Effect of Pemafibrate on Metabolic Dysfunction‐Associated Steatotic Liver Disease: A Nationwide Multicenter Study

ABSTRACT

Aim

Although pemafibrate, a selective peroxisome proliferator‐activated receptor α (PPARα) modulator primarily prescribed for hypertriglyceridemia, may improve liver function in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), its efficacy has not been sufficiently evaluated. This study aimed to assess the effect of pemafibrate on liver function in patients with MASLD using a nationwide multicenter cohort.

Methods

In this nationwide multicenter study, we analyzed 352 patients diagnosed with MASLD and hypertriglyceridemia who newly initiated pemafibrate therapy. The primary outcome was the rate of ALT normalization (ALT ≤ 30 U/L). Laboratory data were collected at baseline and 3, 6, and 12 months after pemafibrate initiation, and longitudinal changes were evaluated.

Results

The mean ALT levels decreased significantly from 60.1 ± 1.8 U/L at baseline to 44.9 ± 1.4, 41.6 ± 1.3, and 38.1 ± 1.3 U/L at 3, 6, and 12 months, respectively (all p < 0.001). The ALT normalization rate increased from 30.4% at baseline to 46.0%, 50.9%, and 56.6% at 3, 6, and 12 months (p < 0.001), respectively, with marked improvement at three months and maintenance throughout follow‐up.

Conclusions

Pemafibrate treatment significantly improved ALT levels and ALT normalization rates in MASLD patients with hypertriglyceridemia, with improvement observed at three months and a sustained effect up to 12 months. This is a large‐scale multicenter study to date evaluating pemafibrate in MASLD, providing robust evidence for its potential as a therapeutic option in this population.

Abbreviations

Alb

albumin

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BMI

body mass index

GGT

gamma‐glutamyl transferase

HDL‐C

high‐density lipoprotein cholesterol

IQR

interquartile range

LDL‐C

low‐density lipoprotein cholesterol

MASLD

metabolic dysfunction‐associated steatotic liver disease

NAFLD

nonalcoholic fatty liver disease

SE

standard error

T‐Bil

total bilirubin

TG

triglycerides

1. Introduction

Metabolic dysfunction‐associated steatotic liver disease (MASLD) has recently undergone a global redefinition and is drawing increasing attention in the field of hepatology [1, 2, 3, 4]. MASLD, which encompasses the former concept of nonalcoholic fatty liver disease (NAFLD) [5, 6, 7], is associated not only with the pathogenesis of hepatocellular carcinoma and hepatic fibrosis progression but also with an increased risk of cardiovascular events and extrahepatic malignancies, making it a medical condition of significant social and clinical importance [8, 9, 10, 11, 12].

While preventing MASLD‐induced cirrhosis and liver cancer is an important treatment goal, there is still a paucity of effective pharmacotherapies for MASLD. However, many patients with MASLD have comorbidities such as diabetes mellitus and dyslipidemia, and some drugs used to treat these conditions may also have beneficial effects on MASLD itself. Pemafibrate, a selective peroxisome proliferator‐activated receptor α (PPARα) modulator, is mainly prescribed for hypertriglyceridemia [13]. Recent multicenter studies have reported that pemafibrate improves liver biochemistry and prognostic scores in patients with primary biliary cholangitis [14]. Several reports have suggested that this medication may improve the levels of ALT and noninvasive fibrosis markers in MASLD [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]; however, these studies have generally been single‐center or relatively small in scale, with limited sample sizes. To date, the effect of pemafibrate on ALT improvement in patients with MASLD has not been sufficiently evaluated in large, multicenter cohort studies.

Therefore, to fill this knowledge gap, we conducted a nationwide multicenter study including 13 Japanese Red Cross hospitals, which comprise hospitals distributed throughout Japan and facilitate robust multicenter data collection, to evaluate the impact of pemafibrate therapy on longitudinal changes in ALT levels and the rate of ALT normalization in patients with MASLD.

2. Materials and Methods

2.1. Study Protocol

This was a nationwide, multicenter, retrospective cohort study conducted by the Japanese Red Cross Liver Study Group. Patients diagnosed with MASLD and hypertriglyceridemia who had newly initiated pemafibrate therapy (0.2 mg/day) between 2019 and 2023 were included. In this study, fatty liver was diagnosed based on evidence of hepatic steatosis on abdominal ultrasonography, computed tomography, and magnetic resonance imaging (MRI).

Patients with active viral hepatitis (Patients who were HBsAg‐positive or HCV RNA‐positive were excluded, whereas those with SVR more than 3 years after HCV treatment were included), autoimmune liver diseases, primary biliary cholangitis, drug‐induced liver injury, or alcoholic liver disease were excluded from the analysis.

Informed consent was obtained from all patients using the opt‐out method. This retrospective cohort study was approved by the ethics review committees of Musashino Red Cross Hospital (approval number: 4072) and conformed to the ethical guidelines of the Declaration of Helsinki.

2.2. Clinical and Laboratory Data

Clinical background data (including age, sex, comorbidities, body mass index [BMI], and the presence of diabetes mellitus, hypertension, or dyslipidemia) and laboratory values at baseline (pretreatment) and 3, 6, and 12 months after initiation of therapy were collected. The laboratory parameters analyzed included serum levels of alanine aminotransferase (ALT), gamma‐glutamyl transferase (GGT), and triglycerides (TG).

2.3. Primary Outcome

This study's primary outcome was the rate of ALT normalization. ALT values were assessed at baseline and 3, 6, and 12 months after pemafibrate initiation. ALT normalization was defined as an ALT level of ≤ 30 U/L.

2.4. Statistical Analyses

Continuous variables are presented as the mean ± standard error (SE) for normally distributed data and median values with interquartile ranges for non‐normally distributed data. Comparisons between the baseline and each time point (3, 6, and 12 months) were performed using paired t‐tests or the Mann–Whitney U test for normally distributed and non‐normally distributed data, respectively. For changes in the rate of ALT normalization over time, Cochran's Q test was used to assess overall significance.

A two‐sided p‐value of < 0.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [28].

We additionally performed a multivariable logistic regression to identify predictors of ALT normalization at 12 months. Triglycerides were categorized as < 200, 200–299, 300–399, and ≥ 400 mg/dL; covariates included age, sex, BMI, baseline ALT, and platelet count.

3. Results

3.1. Patient Characteristics

A total of 352 patients were included in this study, and their baseline characteristics are summarized in Table 1. The median age was 56 years (IQR, 48–67), and 220 patients (62.5%) were male. The median BMI was 27.1 (24.4–30.1) kg/m². The prevalence of diabetes mellitus and hypertension was 43.4% and 61.2%, respectively. The median (IQR) values for key laboratory parameters at baseline were as follows: albumin, 4.4 (4.1–4.6) g/dL; total bilirubin, 0.7 (0.5–0.8) mg/dL; AST, 35 (24–57) U/L; ALT, 45 (25–81) U/L; GGT, 65 (35–128) U/L; and triglycerides, 300 (192–472) mg/dL.

TABLE 1.

Baseline characteristics of the study participants.

	n = 352
Age, years	56 (48–67)
Male, %	220 (62.5)
BMI, kg/m2	27.1 (24.4–30.1)
Diabetes, %	126 (43.4)
Hypertension, %	194 (61.2)
Alb, g/dL	4.4 (4.1–4.6)
T–Bli, mg/dL	0.7 (0.5–0.8)
AST, U/L	35 (24–57)
ALT, U/L	45 (25–81)
GGT, U/L	65 (35–128)
LDL–C, mg/dL	114 (89–140)
HDL–C, mg/dL	45 (3855)
TG, mg/dL	300 (192–472)
Platelet, 109/L	228 (186–271)

Note: Data are presented as the median (interquartile range) or n (%).

Abbreviations: Alb, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma‐glutamyl transferase; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; T‐Bil, total bilirubin; TG, triglycerides.

3.2. Changes in Biochemical Parameters During Follow‐Up

The longitudinal changes in biochemical parameters are shown in Figure 1. (A) The mean ALT level was 60.1 ± 1.8 U/L at baseline, which significantly decreased to 44.9 ± 1.4 U/L at 3 months, 41.6 ± 1.3 U/L at 6 months, and 38.1 ± 1.3 U/L at 12 months (all p < 0.001 vs. baseline). The mean changes in ALT from baseline were –16.8 ± 38.0 U/L at 3 months, −17.8 ± 34.7 U/L at 6 months, and –18.5 ± 37.2 U/L at 12 months. (B) Mean GGT levels also decreased significantly from 119.9 ± 12.8 U/L at baseline to 77.5 ± 8.2 U/L at 3 months, 71.9 ± 8.9 U/L at 6 months, and 69.1 ± 8.6 U/L at 12 months (all p < 0.01 vs. baseline). (C) The mean TG value decreased from 400.2 ± 19.9 mg/dL at baseline to 206.9 ± 10.3 mg/dL at 3 months, 208.4 ± 11.0 mg/dL at 6 months, and 216.3 ± 15.5 mg/dL at 12 months (all p < 0.001 vs. baseline).

FIGURE 1.

Changes in ALT, GGT, and TG levels during pemafibrate therapy. (A) ALT, (B) GGT, and (C) TG. Mean values (± standard error) at baseline (Pre) and at 3, 6, and 12 months after initiation of pemafibrate are shown. Paired t‐tests were performed to compare the baseline with each time point. Horizontal lines and p‐values above the plots indicate statistically significant differences between the baseline and each follow‐up time point (paired t‐test).

3.3. ALT Normalization Rate in Patients Treated With Pemafibrate

The temporal changes in the proportion of patients with normal ALT levels are shown in Figure 2. The ALT normalization rate significantly increased from 30.4% at baseline to 46.0% at 3 months, 50.9% at 6 months, and 56.6% at 12 months (Cochran's Q test, p < 0.001). Notably, a marked improvement was observed at three months, and this effect was sustained throughout the treatment period. Both triglyceride and ALT levels improved at 3 months and were maintained up to 12 months, with the proportion of ALT normalization gradually increasing during the follow‐up period. In the adjusted model, triglycerides ≥ 400 mg/dL were independently associated with ALT normalization compared with < 200 mg/dL (adjusted OR 3.30; 95% CI, 1.01–10.8; p = 0.048), while age and baseline ALT were also significant; other covariates were not (Table 2).

FIGURE 2.

Changes in the proportion of patients with normal ALT levels during pemafibrate therapy. The bar graph shows the proportion of patients with normal ALT (ALT ≤ 30 U/L) values at baseline (Pre) and at 3, 6, and 12 months after the initiation of pemafibrate therapy. The ALT normalization rate increased significantly over time (Cochran's Q test, p < 0.001).

TABLE 2.

Multivariable logistic regression for predictors of ALT normalization at 12 months.

Variable	Adjusted OR	95% CI	p
TG
< 200 mg/dL	1.00	Reference	—
200–299 mg/dL	0.92	0.32–2.69	0.883
300–399 mg/dL	1.10	0.31–3.93	0.885
≥ 400 mg/dL	3.30	1.01–10.8	0.048
Age (per 1 year)	1.04	1.00–1.08	0.033
Male sex	1.58	0.61–4.07	0.349
BMI (per 1 kg/m2)	0.97	0.89–1.05	0.447
ALT (per 10 U/L)	0.68	0.57–0.79	< 0.001
Platelet (per 10 × 109/L)	1.22	0.67–2.16	0.585

Note: Data are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Triglycerides < 200 mg/dL were used as the reference category. ALT was modeled per 10 U/L, and platelet count per 10 × 10⁹/L increase.

Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; OR, odds ratio; TG, triglycerides.

4. Discussion

4.1. Main Findings

This study demonstrated that pemafibrate therapy led to sustained improvements in ALT levels and increased rates of ALT normalization in patients with MASLD. Importantly, this represents a large‐scale multicenter investigation of pemafibrate in MASLD to date, providing more robust evidence than previous smaller studies.

4.2. In the Context of Published Literature

In MASLD, hepatic fibrosis is most strongly associated with prognosis, and an improvement in fibrosis is considered the key therapeutic target. However, repeated liver biopsies are required to assess fibrosis, which is unfeasible in routine clinical practice. Although ALT is a marker of liver injury, a longitudinal improvement in ALT levels correlates with improvements in fibrosis and inflammation per previous reports, making it a practical short‐term indicator of treatment efficacy [29, 30, 31, 32, 33]. Therefore, ALT normalization serves as a clinically meaningful surrogate endpoint. Diet and exercise are the cornerstone of MASLD treatment, and structured lifestyle programs have been shown to improve liver function tests and body weight [34]. However, these interventions often fail, indicating that pharmacological treatment is also desirable. Early identification and treatment of high‐risk MASLD patients is essential, as delayed intervention may worsen hepatic and extrahepatic outcomes [35]. In the present study, we demonstrated that pemafibrate administration in MASLD patients with hypertriglyceridemia led to significant improvements and the normalization of ALT levels. Notably, this effect appeared as early as 3 months and was sustained through 12 months. While previous studies have reported the beneficial effects of pemafibrate on MASLD, these were limited to single‐center or small‐scale investigations to the best of our knowledge [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. The present multicenter cohort provides more robust evidence supporting the efficacy of pemafibrate for MASLD. As the development of effective pharmacotherapies for MASLD remains an unmet need, our findings suggest that pemafibrate could be a promising treatment option for this condition.

4.3. Strengths and Limitations

The main strength of this study is its large‐scale cohort design using a nationwide, multicenter database. However, several limitations should be noted. First, this was a retrospective study, which may be subject to unmeasured confounders and selection bias. Second, liver biopsy was not performed at baseline or during follow‐up; therefore, histological diagnoses of MASH and longitudinal assessment of fibrosis were not available. Third, liver‐related outcomes other than ALT levels, as well as broader clinical endpoints, could not be fully evaluated. Finally, the observation period was limited to 12 months, which may not capture long‐term effects.

4.4. Future Implications

The development of effective pharmacotherapies for MASLD remains an important unmet clinical need. While statins are recommended in current guidelines for the management of dyslipidemia in MASLD, fibrates are not currently endorsed [29, 30, 31, 32]. Our findings suggest that pemafibrate may improve ALT levels and could be considered a promising therapeutic option for patients with MASLD. In addition to triglyceride lowering, pemafibrate has been reported to promote hepatic β‐oxidation, improve lipid transport and mitochondrial function, and exert anti‐inflammatory and antioxidant effects, which may collectively contribute to improvements in liver function [16]. Further studies are warranted to determine whether pemafibrate can also improve hepatic fibrosis and long‐term outcomes—such as the prevention of cirrhosis and hepatocellular carcinoma—in MASLD.

In conclusion, pemafibrate treatment resulted in a significant reduction in ALT levels and an increased rate of ALT normalization in patients with MASLD and hypertriglyceridemia.

Conflicts of Interest

Nobuharu Tamaki received a lecture fee from Kowa Company. The other authors declare no conflicts of interest.

Komiyama Y., Tamaki N., Tsuji K., et al., “Effect of Pemafibrate on Metabolic Dysfunction‐Associated Steatotic Liver Disease: A Nationwide Multicenter Study,” JGH Open 9, no. 9 (2025): e70277, 10.1002/jgh3.70277.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.