Mortality risk and causes of death in exogenous Cushing's syndrome: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: SMR 1.87 (87% increased mortality risk)

• Primary Outcome: Overall mortality risk

• Nnt Or Sensitivity: Pooled death proportion 12.0% (95% CI 10-14%); highest risk in inflammatory diseases (30.0%) and vasculitides (18.0%)

• Confidence Interval: 95% CI 1.32-2.61

Clinical Application

Highly applicable - findings support existing TGA safety warnings and RACGP guidelines for glucocorticoid monitoring and stewardship Relevant to PBS prescribing patterns and supports current Australian guidelines emphasizing lowest effective doses, bone protection protocols, and cardiovascular risk assessment in chronic steroid users Australian patients receiving chronic oral glucocorticoids for inflammatory conditions, autoimmune diseases, and other chronic conditions requiring long-term steroid therapy

Abstract

CONTEXT: Chronic oral glucocorticoids (GCs) are widely prescribed for multiple diseases. Although long-term GC exposure causes systemic toxicity, the magnitude, dose-response relationship, and causes of GC-associated mortality remain incompletely defined. OBJECTIVE: To quantify overall and cause-specific mortality associated with chronic oral GC exposure and evaluate dose-response relationships across underlying disease groups. METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO CRD42017067530). PubMed/MEDLINE, EMBASE, Cochrane Library, Web of Science, and CINAHL were searched from 1945 to March 2019. Eligible studies reported standardized mortality ratios (SMRs) or absolute deaths among adults receiving chronic oral GCs. Random-effects meta-analysis and mixed-effects meta-regression were used to synthesize mortality and dose-response associations across GC exposure metrics, exposure duration, and disease subgroups. RESULTS: One-hundred and sixteen studies encompassing 128 cohorts and 51 380 patients were included. Chronic GC exposure was associated with excess mortality (pooled SMR 1.87; 95%CI 1.32-2.61; I2 74.0%). The pooled proportion of death was 12.0% (95%CI 10-14%). Mortality risk was highest in inflammatory diseases (30.0%) and the vasculitides (18.0%). Higher cumulative dose (≥5 g prednisolone-equivalent), average daily dose >5 mg/day, and higher initial dose were each independently associated with increased mortality. Cardiovascular disease was the leading causes of death (25.6%), followed by malignancy (15.7%) and infection (13.4%). CONCLUSION: Chronic oral GC exposure was associated with increased mortality across disease groups, with higher cumulative and early-treatment doses correlating with higher risk. However, causal attribution remains uncertain due to confounding by indication, limited disease-severity data, and exposure misclassification. These findings support GC stewardship and targeted cardiovascular and infection risk mitigation, rather than indiscriminate dose reduction.

References

1. 1.Limumpornpetch, P., Stewart, P. M., Pujades-Rodriguez, M., Baxter, P. D., Tiganescu, A., Nyaga, V. N., & Morgan, A. W. (2026). Mortality risk and causes of death in exogenous Cushing's syndrome: a systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgag123