Ecacy and Safety of Luseogliozin in Patient with Type 2 Diabetes Complicated by Hepatic Dysfunction

Background: Improvements in glycemic control and hepatic function are clinically important goals in the treatment of patients with type 2 diabetes mellitus complicated by hepatic dysfunction. The favorable effects of the sodium-glucose co-transporter inhibitor luseogliozin on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have conrmed its real-world ecacy on hepatic dysfunction. This trial was conducted to assess the safety and ecacy of luseogliozin in patients with type 2 diabetes mellitus complicated by hepatic dysfunction. Methods: This prospective, single-site, single-arm, open-label trial included 55 subjects. Subjects were administered with luseogliozin and observed for 52 weeks. The primary endpoints were the change and percent change in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), and hemoglobin A1c (HbA1c) from baseline to week 52. The secondary endpoints included body weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), homeostatic model assessment beta (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), ferritin, Mac-2 binding protein (M2-BP), fatty liver index (FLI), brosis-4 (FIB-4) index, type IV collagen 7S domain, nonalcoholic fatty liver disease (NAFLD) brosis score, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6). Results: AST, ALT, γ-GTP, and HbA1c signicantly decreased from baseline to week 52. Body weight, BMI, waist circumference, and FPG also signicantly decreased. HOMA-IR signicantly decreased but HOMA-β was unchanged. FLI, ferritin, M2-BP, and NAFLD brosis scores signicantly decreased whereas the FIB-4 index and type IV collagen 7S domain did not signicantly change. Data are presented as mean ± standard deviation or n (%) among 55 subjects in the full analysis set. BMI, body mass index; DPP-4, dipeptidyl peptidase-4; SGLT2, sodium-glucose transport protein 2; GLP-1, glucagon-like peptide-1. 4.4 ± 13.0 mmHg (P 0.0172) and signicant decreases disappeared after No signicant changes were observed for diastolic blood pressure or pulse.

70% [3,4]. Hepatic dysfunction was a major cause of death in T2DM patients [5][6][7]. Therefore, improvements in glycemic control and hepatic function are clinically important goals in the treatment of patients with T2DM complicated by hepatic dysfunction.
Novel oral hypoglycemic agents known as sodium glucose co-transporter 2 (SGLT2) inhibitors have been recently launched. They are widely used in T2DM treatment. SGLT2 inhibitors block renal glucose reabsorption, promote urinary glucose excretion, and lower plasma glucose levels in an insulinindependent manner. Hence, there is a reduced risk of induction of hypoglycemia associated with them.
The safety of SGLT2 inhibitors in combination with other hypoglycemic agents has been con rmed [8].
Luseogli ozin is a type of SGLT2 inhibitor. It improved NASH in an animal T2DM model [15]. Its favorable effects on hepatic dysfunction were anticipated for humans. Nevertheless, few clinical studies have con rmed its real-world e cacy on hepatic dysfunction. Therefore, the aim of this study was to evaluate luseogli ozin safety and e cacy in patients with T2DM complicated by hepatic dysfunction. legal regulations in Japan. Written informed consent was obtained from all participants after the study was fully explained to them. To minimize bias, data management and statistical analyses were conducted by third-party entities (DOT World Co. Ltd., Tokyo, Japan; Soiken Inc., Tokyo, Japan).

Study intervention
As this study was a single-arm trial, randomization was not conducted. The subjects furnished informed consent and then began to consume 2.5 mg oral luseogli ozin once daily either before or after breakfast. The study intervention was conducted for 52 wks and the subjects were observed at baseline (week 0) and at weeks 12, 24, and 52. All enrolled subjects were prohibited from using any SGLT2 inhibitor other than luseogli ozin during the trial. Moreover, enrolled subjects were not permitted to change the type, usage, or dose of any other therapeutic agents such as antiplatelet, antihypertensive, or antidyslipidemia drugs. They were not allowed to alter the type or degree of diet and exercise therapy during the study, provided that these treatments were safely regulated.

Sample size calculation and statistical analysis
The target number of enrolled subjects was 50 and was based on the possible number of subjects who could give their consent following daily medical examinations at the Seino Internal Medical Clinic.
The primary and secondary endpoints were evaluated on the Full Analysis Set (FAS) which includes all subjects assigned to a study intervention. However, subjects who did not receive the study agent were excluded from the FAS. Subjects for whom no data related to the e cacy endpoints could be obtained after study agent initiation were also excluded from the FAS. The Per-Protocol Set (PPS) excluded subjects from the FAS if they presented with substantial protocol violations such as eligible criteria nonconformance, use of prohibited drugs, and poor adherence to the study agent. The safety analysis included all treated patients. All two-sided tests were performed and P < 0.05 was considered as statistically signi cant. Summary statistics (number of subjects, mean, standard deviation, minima, median, and maxima) and changes from baseline were calculated for continuous data. A one-sample ttest was conducted to identify the change from baseline. Frequencies and proportions were calculated for the categorical data. SAS version 9.4 (SAS, Cary, NC, USA) was used to perform all statistical analyses.

Results
Baseline characteristics of the study participants Between April 2017 and September 2018, 55 subjects were enrolled in this study and received the intervention (luseogli ozin administration). One subject discontinued the visit to the institution during the study. Five subjects discontinued luseogli ozin use because of adverse events during the study. Hence, 55 subjects were included in both the safety analysis set and the FAS (Fig. 1) and 49 subjects completed the study intervention. The baseline characteristics of the subjects are summarized in Table 1. Data are presented as mean ± standard deviation or n (%) among 55 subjects in the full analysis set. BMI, body mass index; DPP-4, dipeptidyl peptidase-4; SGLT2, sodium-glucose transport protein 2; GLP-1, glucagon-like peptide-1.

In ammation biomarkers
The hs-CRP and IL-6 levels did not signi cantly change from baseline (Table 4).

Safety outcomes
Twenty-four adverse events were reported in eighteen out of fty-ve subjects (32.7%) ( Table 5). The most common adverse events were genital infection and dry skin (six subjects each; 10.9%). Four serious adverse events (facial paresis, venous thrombosis, Báker's cyst, and gastric cancer) were reported during the study. Nevertheless, none of them was considered to be related to luseogli ozin administration. No hypoglycemia or severe hypoglycemia was reported during the study. Data are presented as n (%).

Discussion
The purpose of this study was to assess the safety and e cacy of the SGLT2 inhibitor luseogli ozin 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 brosis score (hepatic brosis biomarkers) were signi cantly improved in response to luseogli ozin administration.
Several previous studies in T2DM patients showed that luseogli ozin administration decreased hepatic function biomarkers [8, 14,16]. A recent single-arm LEAD trial in T2DM patients with NAFLD demonstrated a signi cant decrease in hepatic function biomarkers [17]. The results of the present study were consistent with those of previous reports. The present study con rmed that luseogli ozin 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 brosis biomarkers M2-BP and NAFLD brosis score following luseogli ozin 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 brosis markers FIB4 index, NAFLD brosis score, type IV collagen 7S, and M2BP were unchanged [17]. Hence, luseogli ozin may only be able to ameliorate mild to moderate hepatic dysfunction but not established NAFLD.
The present study demonstrated signi cant reduction in body weight, BMI, and waist circumstance after luseogli ozin administration. The surrogate liver fat marker FLI signi cantly decreased in the present study. This nding was consistent with that reported by previous studies which demonstrated decrease in liver fat following SGLT2 inhibitor treatment [22][23][24] and might explain the hepatic function improvement observed here.
This trial also disclosed that that plasma insulin levels and HOMA-IR were signi cantly decreased by luseogli ozin administration. This nding was consistent with earlier reports of reductions in HOMA-IR (insulin resistance improvement) by SGLT2 inhibitors [25,26]. In contrast, HOMA-β did not signi cantly improve in the present study. SGLT2 inhibitors apparently improved pancreatic β-cell function in animal models [27]. 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 [28]. 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, luseogli ozin administration did not improve in ammation because it did not lower the hs-CRP or IL-6 levels. It has been previously reported that SGLT2 inhibitors suppress in ammation in animal models [29,30]. However, only a few human trials reported an association between SGLT2 inhibitors and in ammation [31,32]. Further studies are needed to assess the e cacy of SGLT2 inhibitors in attenuation of in ammation.
No serious adverse events associated with luseogli ozin 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 [33]. Health, Labour and Welfare in Japan, the Clinical Trials Act, and other current legal regulations in Japan.
Written informed consent was obtained from all participants after full explanation of the study.

Consent for publication
As this manuscript does not contain any individual personal data, consent for publication was not required or applicable.

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available as there is no third-party data sharing statement in the study protocol. Furthermore, we did not secure approval for sharing the informed consent documents from the Institutional Review Board of the Seino Internal Medical Clinic or the Fukushima Medical University Certi ed Review Board. Flowchart depicting study participant enrolment, allocation, and analysis 55 eligible subjects were enrolled in this study. All 55 subjects were included and analyzed in the Safety Analysis Set and Full Analysis Set in this study.