Richard Auchus, MD, PhD

In their closing remarks, Auchus and DeFronzo emphasize routine screening of high-risk patients, the persistent cardiovascular burden of hypercortisolism despite risk-factor treatment, and the necessity of targeting cortisol excess itself.

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.

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Auchus and DeFronzo survey the broader pharmacologic armamentarium for Cushing syndrome and hypercortisolism, including metyrapone, osilodrostat, ketoconazole, levoketoconazole, pasireotide, and investigational agents such as relacorilant and ACTH receptor antagonists.

Beyond Mifepristone: Enzyme Inhibitors, Pituitary-targeted Agents, and Emerging Therapies

In this segment, Richard Auchus, MD, broadens the discussion beyond mifepristone to review other medical therapies targeting cortisol synthesis and pituitary drivers of Cushing syndrome. He begins with metyrapone, a relatively weak 11β-hydroxylase inhibitor that has been used off label for many years. Metyrapone requires high total daily doses (often 1–3 g or more) divided three or four times a day, making it more suitable for inpatient settings where rapid titration and close monitoring are feasible. The newer 11β-hydroxylase inhibitor osilodrostat is highlighted as approximately 1000 times more potent, dosed once or twice daily in milligram rather than gram quantities, but with an attendant risk of overtreatment and adrenal insufficiency if not carefully managed—considerations that make endocrinology oversight essential.

Dr Auchus then reviews steroidogenesis inhibitors that have been used chronically, including ketoconazole and levoketoconazole. Ketoconazole, long employed off label for Cushing syndrome, is limited by a black box warning regarding hepatotoxicity and by the risk of QT prolongation. Levoketoconazole, the more potent 2S,4R stereoisomer, allows roughly half the dose and twice-daily rather than three-times-daily dosing, potentially improving tolerability and adherence. For pituitary-dependent Cushing disease, pasireotide—a somatostatin analog targeting somatostatin receptor subtype 5—can be useful, but is ineffective in ACTH-independent forms such as adrenal adenomas, reinforcing the importance of accurate etiologic classification before selecting therapy.

Finally, Ralph DeFronzo, MD, and Dr Auchus discuss emerging and investigational therapies. Relacorilant, a selective glucocorticoid receptor modulator that does not significantly block progesterone receptors, has completed major trials (GRACE and GRADIENT) and may avoid some gynecologic adverse effects seen with mifepristone, such as endometrial thickening and bleeding. Additional pipeline agents include ACTH receptor antagonists (eg, agents targeting melanocortin 2 receptor) for ACTH-dependent disease. Together, these agents expand the therapeutic landscape, providing multiple pharmacologic “Plan A, B, C, and D” options for patients who are not surgical candidates, have persistent or recurrent disease after surgery, or have non-neoplastic hypercortisolism. The segment underscores that, unlike in past decades, clinicians now have a diverse toolkit to tailor therapy to disease etiology, severity, and patient-specific risk profiles.

DeFronzo and Auchus underscore the magnitude of metabolic benefit with mifepristone, the complexity of managing withdrawal and electrolyte issues, and the importance of specialist support and education for primary care physicians.

Practical Use of Mifepristone and the Need for Endocrinology–Primary Care Collaboration

In this segment, Ralph DeFronzo, MD, elaborates on the practical magnitude of benefit observed with mifepristone in hypercortisolism, particularly in patients enrolled in trials like CATALYST. He reiterates that beyond the approximately 1.5–percentage point drop in hemoglobin A1c, patients experienced average weight loss of roughly 5 kg and a 5.1-cm reduction in waist circumference—changes that translate to meaningful alterations in body habitus. From a diabetes-management perspective, such improvements, combined with marked reductions in insulin dose, signal a fundamental shift in the underlying pathophysiology rather than incremental pharmacologic fine-tuning.

However, Dr DeFronzo and Richard Auchus, MD, candidly describe real-world barriers to safe and confident use of mifepristone, particularly in primary care. DeFronzo recounts an early CATALYST patient who developed glucocorticoid withdrawal symptoms, sought care from a primary physician unfamiliar with the trial, and was advised to stop the medication over concerns about adrenal crisis. This anecdote highlights how lack of familiarity with withdrawal phenomena and the expected rise in serum cortisol can lead to premature discontinuation or misinterpretation of adverse effects. Managing hypokalemia via spironolactone and other supportive strategies requires an understanding of the drug’s mechanistic profile and a proactive approach to monitoring.

To address these challenges, the faculty advocate for close collaboration between primary care and endocrinology. Primary care clinicians are best positioned to recognize high-risk patients—those with refractory diabetes and hypertension on multiple agents—whereas endocrinologists bring experience in interpreting hormone tests, managing cortisol-directed therapies, and counseling patients through withdrawal symptoms. Dr DeFronzo notes that manufacturers of mifepristone sponsor support programs that can help guide dosing, monitoring, and side-effect management for clinicians new to the therapy. Collectively, the speakers argue that a team-based model, with clear referral pathways and shared care, is essential to realizing the full potential of mifepristone in broader hypercortisolism management.

Auchus and DeFronzo review mifepristone (RU-486) as a glucocorticoid receptor antagonist for Cushing syndrome and refractory hypercortisolism, detailing its effects on glycemic control, weight, and safety considerations from the SEISMIC and CATALYST trials.

Mifepristone in Hypercortisolism: Mechanism, Metabolic Benefits, and Management Challenges

In this segment, Richard Auchus, MD, introduces mifepristone as a cornerstone medical therapy for Cushing syndrome and, increasingly, for hypercortisolism in difficult-to-control diabetes. Mifepristone (RU-486) is characterized as a potent oral glucocorticoid receptor antagonist that also blocks the progesterone receptor. Initially studied in the SEISMIC trial for overt Cushing syndrome, mifepristone is now leveraged in contexts like CATALYST where cortisol excess contributes to refractory metabolic disease. Dr Auchus notes that typical dosing ranges from 300 to 1200 mg once daily, with the drug acting primarily by blocking cortisol action at the receptor level rather than reducing cortisol production.

Clinical data from SEISMIC demonstrated robust metabolic benefits: approximately 7% weight loss over 6 months, reductions in waist circumference and body fat, and substantial improvement in glycemic control. The primary endpoints of improved glucose area under the curve on oral glucose tolerance testing and reduction in hemoglobin A1c were met, with early and clinically meaningful changes. In CATALYST, mifepristone similarly produced an A1c reduction of about 1.5 percentage points, meeting thresholds typically required for FDA approval of glucose-lowering agents. Ralph DeFronzo, MD, further underscores that patients achieved approximately 40% reductions in basal insulin requirements and significant decreases in prandial insulin, suggesting that the A1c improvement may understate the true therapeutic impact.

The faculty also review important safety and tolerability concerns. Because mifepristone blocks glucocorticoid receptors at the pituitary and peripheral tissues, serum cortisol levels often rise in compensation and can activate mineralocorticoid receptors, leading to hypertension and hypokalemia. In blinded trials such as CATALYST, investigators could not readily pre-empt these issues, leading to more frequent episodes of hypokalemia and blood pressure elevation than would be expected in open-label practice. Patients commonly experience a glucocorticoid withdrawal syndrome—fatigue, myalgias, and anorexia—analogous to postoperative recovery in surgically cured Cushing syndrome. Dr Auchus emphasizes that in routine clinical care, these effects can be mitigated by anticipatory monitoring, early use of spironolactone, potassium supplementation, and patient counseling, but they may challenge primary care clinicians less familiar with the drug’s nuances.

Richard Auchus, MD, PhD

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