Associations of Plasma Concentration Profiles of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-Transporter Type 2, with Its Effects in Japanese Patients with Type 2 Diabetes Mellitus.

Tetsuo Hayakawa,Shinji Kobuchi,Toshiyuki Sakaeda,Kaede Kataoka,Kenichiro Kato

doi:10.3390/ph15020203

Tetsuo Hayakawa, Shinji Kobuchi + Show 3 more

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https://doi.org/10.3390/ph15020203

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Abstract

This study was conducted to evaluate the long-term plasma concentration profiles of dapagliflozin and its effects on the glycated hemoglobin (HbA1c) level, body weight, and estimated glomerular filtration rate (eGFR) in 72 Japanese outpatients with type 2 diabetes mellitus (T2DM) receiving metformin and a dipeptidyl peptidase-4 inhibitor. At baseline, HbA1c level, body weight, and eGFR were 6.9 ± 0.6%, 77.9 ± 13.5 kg, and 78.8 ± 20.7 mL/min/1.73 m2, respectively. A once-daily oral dose of 5 mg dapagliflozin was administered, and its trough plasma concentrations were evaluated at 1, 3, 6, 9, and 12 months. In this study, the patients with stable dapagliflozin concentrations were defined, based on a well-organized clinical trial, as those with average plasma concentrations of 2–5 ng/mL with a coefficient of variation <30%; these values were achieved if patients complied with their once-daily dosage. Multivariate analysis showed a significant decrease in the HbA1c levels among patients with stable concentrations (−0.6 ± 0.4%, p < 0.01), which was greater than the mean change among all 72 patients (−0.2 ± 0.5%, p < 0.01). The patients’ mean body weight also decreased (−2.3 ± 4.0 kg, p = 0.060). Average plasma concentrations ranged from 1.6 to 11.8 ng/mL; however, multivariate analysis indicated it was unrelated to the HbA1c-lowering effect. In conclusion, the long-term stability of plasma dapagliflozin concentration was important in lowering HbA1c level, and a once-daily oral dose of 5 mg was sufficient in achieving this effect.

Highlights

Sodium–glucose co-transporters (SGLTs), which are expressed in the proximal tubule, are involved in the renal reabsorption of glucose, and this process is mostly controlled by SGLT2 in the S1 segment [1,2]
SGLT2 inhibitors are a new class of agents used to treat type 2 diabetes mellitus (T2DM); they reduce glucose reabsorption and thereby reduce blood glucose without stimulating insulin release [1,2]
The incidence of fracture and amputation was reportedly similar between the dapagliflozin and placebo/control groups [13]; these events are more specific for canagliflozin [10]

Summary

Introduction

Sodium–glucose co-transporters (SGLTs), which are expressed in the proximal tubule, are involved in the renal reabsorption of glucose, and this process is mostly controlled by SGLT2 in the S1 segment [1,2]. SGLT2 inhibitors are a new class of agents used to treat type 2 diabetes mellitus (T2DM); they reduce glucose reabsorption and thereby reduce blood glucose without stimulating insulin release [1,2]. Placebo-controlled studies have suggested that SGLT2 inhibitors reduce the risk of cardiovascular adverse events [7,8,9,10], and they are considered key drugs for treating cardiovascular diseases. The adverse effects of dapagliflozin include transient renal impairment, volume depletion, and genital and urinary tract infections [13]. The incidence of fracture and amputation was reportedly similar between the dapagliflozin and placebo/control groups [13]; these events are more specific for canagliflozin [10]

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