Mortality in Cushing's syndrome: declining over 2 decades but remaining higher than the general population

Objective: Patients with endogenous Cushing's syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls. Methods: Nationwide retrospective study (2000-2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and body mass index (BMI). Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors. Results: The cohort included 609 cases with CS (mean age 48.1 ± 17.2 years; 65.0% women) and 3018 matched controls (47.9 ± 17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR = 1.44, 95% CI, 1.19-1.75). Both patients with CD (HR = 1.73, 95% CI, 1.27-2.36) and adrenal CS (HR = 1.31, 95% CI, 1.00-1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR = 1.44, 95% CI, 1.00-2.17). Mortality was similar for CD and adrenal CS (HR = .83, 95% CI, .56-1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality. Conclusion: This is the largest national cohort study on mortality risk in CS over the past 2 decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.