Effects of a sodium‐glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: Preliminary prospective study based on serial liver biopsies

Akuta, Norio; Watanabe, Chihiro; Kawamura, Yusuke; Arase, Yasuji; Saitoh, Satoshi; Fujiyama, Shunichiro; Sezaki, Hitomi; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Suzuki, Yoshiyuki; Suzuki, Fumitaka; Ikeda, Kenji; Kumada, Hiromitsu

doi:10.1002/hep4.1019

Cited by 99 publications

(118 citation statements)

References 26 publications

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“…In contrast, antidiabetic agents affect the pathophysiology of NASH. Pioglitazone, GLP-1RA and SGLT2i are expected to improve inflammation and fibrosis of NASH [35][36][37][38] . However, in the present study, the relationship between liver fibrosis markers and antidiabetic agents, such as GLP-1RA and SGLT2i, were not significant.…”

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus

Miyauchi

Miyake

Miyazaki

et al. 2019

J of Diabetes Invest

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Aims/Introduction Insulin‐like growth factor‐1 (IGF‐1) regulates mitochondrial function, oxidative stress, inflammation, stellate cells and insulin sensitivity in the liver, and it might be associated with liver fibrosis from non‐alcoholic steatohepatitis. In contrast, type 2 diabetes mellitus is closely associated with the progression from non‐alcoholic fatty liver to non‐alcoholic steatohepatitis and cirrhosis, so careful evaluation of liver fibrosis is required for patients with type 2 diabetes mellitus. Therefore, we examined the relationship between IGF‐1 and liver fibrosis markers in type 2 diabetes patients without obvious alcoholic consumption and determined whether IGF‐1 is associated with fibrosis of non‐alcoholic fatty liver disease. Materials and Methods We selected 415 patients with type 2 diabetes without obvious alcohol consumption, who were admitted to Uwajima City Hospital between May 2013 and December 2016. We collected and analyzed clinical data to determine correlations between IGF‐1 or IGF‐1 standard deviation score and fibrosis‐4 index or 7S domain of type IV collagen. Results Multiple linear regression analysis showed that the fibrosis‐4 index was inversely correlated with IGF‐1 and IGF‐1 standard deviation score. Furthermore, the 7S domain of type IV collagen was also inversely correlated with IGF‐1 and IGF‐1 standard deviation score. Conclusions IGF‐1 was inversely correlated with liver fibrosis markers in type 2 diabetes mellitus patients without obvious alcoholic consumption. Measuring serum IGF‐1 levels might help clinicians to identify type 2 diabetes mellitus patients with advanced non‐alcoholic steatohepatitis.

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Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus

Miyauchi

Miyake

Miyazaki

et al. 2019

J of Diabetes Invest

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“…Previous reports indicated that the levels of serum microRNA‐122 (miR‐122) were particularly associated with histopathological severity of liver disease and the risk of developing metabolic syndrome and type 2 DM . Our first study found that serum miR‐122 might be useful for the early prediction of histological improvement of NAFLD by SGLT2I . MicroRNAs are secreted by various lipid‐containing vesicles, including exosomes, microvesicles, and apoptotic bodies.…”

Section: Introductionmentioning

confidence: 86%

“…In our recent first report, a preliminary prospective study based on serial liver biopsies was undertaken to investigate the efficacy of SGLT2I for NAFLD complicated with type 2 DM. Treatment for 24 weeks resulted in improvement in histopathological features in all five patients …”

Section: Introductionmentioning

confidence: 88%

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Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non‐alcoholic fatty liver disease complicated by diabetes mellitus

Akuta

Kawamura

Watanabe

et al. 2019

Hepatology Research

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Aim The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non‐alcoholic fatty liver disease (NAFLD). Methods In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA‐122 (miR‐122) as early predictors of histological improvement was investigated. Results All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR‐122 ratios (the ratio of miR‐122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR‐122 ratios regardless of the increase in extracellular miR‐122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. Conclusion A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166.

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“…Therefore, SGLT2 inhibitors have become promising therapeutic agents in NASH and NAFLD patients. Several pilot studies have found a significant reduction in transaminase activity, body weight, the fatty liver index, and liver histology (steatosis and fibrosis) in NAFLD patients [50][51][52][53][54][55]. Two open randomized controlled trials (RCTs) have been performed in Japan to compare the efficacy of SGLT2 inhibitor with other oral diabetic agents, including pioglitazone and metformin.…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

Sumida

Yoneda

Tokushige

et al. 2020

IJMS

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Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are Int.expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

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Effects of a sodium‐glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: Preliminary prospective study based on serial liver biopsies

Cited by 99 publications

References 26 publications

Insulin‐like growth factor‐1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus

Insulin‐like growth factor‐1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus

Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non‐alcoholic fatty liver disease complicated by diabetes mellitus

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

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