Final Takeaways: Screening, Cardiovascular Risk, and Treating Cortisol as the Root Cause

In the concluding segment, Ralph DeFronzo, MD, returns to a central message: hypercortisolism in difficult-to-control type 2 diabetes is substantially more common than many clinicians appreciate. He compares the evolution of thinking around primary aldosteronism—once deemed rare, now recognized as prevalent in resistant hypertension—to the growing recognition of cortisol excess in refractory diabetes. Just as guidelines now recommend screening for primary aldosteronism in resistant hypertension, Dr DeFronzo argues that clinicians should adopt a similar posture toward hypercortisolism in complex diabetic patients, particularly those on advanced therapies such as glucagon-like peptide-1 receptor agonists and tirzepatide who nonetheless remain poorly controlled.

Richard Auchus, MD, underscores that the overnight 1-mg dexamethasone suppression test is inexpensive, technically simple, and well suited to broad use. A single tablet at bedtime and one morning cortisol measurement can identify a meaningful subset of patients—on the order of 1 in 4 in enriched populations—who warrant further evaluation. Rather than viewing this as an additional burden, he frames it as an opportunity: when potent agents such as semaglutide, tirzepatide, and sodium-glucose cotransporter 2 inhibitors fail to normalize glycemia or blood pressure, uncovering hypercortisolism offers a clear, pathophysiologic explanation and a new therapeutic avenue.

Both faculty members close by highlighting that hypercortisolism is not solely a glycemic or blood pressure issue; it is a major driver of atherosclerotic cardiovascular disease, atrial fibrillation, stroke, and myocardial infarction. Dr DeFronzo notes that even when traditional risk factors such as hypertension and dyslipidemia are well treated, cardiovascular risk remains elevated because cortisol exerts direct detrimental effects on the arterial wall, skeletal muscle, skin, and bone quality. Surgical removal of cortisol-producing adenomas or medical blockade of cortisol action is therefore essential to normalize risk. The discussion ends with a call for heightened awareness, systematic screening, and proactive cortisol-directed therapy to improve long-term outcomes in patients with complex metabolic disease.