The Potential Role of SGLT2 Inhibitors in Cushing's Disease

Cushing's disease (CD) is a rare endocrine disorder caused by the overproduction of adrenocorticotrophin hormone (ACTH) from a pituitary tumour, leading to excessive secretion of cortisol. The chronic exposure to cortisol leads to endocrine and cardiovascular complications that persist even after remission of hypercortisolism. CD is associated with a significant clinical burden characterised by insulin resistance, renal dysfunction and cardiovascular complications. In addition, patients frequently experience impaired health-related quality of life (HRQoL) and have an increased risk of mortality. There are currently no approved therapies targeting these complications. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycaemic agents that target SGLT2 transporters in the renal proximal convoluted tubules, thus leading to glycosuria and reduction of glycaemia. Initially approved as anti-diabetic agents, SGLT2i have subsequently revealed to exert a wide range of beneficial effects, namely cardiorenal protection; therefore having been recently approved as a first-line treatment for chronic kidney disease and heart failure, regardless of the presence of diabetes. While the clinical and metabolic efficacy of SGLT2i has been extensively documented in type 2 diabetes, heart failure and chronic kidney disease, their systemic effects may also be relevant in patients with CD, who exhibit cardiovascular, renal and metabolic alterations even after biochemical remission. The myriad benefits of SGLT2i align closely with the unmet clinical needs for new medical treatment for patients with CD, supporting their potential therapeutic relevance in this disease. Accordingly, we herein review the pathophysiology, clinical presentation and treatment of CD, and explore the potential therapeutic benefit of SGLT2i in this disorder.