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Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). DECLARE–TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231. The DECLARE–TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE–TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

•Fixed-dose combination (FDC) was bioequivalent to individual components (ICs) in Western and Korean adults.•Pharmacokinetic parameters of FDC and IC were generally similar.•No clinically relevant pharmacokinetic differences in Western vs Korean participants.•FDC and ICs were well tolerated, with no serious adverse events. We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM). Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18–55 years; Western study) and South Korean participants (aged 19–55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration–time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration–time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study. Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000–1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations. The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen. Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).

The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were C max , T max , t 1/2 , elimination rate constant, AUC 0-t and AUC 0-inf . The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25–600 ng mL −1 ) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

Envlo (enavogliflozin) 0.3 mg, an SGLT2 inhibitor, was approved in Korea in 2022 for glycemic control in type 2 diabetes (T2DM). This study evaluates its safety, pharmacokinetics, and food effects. Healthy subjects (age ≥ 19, weight ≥ 50.0 kg, body mass index (BMI) 18.0–30.0 kg/m2) were enrolled. Study I was a randomized, two‐way crossover study with an 8‐day washout, where subjects received either a separate or a fixed‐dose combination (FDC) of enavogliflozin 0.3 mg/gemigliptin 50 mg. Study II, a randomized, open‐label, two‐way crossover design with a 7‐day washout, compared the food effect of a single dose of enavogliflozin in fed versus fasted after a high‐fat meal. In study I, enavogliflozin reached peak plasma concentration at 1.25 h (median) in both groups. The mean half‐life (t1/2) was also comparable, recorded as 12.56 ± 4.04 h for the separate combination and 12.23 ± 3.46 h for the FDC. Gemigliptin peaked at 2.00 h in the separate combination and at 3.00 h in the FDC. The mean t1/2 was 18.04 ± 1.75 h for the separate combination and 18.67 ± 2.54 h for the FDC. In study II, the plasma concentration of enavogliflozin 0.3 mg peaked at 1.25 and 2.00 h (median), indicating a delayed Tmax in the fed group. The average t1/2 was similar at 12.49 ± 2.12 h and 12.30 ± 2.81 h, respectively. The FDC of enavogliflozin and gemigliptin demonstrated pharmacokinetic equivalence and comparable safety to their co‐administration as separate agents. Furthermore, the systemic exposure of enavogliflozin was not affected by food intake, supporting its potential for flexible, meal‐independent use in clinical settings.

Empagliflozin is an oral, potent, and selective inhibitor of sodium glucose cotransporter 2, inhibition of which reduces renal glucose reabsorption and results in increased urinary glucose excretion. Linagliptin is an oral inhibitor of dipeptidyl peptidase-4 approved for the treatment of type 2 diabetes in the United States, Europe, Japan, and Canada. Due to their complementary modes of action, there is a good rationale to combine empagliflozin with linagliptin to improve glycemic control in patients with type 2 diabetes. This study was conducted to investigate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy volunteers. This was an open-label, randomized, multiple-dose, crossover study with 3 treatments in 2 treatment sequences. Sixteen healthy male subjects received treatment A (empagliflozin 50 mg once daily [QD] for 5 days), treatment B (empagliflozin 50 mg QD and linagliptin 5 mg QD for 7 days), and treatment C (linagliptin 5 mg QD for 7 days) in sequence AB then C, or sequence C then AB. Sixteen healthy male subjects aged between 18 and 50 years with a body mass index of 18.5 to 29.9 kg/m2 were included in the study. Linagliptin total exposure (AUC over a uniform dosing interval τ at steady state geometric mean ratio [GMR], 1.03 [90% CI, 0.96–1.11]) and peak exposure (Cmax at steady state GMR, 1.01 [90% CI, 0.87–1.19) exposure was unaffected by coadministration of empagliflozin. Empagliflozin total exposure (AUC over a uniform dosing interval τ at steady state GMR, 1.02 [90% CI, 0.97–1.07]) was unaffected by coadministration of linagliptin. There was a reduction in empagliflozin peak exposure (Cmax at steady state GMR, 0.88 [90% CI, 0.79–0.99]) when linagliptin was coadministered that was not considered clinically meaningful. No adverse events were reported during the coadministration period. No hypoglycemia was reported. Empagliflozin and linagliptin were well tolerated. These data support the coadministration of empagliflozin and linagliptin without dose adjustments. European Union Drug Regulating Authorities Clinical Trials Registration: EudraCT 2008-006089-27.

Fixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR. This randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC0–∞, AUC0–t, and Cmax) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The Cmax and AUC0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments. Both dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin Cmax was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported. These data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.

Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation. Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0–t, Cmax, and Cmax/AUC0–t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed. Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events. Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239.

Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose–lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%–125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%–125%. Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392

Empagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug−drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR). This was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%−125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability. Mean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m2. Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1−118.1) and 102.8% (90% CI, 88.6−119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1−116.1) and 107.5% (90% CI, 97.9−118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1−104.0) and 101.8% (90% CI, 88.6−116.9), respectively, and for TOR were 101.4% (90% CI, 99.1−103.9) and 104.4% (90% CI, 93.8−116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported. No pharmacokinetic drug−drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288.

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug–drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug–drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0–∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87–107.20; Cmax: GMR, 92.39%; 90% CI, 85.38–99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05–100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65–111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51–116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73–119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00–101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67–104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0–∞ (GMR, 106.11%; 90% CI, 96.71–116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33–130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).