Ralph DeFronzo, MD is a Professor of Medicine and Chief, Diabetes Division at UT Health San Antonio.

Ralph DeFronzo, MD 

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.

Key Takeaways on Hypercortisolism Management

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The clinical approach to hypercortisolism management emphasizes the critical importance of high clinical suspicion, particularly in patients who do not fit the typical phenotype for difficult-to-control diabetes. The “start low, go slow” principle is fundamental to successful treatment, with particular attention needed for older patients who may require dosing as infrequently as 2 to 3 times per week initially. Patient education about expected withdrawal symptoms and the timeline for improvement is crucial for treatment adherence and success.

Screening should become routine practice for patients meeting specific criteria: those on multiple diabetes medications with poor control, particularly when combined with multiple antihypertensive agents. The screening process using dexamethasone suppression testing is simple and cost-effective yet dramatically underused in clinical practice. Primary care physicians play a crucial role in initial recognition and screening, even if they refer patients to specialists for treatment management. The big 4 clinical indicators—difficult-to-treat diabetes, hypertension, central obesity, and bone disease—should trigger screening consideration.

The field represents a paradigm shift toward precision medicine in endocrinology, moving beyond broad-spectrum treatments to targeted, biomarker-driven therapy. The prevalence of hypercortisolism in clinical practice is likely much higher than currently recognized, suggesting that inadequate screening rather than disease rarity explains the apparent low incidence. Successful management requires not only biochemical control but also attention to the psychological and quality-of-life improvements that often accompany treatment, as patients frequently experience resolution of depression, cognitive improvement, and enhanced overall well-being alongside metabolic improvements.

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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.

Unmet Needs and Future Research Directions for Hypercortisolism

The fundamental question driving future research centers on understanding why hypercortisolism appears to be increasingly prevalent in modern society. Researchers propose that chronic stress from contemporary lifestyle factors—including constant connectivity, social media, and persistent stimulation—may be driving autonomous cortisol production. This parallels the historical evolution of subclinical hypothyroidism recognition, which progressed from being considered rare to becoming one of the most common referral reasons to endocrinology clinics. The pathophysiological mechanisms underlying this apparent epidemic require urgent investigation.

Future therapeutic developments focus on more selective and refined treatment options. The development of relacorilant, a more specific glucocorticoid receptor antagonist, promises to reduce adverse effects associated with mifepristone, including vaginal bleeding and endometrial thickening. Early data suggest relacorilant causes less corticotropin elevation and associated mineralocorticoid effects while maintaining efficacy in blood pressure reduction and glucose control. Additional compounds in development include CRH receptor antagonists and 11β-HSD type 1 inhibitors, which could provide tissue-specific cortisol modulation in liver and adipose tissue.

Research priorities include establishing thresholds for clinically significant circadian rhythm dysfunction and developing noninvasive continuous cortisol monitoring technologies. The potential for temporary treatment to reset circadian rhythms represents an intriguing therapeutic possibility that could transform hypercortisolism from a chronic condition to a potentially curable disorder. Understanding the relationship between insulin resistance and circadian disruption may reveal whether insulin sensitizers could help restore normal cortisol rhythms. The field also needs to address long-term management questions, including optimal treatment duration and strategies for preventing disease recurrence.

Monitoring for Treatment Effectiveness and Safety in Hypercortisolism Management.

New Data for Osilodrostat in Cushing Syndrome

Practical monitoring of patients on hypercortisolism treatment presents significant challenges, particularly with traditional markers such as 24-hour urinary-free cortisol collection, which suffers from poor patient adherence and collection accuracy. Most clinicians have moved toward a multimodal monitoring approach that balances safety concerns with therapeutic goals. Morning cortisol levels serve primarily as a safety measure to prevent overtreatment rather than as a therapeutic target, whereas late-night salivary cortisol provides a more practical assessment of treatment efficacy.

The monitoring strategy must account for the complex physiology of normal cortisol rhythm, which requires high morning levels and near-zero overnight values. Enzyme inhibitors such as osilodrostat can potentially flatten this natural rhythm, creating an artificial but not necessarily optimal cortisol pattern. The challenge lies in achieving adequate cortisol suppression without inducing adrenal insufficiency, requiring careful dose titration and frequent monitoring, especially during treatment initiation.

Clinical experience suggests that most practitioners are still developing optimal monitoring protocols for this emerging field. The approach typically involves periodic urinary-free cortisol measurements to ensure overall control, combined with regular morning cortisol checks to prevent dangerous overtreatment. The glucocorticoid receptor antagonist mifepristone offers some protection against adrenal crisis due to its mechanism of action, which allows the pituitary gland to increase ACTH production and drive cortisol levels up when needed. However, this can lead to secondary effects including hypertension and hypokalemia due to cortisol’s mineralocorticoid activity, requiring careful monitoring of blood pressure and electrolytes.

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.

Monitoring for Treatment Effectiveness and Safety in Hypercortisolism Management

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.

The FDA recently expanded osilodrostat’s label to include Cushing syndrome, extending beyond its previous indication limited to Cushing disease. This expansion was based on compelling data from the LINKS-6 and LINKS-7 studies, which demonstrated long-term efficacy in normalizing urinary-free cortisol across various causes of hypercortisolism. The LINKS-6 phase 4 study results showed that patients previously treated with osilodrostat maintained normal urinary-free cortisol levels over extended periods, with particular success in those achieving normal late-night salivary cortisol levels.

The LINKS-7 retrospective European study results revealed that 44% of patients with adrenal tumors or ectopic corticotropin syndrome maintained normal mean urinary-free cortisol at 12 weeks. These studies focused on patients with elevated urinary-free cortisol as the target for normalization, representing more severe hypercortisolism than the CATALYST study population. Although diabetes improvement was noted, these patients typically entered with hemoglobin A

 levels of approximately 7% to 7.5%, indicating less severe diabetes compared with the treatment-resistant population studied in CATALYST.

Recent research has explored circadian dosing strategies for osilodrostat, recognizing that the loss of normal cortisol circadian rhythm is central to the pathophysiology of hypercortisolism. The dexamethasone suppression test specifically evaluates the ability to suppress cortisol during early morning hours, and maintaining this natural rhythm may be crucial for optimal treatment outcomes. This approach addresses the fundamental issue that cortisol’s harmful effects are most pronounced when present during periods when it should naturally be suppressed, particularly overnight.

Ralph DeFronzo, MD

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