Urinary glucose excretion after dapagliflozin treatment: An exposure‐response modelling comparison between Japanese and non‐Japanese patients diagnosed with type 1 diabetes mellitus

Соколов, В. В.; Yakovleva, Tatiana A.; Ueda, Shinya; Parkinson, Joanna; Boulton, David W.; Penland, Robert C.; Tang, Weifeng

doi:10.1111/dom.13586

Cited by 6 publications

(7 citation statements)

References 20 publications

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“…The identified covariates, baseline eGFR and 24‐hour median blood glucose had significant impact on dapagliflozin efficacy (as measured by UGE) in both studies. This is consistent with the previously developed PK/PD model for T1DM in adults, where baseline eGFR and 24‐hour median blood glucose were found to affect dapagliflozin E max and AUC24 50 …”

Section: Discussionsupporting

confidence: 91%

“…For example, Sokolov et al . reported that blood glucose was the most influential covariate on dapagliflozin UGE efficacy in adult patients with T1DM while fasting plasma glucose had a larger impact on dapagliflozin efficacy than renal function in adult and paediatric patients with T2DM …”

Section: Discussionmentioning

confidence: 99%

“…Baseline eGFR, fasting plasma glucose and sex were significant covariates that affected dapagliflozin UGE response (additionally race was identified as a covariate in paediatric patients; this was suggested to be related to the potentially inaccurate assessment of the true renal function in black paediatric patients with T2DM). The ER model developed using data from adult patients with T1DM showed that average self‐monitored blood glucose, change from baseline in total insulin dose, and baseline eGFR had a significant effect on 24‐hour UGE, with self‐monitored blood glucose being the most influential …”

Section: Methodsmentioning

confidence: 99%

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Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus

Busse

Tang

Scheerer

et al. 2019

Brit J Clinical Pharma

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Funding information AstraZenecaAims: To quantitatively compare pharmacokinetics (PK) and the exposure-response (ER) relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM).Methods: Data from 2 clinical studies for dapagliflozin were analysed using a nonlinear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-hour urinary glucose excretion) were characterized. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model.The 24-hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates. Results:A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24-hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model-predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-hour median blood glucose in this trial.Conclusions: Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus

Busse

Tang

Scheerer

et al. 2019

Brit J Clinical Pharma

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“…The impact of insulin dose reduction on SGLT2 inhibitor efficacy has been previously described in terms of urinary glucose excretion, where T1DM patients who had greater total insulin dose reduction were also observed to have a more pronounced urinary glucose excretion response. 28,29 It is unclear why a similar covariate effect was not identified in the current analysis.…”

Section: Discussionmentioning

confidence: 70%

“…28,29 It is unclear why a similar covariate effect was not identified in the current analysis. The impact of insulin dose reduction on SGLT2 inhibitor efficacy has been previously described in terms of urinary glucose excretion, where T1DM patients who had greater total insulin dose reduction were also observed to have a more pronounced urinary glucose excretion response.…”

Section: Exposure-response Modelmentioning

confidence: 70%

Model‐based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Parkinson

Tang

Åstrand

et al. 2019

Diabetes Obesity Metabolism

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Aims To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects. Materials and Methods Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24‐week treatment with once‐daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non‐linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non‐Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates. Results A maximum effect (Emax) model identified a positive exposure–response relationship. Model‐predicted placebo‐corrected HbA1c reductions after 24 weeks for dapagliflozin 5‐ and 10‐mg doses were − 0.42% [95% confidence interval (CI) −0.47 to −0.36) and − 0.45% (95% CI −0.50 to −0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions. Conclusions The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. http://ClinicalTrials.gov, NCT02268214; NCT02460978.

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Sodium–glucose cotransporter 2 inhibitors as an add-on therapy to insulin for type 1 diabetes mellitus: Meta-analysis of randomized controlled trials

Rao¹,

Ren

Luo

et al. 2021

Acta Diabetol

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Aims The aim was to systematically review the efficacy and safety of sodium–glucose cotransporter inhibitor (SGLT2i) as an adjunct to insulin at different follow-up durations in randomized, double-blind clinical trials in patients with type 1 diabetes. Methods We conducted a search on Medline, Embase, and the Cochrane Library for relevant studies published before May 2020. According to the duration of follow-up, the subgroup analysis included four periods: 1–4, 12–18, 24–26, and 52 weeks. In the five trials included both 24–26 and 52 weeks of follow-up, we compared the efficacy by the placebo-subtracted difference and changes in SGLT2i groups. Results Fifteen trials including 7109 participants were analyzed. The combination of SGLT2i and insulin improved hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), daily insulin dose, body weight, and blood pressure, which varied greatly by different follow-ups. Compared with %HbA1c at 24–26 weeks, placebo-subtracted differences and changes in the SGLT2i groups slightly increased. SGLT2i plus insulin treatment showed no difference in the occurrence of urinary tract infections (UTIs), hypoglycemia, or severe hypoglycemia but increased the risk of genital tract infections (GTIs) in a duration-dependent manner. SGLT2i treatment was associated with a significantly higher rate of ketone-related SAEs and diabetic ketoacidosis (DKA) at 52 weeks. Conclusion SGLT2i as an add-on therapy to insulin improved glycemic control and body weight and decreased the required dose of insulin without increasing the risk of hypoglycemia. However, after 6 months the benefits of SGLT2is on glycemic control may weaken and the risks of GTIs and DKA increased.

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Urinary glucose excretion after dapagliflozin treatment: An exposure‐response modelling comparison between Japanese and non‐Japanese patients diagnosed with type 1 diabetes mellitus

Cited by 6 publications

References 20 publications

Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus

Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus

Model‐based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Sodium–glucose cotransporter 2 inhibitors as an add-on therapy to insulin for type 1 diabetes mellitus: Meta-analysis of randomized controlled trials

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