Effect of the sodium-glucose cotransporter-2 inhibitor, DWP16001, as an add-on therapy to insulin for diabetic dogs: A pilot study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic agents. OBJECTIVE: This study aimed to evaluate the safety and the adjuvant glycaemic control effect of an SGLT2 inhibitor, DWP16001, in diabetic dogs receiving insulin treatment. METHODS: Nineteen diabetic dogs receiving insulin treatment (NPH, porcine lente and glargine insulin) were divided into two groups according to dosing frequency: DWP TOD group (n = 10) and DWP SID group (n = 9). In the DWP TOD group, 0.025 mg/kg of DWP16001 was administered once every 3 days, whereas, in the DWP SID group, 0.025 mg/kg of DWP16001 was administered once a day. Food intake was maintained during the trial period. Hypoglycaemia, ketoacidosis or unexpected life-threatening reactions were assessed as adverse effects before and after DWP16001 administration. We compared insulin requirement reduction and blood glucose level control between two groups. RESULTS: No specific adverse effects were observed during the clinical trial, and haematological parameter remained unchanged. Moreover, the fasting glucose levels and daily insulin dose in the DWP TOD group were lower than the pre-administration values, but not significantly different for 8 weeks. Systolic blood pressure, fructosamine and insulin dose decreased significantly in the DWP SID group compared to the DWP TOD group at 8 weeks (p < 0.05) without affecting food consumption. Among these patients, 10 patients were monitored while receiving DWP16001 for 12 months (DWP TOD group n = 5, DWP SID group n = 5). The fasting glucose and fructosamine levels and daily insulin dose were reduced in both groups at 12 months compared with those before receiving DWP16001. CONCLUSION: When DWP16001, an SGLT2 inhibitor, was supplied to dogs with type 1 diabetes, no adverse effects were observed, and it was confirmed that the administered insulin dose can be reduced in controlling blood glucose.

The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes.

AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.

A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.

AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter-2 inhibitor, with phentermine in healthy subjects.

BACKGROUND: DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine. METHODS: We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD. RESULTS: The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of Cmax,ss, and AUCtau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance. CONCLUSIONS: Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes. CLINICAL TRIAL REGISTRATION: NCT05321732.

Efficacy and safety of monotherapy with enavogliflozin in Korean patients with type 2 diabetes mellitus: Results of a 12-week, multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIMS: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium-glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with glycated haemoglobin (HbA1c) of 7.0-10.0%, entered a 2-week placebo run-in period, and were randomized to receive once-daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. RESULTS: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (-0.79%, -0.89%, -0.92% and -0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were -30.5, -31.1, -35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. CONCLUSIONS: Once-daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well-tolerated treatment for Korean patients with type 2 diabetes mellitus.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter 2 inhibitor, with gemigliptin and metformin in healthy adults.

AIMS: DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, is under clinical development for the treatment of type 2 diabetes mellitus. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics interaction of DWP16001 with gemigliptin and metformin. METHODS: A randomized, open-label, 2-sequence, 2-period crossover study was conducted in 34 healthy male subjects. All subjects received a single oral dose of DWP16001 2 mg with and without gemigliptin and metformin (8 days of 50 mg once-daily dose and 1000 mg twice daily dose for gemigliptin and metformin, respectively). Serial blood samples were collected for PK and serum glucose analysis, and timed urine samples were collected to analyse urine glucose excretion (UGE). The PK and pharmacodynamic parameters were analysed by the noncompartmental method. RESULTS: The PK interactions of DWP16001, gemigliptin and metformin were not clinically significant. The geometric mean ratios (with 90% confidence intervals) of coadministration to separate administration for area under the time-concentration curves were 1.04 (1.02-1.06), 1.03 (0.98-1.09) and 1.17 (1.12-1.22), for gemigliptin, metformin and DWP16001 respectively. The UGE induced by DWP16001 was not affected by the coadministration of gemigliptin and metformin. CONCLUSION: The results suggest that the DWP16001 could be added to metformin and gemigliptin combination therapy without dose adjustment.

Pharmacokinetic and pharmacodynamic interaction between DWP16001, an sodium-glucose cotransporter 2 inhibitor and metformin in healthy subjects.

AIMS: DWP16001 is a novel sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium-glucose cotransporter 2 inhibition. We aimed to evaluate whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD). METHODS: A randomized, open-label, single- and multiple-dose, 2-sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady-state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study. RESULTS: DWP+MET displayed increased peak concentration and area under the concentration-time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8-1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13-1.31) and 1.09 (1.05-1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration-time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90-1.06) and 1.05 (0.98-1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94-1.05). CONCLUSION: The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.

Evaluation of safety and anti-obesity effects of DWP16001 in naturally obese dogs.

BACKGROUND: The aim of this study was to investigate the anti-obesity effects of DWP16001, a sodium-glucose cotransporter-2 (SGLT2 inhibitor), in naturally obese dogs. A total of 20 dogs were divided into four equal groups: one obese control (OC group), and three treated groups; DWP0.2 group, DWP0.5 group, and DWP1 group. OC group fed with food for maintenance and treated groups were fed with food for maintenance with 0.2 mg/kg DWP16001, 0.5 mg/kg DWP16001 and 1 mg/kg DWP16001, respectively. The food for maintenance was provided to dogs as 2 RER (Resting energy requirement) in kcal and DWP16001-supplemented food was administered once a day for 8 weeks. RESULTS: Body condition score, body weight, and fat thickness were significantly reduced (P < 0.05) in the DWP0.2 group compared with the OC group, respectively without affecting the food consumption. At the 10th week the food consumption rate was 101.35 ± 2.56, 166.59 ± 4.72, 98.47 ± 1.44 and 123.15 ± 2.45% compared with initial food consumption rate. Body fat percentage, chest and waist circumference, blood glucose, and insulin were reduced compared to OC group but not significantly different from those of the OC group during experimental period. Serum alanine aminotransferase, alkaline phosphatase, creatine phosphokinase, and creatinine were significantly reduced in DWP0.2 group on 8 weeks. Serum cholesterol and triglycerides were reduced but not significantly. No specific adverse effects were observed throughout the experiment, and hematological parameters were unchanged. The results indicate that DWP16001 was not harmful to the dogs in our study and might have anti-obesity effects in naturally obese dogs. CONCLUSIONS: The above results and discussion suggest that DWP16001 is safe and might have anti-obesity effects in naturally obese dogs.

Dose-dependent glucosuria of DWP16001, a novel selective sodium-glucose cotransporter-2 inhibitor, in healthy subjects.

AIMS: DWP16001 is a novel sodium-glucose cotransporter-2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed. RESULTS: A dose-dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50-60 g/d after multiple doses in the dose range of 0.3-2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0-3.0 hours, and it exhibited a mean elimination half-life of 13-29 hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1-2.0 mg. DWP16001 was well tolerated in all dose groups. CONCLUSION: DWP16001 induced glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0 mg and in multiple oral doses of up to 2.0 mg.

Effects of poloxamer-based thermo-sensitive sol-gel agent on urethral stricture after transurethral resection of the prostate for benign prostatic hyperplasia: a multicentre, single-blinded, randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of poloxamer-based thermo-sensitive sol-gel instillation, after transurethral resection of the prostate (TURP), for preventing urethral stricture. PATIENTS AND METHODS: In all, 198 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: groups A and B. Patients in Group A (100 patients, experimental group) received poloxamer-based thermo-sensitive sol-gel instillation and patients in the Group B (98 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 (V1), 12 (V2), and 24 weeks (V3) after TURP. The effectiveness of poloxamer-based thermo-sensitive sol-gel instillation was evaluated based on the International Prostate Symptom Score (IPSS), IPSS-Quality of Life (QoL), Overactive bladder questionnaire (OAB-q), maximum urinary flow rate (Qmax ), post-void residual urine volume (PVR), and cystoscopy. RESULTS: Amongst the initial 198 participants, 80 patients in Group A and 83 in Group B completed the study. There were no significant differences in IPSS-QoL and OAB-q between the groups. However, Qmax was significantly different between groups A and B, at a mean (SD) of 18.92 (9.98) vs 15.58 (9.24) mL/s (P = 0.028) at 24 weeks after TURP. On cystoscopic examination, urethral stricture after TURP was found in two of the 80 patients in Group A and 10 of 83 in Group B (P = 0.023). CONCLUSIONS: Poloxamer-based thermo-sensitive sol-gel instillation after TURP lowered the incidence of urethral stricture.