Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist.
J Clin Endocrinol Metab
; 105(3)2020 03 01.
Article
in En
| MEDLINE
| ID: mdl-31608926
ABSTRACT
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Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.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 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). MAIN OUTCOMEMEASURES:
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 (t½ 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides
/
Receptors, Glucagon
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Diabetes Mellitus, Type 2
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Overweight
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Glucagon-Like Peptide-1 Receptor
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Obesity
Type of study:
Clinical_trials
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
J Clin Endocrinol Metab
Year:
2020
Document type:
Article
Affiliation country:
United kingdom