PMID- 36890732
OWN - NLM
STAT- MEDLINE
DCOM- 20230412
LR  - 20230420
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 12
IP  - 4
DP  - 2023 Apr
TI  - A model-based meta analysis study of sodium glucose co-transporter-2 inhibitors.
PG  - 487-499
LID - 10.1002/psp4.12934 [doi]
AB  - Type 2 diabetes mellitus (T2DM) agent sodium-glucose co-transporter 2 (SGLT2) 
      inhibitors show special benefits in reducing body weight and heart failure risks. 
      To accelerate clinical development for novel SGLT2 inhibitors, a quantitative 
      relationship among pharmacokinetics, pharmacodynamics, and disease end points 
      (PK/PD/end points) in healthy subjects and patients with T2DM was developed. 
      PK/PD/end point data in published clinical studies for three globally marketed 
      SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected 
      according to pre-set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting 
      plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A 
      two-compartmental model with Hill's equation was utilized to capture PK/PD 
      profiles. A novel translational biomarker, the change of urine glucose excretion 
      (UGE) from baseline normalized by FPG (DeltaUGE(c) ) was identified to bridge healthy 
      subjects and patients with T2DM with different disease statuses. DeltaUGE(c) was 
      found to have a similar maximum increase with different half-maximal effective 
      concentration values of 56.6, 2310, and 841 mg/mL.h for dapagliflozin, 
      canagliflozin, and empagliflozin respectively. DeltaUGE(c) will change FPG based on 
      linear function. HbA1c profiles were captured by indirect response model. 
      Additional placebo effect was also considered for both end points. The PK/DeltaUGE(c) 
      /FPG/HbA1c relationship was validated internally using diagnostic plots and 
      visual assessment and further validated externally using the fourth globally 
      approved same-in-class drug (ertugliflozin). This validated quantitative 
      PK/PD/end point relationship offers novel insight into long-term efficacy 
      prediction for SGLT2 inhibitors. The novelty identified DeltaUGE(c) could make the 
      comparison of different SGLT2 inhibitors' efficacy characteristics easier, and 
      achieve early prediction from healthy subjects to patients.
CI  - (c) 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by 
      Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Yao, Xueting
AU  - Yao X
AD  - Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking 
      University Third Hospital, Beijing, China.
AD  - Center of Clinical Medical Research, Institute of Medical Innovation and 
      Research, Peking University Third Hospital, Beijing, China.
FAU - Zhou, Jiawei
AU  - Zhou J
AD  - Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, 
      University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
FAU - Song, Ling
AU  - Song L
AD  - Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking 
      University Third Hospital, Beijing, China.
AD  - Center of Clinical Medical Research, Institute of Medical Innovation and 
      Research, Peking University Third Hospital, Beijing, China.
FAU - Ren, Yupeng
AU  - Ren Y
AD  - Johnson & Johnson Pharmaceuticals (Shanghai) Ltd., Shanghai, China.
FAU - Hu, Pei
AU  - Hu P
AD  - Clinical Pharmacology Research Center, Peking Union Medical College Hospital & 
      Chinese Academy of Medical Sciences, Beijing, China.
FAU - Liu, Dongyang
AU  - Liu D
AUID- ORCID: 0000-0002-0608-8192
AD  - Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking 
      University Third Hospital, Beijing, China.
AD  - Center of Clinical Medical Research, Institute of Medical Innovation and 
      Research, Peking University Third Hospital, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20230308
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - HDC1R2M35U (empagliflozin)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 0SAC974Z85 (Canagliflozin)
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Glycated Hemoglobin)
RN  - 0 (Symporters)
RN  - IY9XDZ35W2 (Glucose)
RN  - 9NEZ333N27 (Sodium)
RN  - Diabetes Mellitus, Noninsulin-Dependent, 2
SB  - IM
MH  - Humans
MH  - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Canagliflozin/pharmacology
MH  - Hypoglycemic Agents/pharmacology/therapeutic use
MH  - Glycated Hemoglobin
MH  - *Symporters/therapeutic use
MH  - Glucose/therapeutic use
MH  - Sodium
PMC - PMC10088079
COIS- The authors declared no competing interests for this work.
EDAT- 2023/03/10 06:00
MHDA- 2023/04/12 06:42
PMCR- 2023/03/08
CRDT- 2023/03/09 01:43
PHST- 2022/12/31 00:00 [revised]
PHST- 2022/07/12 00:00 [received]
PHST- 2023/01/26 00:00 [accepted]
PHST- 2023/04/12 06:42 [medline]
PHST- 2023/03/10 06:00 [pubmed]
PHST- 2023/03/09 01:43 [entrez]
PHST- 2023/03/08 00:00 [pmc-release]
AID - PSP412934 [pii]
AID - 10.1002/psp4.12934 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2023 Apr;12(4):487-499. doi: 
      10.1002/psp4.12934. Epub 2023 Mar 8.