Why Pharmacists Are the New Frontline in Identifying Hypercortisolism

The traditional clinical image of Cushing syndrome is increasingly being recognized as an outdated diagnostic anchor that overlooks a vast spectrum of patients. Modern endocrinology has shifted toward the term hypercortisolism to better describe the pathophysiologic state of excess tissue exposure to glucocorticoids, which often presents without these classic phenotypic markers.

In the Drug Topics Practice and Innovation Collaborative, endocrinologists, cardiologists, and pharmacists highlighted that many patients with seemingly primary hypertension or type 2 diabetes (T2D) may actually be suffering from undiagnosed endogenous cortisol excess. As the health care professionals most closely attuned to medication adherence and therapeutic response, pharmacists are uniquely positioned to identify the nonresponders whose underlying cortisol levels may be driving their treatment resistance.

Participants in the conversation were from Duke University Health System, Baptist Health in Kentucky, the University of Texas Southwestern Medical Center, and Cleveland Clinic.

Understanding the Hypercortisolism Spectrum

The medical community is moving away from a binary view of Cushing syndrome toward a more nuanced understanding of hypercortisolism as a dynamic spectrum of disease. Although Cushing disease specifically refers to adrenocorticotropic hormone (ACTH)-dependent hypercortisolism caused by a pituitary tumor, hypercortisolism encompasses a broader range of conditions. This includes mild autonomous cortisol secretion, characterized by patients with biochemical evidence of cortisol excess who lack overt physical signs.

To understand this, one must look at the hypothalamic-pituitary-adrenal (HPA) axis, in which the hypothalamus releases corticotropin-releasing hormone. This stimulates the anterior pituitary to release ACTH, which then signals the adrenal cortex to produce cortisol. In normal physiology, cortisol serves as a negative feedback loop to maintain homeostasis, but in hypercortisolism, this balance is skewed. This realization is critical because even subclinical or mild elevations in cortisol can lead to significant long-term cardiometabolic complications, such as resistant hypertension and accelerated bone mineral loss.

Cortisol’s Role in Treatment-Resistant Diabetes

The conversation also addresses a newer concept in metabolic health, which is the classification of cortisol as the "noxious nine," the ninth pathway of pathophysiology contributing to T2D. Recent prospective screening studies, such as the CATALYST trial (NCT05772169), have shown that up to 24% of patients with difficult-to-control T2D actually have undiagnosed hypercortisolism.

For pharmacists, the most reliable red flag is not a physical feature but a patient’s lack of response to high-efficacy, evidence-based therapies. Pharmacists should maintain a high index of suspicion for patients on state-of-the-art 2025 glycemic agents, such as glucagon-like peptide-1 receptor agonists or glucose-dependent insulinotropic polypeptide co-agonists, who fail to see the expected 1.0% to 1.5% improvement in hemoglobin A_1c or significant weight loss. When a patient remains on high doses of insulin, particularly prandial insulin, despite intensification of therapy, this suggests an underlying driver, such as cortisol, that promotes insulin resistance and prevents weight loss.

How Cortisol Drives Hypertension

The link between hypercortisolism and resistant hypertension is multifaceted and often overlooked in favor of more exciting but rarer diagnoses such as pheochromocytoma. Cortisol causes hypertension through 3 primary pathways: It acts as a mineralocorticoid to increase sodium reabsorption and water retention; it ramps up the renin-angiotensin-aldosterone system; and it inhibits nitric oxide synthase, leading to vasoconstriction.

This pseudoaldosteronism effect means that patients with excess cortisol will often require 4 or more antihypertensives without reaching their blood pressure goals. Physicians emphasize that if a provider is thinking about screening a patient for primary aldosteronism due to resistant hypertension, they should almost always concurrently screen for hypercortisolism. Identifying this early is paramount, as chronic exposure to excess cortisol leads to irreversible cardiac remodeling and early-onset heart failure.

Navigating Diagnostic Testing and Drug Interference

Diagnosing hypercortisolism remains a significant challenge due to the complexity of tests and the high potential for medication interference, a domain where pharmacists must take the lead. The 3 primary screening tools—the overnight dexamethasone suppression test (DST), 24-hour urinary free cortisol, and late-night salivary cortisol—each assess different aspects of the HPA feedback loop.

Pharmacists are essential for ensuring diagnostic accuracy by identifying drugs that cause false positives in the DST, such as oral estrogens, which increase cortisol-binding globulin, and antiepileptics such as phenytoin or phenobarbital, which induce CYP3A4 and accelerate dexamethasone metabolism. To validate an abnormal DST result, pharmacists should ensure a dexamethasone level is ordered concurrently with the cortisol level. A level between 140 and 200 ng/dL confirms adequate drug exposure to suppress the HPA axis.

Furthermore, the common use of biotin supplements can interfere with various endocrine assays, and even microtrauma from tooth brushing can cause false elevations in salivary cortisol tests.

The Pharmacist’s Role in Multidisciplinary Care

Ambulatory care and clinical pharmacists often have their fingers on the pulse of the therapy-effect relationship, allowing them to notice when a patient’s clinical trajectory does not match their adherence. This sense is a vital component of a multidisciplinary team, as pharmacists can identify adherent patients who are simply failing to respond to guideline-directed medical therapy.

Beyond identifying red flags, pharmacists can manage the administrative hurdles of treatment, such as navigating the prior authorization process for costly steroidogenesis inhibitors or cortisol receptor antagonists. In many advanced health systems, pharmacists now lead cardiometabolic clinics, using their expertise to bridge the gap between primary care and specialized endocrine workups, ensuring that nonresponders are not dismissed as nonadherent.

Leveraging Technology and Systems for Timely Diagnosis

To combat the average delay of nearly 3 years in diagnosing hypercortisolism, health care systems are exploring the use of electronic health record tools and artificial intelligence-driven alerts. Standardized order sets can help nonspecialists navigate the nuances of testing, such as automatically suggesting a dexamethasone level alongside a morning cortisol test.

Some organizations are developing population health dashboards that flag high-risk patients—such as those on 4 or more antihypertensives or high-dose insulin with a high body mass index—for opportunistic screening. These system-based solutions, combined with pharmacists’ clinical vigilance, offer the best hope for moving away from piecemeal medicine toward a holistic, value-based care model that addresses the root causes of metabolic disease.