Metabolic comorbidities of adrenal insufficiency: Focus on steroid replacement therapy and chronopharmacology.

Adrenal insufficiency (AI) is characterized by higher mortality and morbidity compared with the general population. Conventional replacement steroid therapy, currently recommended for the treatment of AI, is associated with increased frequency of metabolic comorbidities due to daily overexposure. By contrast, dual-release hydrocortisone is associated with a decreased risk of metabolic comorbidities, providing an adequate release of hydrocortisone and mimicking the physiological profile of cortisol. These favorable effects are due to a reduced daily steroid exposure that does not affect the expression of the clock genes which are involved in metabolic pathways and are regulated by the normal physiological circadian rhythm of endogenous cortisol. This narrative review focuses on the possible metabolic comorbidities of AI due to steroid replacement therapy, which evaluates the effects of conventional and novel drugs with attention to chronopharmacology.