PMID- 31608926
OWN - NLM
STAT- MEDLINE
DCOM- 20201109
LR  - 20201109
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 105
IP  - 3
DP  - 2020 Mar 1
TI  - Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor 
      Glucagon-Like Peptide-1 and Glucagon Agonist.
LID - dgz047 [pii]
LID - 10.1210/clinem/dgz047 [doi]
AB  - CONTEXT: Cotadutide is a dual receptor agonist with balanced glucagon-like 
      peptide-1 and glucagon activity. OBJECTIVE: To evaluate different doses of 
      cotadutide and investigate underlying mechanisms for its glucose-lowering 
      effects. DESIGN/SETTING: Randomized, double-blind, phase 2a study conducted in 2 
      cohorts at 5 clinical trial sites. PATIENTS: Participants were 65 adult 
      overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 
      2 were withdrawn due to AEs. INTERVENTION: Once-daily subcutaneous cotadutide or 
      placebo for 49 days. Doses (50-300 microg) were uptitrated weekly (cohort 1) or 
      biweekly (cohort 2). MAIN OUTCOME MEASURES: Co-primary end points (cohort 1) were 
      percentage changes from baseline to end of treatment in glucose (area under the 
      curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and 
      weight. Exploratory measures included postprandial insulin and gastric emptying 
      time (GET; cohort 2). RESULTS: Patients received cotadutide (cohort 1, n = 26; 
      cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant 
      reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT 
      (least squares mean [90% CI], -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P 
      < 0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P = 
      0.002). A significant increase in insulin AUC0-4h post MMTT was observed with 
      cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 
      with cotadutide vs placebo (t(1/2): 117.2 minutes vs -42.9 minutes; P = 0.0392). 
      CONCLUSION: These results suggest that the glucose-lowering effects of cotadutide 
      are mediated by enhanced insulin secretion and delayed gastric emptying. TRIAL 
      REGISTRATION: ClinicalTrials.gov, NCT03244800.
CI  - (c) Endocrine Society 2019. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Parker, Victoria E R
AU  - Parker VER
AD  - AstraZeneca, Cambridge, England, UK.
FAU - Robertson, Darren
AU  - Robertson D
AD  - AstraZeneca, Cambridge, England, UK.
FAU - Wang, Tao
AU  - Wang T
AD  - AstraZeneca, Gaithersburg, MD, USA.
FAU - Hornigold, David C
AU  - Hornigold DC
AD  - AstraZeneca, Cambridge, England, UK.
FAU - Petrone, Marcella
AU  - Petrone M
AD  - AstraZeneca, Cambridge, England, UK.
FAU - Cooper, Aidan T
AU  - Cooper AT
AD  - AstraZeneca, Cambridge, England, UK.
FAU - Posch, Maximilian G
AU  - Posch MG
AD  - Charite Research Organisation GmbH, Berlin, Germany.
FAU - Heise, Tim
AU  - Heise T
AD  - Profil, Neuss, Germany.
FAU - Plum-Moerschel, Leona
AU  - Plum-Moerschel L
AD  - Profil, Mainz, Germany.
FAU - Schlichthaar, Heike
AU  - Schlichthaar H
AD  - SMO.MD, Magdeburg, Germany.
FAU - Klaus, Beate
AU  - Klaus B
AD  - Nuvisan Pharma Services, Ulm, Germany.
FAU - Ambery, Philip D
AU  - Ambery PD
AD  - AstraZeneca, Gothenburg, Sweden.
FAU - Meier, Juris J
AU  - Meier JJ
AD  - St Josef-Hospital, Ruhr-University, Bochum, Germany.
FAU - Hirshberg, Boaz
AU  - Hirshberg B
AD  - AstraZeneca, Gaithersburg, MD, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03244800
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Biomarkers)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Glucagon)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9007-92-5 (Glucagon)
RN  - QL6A9B13HW (cotadutide)
SB  - IM
MH  - Biomarkers/analysis
MH  - Diabetes Mellitus, Type 2/*drug therapy/epidemiology/metabolism/pathology
MH  - Double-Blind Method
MH  - Female
MH  - Follow-Up Studies
MH  - Glucagon/metabolism
MH  - Glucagon-Like Peptide 1/metabolism
MH  - Glucagon-Like Peptide-1 Receptor/*agonists
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Obesity/*physiopathology
MH  - Overweight/*physiopathology
MH  - Peptides/*therapeutic use
MH  - Prognosis
MH  - Receptors, Glucagon/*agonists
EDAT- 2019/10/15 06:00
MHDA- 2020/11/11 06:00
CRDT- 2019/10/15 06:00
PHST- 2019/05/14 00:00 [received]
PHST- 2019/09/20 00:00 [accepted]
PHST- 2019/10/15 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2019/10/15 06:00 [entrez]
AID - 5586886 [pii]
AID - 10.1210/clinem/dgz047 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz047. doi: 10.1210/clinem/dgz047.