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.