Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Haleh Chehrehgosha; Masoud Reza Sohrabi; Faramarz Ismail-Beigi; Mojtaba Malek; Mohammad Reza Babaei; Farhad Zamani; Hossein Ajdarkosh; Mahmood Khoonsari; Afshin Eshghi Fallah; Mohammad E Khamseh

doi:10.1007/s13300-021-01011-3

Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Diabetes Ther. 2021 Mar;12(3):843-861. doi: 10.1007/s13300-021-01011-3. Epub 2021 Feb 14.

Affiliations

¹ Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
² Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
³ Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
⁴ Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
⁵ Department of Interventional Radiology, Firouzgar Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran.
⁶ Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. khamseh.m@iums.ac.ir.

Abstract

Introduction: To evaluate the efficacy of empagliflozin compared to pioglitazone in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM).

Methods: In this prospective randomized, double-blind, placebo-controlled trial, we assigned 106 patients with NAFLD and T2DM to receive empagliflozin 10 mg (n = 35), pioglitazone 30 mg (n = 34), or placebo (n = 37) for 24 weeks. Liver fat content and liver stiffness were measured using fibroscans. Body composition assessment was performed by dual-energy x-ray absorptiometry (DEXA) scans. The primary end point was change from baseline in liver steatosis, using the controlled attenuation parameter (CAP) score.

Results: A borderline significant decrease in CAP score was observed with empagliflozin compared to placebo, mean difference: - 29.6 dB/m (- 39.5 to - 19.6) versus - 16.4 dB/m (- 25.0 to - 7.8), respectively; p = 0.05. Using multivariate analysis, we observed a significant reduction in the placebo-corrected change in liver stiffness measurement (LSM) with empagliflozin compared to pioglitazone: - 0.77 kPa (- 1.45, - 0.09), p = 0.02, versus 0.01 kPa (95% CI - 0.70, 0.71, p = 0.98), p for comparison = 0.03. Changes in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), HOMA2-IR, fibrosis-4 index (FIB4 index), NAFLD fibrosis score, aspartate aminotransferase to platelet ratio index (APRI), android/gynecoid ratio (A/G ratio), and skeletal muscle index (SMI) were comparable between the two treatment groups, while significant reductions of the body weight and visceral fat area were observed only in the empagliflozin group (p < 0.001 and p = 0.01, respectively) and both were increased in the placebo and pioglitazone groups. There were no serious adverse events in either group.

Conclusion: Treatment for 24 weeks with empagliflozin, in contrast to pioglitazone, was associated with improvement of liver steatosis and fibrosis in patients with NAFLD and T2DM. In addition, body weight and abdominal fat area were decreased in the empagliflozin group.

Trial registration: Iranian Registry of Clinical Trials (IRCT), IRCT20190122042450N3.

Keywords: Body composition; Empagliflozin; Fibroscan; Liver fibrosis; Non-alcoholic fatty liver disease (NAFLD); Nonalcoholic steato-hepatitis (NASH); Pioglitazone; Steatosis.