Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease

Abstract

Aims Soluble dipeptidyl peptidase‐4 (sDPP‐4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD). Methods Fifty‐seven patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d for 24 weeks) (n = 33) or the control group (n = 24). Serum levels of sDPP‐4 were measured with a commercial ELISA kit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by dual bioelectrical impedance analysis. Results In a total of 57 patients, baseline serum sDPP‐4 was positively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ‐glutamyl transferase (GGT) and HOMA‐IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone. Liver enzymes were decreased at 24 weeks in the dapagliflozin group, but were unchanged in the control group. Although both groups showed significant reduction of serum sDPP‐4 after 24 weeks of treatment, the magnitude of decrease was significantly larger in the dapagliflozin group. Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP‐4, but not with changes in VAT volume or HbA1c. Conclusions Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP‐4, suggesting that reduction of serum sDPP‐4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss.

<p>Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice</p>

“…13 Concerning diabetes-associated liver disease, SGLT2 inhibitors such as ipragliflozin, 14,15,18,20 remogliflozin etabonate, 17 empagliflozin 16 and luseogliflozin 19 have been reported to be able to prevent and/or to alleviate the development of NAFLD in several experimental models of NAFLD. Besides, ipragliflozin 20 and dapagliflozin 44 were also reported to ameliorate steatosis-associated hepatic enzymatic markers in T2D subjects with NAFLD. However, these studies investigated neither the effects of a dual SGLT1/2 inhibitor nor the NAFLD relationship with hepatic glucose metabolism.…”

Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

“…In addition, multivariate analysis indicated that the increase in %△HIC CIR was independently correlated with the increase in %△active GLP‐1 AUC 0‐120min (Table S7; see Supporting Information). Although it is difficult to clarify this mechanism in the present study, a previous study indicated that dapagliflozin administration reduced the serum level of soluble dipeptidyl peptidase‐4 (sDPP‐4) in patients with type 2 diabetes with non‐alcoholic FL disease; therefore, a decrease in serum sDPP‐4 via an SGLT2‐i may be partly involved.…”

Favourable effect of the sodium‐glucose co‐transporter‐2 inhibitor canagliflozin plus the dipeptidyl peptidase‐4 inhibitor teneligliptin in combination on glycaemic fluctuation: An open‐label, prospective, randomized, parallel‐group comparison trial (the CALMER study)

“…Attenuation of the glucose‐lowering effect of DPP‐4 inhibitors in obese patients can be partially explained by the higher circulating level of a hepatokine, soluble DPP‐4/CD26 . The reduction in the high liver enzyme levels after treatment with SGLT2 inhibitors was associated with a decrease in serum soluble DPP‐4, suggesting that reducing serum soluble DPP‐4 levels by SGLT2 inhibitors can restore the glucose‐lowering effect of DPP‐4 inhibitors.…”