Dataset Information

Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

ABSTRACT:

Aims

To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development.

Methods

We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years.

Results

Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration).

Conclusions

After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).

SUBMITTER: Laffel LMB

PROVIDER: S-EPMC6099360 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

Laffel L M B LMB Tamborlane W V WV Yver A A Simons G G Wu J J Nock V V Hobson D D Hughan K S KS Kaspers S S Marquard J J

Diabetic medicine : a journal of the British Diabetic Association 20180506 8

<h4>Aims</h4>To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development.<h4>Methods</h4>We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years.<h4>Results</h4>Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd ...[more]

PMID: 29655290

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Project description:PurposeCombination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects.Subjects and methodsA randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25.ResultsThe steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well.ConclusionThe lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment.Trial registration numberNCT02854748, Registered on August 7, 2016.

Project description:BackgroundThe treatment duration of insulin-sodium-glucose co-transporter inhibitors (SGLTis) co-treatment of type 1 diabetes mellitus (T1DM) patients in randomized controlled trials (RCTs) varies by 1-52 weeks. Henceforth, treatment duration-wise, we compared the following insulin-treatment adjuncts- mega- versus low-dose SGLTis, SGLTis versus placebo, and different SGLTi dosages.MethodDouble-blinded RCTs reporting the above were searched (using terms like insulin-dependent, "juvenile-onset diabetes," and "sodium glucose cotransport*") in the PubMed, Embase, and Scopus databases and appraised using a Cochrane tool. The risks across different SGLTi-dosages were compared using network meta-analysis. Random-effect pairwise meta-analysis was performed for the remaining harm juxtapositions. Meta-analyses were performed for the following treatment durations- < 4 weeks, 4 to < 24 weeks, and ≥ 24 weeks. For meta-analysis and certainty of evidence assessment, we used the Stata statistical software and the GRADE method, respectively.ResultsA total of 15 (low risks of bias) studies sourcing data from about 7,330 T1DM patients were reviewed. Meta-analysis findings of ≥ 24 weeks long trials were- a. SGLTi-insulin co-treatment increased the genital infection (GI) (RR: 3.51; 95% CI: 2.59, 4.77), diabetic ketoacidosis (DKA) and (RR: 3.25; 95% CI:1.29, 8.16), and serious side effects (RR: 1.43; 95% CI: 1.05, 1.94) risk. b. SGLT2i-insulin increased the GI risk (RR: 3.77; 95% CI: 2.31, 6.16; high-quality evidence). c. Sotagliflozin-insulin increased the GI (RR: 3.36; 95% CI: 2.28, 4.96) and DKA (RR: 6.69; 95% CI: 2.75, 16.32) risk (both high-quality evidence). Compared to low-dose, megadose SGLTi treatment for 4 to < 24 weeks increased the GI risk. The remaining analyses were not statistically significantly different.ConclusionOn moderate to long-term treatment (24-52 weeks) of T1DM patients, insulin-SGLT2i co-treatment was associated with GI risk, and insulin-sotagliflozin co-treatment was associated with DKA and GI risk.Supplementary informationThe online version contains supplementary material available at 10.1007/s40200-023-01192-7.

Project description:Background We determined if the sodium glucose co-transporter 2 inhibitor empagliflozin attenuates pressure overload-induced heart failure in non-diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4-6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction-induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate-activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate-activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure-overload in non-diabetic mellitus mice.

Project description:IntroductionThis randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.MethodsPatients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.ResultsCanagliflozin increased UGE dose-dependently (∼80-120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.ConclusionsCanagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.Trial registrationClinicalTrials.gov NCT00963768.

Project description:IntroductionThis randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.MethodsPatients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.ResultsCanagliflozin increased UGE dose-dependently (,80-120 g/day with canagliflozin $100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ,4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.ConclusionsCanagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.Trial registrationClinicalTrials.gov NCT00963768.

Dataset Information

Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

Aims

Methods

Results

Conclusions

Publications

Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

Similar Datasets

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