Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Subanalysis of placebo-controlled, double-blind clinical trials.

We evaluated the changes in heart rate on the treatment with SGLT2 inhibitor, luseogliflozin, in Japanese patients with type 2 diabetes mellitus (T2DM). It is suggested that luseogliflozin can effectively decrease in heart rate in patients with higher baseline.

Efficacy and safety of luseogliflozin added to insulin therapy in Japanese patients with type 2 diabetes: a multicenter, 52-week, clinical study with a 16-week, double-blind period and a 36-week, open-label period.

OBJECTIVE: To evaluate the efficacy and safety of luseogliflozin in Japanese patients with type 2 diabetes (T2D) inadequately controlled with insulin monotherapy. METHODS: This 52-week multicenter study entailed a 16-week, double-blind period followed by a 36-week, open-label period. Patients were randomized to receive either luseogliflozin 2.5 mg (n = 159) or placebo (n = 74) during the double-blind period. All patients who entered the open-label period received luseogliflozin. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and bodyweight. Safety assessments included adverse events, laboratory tests and vital signs. RESULTS: In the double-blind period, luseogliflozin significantly decreased HbA1c (-1.18%), FPG (-42.4 mg/dL), 2 hour PPG (-68.7 mg/dL) and bodyweight (-1.27 kg) compared with placebo (all p < .001); these reductions were maintained over 52 weeks. The changes from baseline at Week 52 were -1.00%, -35.1 mg/dL, -68.8 mg/dL and -1.81 kg, respectively (all p < .001). In the placebo group, favorable glycemic control and bodyweight reduction were also observed after switching to luseogliflozin. Most adverse events were mild in severity. During the double-blind period, the incidences of hypoglycemia were 20.8% and 13.5% in the luseogliflozin and placebo groups, respectively. During the 52 weeks of luseogliflozin treatment, the frequency of hypoglycemia was 33.3%, but no serious hypoglycemia occurred. The safety profile other than hypoglycemia was also acceptable. There were no new safety concerns about luseogliflozin added to insulin. CONCLUSION: Luseogliflozin added to insulin therapy significantly improved glycemic control with bodyweight reduction and was well tolerated in Japanese patients with T2D. CLINICAL TRIAL REGISTRATION: Japan Pharmaceutical Information Center (JapicCTI-142582).

Sodium-glucose cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: A 52-week, open-label, single-arm study.

AIMS/INTRODUCTION: The aim of the present study was to evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes. MATERIALS AND METHODS: This 52-week, multicenter, open-label, single-arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy. Major efficacy end-points included the changes from baseline in glycated hemoglobin, fasting plasma glucose and bodyweight. Body composition was also assessed in individuals who had access to bioelectrical impedance analysis. Safety assessments included adverse events, clinical laboratory tests, vital signs and 12-lead electrocardiograms. RESULTS: Of 76 patients who received luseogliflozin, 62 completed the study. The changes from baseline in glycated hemoglobin, fasting plasma glucose, and bodyweight (mean ± SE) were -0.68 ± 0.10%, -32.1 ± 3.6 mg/dL and -2.71 ± 0.24 kg at week 52, respectively (all, P < 0.001 vs baseline). Luseogliflozin was associated with greater reductions in fat mass than lean mass at all measuring points (n = 22): fat vs lean mass changes (mean ± SE) at week 52 were -2.49 ± 0.45 kg (P < 0.001 vs baseline) and -0.44 ± 0.26 kg (P = 0.107 vs baseline), respectively. Insulin secretion and Matsuda Index were also improved at weeks 12 and 52 compared with baseline. Adverse events and adverse drug reactions occurred in 65.8 and 27.6% of patients, respectively. The overall safety profile, including frequency of hypoglycemia, was found to be consistent with those of previous studies and there were no new safety concerns. CONCLUSIONS: Luseogliflozin added to liraglutide was well tolerated, and improved glycemic control with bodyweight and fat mass reductions in Japanese type 2 diabetes patients.

A peptide derived from tenascin-C induces beta1 integrin activation through syndecan-4.

Tenascin-C (TN-C) is unique for its cell adhesion modulatory function. We have shown that TNIIIA2, a synthetic 22-mer peptide derived from TN-C, stimulated beta1 integrin-mediated cell adhesion of nonadherent and adherent cell types, by inducing activation of beta1 integrin. The active site of TNIIIA2 appeared cryptic in the TN-C molecule but was exposed by MMP-2 processing of TN-C. The following results suggest that cell surface heparan sulfate (HS) proteoglycan (HSPG), including syndecan-4, participated in TNIIIA2-induced beta1 integrin activation: 1) TNIIIA2 bound to cell surface HSPG via its HS chains, as examined by photoaffinity labeling; 2) heparitinase I treatment of cells abrogated beta1 integrin activation induced by TNIIIA2; 3) syndecan-4 was isolated by affinity chromatography using TNIIIA2-immobilized beads; 4) small interfering RNA-based down-regulation of syndecan-4 expression reduced TNIIIA2-induced beta1 integrin activation, and consequent cell adhesion to fibronectin; 5) overexpression of syndecan-4 core protein enhanced TNIIIA2-induced activation of beta1 integrin. However, treatments that targeted the cytoplasmic region of syndecan-4, including ectopic expression of its mutant truncated with the cytoplasmic domains and treatment with protein kinase Calpha inhibitor Gö6976, did not influence the TNIIIA2 activity. These results suggest that a TNIIIA2-related matricryptic site of the TN-C molecule, exposed by MMP-2 processing, may have bound to syndecan-4 via its HS chains and then induced conformational change in beta1 integrin necessary for its functional activation. A lateral interaction of beta1 integrin with the extracellular region of the syndecan-4 molecule may be involved in this conformation change.