured by an automated HPLC method (HLC-723GX, Tosoh Corporation, Tokyo, Japan), and the serum insulin levels were measured by ELISA.

 

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Statistical analysis

Data are expressed as the means ± standard deviation. A paired t-test was employed for testing the significance of differences between the pre-treatment levels and the levels measured after 1 and 3 years of treatment. The significance level was set at p<0.05.

A regression analysis was also carried out for comparisons between the two groups, with the pre-treatment levels serving as covariates.

 

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Results

Pemafibrate treatment

[Table 1] shows the effects of treatment on the blood parameters in the two groups after 1 and 3 years of treatment (overall, in the pemafibrate-alone and combined pemafibrate+statin treatment group, n=23).

Table 1 Changes in various parameters in patients receiving pemafibrate.

	n=23 (16 male, 7 female)
	Baseline	After 1 year	After 3 years
Body weight (kg)	69.3±16.2	70.1±16.2	69.7±17.0
BMI (kg/m2)	25.3±3.9	25.4±3.8	25.5±4.0
HbA1c (%)	6.9±0.8	6.9±0.5	6.9±0.7
glucose (mg/dl)	100±27	96±22	104±26
insulin (μU/ml)	8.9±6.7	13.9±24.7	17.0±31.2
creatinine (mg/dl)	0.8±0.2	0.8±0.2	0.8±0.1
eGFR (ml/min/1.73m2)	75±12	75±13	76±12
CK (IU/L)	121±48	106±69	102±42*
AST (U/L)	23±7	20±4*	21±5
ALT (U/L)	31±15	22±12**	23±11**
γ-GTP (U/L)	62±56	34±21**	45±45*
ALP (U/L)	191±50	116±37**	44±11**
uric acid (mg/dl)	5.2±1.9	5.2±1.3	5.0±1.2
Total cholesterol (mg/dl)	204±40	188±33**	192±32
HDL-C (mg/dl)	51±14	56±15**	54±14
LDL-C (mg/dl)	115±28	110±24	118±25
non-HDL-C (mg/dl)	151±36	133±28**	138±28
Triglycerides (mg/dl)	286±257	141±64**	122±53**
AI (atherosclerosis index)	3.2±1.1	2.5±0.8**	2.7±0.9*
AI: (TC-LDL-C)/HDL-C

Data are expressed as means±SD. *p<0.05, **p<0.01 vs. Baseline.

According to the results of evaluation of the effects of pemafibrate treatment on the blood lipid profile, the serum levels of total cholesterol, triglyceride (TG), and non-HDL-cholesterol (non-HDL-C) decreased significantly, while the serum HDL-C level increased significantly after 1 year of treatment. Significant decrease of the serum TG level was observed after both 1 year and 3 years of treatment. The atherosclerosis index (AI: TC – LDL-C/HDL-C) was lower after 1 and 3 years of treatment than the value recorded before the start of treatment.

Pemafibrate treatment had no effect on the body weight or body mass index (BMI).

Pemafibrate treatment had no effect on the markers of diabetes mellitus (blood HbA1c, glucose, and insulin levels) or on the renal function parameters (serum creatinine and estimated glomerular filtration rate [eGFR]). Significant decrease of the serum level of creatine kinase (CK), a marker of myopathy (rhabdomyolysis) was observed after 3 years of treatment. The treatment had no effect on the serum uric acid levels. Serum levels of AST, ALT, γ-GTP and ALP, which are hepatic function parameters, were significantly lower after 1 year of treatment than before the start of treatment. Serum ALT, γ-GTP and ALP levels were also significantly lower after 3 years of treatment as compared with the pre-treatment levels.

 

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Comparison between the pemafibrate-alone group (n=10) and the pemafibrate+statin group (n=13)

[Table 2] shows the effects of the treatments on various parameters after 1 and 3 years of treatment.

Table 2 Comparison of the changes in parameters between the group treated with pemafibrate alone and the group treated with combined pemafibrate+a statin.

	Pemafibrate-alone group (n=10)			Pemafibrate+Statin group (n=13)
Age (yrs)	63±14			53±12
	Baseline	1 year	3 years	Baseline	1 year	3 years
Body weight (kg)	74.3±17.4	74.6±17.0	74.4±17.1	65.6±14.9	66.6±15.4*	65.4±16.4
BMI (kg/m2)	26.9±4.2	27.1±3.8	27.0±3.8	23.8±3.3	24.1±3.4	24.1±3.8
HbA1c (%)	6.7±0.7	6.8±0.4	6.9±0.7	7.1±0.9	7.0±0.6	6.9±0.7
glucose (mg/dl)	96±17	91±14	101±25	104±33	99±26	106±28
Plasma insulin (μU/ml)	10.7±9.6	13.1±15.6	16.5±30.2	7.4±2.8	14.5±30.6	17.4±33.4
creatinine (mg/dl)	0.8±0.2	0.8±0.2	0.8±0.2	0.8±0.1	0.8±0.1	0.8±0.1
eGFR (ml/min/1.73m2)	76±14	78±17	78±15	74±11	73±9	74±7
Serum CK (IU/L)	134±51	101±56*	104±52**	111±46	110±80	100±35
AST (U/L)	24±9	19±4*	22±6	22±5	21±4	21±5
ALT (U/L)	36±19	21±9*	24±8*	28±11	23±15	22±13**
γ-GTP (U/L)	87±72	40±25*	59±61	44±32	29±17*	32±18
ALP (U/L)	170±31	104±33**	41±8**	207±57	126±39**	47±12**
uric acid (mg/dl)	6.2±2.6	5.9±1.6	5.5±1.3	4.5±0.7	4.8±1.0	4.5±0.9
Total cholesterol (mg/dl)	212±29	194±24*	196±21*	198±47	184±39*	189±40
HDL-C (mg/dl)	50±13	56±16**	55±13	52±15	55±15	54±16
LDL-C (mg/dl)	119±31	117±15	121±16	112±26	104±29	114±31
non-HDL-C (mg/dl)	160±28	139±20	142±20	145±41	129±33**	135±34
Triglycerides (mg/dl)	357±353	149±67	125±57*	231±141	136±63*	118±52*
AI (atherosclerosis index)	3.5±1.3	2.6±0.9*	2.7±0.9**	2.9±0.9	2.4±0.8*	2.7±0.9

Data are expressed as means±SD. *p<0.05, **p<0.01 vs. baseline.

In the pemafibrate-alone group, no effect of the treatment was observed on the body weight or BMI.

The treatment also had no effect on the markers of diabetes mellitus (blood HbA1c, glucose and insulin levels) or renal function parameters (serum creatinine and GFR). There was no effect on the serum CK (a marker of myopathy) or serum uric acid either.

Significant decreases of the serum levels of AST, ALT, γ-GTP and ALP, which are hepatic function parameters, were observed after 1 year of treatment. Significant decreases of the serum ALT and ALP were also observed after 3 years of treatment. Evaluation of the treatment effects on the blood lipid profile revealed a significant decrease of the serum total cholesterol after both 1 and 3 years of treatment, and significant increase of the serum HDL-C after 1 year of treatment. Significant decrease of the serum TG was also observed after 3 years of treatment. Significant decrease of the AI was observed after 1 and 3 years of treatment.

In the pemafibrate+statin group, marginal increase of the body weight was observed after 1 year of treatment.

The treatment had no effects on the blood HbA1c, glucose or insulin levels. No effects of the treatment were observed on the renal function parameters (serum creatinine and GFR), serum CK (a marker of myopathy) or serum uric acid.

Significant ALT, γ-GTP and ALP (indicators of hepatic dysfunction) decreased significantly at 1 year after the start of treatment. Significant decrease of the serum ALT was observed after 3 years of treatment.

The serum total cholesterol and serum non-HDL-C decreased significantly, and the serum HDL-C increased significantly after 1 year of treatment. Significant decrease of the serum TG was observed after both 1 and 3 years of treatment. The AI decreased significantly after 1 year of treatment.

A regression analysis of the levels in each of the parameters after treatment (the data of levels after 1 and 3 years of treatment combined) using the pre-treatment levels as a covariate and the groups (the pemafibrate-alone group and the pemafibrate+statin group) and the dosing period as independent variables are performed. The results revealed no significant inter-group differences in any of the parameters.

 

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Discussion

In type 2 diabetes mellitus patients with an abnormal lipid profile, a lipid-lowering drug(s) is often used in combination with an antidiabetic drug (s). In diabetes mellitus patients with hypercholesterolemia and hypertriglyceridemia, one of the possible treatment options is combined administration of a statin and a fibrate, but it has been suggested that combined use of these two drug classes may elevate the risk of hepatic function impairment and myopathy (rhabdomyolysis) [3]. However, combined administration of a statin+fibrate may exert effective anti-atherosclerotic activity due to the potent serum cholesterol-lowering action of statins and triglyceride-lowering and HDL-C-elevating actions of fibrates [4], along with improving endothelial cell function [5], increasing the serum level of adiponectin [6], and increasing insulin sensitivity [7].

Kusunoki et al. [8] conducted a study of combined pemafibrate+statin treatment and, even though the study period was short (6 months), reported that there was no safety problem with the combined use of the two drug classes. However, there are few published studies on the effects of prolonged fibrate+statin treatment.

In the present study conducted in type 2 diabetes mellitus patients with an abnormal lipid profile, we compared the efficacy and safety of pemafibrate+statin treatment versus pemafibrate-alone treatment administered for a prolonged period (3 years).

Pemafibrate is a new drug of the fibrate family that has been marketed recently in Japan, whose actions are mediated by peroxisome proliferator-activated receptor (PPAR)-α. It resembles existing drugs of the fibrate family in terms of its agonist activity which stimulates the expression of genes related to lipid metabolism, but it exhibits higher selectivity for PPARα, so that it exerts more potent effects on lipid metabolism with less adverse effects as compared with other drugs of the fibrate family [9] [10]. In the evaluation of safety, there was no increase in any of the hepatic function and kidney function parameters in the 6-months treatment [8] [9].

Regarding the hepatic function, Kusunoki et al. reported that Pemafibrate did not increase these parameters, but decreased these parameters [8]. Also, Ishibasi et al. reported that Pemafibrate did not increase the ALT and γ-GTP with a decrease of such parameters [9]

In evaluation of efficacy in the present study, the pemafibrate alone treatment group showed significant reduction in serum total cholesterol until 3 years after the start of treatment and significant reduction in triglyceride at 3 years after the start of treatment. HDL-C increased at 1 year after the start of treatment. The atherosclerosis index [(TC – HDL-C)/HDL-C] decreased significantly from the pre-treatment level.

In the combined treatment group, significant decrease of the serum total cholesterol was observed after 1 year of treatment and significant decrease of the serum triglyceride levels was observed until 3 years after treatment. The serum HDL-C increased after 1 year of treatment. Significant decrease of the serum non-HDL-C (total cholesterol – HDL-C), which is a risk factor for atherosclerosis [11] [12], was observed after 1 of treatment. The atherosclerosis index after 1 year of treatment was significantly lower than that before the start of treatment.

Thus, the efficacy did not differ greatly between the pemafibrate-alone group and the fibrate+statin group, even for prolonged treatment (3 years). In addition, decrease of the atherosclerosis index (AI) was observed in both the groups. Thus, anti-atherosclerotic effects were observed in both the treatment groups.

Pemafibrate had no effects on the parameters of glucose metabolism (blood HbA1c, glucose, and insulin levels).

In the evaluation of safety, no increase in any of the hepatic function parameters (blood AST, ALT, γ-GTP and ALP levels) was observed after treatment as compared with the pre-treatment levels in either of the two groups. In fact, decreases in the levels of many of these parameters were observed after the treatment. These results suggest that prolonged pemafibrate+statin treatment is associated with a low risk of hepatic function impairment.

Regarding the influence of the treatments on the renal function, renal function parameters (serum creatinine and eGFR) remained unchanged after treatment as compared with the pre-treatment levels in both the treatment groups. These results suggest that combined pemafibrate+statin treatment is associated with a low risk of renal function impairment. In this connection, Arai et al. [10] treated patients with hypertriglyceridemia with the pemafibrate+statin combination and reported a slight increase of the creatinine and slight decrease of the eGFR, but considered the changes as being of negligible clinical significance.

In regard to the treatment effect on the serum CK, a marker of myopathy (rhabdomyolysis), comparison of the post-treatment and pre-treatment levels revealed no significant effect of the treatment on the serum CK in either of the treatment groups.

A regression analysis was conducted for each parameter, and no significant differences were found in the groups. The confidence region was additionally checked for the serum CK. The results revealed no problem of clinical concern ([Fig. 1]).

Fig. 1 Regression analysis of CK (after 3 years). The confidence interval for each group after 3 years of treatment in a regression model using the pre-treatment level as a covariate and the group and the dosing period as independent variables. The broken lines indicate the 95% confidence intervals for the regression model. The dotted lines indicate the 95% confidence intervals for the dependent variables.

Therefore, we consider it safe to administer pemafibrate in combination with a statin in patients with type 2 diabetes mellitus.

Marginal increase of the body weight of the patients was observed after 1 year of combined pemafibrate+statin treatment. The reason remains unclarified.

The results of the present study suggest that in Japanese type 2 diabetes mellitus patients with hyperlipidemia, prolonged statin+pemafibrate treatment could be expected to improve the blood lipid profile in a safe manner, without increasing the risk of hepatic or renal function impairment, or of myopathy.

A limitation of this clinical study was that the study cohort was rather small (23 cases). We plan to conduct a similar study on a larger number of subjects in the future.

 

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Conclusions

Pemafibrate, a newly launched drug for the treatment of hyperlipidemia, improved the blood lipid profile, without showing any attenuation of efficacy over a prolonged (3 years) treatment period. Our results also confirmed the safety of this drug administered in combination with a statin, with no adverse effects observed on the hepatic or renal function parameters, and no increase in the risk of myopathy.

 

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Conflict of Interest

The authors declare that they have no financial or non-financial conflict of interest to report.

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Publication History

Received: 24 September 2024

Accepted: 15 March 2025

Article published online:
21 May 2025