sitagliptin-phosphate and ipragliflozin

In patients with type 2 diabetes who were inadequately controlled with metformin and sulphonylurea, we compared the glucose-lowering efficacy, cardiometabolic parameters and safety of two drugs, ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, and sitagliptin, a dipeptidyl peptidase-4 inhibitor. MATERIALS AND METHODS: Patients with 7.5%-9.0% glycated haemoglobin treated with metformin and sulphonylurea were randomly assigned to ipragliflozin (50 mg, n = 70) or sitagliptin (100 mg, n = 70) therapy for 24 weeks. Measures of glycaemic control, fatty liver indices, other metabolic parameters and subclinical atherosclerosis were compared by a paired t-test before and after 24 weeks of treatment.. Mean glycated haemoglobin levels decreased from 8.5% to 7.5% in the ipragliflozin group and from 8.5% to 7.8% in the sitagliptin group, resulting in a 0.34% between-group difference (95% confidence interval, 0.10%-0.43%, p = .088). Fasting and postprandial 2-h glucose levels also showed a similar trend, with a greater reduction with ipragliflozin therapy. An increase of over 70% in ketone levels and a decrease in whole body and abdominal fat masses were observed with ipragliflozin treatment. Fatty liver indices also improved with ipragliflozin treatment. Despite no difference in carotid intima-media thickness and ankle-brachial index, ipragliflozin therapy improved flow-mediated vasodilation, reflecting endothelial function, while sitagliptin did not. The safety profile did not differ between the two groups.. Ipragliflozin add-on therapy can be a viable option for better glycaemic control with multiple vascular and metabolic benefits in patients with type 2 diabetes who are inadequately controlled with metformin and sulphonylurea.

Topics: Blood Glucose; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Fatty Liver; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Treatment Outcome

Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear.. A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m. After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption.. There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Bone and Bones; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glucosides; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Muscles; Prognosis; Prospective Studies; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Young Adult

To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD).. In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks.. Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m. The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Thiophenes; Treatment Outcome

To investigate the efficacy, safety and tolerability of sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D).. Japanese patients with T2D and glycated haemoglobin (HbA1c) 7.0% to 10.0% while treated with ipragliflozin 50 mg once daily were randomized 1:1 to additional treatment with sitagliptin 50 mg once daily (N = 70) or matching placebo (N = 71) for 24 weeks. The primary efficacy endpoint was change in HbA1c at Week 24. Secondary efficacy endpoints were changes in 2-hour post-meal glucose (PMG), total PMG 0- to 2-hour area under the curve (AUC. In Japanese patients with T2D, sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated. ClinicalTrials.gov: NCT02577016.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glucosides; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Japan; Metformin; Middle Aged; Sitagliptin Phosphate; Thiophenes; Treatment Outcome

To assess the efficacy, safety and tolerability of ipragliflozin 50 mg once daily added to sitagliptin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D).. The results of two clinical trials are reported. In both trials, patients had glycated haemoglobin (HbA1c) levels of 7.0% to 10.0% on sitagliptin 50 mg once daily 2 weeks prior to addition of ipragliflozin or placebo. In one trial (Trial 843), patients were randomized 1:1 to addition of blinded ipragliflozin 50 mg once daily (n = 73) or placebo (n = 70) for 24 weeks; the primary endpoint was efficacy (change in HbA1c at Week 24). In the other trial (Trial 849), open-label ipragliflozin 50 mg once daily was added for 52 weeks (n = 77); the primary objective was to assess safety/tolerability.. In Trial 843, baseline characteristics were similar between groups (mean age 60.5 years, HbA1c 8.0%); after 24 weeks, adding ipragliflozin provided significantly greater reduction in HbA1c compared to placebo: least squares mean difference -0.77% (95% confidence interval -0.98, -0.57; P <0.001). In Trial 843, the incidences of adverse events (AEs) overall and prespecified AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia, and polyuria/pollakiuria) were similar between groups. In Trial 849, specific AEs with incidence ≥5% were nasopharyngitis, pollakiuria, back pain, thirst, constipation, influenza and arthralgia; drug-related AEs reported in ≥2 patients were pollakiuria, thirst and constipation.. Ipragliflozin 50 mg once daily added on to sitagliptin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated in Japanese patients with T2D. ClinicalTrials.gov: NCT02577003, NCT02564211.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glucosides; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Japan; Metformin; Middle Aged; Sitagliptin Phosphate; Thiophenes; Treatment Outcome

Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (T

Topics: Adult; Benzhydryl Compounds; Blood Glucose; Canagliflozin; Diabetes Mellitus, Type 2; Female; Glucose; Glucosides; Humans; Intestinal Absorption; Kidney; Male; Middle Aged; Models, Biological; Postprandial Period; Pyrazoles; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidines; Thiophenes; Young Adult

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Japan; Male; Metformin; Middle Aged; Prospective Studies; Single-Blind Method; Sitagliptin Phosphate; Thiophenes; Treatment Outcome

To evaluate the efficacy and safety of ipragliflozin vs placebo as add-on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).. This double-blind, placebo-controlled, multi-centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).. In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add-on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were -0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference -0.83% [95% CI -1.07 to -0.59]; P < .0001). More ipragliflozin-treated patients than placebo-treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference -1.64 mmol/L, -1.50 μU/mL, -1.72 kg, and -0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.. Ipragliflozin as add-on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Male; Metformin; Middle Aged; Republic of Korea; Sitagliptin Phosphate; Thiophenes; Treatment Outcome; Young Adult

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β-cell function.

Topics: Adult; Aged; Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Glucosides; Humans; Japan; Male; Middle Aged; Sitagliptin Phosphate; Thiophenes

To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects.. Three trials with an open-label, randomized, two-way crossover design were conducted in healthy subjects. Ipragliflozin 150 mg, sitagliptin 100 mg, pioglitazone 30 mg or glimepiride 1-2 mg were administered alone or in combination. Primary endpoints were the area under the curve from the time of dosing to infinity (AUC(inf)) and the maximum observed plasma concentration (C(max)) of each drug.. Multiple doses of ipragliflozin did not change the AUC(inf) and C(max) of a single dose of sitagliptin, pioglitazone or glimepiride. All geometric mean ratios and 90% CIs for AUC(inf) and C(max) , with and without ipragliflozin, were within the predefined range of 80-125% (AUC(inf) : sitagliptin 100.1 [96.9-103.5], pioglitazone 101.7 [96.6-107.0], glimepiride 105.1 [101.3-109.0], and C(max) : sitagliptin 92.4 [82.8-103.1], pioglitazone 98.6 [87.7-110.8], glimepiride 110.0 [101.9-118.8]). Similarly, multiple doses of sitagliptin, pioglitazone or glimepiride did not change the pharmacokinetics of a single dose of ipragliflozin (AUC(inf) : 95.0 [93.4-103.1], 100.0 [98.1-102.0], 99.1 [96.6-101.6]; and C(max) : 96.5 [90.4-103.1], 93.5 [86.3-101.2], 97.3 [89.2-106.2]). Ipragliflozin either alone or in combination with any of the three glucose-lowering drugs was well tolerated in healthy subjects.. Ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa, suggesting that no dose-adjustments are likely to be required when ipragliflozin is given in combination with other glucose-lowering drugs in patients with type 2 diabetes mellitus.

Topics: Adolescent; Adult; Area Under Curve; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Female; Glucosides; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Thiophenes; Triazoles

Dipeptidyl peptidase-4 inhibitors have limited efficacy in improving glycemic control for obese Japanese patients with type 2 diabetes mellitus. Sodium-glucose co-transporter 2 inhibitors are recommended for use in patients with type 2 diabetes with obesity. Nevertheless, there has been no previously published study on the effect of switching from dipeptidyl peptidase-4 inhibitors to sodium-glucose co-transporter 2 inhibitors on the systemic and organic effects in obese Japanese patients with type 2 diabetes.. We evaluated the efficacy and safety of switching from sitagliptin to ipragliflozin for 24 weeks in obese Japanese patients with inadequately controlled type 2 diabetes.. Fifty-one obese patients with type 2 diabetes (body mass index > 25 kg/m. Switching from sitagliptin to ipragliflozin did not alter HbA1c in obese patients with type 2 diabetes, while improving parameters related to organ homeostasis. These data provide novel information useful for selecting oral anti-diabetic agents for patients with type 2 diabetes with obesity, a risk factor for developing various complications of diabetes.. Japan Registry of Clinical Trials identifier: jRCT#031190022.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Therapy, Combination; East Asian People; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Obesity; Sitagliptin Phosphate; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Symporters; Treatment Outcome