Cortisol in cardio-kidney-metabolic disease

Despite guideline-directed therapy, many patients with cardio-kidney-metabolic (CKM) disease remain uncontrolled due to therapeutic inertia, adherence barriers, and underrecognized secondary causes. Hypercortisolism, ranging from mild autonomous cortisol secretion (MACS) to overt Cushing syndrome, is an increasingly recognized contributor. MACS is associated with a 2.5-fold higher risk of cardiovascular death and increased prevalence of hypertension, type 2 diabetes mellitus (T2DM), and kidney impairment. Cortisol excess promotes muscle insulin resistance, hepatic gluconeogenesis, β-cell dysfunction, sodium retention, and vascular remodelling, worsening glycaemia and blood pressure, leading to poor CKM outcomes. Recent prospective studies suggest that hypercortisolism is more prevalent than previously suspected in selected CKM phenotypes, including 24% in patients with difficult-to-control T2DM in CATALYST and 27% in patients with resistant hypertension in MOMENTUM. The overnight 1 mg dexamethasone suppression test remains the diagnostic test of choice. Therapeutic strategies include adrenal steroidogenesis inhibitors, glucocorticoid receptor antagonists, and pituitary-directed therapies in selected cases, while surgery remains the first-line treatment for surgically remediable disease. This review summarizes the epidemiology and mechanisms linking cortisol excess to CKM dysfunction, and also highlights the need for clinical trials, standardized diagnostic thresholds, and assays to enable integration of cortisol-targeted therapies into management pathways to mitigate residual CKM risk. This review will serve as a practical guide for cardiologists to manage a potentially reversible contributor to poor CKM control.