Comparison of the effects of three kinds of glucose‐lowering drugs on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open‐label, three‐arm, active control study

Abstract

Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. Materials and Methods We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin ( n = 32), pioglitazone ( n = 33) or glimepiride ( n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography. Results There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable. Conclusions The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials

“…Supplementary Figure S1 summarizes the results of the literature research and study selection. We initially found 14 potentially eligible RCTs from three large electronic databases prior to 31 October 2020 [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. After examining the full text of these publications, we excluded two studies [ 31 , 32 ] for reasons mainly due to unsatisfactory study design (as specified in Supplementary Table S1 ).…”

“…After examining the full text of these publications, we excluded two studies [ 31 , 32 ] for reasons mainly due to unsatisfactory study design (as specified in Supplementary Table S1 ). Therefore, a total of twelve RCTs (seven placebo-controlled studies [ 19 , 21 , 23 , 24 , 25 , 26 , 28 ] and five active-controlled studies [ 20 , 22 , 27 , 29 , 30 ]) were considered eligible for inclusion in the meta-analysis and were assessed for quality.…”

“…In total, there were 850 middle-aged overweight or obese individuals with NAFLD (59% men; mean (±SD) age 57 ± 6 years; mean body mass index 31 ± 2 kg/m 2 ; mean alanine aminotransferase (ALT) 41 ± 11 IU/L; mean aspartate aminotransferase (AST) 31 ± 7 IU/L; mean gamma-glutamyltransferase (GGT) 59 ± 17 IU/L), who were followed-up for a median period of 24 weeks (interquartile range: 21–25 weeks). Among these individuals, 414 were randomly assigned to either placebo or reference therapy, whereas 436 were randomly assigned to active treatment with dapagliflozin ( n = 6 RCTs [ 19 , 22 , 24 , 25 , 27 , 30 ]), empagliflozin ( n = 3 RCTs [ 21 , 26 , 28 ]), ipragliflozin ( n = 2 RCTs [ 20 , 29 ]) or canagliflozin ( n = 1 RCT [ 23 ]) in order to specifically treat NAFLD. As shown in Supplementary Table S2 , the vast majority of the eligible RCTs ( n = 11 studies [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 ]) included patients with NAFLD and T2DM ( n = 760, 90% of total participants), whereas only one RCT [ 28 ], involving 90 individuals, was conducted in patients without T2DM.…”

“…Among these individuals, 414 were randomly assigned to either placebo or reference therapy, whereas 436 were randomly assigned to active treatment with dapagliflozin ( n = 6 RCTs [ 19 , 22 , 24 , 25 , 27 , 30 ]), empagliflozin ( n = 3 RCTs [ 21 , 26 , 28 ]), ipragliflozin ( n = 2 RCTs [ 20 , 29 ]) or canagliflozin ( n = 1 RCT [ 23 ]) in order to specifically treat NAFLD. As shown in Supplementary Table S2 , the vast majority of the eligible RCTs ( n = 11 studies [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 ]) included patients with NAFLD and T2DM ( n = 760, 90% of total participants), whereas only one RCT [ 28 ], involving 90 individuals, was conducted in patients without T2DM. Two RCTs [ 19 , 27 ] included international cohorts of individuals with NAFLD, six RCTs [ 20 , 21 , 25 , 28 , 29 , 30 ] were carried out in Asia (Japan, South Korea, India and Iran), three RCTs [ 22 , 24 , 26 ] were carried out in Europe (Germany and Sweden) and one RCT was carried out in the United States [ 23 ].…”

“…As shown in Supplementary Table S2 , the vast majority of the eligible RCTs ( n = 11 studies [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 ]) included patients with NAFLD and T2DM ( n = 760, 90% of total participants), whereas only one RCT [ 28 ], involving 90 individuals, was conducted in patients without T2DM. Two RCTs [ 19 , 27 ] included international cohorts of individuals with NAFLD, six RCTs [ 20 , 21 , 25 , 28 , 29 , 30 ] were carried out in Asia (Japan, South Korea, India and Iran), three RCTs [ 22 , 24 , 26 ] were carried out in Europe (Germany and Sweden) and one RCT was carried out in the United States [ 23 ]. In all eligible RCTs, the diagnosis of NAFLD was based on imaging techniques, such as Fibroscan ® with associated with controlled attenuation parameter (CAP) [ 25 , 28 , 29 ], computed tomography [ 20 , 30 ], magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or magnetic resonance spectroscopy (MRS) [ 19 , 21 , 22 , 23 , 24 , 26 , 27 ].…”