PMID- 33368935
OWN - NLM
STAT- MEDLINE
DCOM- 20210709
LR  - 20220531
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Linking)
VI  - 23
IP  - 4
DP  - 2021 Apr
TI  - A model-based approach to investigating the relationship between glucose-insulin 
      dynamics and dapagliflozin treatment effect in patients with type 2 diabetes.
PG  - 991-1000
LID - 10.1111/dom.14305 [doi]
AB  - AIMS: To develop a quantitative systems pharmacology model to describe the effect 
      of dapagliflozin (a sodium-glucose co-transporter-2 [SGLT2] inhibitor) on 
      glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients, and to 
      identify key determinants of treatment-mediated glycated haemoglobin (HbA1c) 
      reduction. MATERIALS AND METHODS: Glycaemic control during dapagliflozin 
      treatment was mechanistically characterized by integrating components 
      representing dapagliflozin pharmacokinetics (PK), glucose-insulin homeostasis, 
      renal glucose reabsorption, and HbA1c formation. The model was developed using PK 
      variables, glucose, plasma insulin, and urinary glucose excretion (UGE) from a 
      phase IIa dapagliflozin trial in patients with T2DM (NCT00162305). The model was 
      used to predict dapagliflozin-induced HbA1c reduction; model predictions were 
      compared to actual data from phase III trials (NCT00528879, NCT00683878, 
      NCT00680745 and NCT00673231). RESULTS: The integrated 
      glucose-insulin-dapagliflozin model successfully described plasma glucose and 
      insulin levels, as well as UGE in response to oral glucose tolerance tests and 
      meal intake. HbA1c reduction was also well predicted. The results show that 
      dapagliflozin-mediated glycaemic control is anticorrelated to steady-state 
      insulin concentration and insulin sensitivity. CONCLUSIONS: The developed model 
      framework is the first to integrate SGLT2 inhibitor mechanism of action with both 
      short-term glucose-insulin dynamics and long-term glucose control (HbA1c). The 
      results suggest that dapagliflozin treatment is beneficial in patients with 
      inadequate glycaemic control from insulin alone and this benefit increases as 
      insulin control diminishes.
CI  - (c) 2020 John Wiley & Sons Ltd.
FAU - Shah, Millie
AU  - Shah M
AUID- ORCID: 0000-0002-7611-5504
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland.
FAU - Stolbov, Leonid
AU  - Stolbov L
AUID- ORCID: 0000-0002-3258-8350
AD  - M&S Decisions, Moscow, Russia.
FAU - Yakovleva, Tatiana
AU  - Yakovleva T
AUID- ORCID: 0000-0002-9715-0931
AD  - M&S Decisions, Moscow, Russia.
FAU - Tang, Weifeng
AU  - Tang W
AUID- ORCID: 0000-0002-8261-8116
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland.
FAU - Sokolov, Victor
AU  - Sokolov V
AUID- ORCID: 0000-0001-7066-0811
AD  - M&S Decisions, Moscow, Russia.
FAU - Penland, Robert C
AU  - Penland RC
AUID- ORCID: 0000-0003-2706-8913
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts.
FAU - Boulton, David
AU  - Boulton D
AUID- ORCID: 0000-0002-0668-7304
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland.
FAU - Parkinson, Joanna
AU  - Parkinson J
AUID- ORCID: 0000-0003-4492-5243
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
LA  - eng
SI  - ClinicalTrials.gov/NCT00680745
SI  - ClinicalTrials.gov/NCT00673231
SI  - ClinicalTrials.gov/NCT00683878
SI  - ClinicalTrials.gov/NCT00528879
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210125
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Blood Glucose)
RN  - 0 (Glucosides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Benzhydryl Compounds
MH  - Blood Glucose
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Glucose
MH  - Glucosides
MH  - Humans
MH  - Hypoglycemic Agents/therapeutic use
MH  - Insulin
MH  - Treatment Outcome
OTO - NOTNLM
OT  - SGLT2 inhibitor
OT  - dapagliflozin
OT  - drug
OT  - mechanism
OT  - pharmacodynamics
OT  - type 2 diabetes
EDAT- 2020/12/29 06:00
MHDA- 2021/07/10 06:00
CRDT- 2020/12/28 12:38
PHST- 2020/12/04 00:00 [revised]
PHST- 2020/09/17 00:00 [received]
PHST- 2020/12/15 00:00 [accepted]
PHST- 2020/12/29 06:00 [pubmed]
PHST- 2021/07/10 06:00 [medline]
PHST- 2020/12/28 12:38 [entrez]
AID - 10.1111/dom.14305 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2021 Apr;23(4):991-1000. doi: 10.1111/dom.14305. Epub 2021 
      Jan 25.