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Randomized Controlled Trial
. 2025 Jul 1;32(7):823-839.
doi: 10.5551/jat.65395. Epub 2024 Dec 18.

Effects of Pemafibrate on LDL-C and Related Lipid Markers in Patients with MASLD: A Sub-Analysis of the PEMA-FL Study

Ryohei Tanigawa  1   2 , Atsushi Nakajima  3 , Yuichiro Eguchi  4 , Hirokazu Takahashi  2 , Rohit Loomba  5 , Hideki Suganami  6 , Masaya Tanahashi  6 , Ayumi Saito  1 , Yuki Iida  1 , Shizuya Yamashita  7
Affiliations
Randomized Controlled Trial

Effects of Pemafibrate on LDL-C and Related Lipid Markers in Patients with MASLD: A Sub-Analysis of the PEMA-FL Study

Ryohei Tanigawa et al. J Atheroscler Thromb. .

Abstract

Aim: In the PEMA-FL study in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), pemafibrate was shown to significantly decrease low-density lipoprotein cholesterol (LDL-C) levels. We aimed to investigate the mechanisms of pemafibrate-induced LDL-C reduction in patients with MASLD by conducting an additional sub-analysis of the PEMA-FL study.

Methods: The PEMA-FL study randomized 118 patients with MASLD to receive pemafibrate or placebo for 72 weeks. This sub-analysis examined the percentage change in LDL-C and related lipid markers by tertile of baseline LDL-C levels and the correlation between these changes in the pemafibrate group.

Results: Pemafibrate significantly decreased LDL-C levels approximately 25% (p＜0.001 at all timepoints) from baseline in the highest tertile of baseline LDL-C levels (≥ 137.5 mg/dL), with similar trends for non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) levels. Lipoprotein (a) [Lp(a)] levels decreased only in patients with the highest baseline LDL-C levels. Regardless of the baseline LDL-C levels, pemafibrate altered the LDL particle profile (increased LDL particle size and decreased the number); reduced lathosterol, β-sitosterol, and campesterol; and increased angiopoietin-like protein 3 (ANGPTL3). The percentage change in LDL-C positively correlated with that in ApoB, non-HDL-C, Lp(a), lathosterol, β-sitosterol, and campesterol but not HDL-C and ANGPTL3.

Conclusion: Pemafibrate reduced LDL-C, ApoB, and non-HDL-C levels in patients with MASLD, and the effect was greater in those with higher baseline LDL-C levels. Pemafibrate may clinically benefit patients with MASLD by improving LDL-C levels and the LDL particle profile.

Keywords: Cholesterol absorption; Cholesterol synthesis; Lipoprotein (a); Low-density lipoprotein; Metabolic dysfunction-associated steatotic liver disease.

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Conflict of interest statement

Declaration of personal interests: A Nakajima has received research funding and grants from Kowa Company, Ltd; Y Eguchi has nothing to disclose. H Takahashi has received grants from Abbvie, GSK; payments for speaker from Kowa Company Ltd, Taisho Pharma, and Novo Nordisk. R Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. Also, he has stock options in Sagimet biosciences. In addition, his institution received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc. S Yamashita has received consulting fees from Kowa Company, Ltd., Otsuka Pharmaceutical Co., Ltd., and Immuno-Biological Laboratories Co., Ltd.; payment for lecture from Kowa Company, Ltd., Novartis Pharma K.K., MSD, and Tsumura & CO; R Tanigawa, H Suganami, M Tanahashi, A Saito, and Y Iida are employees of Kowa Company, Ltd.

Figures

Fig.1. Percentage change in the levels of LDL-C by baseline LDL-C levels
Fig.1. Percentage change in the levels of LDL-C by baseline LDL-C levels
Each section of (A) to (C) contains a line graph of percentage change from baseline LDL-C levels (LS mean±95% CI) throughout the study period. The results are in (A) baseline LDL-C high group, (B) baseline LDL-C medium group, and (C) baseline LDL-C low group. CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; LS, least squares
Fig.2. Percentage change in the levels of LDL-C related lipid markers by baseline LDL-C levels
Fig.2. Percentage change in the levels of LDL-C related lipid markers by baseline LDL-C levels
Each section of (A) to (C) contains bar graphs of percentage change from baseline (LS mean±95% CI) to week 12 (LDL-C, non-HDL-C, ApoB, Lp(a)) or 8 (lathosterol, β-sitosterol, and campesterol). The results are in (A) baseline LDL-C high group, (B) baseline LDL-C medium group, and (C) baseline LDL-C low group. ANGPTL3, angiopoietin-like protein 3; ApoB, apolipoprotein B; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); LS, least squares
Fig.3. HPLC analysis for LDL subclasses and particles
Fig.3. HPLC analysis for LDL subclasses and particles
(A) Percentage changes from baseline to week 12 in LDL-C by subclass. (B) Percentage changes from baseline to week 12 in LDL-C by subclass and baseline LDL-C levels. (C) Percentage changes from baseline to week 12 in LDL particle size and number. Data are expressed as LS mean, and error bars indicate 95% CIs. ＊p＜0.05, ＊＊p＜0.01 and, ＊＊＊p＜0.001 vs. baseline. †p＜0.05, ††p＜0.01 and, †††p＜0.001 vs. placebo. CI, confidence interval; HPLC, high performance liquid chromatography; LDL-C, low-density lipoprotein cholesterol; LS, least squares
Fig.4. Scatter plots of percentage change in LDL-C level versus percentage changes in lipid parameter levels in patients treated with pemafibrate
Fig.4. Scatter plots of percentage change in LDL-C level versus percentage changes in lipid parameter levels in patients treated with pemafibrate
Percentage changes from baseline to week 12 (for non-HDL-C, apolipoprotein B, HDL-C, lipoprotein (a), and ANGPTL3) or 8 (for lathosterol, β-sitosterol, and campesterol) are shown on the x-axis. The percentage change in LDL-C level is shown on the y-axis for each graph. ANGPTL3, angiopoietin-like protein 3; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol
Fig.5. Forest plot of treatment difference between pemafibrate and placebo in LDL-C percentage change from baseline by subgroups
Fig.5. Forest plot of treatment difference between pemafibrate and placebo in LDL-C percentage change from baseline by subgroups
Subgroup analysis of the difference in percentage changes in LDL-C levels from baseline to week 12 between the treatment groups. Data are expressed as LS mean (vs. placebo). Error bars indicate 95% CIs. ＊p＜0.05, ＊＊p＜0.01, and ＊＊＊p＜0.001. ANGPTL3, angiopoietin-like protein 3; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; MRE, magnetic resonance elastography
Supplementary Fig.3.
Supplementary Fig.3.
Scatter plots of percentage change in ANGPTL3 level versus percentage changes in lipid and hepatic markers
Supplementary Fig.1.
Supplementary Fig.1.
Percentage change and change value from baseline in LDL-C related lipid markers by each baseline tertile
Supplementary Fig.2.
Supplementary Fig.2.
Scatter plots of percentage change or change value versus baseline value in LDL-C related lipid markers
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