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

Abstract

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.

Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes

“…However, the number of participants with fibrosis or severe fibrosis was small, which affects the interpretability of these results. Extending recent data demonstrating the individual effects of GLP‐1RAs or SGLT2 inhibitors on NAFLD, the present results are the first to demonstrate the effect of this combination in reducing NAFLD biomarkers in people with type 2 diabetes, and indicate that combining these two agents may exert stronger beneficial effects on NAFLD than each drug alone. Moreover, as NAFLD is independently associated with cardiovascular disease, and the cardiovascular benefits of GLP‐1RAs and SGLT2 inhibitors are now well established, the EXE once weekly + DAPA combination may confer a reduction in cardiovascular risk in patients with type 2 diabetes and NAFLD.…”

“…With regard to SGLT2 inhibitors, a 24‐week, open‐label, randomized trial of dapagliflozin (DAPA) monotherapy in patients with type 2 diabetes and NAFLD reported overall improvements in hepatic steatosis, along with attenuation of fibrosis in a subset of patients with significant fibrosis . Additionally, 24 weeks of canagliflozin treatment demonstrated improvements in the individual histological components of NASH (eg, steatosis, lobular inflammation and ballooning) in patients with type 2 diabetes and NAFLD . Building on these results, the GLP‐1RA and SGLT2 inhibitor combination could have a synergistic effect on improving steatosis, steatohepatitis and/or fibrosis in patients with type 2 diabetes and NAFLD; however, this remains to be examined in a randomized controlled trial.…”

“…Pioglitazone has demonstrated reductions in fatty liver content and has provided some resolution of NASH in patients with type 2 diabetes, but with the side effect of significant weight gain . Evidence indicates that glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have some benefits in patients with type 2 diabetes and NAFLD/NASH . For example, in a phase 2 study, 48 weeks of liraglutide treatment led to biopsy‐confirmed resolution of NASH in 39% of overweight patients with or without type 2 diabetes .…”

“…2,13 Evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors have some benefits in patients with type 2 diabetes and NAFLD/ NASH. [14][15][16][17][18][19] For example, in a phase 2 study, 48 weeks of liraglutide treatment led to biopsy-confirmed resolution of NASH in 39% of overweight patients with or without type 2 diabetes. 14 Furthermore, semaglutide treatment reduced markers of NAFLD (ie, alanine aminotransferase [ALT] and high-sensitivity C-reactive protein) in patients with obesity and/or type 2 diabetes.…”

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…At present there are only small uncontrolled studies reporting anecdotal benefits to liver histology with SGLT2 inhibitors with improvement that is somewhat beyond what would be expected from the modest 2%‐3% weight loss. Whether this is an indication of weight‐independent mechanisms of action remains to be established.…”