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Effects of Pemafibrate on Glucose Metabolism Markers and Liver

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Effects of Pemafibrate on Glucose Metabolism Markers and Liver Yokote et al. Cardiovasc Diabetol (2021) 20:96 https://doi.org/10.1186/s12933-021-01291-w Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efects of pemafbrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double‐blind placebo‐controlled clinical trials Koutaro Yokote1,2*, Shizuya Yamashita3, Hidenori Arai4, Eiichi Araki5, Mitsunori Matsushita6, Toshiaki Nojima7, Hideki Suganami7 and Shun Ishibashi8 Abstract Background: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnor- malities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth efects of pemafbrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. Methods: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo- controlled trials that examined the efects of daily pemafbrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafbrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. Results: The study population was 1253 patients randomized to placebo (n 298) or pemafbrate 0.1 mg/day (n 127), 0.2 mg/day (n 584), or 0.4 mg/day (n 244). Participant mean age= was 54.3 years, 65.4 % had BMI 25 kg/ m2=, 35.8 % had type 2 diabetes,= and 42.6 % had fatty= liver. Fasting glucose, fasting insulin, and HOMA-IR decreased≥ signifcantly in all pemafbrate groups compared to placebo. The greatest decrease was for pemafbrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose 0.25 mmol/L; fasting insulin 3.31 µU/mL; HOMA-IR 1.28. ALT, γ-GT, ALP, and total bilirubin decreased signifcantly −at all pemafbrate doses vs. placebo,− with the greatest decrease− in the pemafbrate 0.4 mg/day group: LS mean change from baseline in ALT 7.6 U/L; γ-GT 37.3 U/L; ALP 84.7 U/L; and total bilirubin 2.27 µmol/L. Changes in HbA1c and AST did not difer− signifcantly from− placebo in any− pemafbrate groups in the− overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased signifcantly *Correspondence: [email protected] 1 Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yokote et al. Cardiovasc Diabetol (2021) 20:96 Page 2 of 13 in all pemafbrate groups compared to placebo, with the greatest increase in the pemafbrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo. Conclusions: In patients with hypertriglyceridemia, pemafbrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk. Keywords: Pemafbrate, Glucose metabolism, Liver function, FGF21 Background To gain more insight into these efects of pemafbrate, Dyslipidemia is frequently associated with type 2 dia- we applied a post-hoc analysis to fndings from six pla- betes (T2D) and with non-alcoholic fatty liver disease cebo-controlled studies of pemafbrate in Japanese hyper- (NAFLD) [1, 2], and hypertriglyceridemia is a known triglyceridemic subjects. We focused on how pemafbrate risk factor for developing newly onset T2D and NAFLD afected glucose metabolism and LFTs in relation to [3, 4]. Cardiovascular events are common not only in baseline values, the presence of T2D and fatty liver, and patients with T2D and NAFLD [5, 6] but also even in changes in TG. We also investigated the relationships patients with milder abnormalities of laboratory tests between FGF21 and glucose metabolism or liver function such as glucose metabolism and liver function [7, 8], in those patients. suggesting that insulin resistance may contribute to increased risk of cardiovascular diseases. Tese fnd- Methods ings emphasize the importance of identifying patients Study design and setting with abnormal laboratory results in glucose metabo- We performed a post-hoc analysis on data combined lism, liver function and plasma lipids as part of ongoing from six phase 2 and phase 3 Japanese randomized eforts toward cardiovascular disease prevention. double-blind placebo-controlled studies in patients with Peroxisome proliferator-activated receptor (PPAR) hypertriglyceridemia [16–19, 29]. Te studies enrolled α agonists can reduce triglyceride (TG) and TG-rich a placebo group and pemafbrate groups (0.1 mg/day, lipoprotein cholesterol levels and improve atherogenic 0.2 mg/day, and 0.4 mg/day). Te drug was taken twice dyslipidemia [9]. Pemafbrate, also known as K-877, was daily. Te six individual studies are summarized in developed as a selective PPARα modulator (SPPARMα), Table S1 in Additional fle 1. Each study was approved which provides a favorable beneft-risk ratio supe- by the Institutional Review Board for that study site. All rior to that of other conventional PPARα agonists [10, studies were conducted in accordance with the Declara- 11]. Te high specifcity and selectivity of pemafbrate tion of Helsinki after written informed consent had been as SPPARMα are achieved by its Y-shaped molecu- obtained from each subject. Tis pooled analysis was lar structure, which allows pemafbrate to bind opti- approved by the Ethics Committee of Chiba University mally to the PPARα ligand binding domain [12, 13]. Graduate School of Medicine. After binding to the PPARα, pemafbrate up-regulates the expression of specifc genes involved in fatty acid Endpoints metabolism, primarily in human hepatocytes [14]. Te primary endpoints consisted of changes from base- Pemafbrate reduces TG by 45–51 %, while increas- line in glucose metabolism markers (fasting plasma ing high-density lipoprotein cholesterol (HDL-C) by glucose, fasting serum insulin, the homeostatic model 12–20 % [15]. Pemafbrate also decreases the value of assessment of insulin resistance [HOMA-IR], and hemo- liver function tests (LFTs) such as alanine aminotrans- globin A1c [HbA1c]) and the LFTs (ALP, aspartate ami- ferase (ALT), γ-glutamyl transferase (γ-GT), and notransferase [AST], ALT, γ-GT, and total bilirubin). alkaline phosphatase (ALP), and fasting plasma glu- HOMA-IR was calculated using the following formula: cose levels, and improves insulin sensitivity [16–23]. HOMA-IR = fasting serum insulin (µU/mL) × fasting Although pemafbrate provides uniquely favorable plasma glucose (mmol/L)/22.5. efects on the parameters of glucose metabolism and Te secondary endpoints included the changes from liver functions, few reports have addressed these issues baseline in glucose metabolism markers and LFTs as systematically. In addition, the efects of pemafbrate analyzed in subgroups of patients with high baseline lev- on glucose metabolism may be mediated by its efects els for glucose metabolism or liver function, and on the on plasma levels of fbroblast growth factor (FGF) 21, presence or absence of T2D or fatty liver. Te diagnosis a member of the FGF family that improves energy of T2D or fatty liver was made by individual clinicians metabolism and that is induced in response to fasting at each study site. Te group with high baseline values or PPARα activation [24–28]. for glucose metabolism markers consisted of patients Yokote et al. Cardiovasc Diabetol (2021) 20:96 Page 3 of 13 with baseline fasting plasma glucose ≥ 7.0 mmol/L (dia- analysis in this study. SAS ver. 9.4 was used for the betes as defned by the World Health Organization’s analyses. diagnostic criteria) or fasting serum insulin 15 µU/mL ≥ Results or HOMA-IR ≥ 2.5 (insulin resistance as defned by the Japanese Diabetes Treatment Guideline) [30]. Te group Patient characteristics with high baseline values for LFTs consisted of patients Te FAS population consisted of 1253 patients from whose LFTs values exceeded the upper normal limits the six studies, of whom 298 were randomized to pla- (AST > 40 U/L, ALT > 45 U/L, γ-GT > 80 U/L for males cebo, 127 to pemafbrate 0.1 mg/day, 584 to pemafbrate or > 30 U/L for females, respectively, ALP > 325 U/L, and 0.2 mg/day, and 244 to pemafbrate 0.4 mg/day (Addi- total bilirubin > 20.5 µmol/L [1.2 mg/dL]). Additional sec- tional fle 1: Figure S1). ondary endpoints were the proportion of patients having Te mean age was 54.3 years, 14.7 % were female, 2 high baseline LFTs that were reduced to normal levels; 65.4 % had body mass index (BMI) ≥ 25 kg/m , 35.8 % the percent changes in TG and HDL-C from baseline; the were diagnosed with T2D, and 42.6 % had fatty liver.
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