Oral 11ß-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial.
Eur J Endocrinol
; 186(4): 441-455, 2022 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-35113805
ABSTRACT
BACKGROUND:
Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11ß-hydroxysteroid dehydrogenase type 1, 11ß-HSD1) impair wound healing.OBJECTIVES:
Efficacy, safety, and feasibility of 11ß-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 11ß-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 11 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 vivoskin 11ß-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI -3.4 to 5.5) but reduced systemic 11ß-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. SIGNIFICANCE STATEMENT Stress hormone activation by the enzyme 11ß-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11ß-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11ß-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11ß-HSD type 1 as a novel therapeutic target forchronic wounds.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
1_ASSA2030
/
2_ODS3
Problema de saúde:
1_doencas_nao_transmissiveis
/
2_muertes_prematuras_enfermedades_notrasmisibles
Assunto principal:
Piperidinas
/
Pele
/
Cicatrização
/
Niacinamida
/
Pé Diabético
/
11-beta-Hidroxiesteroide Desidrogenase Tipo 1
/
Diabetes Mellitus Tipo 2
Tipo de estudo:
Clinical_trials
Aspecto:
Patient_preference
Limite:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur J Endocrinol
Assunto da revista:
ENDOCRINOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido