Elevated Cortisol Links Depression Severity to Poorer Glycemic Control in Diabetes

Investigators from Dow University of Health Sciences in Karachi, Pakistan, have published a case-control study in Discover Mental Health examining how cortisol levels relate to depressive symptoms and glycemic control in patients with type 2 diabetes (T2D). The study enrolled 300 adults—200 with previously diagnosed T2D and 100 patients without diabetes. Participants were screened for depressive and anxiety symptoms using the Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A), and morning fasting cortisol, insulin, and hemoglobin A_1C (HbA1c) were measured between 8 and 9 in the morning to minimize circadian variation.¹

Clinically significant depressive symptoms were present in 38% of patients with T2D compared with 13% of healthy controls (P < .001), and clinically significant anxiety symptoms were present in 14.5% versus 9% (P = .03). Morning cortisol was significantly higher among patients with T2D than controls (25.75 ± 7.87 mcg/dL vs 21.53 ± 4.16 mcg/dL; P < .001), while fasting insulin was lower (P = .03).¹

This bidirectional relationship between diabetes and depression is not a new observation. Kathleen Vest, PharmD, BCACP, CDCES, FCCP, of Midwestern University, and Sarah E. Grady, PharmD, BCPP, BCPS, of Drake University College of Pharmacy and Health Sciences, made a similar point at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting and Exhibition 2025, noting that individuals living with diabetes are at least twice as likely to develop depression as the general population, and that preexisting depression can itself raise the risk of developing T2D.²

"In the literature there's a lot of talk about depression and diabetes in a bidirectional relationship," Vest said at the meeting.²

Severity of Depression Tracks With Worse Metabolic Markers

Among the 76 patients with T2D who screened positive for clinically significant depressive symptoms, more than half (52.6%) had severe symptoms, 29% had mild symptoms, and 18.4% had moderate symptoms. Severe depressive symptoms were significantly associated with HbA1c greater than 8%, a diabetes duration of 5 years or longer, and the presence of diabetic complications such as retinopathy, nephropathy, or neuropathy.¹

Participants with severe depressive symptoms also had significantly higher mean HbA1c and cortisol levels, along with lower fasting insulin, compared with those who had mild or moderate symptoms (P < .05 for each comparison). Patients on exclusive insulin therapy had the highest HbA1c and cortisol levels and the lowest fasting insulin, and those managed with oral hypoglycemic agents alone had the most favorable metabolic profiles (P < .001).¹

Independent Predictors of Hypercortisolism

In multivariable logistic regression, several factors were independently associated with hypercortisolism, defined in the study as a cortisol level greater than 25 mcg/dL¹:

• Moderate-to-severe depressive symptoms (adjusted OR, 2.57; 95% CI, 1.31-4.88; P = .004)
• Elevated HbA1c (adjusted OR, 1.72; 95% CI, 1.24-2.35; P = .001)
• Diabetes duration of 5 years or more (adjusted OR, 1.98; 95% CI, 1.05-3.28; P = .03)
• Exclusive insulin therapy (adjusted OR, 1.87; 95% CI, 1.02-3.42; P = .04)
• Presence of diabetic complications (adjusted OR, 2.11; 95% CI, 1.21-3.69; P = .01)

Sleep disturbance showed a positive but nonsignificant association with hypercortisolism (adjusted OR, 1.44; 95% CI, 0.88-2.33; P = .15). The study authors noted that chronic hyperglycemia may itself alter the hypothalamic-pituitary-adrenal (HPA) axis, contributing to a cycle in which elevated cortisol worsens insulin resistance and glycemic control, which in turn may deepen psychological distress.¹

Pharmacy's Expanding Role in Screening for Hidden Cortisol Excess

The Dow University findings arrive as pharmacy practice is paying closer attention to cortisol's role in treatment-resistant T2D more broadly, not only in the context of depression.

In the Drug Topics Practice and Innovation Collaborative, endocrinologists, cardiologists, and pharmacists from institutions including Duke University Health System, Baptist Health in Kentucky, the University of Texas Southwestern Medical Center, and Cleveland Clinic discussed how many patients with seemingly primary hypertension or T2D may actually have undiagnosed endogenous cortisol excess.³

That conversation described cortisol as part of the "noxious nine" pathways contributing to T2D and cited prospective screening data, including the CATALYST trial (NCT05772169), showing that up to 24% of patients with difficult-to-control T2D have undiagnosed hypercortisolism. Panelists noted that the most reliable red flag is often not a physical feature but a patient's lack of response to high-efficacy, evidence-based therapies, such as failure to see the expected 1.0% to 1.5% HbA1c improvement with glucagon-like peptide-1 (GLP-1) receptor agonists or glucose-dependent insulinotropic polypeptide co-agonists.³

Pharmacists were described as essential to diagnostic accuracy in that discussion, particularly for identifying medications that can cause false-positive results on the dexamethasone suppression test, such as oral estrogens and enzyme-inducing antiepileptics like phenytoin or phenobarbital. Given the average diagnostic delay of nearly 3 years for hypercortisolism, panelists pointed to standardized order sets and population health dashboards as tools that could help flag high-risk patients, such as those on 4 or more antihypertensives or high-dose insulin, for opportunistic screening.³

Screening and Treatment Considerations for Comorbid Depression

Beyond identifying hypercortisolism, pharmacists are also positioned to help distinguish diabetes distress, the emotional burden of daily disease management, from clinically significant depression, according to Vest and Grady's ASHP Midyear 2025 presentation. They recommended validated screening tools, such as the 2-item Patient Health Questionnaire, and suggested mental health screening at least annually for all patients with diabetes, with more frequent screening after a new stressor, life change, or diabetes complication.²

When pharmacologic treatment for depression is needed, Vest and Grady emphasized that antidepressant selection should account for effects on glucose and weight. Agents such as citalopram, mirtazapine, and paroxetine carry a higher weight-gain risk, and bupropion and fluoxetine tend to be weight-neutral or associated with weight loss. Selective serotonin reuptake inhibitors have shown mixed effects on glucose, with reports of hypoglycemia when combined with sulfonylureas, while tricyclic antidepressants are associated with weight gain and can weaken insulin release.²

Grady and Vest also pointed to early evidence that GLP-1 receptor agonists may have neuroprotective, anxiolytic, and antidepressant effects, while cautioning that pharmacists should counsel patients on the potential for mood changes given ongoing FDA and European regulatory monitoring.²

"It's very important to ensure we don't abruptly discontinue these medications because there are so many benefits in treating their other conditions," Grady said.²

REFERENCES

1. Abbas U, Laghari RN, Tanveer M, et al. Elevated cortisol in patients with type 2 diabetes mellitus and comorbid depressive symptoms is associated with poor glycemic control and reduced insulin levels. Discov Ment Health. 2026. doi:10.1007/s44192-026-00518-0

2. Gallagher A. Pharmacists Help Navigate Comorbid Depression and Diabetes | ASHP Midyear 2025. Drug Topics. December 8, 2025. Accessed July 7, 2026. https://www.drugtopics.com/view/pharmacists-help-navigate-comorbid-depression-and-diabetes

3. Gallagher A. Why Pharmacists Are the New Frontline in Identifying Hypercortisolism. Drug Topics. June 20, 2026. Accessed July 7, 2026. https://www.drugtopics.com/view/why-pharmacists-are-the-new-frontline-in-identifying-hypercortisolism