Incident changes of the 1 mg-overnight dexamethasone suppression test correlate with long-term clinical outcomes in patients with adrenal incidentalomas: results from the multi-centre DEX-AI and CORTEX-AI ENSAT studies

Introduction: Patients with adrenal incidentalomas (AI) should undergo a 1 mg-overnight dexamethasone suppression test (1 mg-DST) to exclude cortisol excess (non-functioning adrenal tumours, NFAT; serum cortisol ≤50 nmol/l) or diagnose mild autonomous cortisol secretion (MACS; serum cortisol >50 nmol/l). Guidelines recommend repeating 1 mg-DST only if treatment is intended; however, data underpinning this recommendation are scarce. Methods: Retrospective multi-centre study including patients with benign AI with at least two 1 mg-DST and follow-up ≥3 years. Incident 1 mg-DST changes were correlated with clinical and radiological characteristics. Cox proportional hazard regression was used to calculate effect estimates of clinical outcomes. Results: 2525 patients from 25 centres were included, with a median follow-up of 6.7 years (range 3-22.9). 1 mg-DST incident changes were observed in 22.5% of patients: 9.0% NFAT developed MACS (NFAT→MACS); 7.7% MACS developed normal 1 mg-DST (MACS→NFAT); 7.7% had 1 mg-DST results fluctuating around the 50 nmol/l cutoff. Most 1 mg-DST changes (~60-70%) occurred within 3 years of the baseline 1 mg-DST. NFAT→MACS patients had larger tumours, more frequently bilateral, were more likely to be smokers and had a higher prevalence of hypertension, type 2 diabetes, osteoporosis, and cardiovascular events than those with persistently normal 1 mg-DST (NFAT→NFAT). MACS→NFAT patients were younger with smaller and more frequently unilateral tumours than those with persistently abnormal 1 mg-DST (MACS→MACS). At the last available clinical follow-up, there was a progressive increased risk of hypertension, type 2 diabetes, dyslipidaemia, and cardiovascular events across the spectrum of NFAT→NFAT, NFAT→MACS, MACS→NFAT, and MACS→MACS. Only MACS→MACS patients had significantly increased age- and sex-adjusted risk of composite cardiovascular events (hazard ratio 1.50 [95%CI 1.04-2.15] vs. NFAT→NFAT, P=0.03). Conclusions: Incident 1 mg-DST changes are frequent in patients with benign AI and correlate with tumour characteristics and clinical outcomes. Repeating 1 mg-DST within 3 years may be advocated to risk-stratify patients during long-term follow-up.