Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Adv Ther (2020) 37:4697–4708 https://doi.org/10.1007/s12325-020-01498-5 ORIGINAL RESEARCH Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial Hoda Taheri . Mojtaba Malek . Faramarz Ismail-Beigi . Farhad Zamani . Masoudreza Sohrabi . Mohammad Reza babaei . Mohammad E. Khamseh Received: August 14, 2020 / Accepted: September 3, 2020 / Published online: September 25, 2020 Ó The Author(s) 2020 ABSTRACT Introduction: Despite the high prevalence of non-alcoholic fatty liver disease (NAFLD) and its associated co-morbidities, no efficient treatment in a high percentage of individuals is available. Beneficial effects of sodium–glucose co-transporter 2 inhibitors on fatty liver have been investigated in people with type 2 diabetes (T2DM). The aim of this study was to explore H. Taheri
M. E. Khamseh Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran M. Malek (&) Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran e-mail: F. Ismail-Beigi Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA F. Zamani
M. Sohrabi Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran M. Reza babaei Department of Interventional Radiology, Firouzgar Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran the effect of empagliflozin on liver steatosis and fibrosis in patients with NAFLD without T2DM. Methods: In this prospective randomized, double-blind, placebo-controlled clinical trial, participants with NAFLD were randomized to empagliflozin (10 mg/day) (n = 43) or placebo (n = 47) for 24 weeks. Hepatic steatosis and fibrosis were assessed using transient elastography to measure the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). The primary outcome was the change in CAP score at 24 weeks. Results: There was significant decrease in CAP score in both groups but no significant difference was observed between the two groups (P = 0.396). LSM was significantly decreased in the empagliflozin-treated group (6.03 ± 1.40 to 5.33 ± 1.08 kPa; P = 0.001), while no change was found in the placebo group. In subgroups analysis of patients with significant steatosis at baseline (CAP C 302 dB/m), steatosis significantly improved in the empagliflozin group (37.2% vs. 17%; P = 0.035). There was a significant decrease in the grade of liver fat on visual analysis of ultrasound images, AST, ALT, and fasting insulin levels in the empagliflozin group, while no changes were observed in the placebo group. Conclusions: Empagliflozin improves liver steatosis and, more importantly, measures of liver fibrosis in patients with NAFLD without T2DM. Adv Ther (2020) 37:4697–4708 4698 Trial registration: ClinicalTrials.gov identifier, IRCT20190122042450N1. Keywords: Empagliflozin; Liver fibrosis; Nonalcoholic fatty liver disease; Steatosis; Transient elastography Key Summary Points Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), and its associated co-morbidities, effective treatment is not yet available. The aim of present study was to explore the effects of empagliflozin on liver steatosis and fibrosis in patients with NAFLD in the absence of type 2 diabetes (T2DM). Empagliflozin reduces ALT and AST levels. Empagliflozin improves liver steatosis and, more importantly, measures of liver fibrosis in patients with NAFLD without T2DM. Improvement in hepatic steatosis was greatest in patients with significant steatosis at baseline (CAP C 302 dB/m). independent risk factor for cardiovascular events and reduced life expectancy [3]. Considering the prevalence of NAFLD and its associated co-morbidities [4], early and appropriate prevention programs and treatment interventions are needed. Although various therapeutic interventions have been reported in recent years, other than sustained weight loss, there are currently no proven therapeutic formats [5]. Sodium–glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion and lead to a decrease in the blood glucose and insulin levels [5, 6]. Their use is associated with a significant increase in fatty acid (FA) mobilization from adipose tissues and FA uptake and b-oxidation in the liver [7]. The beneficial effects of empagliflozin and other SGLT2 inhibitors on liver fat content in patients with T2DM and NAFLD has been reported [8, 9]. To the best of our knowledge, no study has been reported on the effect of SGLT2 inhibitors on hepatic fat content in patients with NAFLD who do not have T2DM. Hence, the aim of present study was to explore the effects of empagliflozin on liver steatosis and fibrosis in patients with NAFLD in the absence of T2DM. The selection of this group of patients with NAFLD in the present study was based on the premise that a host of metabolic and other confounding factors that can alter the response of the fatty liver disease to any proposed treatment would be greatly decreased in the absence of concomitant T2DM. DIGITAL FEATURES This article is published with digital features to facilitate understanding of the article. To view digital features for this article go to https://doi. org/10.6084/m9.figshare.12907526. INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is a wide spectrum progressive disease and can progress to hepatic cirrhosis and in some individuals to hepatocellular carcinoma [1]. The prevalence of NAFLD is increasing worldwide, and its prevalence among Iranian adults is about 12.5% [2]. NAFLD is also considered as an METHODS Study Design and Participants This was a prospective, randomized, doubleblind, placebo-controlled, clinical trial that included patients with NAFLD but without T2DM. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Iran University of Medical Sciences (ethics code IR.IUMS.FMD.REC.1398.464). This trial was registered with ClinicalTrials.gov, number IRCT20190122042450N1. All the participants provided written informed consent before study Adv Ther (2020) 37:4697–4708 entry. The role of Abidi Pharmaceuticals was limited to supply of the medicines, empagliflozin and placebo. Data management was performed by the Institute of Endocrinology and Metabolism monitoring committee that was blinded to the study arms. We screened individuals aged 20–65 years, who had NAFLD, on the basis of evidence of hepatic steatosis in previous ultrasound imaging or liver function test. T2DM was excluded on the basis of a fasting plasma glucose (FPG) level C 126 mg/dL (7.0 mmol/L) or a hemoglobin A1c (HbA1c) level C 6.5% (48 mmol/mol) [10]. Other exclu (...truncated)