ORF05-04 - ACTH-Independent Hypercortisolism Across the Cardiometabolic Spectrum

Background: Accumulating evidence suggests that the prevalence of ACTH-independent hypercortisolism in patients with cardiometabolic risk factors and/or diabetes is higher than previously thought. This study aimed to evaluate the prevalence of ACTH-independent hypercortisolism across three cohorts with increasing cardiometabolic risk.

Methods: This secondary analysis included participants recruited into three cohorts to undergo protocolized assessments of adrenal hormone physiology. Cohort 1 included normotensive participants who were overweight or obese (NT-OB; n=71); Cohort 2 included participants with obesity and hypertension but without diabetes (HTN-OB; n=81); and Cohort 3 included participants with type 2 diabetes and overweight or obesity (DM-OB; n=49). All participants (n=201) underwent overnight 1 mg dexamethasone suppression test followed by a cosyntropin stimulation test, as well as a separate 24-hour urine collection. ACTH-independent hypercortisolism was determined based on post-dexamethasone serum cortisol >1.8 mcg/dL with a concomitant plasma ACTH < 10 pg/mL.

Results: 14/201 participants (7%) were found to have ACTH-independent hypercortisolism, including 5.6% (4/71) of NT-OB participants, 6.2% (5/81) of HTN-OB participants, and 10.2% (5/49) of DM-OB participants. By design, body mass index differed across the cohorts (NT-OB: 29.5±4.8 kg/m2, HTN-OB: 35.2 ±5.4 kg/m2, DM-OB: 31.5±5.0 kg/m2), however, across all participants, body mass index did not differ between those with or without ACTH-independent hypercortisolism (31.3± 3.6 kg/m2 v. 32.3 ± 5.8 kg/m2; P = 0.34). Age, hemoglobin A1c, blood pressure and renal function were similar among those with or without ACTH-independent hypercortisolism, as was 24-hour urine free cortisol. Following cosyntropin stimulation, those with ACTH-independent hypercortisolism had higher production of cortisol following ACTH-stimulation testing: post-cosyntropin cortisol 26.4 ± 4.3 mcg/dL v. 20.6 ± 4.2 mcg/dL (P < 0.001).

Conclusion: In this protocolized study of individuals with overweight or obesity, with normal or high blood pressure, and with or without diabetes, the rate of ACTH-independent hypercortisolism paralleled the burden of cardiometabolic risk features, where those with diabetes and obesity had the greatest burden of hypercortisolism. ACTH-independent hypercortisolism was associated with greater ACTH-stimulable cortisol production, but not increased total daily production of cortisol. These biochemical adrenal hormonal features may represent the cause and/or consequence of heightened cardiometabolic risk profiles.