Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis

Objective: To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; > 1.8 µg/dL (>50 nmol/L) cortisol level cut-off following the 1 mg dexamethasone suppression test). Design: Systematic review and meta-analysis. Methods: Seven databases were searched up to July 14, 2022. Eligible studies were (randomized) trials, cohort studies, and cross-sectional studies assessing comorbidities potentially attributable to cortisol excess or mortality in patients with adrenal incidentaloma with or without MACS or the effects of conservative or surgical management of MACS. Random-effects meta-analysis was performed to estimate pooled proportions (with 95% CIs). Results: In 30 cross-sectional and 16 cohort studies (n = 17 156 patients in total), patients with MACS had a higher prevalence of diabetes (relative risk [RR] 1.44 [1.23-1.69]), hypertension (RR = 1.24 [1.16-1.32]), and dyslipidemia (RR = 1.23 [1.13-1.34]). All-cause mortality (adjusted for confounders) in patients with MACS, assessed in 4 studies (n = 5921), was increased (hazard ratio [HR] = 1.54 [1.27-1.81]). Nine observational studies (n = 856) and 2 randomized trials (n = 107) suggest an improvement in glucometabolic control (RR = 7.99 [2.95-21.90]), hypertension (RR = 8.75 [3.99-19.18]), and dyslipidemia (RR = 3.24 [1.19-8.82]) following adrenalectomy. Conclusions: The present systematic review and meta-analysis highlight the relevance of MACS, since both cardiometabolic morbidities and mortality appeared to have increased in patients with MACS compared to patients with non-functioning incidentalomas. However, due to heterogeneous definitions, various outcomes, selective reporting, and missing data, the reported pooled estimates need to be interpreted with caution. The small number of patients in randomized trials prevents any strong conclusion on the causality between MACS and these comorbidities.