Ralph DeFronzo, MD

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.

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.

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.

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.

Auchus and DeFronzo use the CATALYST trial to illustrate that both tumor-related and non-neoplastic hypercortisolism are common in refractory diabetes and respond to glucocorticoid receptor blockade, redefining “pseudo-Cushing” as a clinically important disease state.

Auchus and DeFronzo describe the underuse of hypercortisolism screening in primary care and outline a straightforward, clinically pragmatic approach to the overnight 1-mg dexamethasone suppression test and subsequent workup.

In this introductory segment, Richard Auchus, MD, and Ralph DeFronzo, MD, frame hypercortisolism as an underrecognized driver of difficult-to-control type 2 diabetes, hypertension, and osteoporosis, challenging the traditional view of Cushing syndrome as a rare disorder.

Panelists discuss how their key takeaways emphasize the importance of having a high index of suspicion for hypercortisolism, implementing routine screening in appropriate patients and educating primary care physicians to recognize the “big 4” symptoms of difficult-to-treat diabetes, hypertension, obesity, and bone disease.

Panelists discuss how future research should focus on understanding why hypercortisolism is becoming more prevalent, developing more specific treatments with fewer adverse effects, and determining optimal thresholds for circadian rhythm dysfunction and treatment duration.

Panelists discuss how monitoring patients on hypercortisolism treatments requires balancing safety (morning cortisol to avoid overtreatment) with efficacy (late-night salivary cortisol) while acknowledging the practical challenges and evolving best practices in this field.

Panelists discuss how new data show osilodrostat’s expanded FDA approval for Cushing syndrome demonstrates long-term efficacy in maintaining normal urinary-free cortisol levels, though careful dosing is required to avoid overtreatment and withdrawal symptoms.

Panelists discuss how the CATALYST study results can be applied to clinical practice by identifying patients on multiple diabetes medications who have poor control, emphasizing that this represents precision medicine for a specific population with an identifiable underlying cause.

Panelists discuss how the CATALYST study’s treatment phase results demonstrated that mifepristone significantly reduced hemoglobin A1C (HbA1C) level by 1.45% in patients with hypercortisolism and difficult-to-control diabetes while also reducing waist circumference and managing blood pressure effects.

Panelists discuss how monitoring effectiveness requires tracking clinical parameters such as glucose and blood pressure rather than cortisol levels when using receptor antagonists while carefully managing expected adverse effects such as hypokalemia and the need for close glucose monitoring, especially in insulin-dependent patients.

Panelists discuss how medical management options include steroidogenesis inhibitors and glucocorticoid receptor antagonists such as mifepristone, with particular emphasis on managing the complex withdrawal symptoms and coordinating care across multiple comorbidities including diabetes, hypertension, and osteoporosis.

Panelists discuss how surgical removal of adrenal adenomas remains first-line treatment when feasible but that many patients require medical therapy due to bilateral disease, surgical ineligibility, or the chronic nature of pituitary Cushing syndrome, with high recurrence rates even after successful surgery.

Panelists discuss how the 1-mg dexamethasone suppression test has become the simple, first-line screening tool for hypercortisolism, replacing more complex tests such as salivary cortisol or 24-hour urine collections, with practical tips for implementation and patient education.

Panelists discuss how hypercortisolism differs from classic Cushing syndrome and how 35% of patients in the CATALYST study had adrenal imaging abnormalities, emphasizing the importance of distinguishing between pituitary-dependent and adrenal-independent sources to guide appropriate treatment strategies.

Panelists discuss how the CATALYST trial results revealed a surprisingly high 25% prevalence of hypercortisolism in patients with difficult-to-control diabetes, fundamentally changing their approach to screening and recognizing this previously underdiagnosed condition affecting an estimated 1.2 million Americans.

Ralph A. DeFronzo, MD discusses the Noxious Nine and the impact of hypercortisolism on difficult-to-control type 2 diabetes.

Panelists discuss how treating hypercortisolism in patients may have long-term effects on glycemic control and overall health, potentially influencing future standards of care for difficult-to-control Type 2 diabetes, while emphasizing the need for clinicians to carefully manage such patients as ongoing research continues.

Experts discuss the CATALYST study's evaluation of mifepristone for hypercortisolism patients with hard-to-manage type 2 diabetes, its mechanism of action, suitable patient populations, treatment approaches for those with adrenal tumors, and factors determining surgical candidacy.

Key opinion leaders explore the diverse clinical manifestations of hypercortisolism across its spectrum of presentations.

Medical experts explore why findings from this study are crucial for clinicians managing diabetes, particularly those in primary care settings, and how these insights can impact their approach to patient care.

Medical experts discuss the implications of finding hypercortisolism in one-third of patients on three or more hypertension medications, the linkage between hypercortisolism and type 2 diabetes as presented in the ‘Pathologic Mechanisms of Hypercortisolism in Type 2 Diabetes’ session, and how hypercortisolism affects diabetes management, including the importance of addressing it and its consequences for patients with difficult-to-control diabetes.

The panel of medical experts discuss the prevalence of hypercortisolism based on the CATALYST trial.

The expert panel analyze data from the CATALYST trial.

Key opinion leaders navigate challenges associated with diabetes management.

The CATALYST study is discussed by a panel of experts led by Natalie Bellini, DNP, FNP-BC, BC-ADM, CDCES.

The panel concludes by discussing the long-term outcomes for patients treated for hypercortisolism, emphasizing the need for further studies and data, and sharing their final thoughts on the disease and its future management.