11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis

Introduction 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function. Methods The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.gov, and Cochrane Central. Results 1925 papers were identified, of which 29 were included in the final narrative synthesis. 11β-HSD1 and its inhibitors have been studied in diabetes, obesity, metabolic syndrome (MetS), and Alzheimer's disease (AD). Higher expression of 11β-HSD1 is seen in obesity and MetS, but has not yet been described in obesity or AD. Genetic studies identify 11β-HSD1 SNPs of interest in populations with diabetes, MetS, and AD. One phase II trial successfully reduced HbA1c in a diabetic population, however trials in MetS, obesity, and AD have not met primary endpoints. Conclusions Translation of this research from preclinical studies has proved challenging so far, however this is a growing area of research and more studies should focus on understanding the complex relationships between 11β-HSD1 and disease pathology, especially given the therapeutic potential of 11β-HSD1 inhibitors in development.