Glucocorticoids are steroid hormones that have been widely adopted as the standard treatment for many inflammatory disorders.¹ However, glucocorticoid receptors are expressed on almost all cell types in the body and their regulation by prolonged administration of glucocorticoids at high dose often produce undesirable or detrimental adverse events.¹ A recent population-based cohort study revealed that glucocorticoids, even at a low dose of <5mg which was previously considered safe, was associated with an increased risk of cardiovascular disease, highlighting the need to avoid long-term steroid treatment for patients with immune-mediated inflammatory diseases.²

With demonstrated anti-inflammatory and immune-suppressive effects, oral glucocorticoids are often prescribed to patients with immune-mediated inflammatory disease to achieve disease control.² Despite their therapeutic benefits, glucocorticoids treatment is also associated with various adverse events including increased risk of cardiovascular diseases.² Where glucocorticoids can lower or neutralize the atherosclerotic and vascular injury effects of chronic inflammatory disease, its prolonged administration at high dose can also directly increase the risk of myocardial infarction, stroke and heart failure as well as indirectly increase the cardiovascular risks through hypokalemia that can lead to atrial arrhythmia.^2,3

To evaluate the daily and cumulative dose-dependent cardiovascular risk of glucocorticoids, Dr. Mar Pujades-Rodriguez, Visiting Research Fellow at the University of Leeds, and her team analyzed the medical records of 87,794 patients diagnosed with common immune-mediated inflammatory diseases with no prior cardiovascular diseases.² After a median follow-up of 5 years, 15.3% of the patients developed cardiovascular events such as atrial fibrillation, heart failure, myocardial infarction, cerebrovascular disease, peripheral arterial disease and abdominal aortic aneurysm.² Compared to the 1.4% cumulative incidence rate of developing all-cause cardiovascular disease at 1^st year during the periods without medication, the incidence rate was increased to 3.8% after a daily exposure of <5mg and to 8.9% with a ≥25mg daily dose of glucocorticoids.² At 5^th year, the incidence rate was increased from 7.1% without medication, to 19.7% and 28.0% with <5mg and ≥25mg daily glucocorticoids exposure, respectively.² Notably, compared to their periods of non-glucocorticoids use, patients who were exposed to periods of ≥25mg glucocorticoids daily had an increased incidence of all-cause cardiovascular disease from 18.5 to 45.6 events per 1,000 person-years.²

Quantitively, the hazard of all-cause cardiovascular disease was increased by 1.08 per 5mg daily dose of glucocorticoids.² Though a low dose of <5mg glucocorticoids was previously considered safe for long-term treatment, this study revealed that <5mg daily glucocorticoids would still increase the risk of developing cardiovascular diseases regardless of the type of underlying immunemediated disease, disease activity level or disease duration (HR=1.74; 95% CI: 1.64-1.84).² In particular, dose-response of glucocorticoids was most strongly associated with heart failure (HR=1.75; 95% CI: 1.56-1.97) and acute myocardial infarction (HR=1.76; 95% CI: 1.51-2.05).²

Based on the results of this population-based study, Dr. Pujades-Rodriguez commented that all patients who require long-term steroid treatment should be prescribed with the lowest effective dose and should have a personalized cardiovascular risk prevention plan that accounts for the current and prior use of steroids before prescribing glucocorticoids.² Indeed, clinicians are often required to adapt their therapeutic strategies based on the individual susceptibilities of their patients. When facing severe inflammatory diseases such as the ongoing coronavirus disease 2019 (COVID-19), glucocorticoids should be carefully prescribed as their benefit may only outweigh their risks in a specific subset of patients, i.e. COVID-19 patients who are receiving either invasive mechanical ventilation or oxygen alone.⁴ “The findings of our study highlight the importance of treating patients with minimal effective dose of steroids for the shortest duration of time, while appropriately, promptly and regularly monitoring the cardiovascular risk,” concluded Dr. Pujades-Rodriguez.