T2DM is strongly associated with NASH and liver-related mortality. The most important problem is what kinds of drugs are the most appropriate for NASH/NAFLD with diabetes among a variety of antidiabetic medications. Ideal anti-diabetic treatments on the view of NASH treatment must have weight-reducing efficacy, reduced cardiovascular event, prevention of HCC, low cost, and improved QOL [
34]. There are no approved diabetic therapies except pioglitazone for NASH [
5‐
8]. Metformin is now positioned as the first-line therapy according to the guideline of ADA/EASD because of its low cost, weight-reducing effect, preventive effect on cardiovascular event, and safety profiles. Unfortunately, metformin has no data regarding improvement in liver enzymes and histology in NASH/NAFLD, although it is associated with a reduced incidence of HCC and extrahepatic malignancies. Novel antidiabetic drugs will become a candidate for the treatment of NASH as we previously reviewed this point [
34]. Incretin-associated drugs are classified into DPP4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RA). Unfortunately, there is conflicting evidence showing efficacy of DPP4 inhibitors in NASH/NAFLD patients with diabetes, although a number of patients involved into these studies is relatively small [
34]. The efficacy of liraglutide, a GLP-1RA, was reported in NASH patients in Western countries (LEAN study [
35]) and Japanese studies (LEAN-J study [
36]). That most of patients naïve to injection therapy will hesitate daily injection therapy. Dulaglutide has some advantages such as weekly injection, disposable and prefilled device, and similar safety profiles to other GLP-1RAs. Semaglutide, a novel GLP-1 RA, is in advanced stages of development for diabetes. To investigate the effect of semaglutide on NASH, a phase 2 RDBPCT comparing the efficacy and safety of three different doses of once-daily subcutaneous semaglutide versus placebo in 372 participants with NASH is now ongoing (NCT02970942). Semaglutide has three advantages over other GLP-1RA. First, the SUSTAIN-6 trial showed that semaglutide has a potential benefit on prevention of cardiovascular events [
37]. Second, semaglutide is superior to dulaglutide on glucose control and weight loss in T2DM patients (SUSTAIN 7 trial). SUSTAIN 7 is a phase 3b, 40-week, efficacy and safety trial of 0.5 mg semaglutide versus 0.75 mg dulaglutide and 1.0 mg semaglutide versus 1.5 mg dulaglutide, both once-weekly, as add-on to metformin in 1201 people with T2DM. Third, oral agent of semaglutide is now under development and of clinical use in the near future. As a result, among a variety of GLP-1 RA, dulaglutide or semaglutide will be the most promising in the treatment of diabetic NASH [
34,
38]. According to the AASLD guidance, however, it is premature to consider GLP-1RA to specifically treat in NASH/NAFLD patients without diabetes [
8] because of insufficient evidence. Sub-analyses of three RDBPCT of SGLT2 inhibitor (canagliflozin [
39,
40], luseogliflozin [
41]) for the treatment of T2DM, serum transaminase activities in SGLT2 inhibitor-treated patients were significantly reduced compared to those in the placebo group. The finding that causes of abnormal ALT level (31 IU/L or above) in a majority of Japanese diabetic patients may be associated with NAFLD [
42] implies that the efficacy of SGLT2 inhibitor on NASH/NAFLD patients can be expected. Several pilot studies found significant reduction in ALT, body weight, and the fatty liver index in NAFLD patients [
43‐
45]. The impact of SGLT2 inhibitor on liver histology is not confirmed. Takeda et al. reported a case of NASH with T2DM who resolved steatosis, inflammation, and hepatocyte ballooning after the ipragliflozin treatment [
46]. Akuta et al. also recently demonstrated that all eight NAFLD patients with SGLT2 administration relieved hepatic steatosis and three of them obtained improvement in liver fibrosis [
47]. Two open RCTs have been reported from Japan to compare the efficacy of SGLT2 inhibitor to other diabetic medications such as pioglitazone and metformin. The first repot is to compare the effect of luseogliflozin to metformin in T2DM patients with NAFLD. Hepatic steatosis, evaluated by liver-to-spleen (
L/
S) ratio on CT, was significantly reduced in the luseogliflozin group compared to in the metformin group [
48]. The aim of another report is to compare the efficacy of ipragliflozin versus pioglitazone in NAFLD patients with T2DM. Serum ALT levels, HbA
1c, and fasting plasma glucose were similarly reduced in the two treatment groups. Nevertheless, body weight and visceral fat area showed significant reductions only in the ipragliflozin group compared with the pioglitazone group [
49]. A few open pilot studies of SGLT2 inhibitor in NAFLD patients are ongoing in the western countries (NCT02696941) or Asia (NCT02875821, NCT02964715). The effect of SGLT2 inhibitors versus other diabetic drugs (metformin, sulfonyl urea) is also investigated (NCT02696941, NCT02649465). The effects of empagliflozin treatment on hepatocellular lipid content, liver energy metabolism, and body composition is now investigated in a multicenter, RDBPCT, interventional, and exploratory pilot study in patients with newly diagnosed T2DM (NCT02637973).