A new study published by researchers from the University of Gothenburg, Sweden has shown that patients receiving oral glucocorticoid treatment for a period of 3-4 years are at twice the risk of death compared with a matched control group - mainly due to increased incidence of pulmonary embolism, pneumonia, and sepsis. These results highlight that steroid-toxicity can be fatal and emphasize the need for steroid-sparing alternatives.^[1]

The study investigated patient outcomes for a group of 223,211 oral steroid users in Västra Götaland, Sweden (55.6% women) and compared them to outcomes for an equal number of matched patients not taking steroids from the same location.

The adjusted all-cause morbidity risk (adjusted for age, sex, and comorbidities) was found to be over 2x greater for the cohort taking steroids than the control group.

The mortality rate was calculated as the number of deaths per follow-up days and then converted to the number of deaths per 1000 observation years. The mortality rate per 1000 patient-years for patients taking glucocorticoids was more than double: 31.98 compared to 14.05 in the control group.

The primary or contributory cause of death for a range of diseases were also compared for the two cohorts.

Mortality risks increased across the board most notably caused by pulmonary embolism (an increase of 2.54x), sepsis (2.07x), pneumonia (1.63x), heart failure (1.55x), and ischemic heart disease (1.33x).

The increased mortality rate from deaths due to pulmonary embolism in the report is in line with the increased incidence of thromboembolism in patients with endogenous hypercortisolism - a condition leading to increased levels of procoagulant factors and impaired fibrinolytic capacity that leads to increased risks of clotting.

Increased doses = increased risks

For high-dose glucocorticoid patients (patients receiving >1.5X Defined Daily Dose*), the risks were even greater - with a 6x increased risk of death from sepsis, and a 3x risk from pneumonia highlighting immunosuppressive effects of steroids that increase susceptibility to infection.

The authors state: “the main strength of our study is the access to large healthcare databases with information about dispensed prescriptions at all Swedish pharmacies, causes of death, and comorbidities. The Swedish Prescribed Drug Register has information on all dispensed prescriptions in Sweden offering the opportunity to evaluate mortality in oral glucocorticoid users, both adults, and children, in a large population-based cohort, in contrast to previous studies which focus on mortality in glucocorticoid users with specific diseases.”

Taper with caution

The authors also discuss a recent study from the UK [3] that showed that sudden cessation of glucocorticoid treatment can lead to acute adrenal crisis and increased mortality rates. The study of 70,638 oral glucocorticoid users showed increased mortality during the first 2 months after cessation of oral steroid treatment and then decreased mortality over time after the first 3 months of cessation.

The authors postulate this may have been caused by adrenal crisis due to undiagnosed glucocorticoid-induced adrenal insufficiency and speculate that the increased mortality in steroid users due to sepsis and pneumonia observed in their recent study may be related to adrenal crisis - although data on treatment tapering was not available.

They suggest this highlights the need for more studies into steroid tapering, glucocorticoid adrenal insufficiency, and the link with premature and avoidable deaths.


*DDD is defined according to the World Health Organization (WHO) definition: 1 DDD = 10mg Prednisolone = 1.5 mg Betamethasone = 1.5mg Dexamethasone = 30mg hydrocortisone.[2]

References

[1] Einarsdottir MJ, Ekman P, Molin M, Trimpou P, Olsson DS, Johannsson G, Ragnarsson O. High Mortality Rate in Oral Glucocorticoid Users: A Population-Based Matched Cohort Study. Front Endocrinol (Lausanne). 2022 Jul 8;13:918356. doi: 10.3389/fendo.2022.918356. PMID: 35872995; PMCID: PMC9304700.

[2] Systemic Hormonal Preparations. Who Collaborating Centre for Drug Statistics Methodology. Systemic Hormonal Preparations (2021). Available at: https://www.whocc.no/atc_ddd_index/?showdescription=yes&code=H02AB [Accessed June 8, 2022]

[3] Mebrahtu TF, Morgan AW, Keeley A, Baxter PD, Stewart PM, Pujades-Rodriguez M. Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England. J Clin Endocrinol Metab (2019) 104(9):3757–67. doi: 10.1210/jc.2019-00153