Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week, open-label, phase IV study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.

Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin.

Sodium glucose co-transporter 2 (SGLT2) inhibitors have been associated with increased serum ketone body levels in patients with type 2 diabetes mellitus (T2DM). In the present analysis we evaluated serum ketone body levels and variability in 1278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. The median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for ß-hydroxybutyrate. Approximately two-thirds of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Patients in the lowest response tertile exhibited no increase in ketones. Those in the highest response tertile tended to be male and have higher fasting plasma glucose levels, lower insulin levels, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese patients with T2DM.

Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus.

AIM: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. MATERIALS AND METHODS: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. RESULTS: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.

Efficacy and safety of teneligliptin added to canagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: A multicentre, randomized, double-blind, placebo-controlled, parallel-group comparative study.

Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (-0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.

Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes.

AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy. METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward). RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52. CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.

Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: Results of a 24-week, randomized, double-blind, placebo-controlled trial.

AIMS: To investigate efficacy and safety of the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin administered as add-on therapy to the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C-peptide ratio, homeostatic model assessment 2-%B and adverse events. Patients also underwent mixed-meal tolerance tests. RESULTS: The difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was -0.88% (least-squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C-peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2-%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2-hour postprandial plasma glucose and plasma glucose area under the curve (AUC)0-2h in a mixed-meal tolerance test. No significant between-group differences were observed for C-peptide AUC0-2h or glucagon AUC0-2h after meals. Incidences of adverse events were 60.0% and 47.1% in the T + C and T + P groups, respectively. No hypoglycaemia was observed. CONCLUSIONS: Canagliflozin administered as add-on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.

Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients. METHODS: Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors. RESULTS: Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast. CONCLUSION: Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and increased plasma renin activity, which may be a compensatory mechanism for sodium retention, leading to subsequent urine output recovery. CLINICAL TRIAL REGISTRATION: UMIN000019462. FUNDING: Mitsubishi Tanabe Pharma Corporation.

Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: Combination therapy with canagliflozin and insulin was investigated in a prescribed substudy of the canagliflozin Cardiovascular Assessment Study (CANVAS); however, it was not evaluated in Japanese patients with type 2 diabetes mellitus (T2DM). Since the usage profile of insulin therapy and pathologic features of Japanese patients differ from those of Caucasian patients, we determined the clinical benefit of such a combination therapy in Japanese patients. METHODS: Patients who had inadequate glycemic control despite insulin, diet and exercise therapies were randomized into placebo (n = 70) and canagliflozin 100 mg (n = 76) groups that were administered once daily in addition to their prior insulin therapy in this double-blind, placebo-controlled study. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from the baseline to week 16. RESULTS: There was a statistically significant decrease in HbA1c levels from the baseline in the canagliflozin group (-0.97 ± 0.08 %) compared with the placebo group (0.13 ± 0.08 %) at week 16 [last observation carried forward (LOCF)]. The decrease in HbA1c levels in the canagliflozin group was independent of the insulin regimen (premixed, long-acting and long-acting plus rapid- or short-acting). Compared with the placebo group, canagliflozin significantly decreased fasting plasma glucose levels (-34.1 ± 4.8 vs -1.4 ± 5.0 mg/dL) and body weights (-2.13 ± 0.25 vs 0.24 ± 0.26 %), and significantly increased HDL cholesterol (3.3 ± 1.0 vs -0.5 ± 1.0 mg/dL) and HOMA2- %B (10.15 ± 1.37 vs 0.88 ± 1.42 %). The overall incidence of adverse events was similar between the two groups. The incidence and incidence per subject-year exposure of hypoglycemia (hypoglycemic symptoms and/or decreased blood glucose) were slightly higher in the canagliflozin group (40.0 % and 7.97) than in the placebo group (29.6 % and 4.51). However, hypoglycemic events in both groups were mild in severity and dose-reduction of insulin by <10 % from the baseline following hypoglycemic events decreased the incidence per subject-year exposure in the canagliflozin group. The incidence of hypoglycemia between the groups did not differ according to the insulin regimen. CONCLUSION: Canagliflozin in combination with insulin was effective in improving glycemic control and reducing body weight and well tolerated by Japanese patients with T2DM. Trial Registration ClinicalTrials.gov identifier: NCT02220920.

Effects of Baseline Blood Pressure and Low-Density Lipoprotein Cholesterol on Safety and Efficacy of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Sodium glucose co-transporter 2 inhibitors decrease hemoglobin A1c (HbA1c) and blood pressure (BP) and slightly increase low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus (T2DM). The effects of baseline BP and LDL-C on the safety and efficacy of canagliflozin in patients were analyzed post hoc in a phase III study. METHODS: Japanese patients with T2DM were classified by baseline systolic BP (SBP) of <130 or ≥130 mmHg, diastolic BP (DBP) of <80 or ≥80 mmHg, and LDL-C of <120 or ≥120 mg/dL. Canagliflozin was administered daily to patients for 52 weeks at doses of either 100 mg (n = 584) or 200 mg (n = 715). The effects of canagliflozin on the incidence of adverse events (AEs), BP, and LDL-C were evaluated. RESULTS: No clear differences were observed in overall safety among the subgroups classified by baseline SBP, DBP, or LDL-C, except for a slight imbalance in AEs associated with volume depletion with 200 mg of canagliflozin. The decrease in mean SBP and DBP was evident in subgroups with baseline SBP ≥130 mmHg and DBP ≥80 mmHg. Mean LDL-C was decreased in subgroups with baseline LDL-C ≥120 mg/dL at both canagliflozin doses, and they were slightly increased, but did not exceed 120 mg/dL in subgroups with baseline LDL-C <120 mg/dL. The changes in HbA1c and body weight from those observed at baseline were not different between subgroups classified by SBP, DBP, and LDL-C at either dose. CONCLUSION: The present post hoc analysis indicates that canagliflozin is well tolerated irrespective of baseline BP and LDL-C in patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01387737. FUNDING: Mitsubishi Tanabe Pharma Corporation.

Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM. METHODS: Canagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs. RESULTS: Plasma canagliflozin maximum concentration and area under the concentration-time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t max) of 1.0 h and elimination half-life (t 1/2) of 10.22-13.26 h on Day 1. No significant changes in t max and t 1/2 were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC0-24h on Day 16 to AUC0-∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0-24h (80-110 g/day with canagliflozin ≥100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit. CONCLUSION: Canagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM. FUNDING: Mitsubishi Tanabe Pharma Corporation. TRIAL REGISTRATION: ClinicalTrials.gov#NCT00707954.

Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study.

BACKGROUND: The safety and efficacy of sodium glucose co-transporter 2 inhibitors in non-obese compared with obese patients with type 2 diabetes mellitus is unknown. METHODS: We conducted post hoc analyses of the results of a 52-week open-label study of Japanese type 2 diabetes mellitus patients treated with 100 or 200 mg canagliflozin. Patients were divided into four subgroups according to their baseline body mass index (BMI): group I, BMI < 22 kg/m(2); group II, BMI ≥ 22 to < 25 kg/m(2); group III, BMI ≥ 25 to < 30 kg/m(2) and group IV, BMI ≥ 30 kg/m(2). RESULTS: The overall safety was similar among the four BMI subgroups, although there were slight differences in terms of the incidences of hypoglycemia, asymptomatic hypoglycemia, female genital infections and proportions of patients with total ketone body levels exceeding 1000 µmol/l at any time for both canagliflozin doses. Hemoglobin A1c, fasting plasma glucose and body weight decreased significantly from baseline to week 52 at both canagliflozin doses. The changes in hemoglobin A1c, and fasting plasma glucose were not significantly different among the four BMI subgroups for either dose. CONCLUSION: Canagliflozin was tolerated in patients irrespective of their BMI at the start of treatment, although some caution may be needed.

Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. METHODS: Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. RESULTS: Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. CONCLUSIONS: TA-8995 is a potent CETP inhibitor and warrants further investigation.