The purpose of this study was to assess the safety and efficacy of the SGLT2 inhibitor luseogliflozin in T2DM patients with hepatic dysfunction. We observed improvement in glycemic control and the hepatic function biomarkers AST, ALT, and γ-GTP. Moreover, FLI (a surrogate liver fat marker), ferritin (a hepatic impairment biomarker), M2-BP, and the NAFLD fibrosis score (hepatic fibrosis biomarkers) were significantly improved in response to luseogliflozin administration.
Several previous studies in T2DM patients showed that luseogliflozin administration decreased hepatic function biomarkers [8, 14, 16]. A recent single-arm LEAD trial in T2DM patients with NAFLD demonstrated a significant decrease in hepatic function biomarkers . The results of the present study were consistent with those of previous reports. The present study confirmed that luseogliflozin improved hepatic function in T2DM patients with hepatic dysfunction and ALT levels > 31 IU/L at enrolment.
Additionally, this study revealed improvement in the hepatic fibrosis biomarkers M2-BP and NAFLD fibrosis score following luseogliflozin administration in T2DM patients with hepatic dysfunction. The LEAD trial showed decrease in the AST, ALT, γ-GTP, and ferritin levels in T2DM patients with NAFLD. However, the hepatic fibrosis markers FIB4 index, NAFLD fibrosis score, type IV collagen 7S, and M2BP were unchanged . Hence, luseogliflozin may only be able to ameliorate mild to moderate hepatic dysfunction but not established NAFLD.
The beneficial effects of SGLT2 inhibitors on body weight and composition have been reported [18–21]. The present study demonstrated significant reduction in body weight, BMI, and waist circumstance after luseogliflozin administration. The surrogate liver fat marker FLI significantly decreased in the present study. This finding was consistent with that reported by previous studies which demonstrated decrease in liver fat following SGLT2 inhibitor treatment [22–24] and might explain the hepatic function improvement observed here.
This trial also disclosed that that plasma insulin levels and HOMA-IR were significantly decreased by luseogliflozin administration. This finding was consistent with earlier reports of reductions in HOMA-IR (insulin resistance improvement) by SGLT2 inhibitors [25, 26]. In contrast, HOMA-β did not significantly improve in the present study. SGLT2 inhibitors apparently improved pancreatic β-cell function in animal models . However, no study has evaluated the effects of SGLT2 inhibitors on pancreatic β-cell function in humans. A Korean clinical study in Korea showed that a group responding well to SGLT2 inhibitors presented with relatively higher HOMA than the group responding poorly to SGLT2 inhibitors. Nevertheless, the HOMA-β level was not associated with SGLT2 inhibitor responsiveness . The results of this study suggested that SGLT2 inhibitors improved insulin resistance but not insulin secretion in the pancreatic β-cells of T2DM patients.
Here, luseogliflozin administration did not improve inflammation because it did not lower the hs-CRP or IL-6 levels. It has been previously reported that SGLT2 inhibitors suppress inflammation in animal models [29, 30]. However, only a few human trials reported an association between SGLT2 inhibitors and inflammation [31, 32]. Further studies are needed to assess the efficacy of SGLT2 inhibitors in attenuation of inflammation.
No serious adverse events associated with luseogliflozin were detected in the present study. Genital infection and dry skin were the most commonly observed adverse reactions here but they are well-known side effects of SGLT2 inhibitors. There were no remarkable occurrences of any unknown side effects. No hypoglycemia was recorded during this trial. It was reported earlier that SGLT2 inhibitors lowered plasma glucose in an insulin-independent manner and posed a low risk of inducing hypoglycemia . Moreover, recent large-scale clinical trials demonstrated that SGLT2 inhibitors prevented mortality, macrovascular complications, and renal impairment progression associated with T2DM [9, 10]. Overall, SGLT2 inhibitors are well tolerated in T2DM patients with hepatic dysfunction.
The study protocol described the enrolment of 50 subjects. Nevertheless, it was feasible for the Seino Internal Medical Clinic to support the enrolment of 55 subjects. The over-registration was reported to the Fukushima Medical University Certified Review Board and approved by them. The last five subjects were excluded and the results of the present study were re-analyzed with only 50 participants. Once again, all primary endpoints (ALT, AST, γ-GTP, and HbA1c) showed significant improvements. Therefore, over-registration by five patients did not influence the outcome of this trial and all 55 subjects were included in the FAS and analyzed.
This study had several limitations. First, there were relatively few enrolled subjects in this trial and it was conducted in only one clinical institution (Seino Internal Medical Clinic) in Japan. Second, it was a single-arm trial. Third, the eligibility criterion hepatic dysfunction was defined only by the ALT level at enrolment. Therefore, the participants in this trial had mild to moderate hepatic dysfunction. These constraints may limit the generalizability of this study and large-scale, multicenter, randomized controlled trials are required to validate its findings.