Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial
Author(s)
Type
Journal Article
Abstract
Background
Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.
Objectives
Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.
Design
Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.
Methods
Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.
Results
Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivo skin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: −3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69–104%). Wound diameter was 34% (7–63%) smaller with AZD4017 at day 2, and 48% (12–85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.
Conclusion
A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.
Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.
Objectives
Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.
Design
Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.
Methods
Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.
Results
Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivo skin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: −3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69–104%). Wound diameter was 34% (7–63%) smaller with AZD4017 at day 2, and 48% (12–85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.
Conclusion
A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.
Date Issued
2022-04-01
Date Acceptance
2022-02-03
Citation
European Journal of Endocrinology (EJE), 2022, 186 (4), pp.441-455
ISSN
0804-4643
Publisher
Oxford University Press
Start Page
441
End Page
455
Journal / Book Title
European Journal of Endocrinology (EJE)
Volume
186
Issue
4
Copyright Statement
© The authors 2022. Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/35113805
Subjects
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1
BLOCKADE
COLLAGEN
DYNAMICS
EFFICACY
Endocrinology & Metabolism
EXPRESSION
GLUCOCORTICOID ACTIVATION
Life Sciences & Biomedicine
PERMEABILITY BARRIER
PSYCHOLOGICAL STRESS
SAFETY
Science & Technology
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2022-02-28