11β-HSD1 inhibitor efficacy in type 2 diabetes is cortisol-dependent

Cortisol excess drives multiple adverse effects including hypertension, dyslipidemia, and delayed wound healing. Activation of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has shown promise as a therapeutic target for these comorbidities but clinical progress has been hampered by variable 11β-HSD1 inhibitor efficacy. Here, transcriptomic profiling of 11β-HSD1 target genes in primary skin fibroblasts as well as skin biopsies from type 2 diabetes individuals treated with the selective 11β-HSD1 inhibitor AZD4017 provide detailed mechanistic insights highlighting new areas of therapeutic potential. We report correlations between changes in 11β-HSD1 target gene expression, blood pressure, lipids, and wound healing with 1) cortisol levels (serum cortisol / dehydroepiandrosterone sulfate) and 2) peripheral 11β-HSD1 activity (serum cortisol / cortisone). Finally, we demonstrate that baseline cortisol levels and changes in placebo group cortisol levels are key determinants of 11β-HSD1 inhibitor efficacy. In conclusion, our findings pave the way for more effective targeting of 11β-HSD1 inhibitor treatment, improving the accuracy of future clinical studies. Larger trials of longer duration are now warranted to fully explore the therapeutic potential of 11β-HSD1 inhibitors across a range of cardiometabolic and age-associated indications. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN74621291 ### Clinical Protocols ### Funding Statement This work was funded by a Medical Research Council Confidence in Concept Award to AT (MC\_PC\_15046), NIHR Senior Investigator Award to PMS (NF-SI-0514-10090), and the NIHR Leeds Biomedical Research Centre. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: North West Greater Manchester Central Research Ethics Committee (17/NW/0283) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials, with exception of the skin differentially expressed gene lists, which are subject to intellectual property due diligence and will be provided as a revised submission in due course.