Is Hypercortisolism Treatable? Which Patients Should Be Treated and How-A Practical Guide for Clinicians

To provide a practical guide on when to suspect endogenous hypercortisolism, how to use the overnight 1-mg dexamethasone suppression test (DST) for targeted case-finding, and which patients are most likely to benefit from treatment.

This narrative review synthesizes evidence from clinical practice guidelines, prospective prevalence studies, randomized controlled trials, systematic reviews, and meta-analyses addressing the recognition, diagnosis, and management of endogenous hypercortisolism in patients with treatment-resistant type 2 diabetes (T2D), resistant hypertension, and adrenal incidentalomas.

Confirmed endogenous hypercortisolism is found in 0.6%-3.4% of broader T2D cohorts after stepwise biochemical evaluation, but recent prospective studies-including CATALYST and MOMENTUM-report abnormal cortisol suppression in approximately one in four patients within selected high-risk groups. Mild autonomous cortisol secretion (MACS), defined as ACTH-independent cortisol production with post-dexamethasone serum cortisol > 50 nmol/L (> 1.8 μg/dL) in the absence of classic Cushingoid features, is associated with clinically meaningful increases in hypertension, T2D, visceral adiposity, and all-cause mortality. Routine screening of all patients with diabetes or hypertension is not recommended; testing should be reserved for those with multiple, progressive, or atypical cardiometabolic features, or with adrenal incidentalomas. Attention to test timing, drug interactions, and physiologic non-neoplastic hypercortisolism is essential for accurate interpretation. When etiology and laterality permit, surgical resection offers the best chance for durable remission. When surgery is not feasible, not curative, or declined, medical alternatives-including glucocorticoid-receptor antagonists (e.g., mifepristone) and steroidogenesis inhibitors (e.g., osilodrostat, ketoconazole)-can reduce cortisol activity or lower cortisol production, each with specific efficacy, tolerability, and safety considerations warranting endocrinologist involvement.

As cortisol activity falls, glucose- and blood-pressure medications often require down-titration. Monitoring for adrenal insufficiency, cortisol withdrawal syndrome, and drug-specific adverse effects requires coordinated multidisciplinary follow-up. Through careful evaluation and targeted treatment, hypercortisolism can be recognized and managed as a modifiable contributor to cardiometabolic risk.