Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-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.MethodsThis 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 (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–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.FindingsBoth 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 C_max 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.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.     

Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice

The combined glucose‐lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single‐dose or 4‐week dosing) in diabetic ob/ob mice. Vehicle‐corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post‐dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.     

Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study

Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was −5.0 U/L (95% confidence interval [CI] –6.4, −3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI –0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was −26.5 U/L (95% CI –28.6, −24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.