Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is increasingly common in patients with type 2 diabetes mellitus. Currently, some studies have found that sodium–glucose cotransporter 2 (SGLT2) inhibitors, a new hypoglycemic drug, can improve non‐alcoholic fatty liver in addition to its hypoglycemic effect. Thus, we undertook a meta‐analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors on the treatment of NAFLD. Materials and Methods PubMed, Embase and the Cochrane Library were searched for randomized controlled trials of SGLT2 inhibitors in patients with NAFLD and type 2 diabetes mellitus up to 1 October 2019. Differences were expressed as weight mean difference (WMD) with 95% confidence interval (CI) for continuous outcomes. The I2 statistic was applied to evaluate the heterogeneity of studies. Results A total of six trials including 309 patients were selected into our meta‐analysis. SGLT2 inhibitors could reduce alanine aminotransferase (WMD −11.05 IU/L, 95% CI −19.85, −2.25, P = 0.01) and magnetic resonance imaging proton density fat fraction (WMD −2.07%, 95% CI −3.86, −0.28, P = 0.02). However, SGLT2 inhibitors did not reduce aspartate aminotransferase (WMD −1.11 IU/L, 95% CI −2.39, 0.17, P = 0.09). In addition, secondary outcomes, such as bodyweight and visceral fat area, were also reduced (WMD −1.62 kg, 95% CI −2.02, −1.23, P < 0.00001; WMD −19.98 cm2, 95% CI −27.18, −12.79, P < 0.00001, respectively). Conclusions SGLT2 inhibitors can significantly decrease alanine aminotransferase and liver fat, accompanied with weight loss, which might have a positive effect on fatty liver in patients with type 2 diabetes mellitus. The limitation is that the sample size of the studies was small. Therefore, more large randomized controlled trials specified on NAFLD are required to evaluate these results.

Accumulating evidence demonstrates the link between glucose and bone metabolism. The receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is an essential signaling axis maintaining the balance between bone resorption and bone formation. In recent years, it has been found that RANKL and RANK are distributed not only in bone but also in the liver, muscle, adipose tissue, pancreas, and other tissues that may influence glucose metabolism. Some scholars have suggested that the blockage of the RANKL signaling may protect islet β-cell function and prevent diabetes; simultaneously, there also exist different views that RANKL can improve insulin resistance through inducing the beige adipocyte differentiation and increase energy expenditure. Currently, the results of the regulatory effect on glucose metabolism of RANKL remain conflicting. Denosumab (Dmab), a fully human monoclonal antibody that can bind to RANKL and prevent osteoclast formation, is a commonly used antiosteoporosis drug. Recent basic studies have found that Dmab seems to regulate glucose homeostasis and β-cell function in humanized mice or in vitro human β-cell models. Besides, some clinical data have also reported the glucometabolic effects of Dmab, however, with limited and inconsistent results. This review mainly describes the impact of the RANKL signaling pathway on glucose metabolism and summarizes clinical evidence that links Dmab and DM to seek a new therapeutic strategy for diabetes.

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