Mortality Risk in Patients With Adrenal Insufficiency Using Prednisolone or Hydrocortisone: A Retrospective Cohort Study

J Clin Endocrinol Metab. 2021 Jul 13;106(8):2242-2251. doi: 10.1210/clinem/dgab347.


Context: Prednisolone has been recommended rather than hydrocortisone for glucocorticoid replacement in adrenal insufficiency due its longer duration of action and lower cost.

Objective: To determine mortality rates with prednisolone versus hydrocortisone.

Methods: In this observational study, we used data extracted from a UK primary care database (Clinical Practice Research Datalink) to measure the relative mortality of patients with primary and secondary adrenal insufficiency, who were treated with either prednisolone or hydrocortisone, and control individuals who were individually matched for age, sex, period, and place of follow-up.

Results: As expected, mortality in adrenal insufficiency irrespective of cause was increased, based on 5478 patients (4228 on hydrocortisone; 1250 on prednisolone) and 54 314 controls (41 934 and 12 380, respectively). Overall, the adjusted hazard ratio (HR) was similar with the 2 treatments (prednisolone, 1.76 [95% CI, 1.54-2.01] vs hydrocortisone 1.69 [1.57-1.82]; P = 0.65). This was also the case for secondary adrenal insufficiency. In primary disease (1405 on hydrocortisone vs 137 on prednisolone; 13 965 and 1347 controls, respectively), prednisolone users were older, more likely to have another autoimmune disease and malignancy, and less likely to have mineralocorticoid replacement. Nevertheless, after adjustment, the HR for prednisolone-treated patients remained higher than for those taking hydrocortisone (2.92 [2.19-3.91] vs 1.90 [1.66-2.16]; P = 0.0020).

Conclusion: In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. The study was large, but the number of prednisolone-treated patients was small, and they had greater risk factors. Nonetheless, the increased mortality associated with prednisolone persisted despite statistical adjustment. Further evidence is needed regarding the long-term safety of prednisolone as routine replacement.

Keywords: adrenal failure; glucocorticoids; replacement therapy; steroids.

MeSH terms

  • Adrenal Insufficiency / drug therapy*
  • Adrenal Insufficiency / mortality*
  • Adult
  • Aged
  • Female
  • Glucocorticoids / adverse effects*
  • Glucocorticoids / therapeutic use
  • Hormone Replacement Therapy / adverse effects*
  • Humans
  • Hydrocortisone / adverse effects*
  • Hydrocortisone / therapeutic use
  • Male
  • Middle Aged
  • Prednisolone / adverse effects*
  • Prednisolone / therapeutic use
  • Retrospective Studies
  • Survival Rate


  • Glucocorticoids
  • Prednisolone
  • Hydrocortisone