Prevalence of Hypercortisolism in Difficult-to-Control Type 2 Diabetes

Objective: Despite the use of multiple glucose-lowering medications, a significant fraction of individuals with type 2 diabetes (T2D) do not meet glycemic targets. This prospective, observational study assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control (NCT05772169). Research Design and Methods: Individuals with T2D and HbA1c 7.5–11.5% (58–102 mmol/mol) on ≥2 glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure-lowering medications were screened with a 1-mg dexamethasone suppression test (DST). Common causes for false-positive DSTs were excluded. The primary endpoint was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed using multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. Results: Post-DST cortisol was unsuppressed in 252/1057 participants (prevalence 23.8%; 95% confidence interval, 21.3 to 26.5). Hypercortisolism prevalence was 33.3% in participants with cardiac disorders and 36.6% in those taking ≥3 blood pressure-lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of SGLT2 inhibitors (odds ratio [OR], 1.558), maximum-dose GLP-1 receptor agonists (OR, 1.544), tirzepatide (OR, 1.981), or a higher number of blood pressure-lowering medications (OR, 1.390), older age (OR, 1.316), body mass index <30 kg/m2 (OR, 1.639), non-Latino/Hispanic ethnicity (OR, 3.718), use of fibrates (OR, 2.676) or analgesics (OR, 1.457) were associated with higher prevalence (all P<0.03). Conclusions: Hypercortisolism was associated with hyperglycemia in approximately one quarter of individuals with inadequately controlled T2D despite multiple medications.