Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad ?

**Background:** Glucocorticoids (GCs) are widely prescribed for their potent anti-inflammatory and immunosuppressive effects, with 1% to 3% of the worldwide population currently receiving GC therapy. Chronic use is reported in 0.5% to 1.8% of patients, and long-term prescriptions have increased by more than 30% over the past 20 years. Despite clinical awareness of adverse effects, GCs remain among the top-10 prescribed drugs by cost, accounting for approximately 6.4% of total public expenditure on medication in the UK. The adverse effects include increased mortality, diabetes, hypertension, osteoporosis, cardiovascular disease, venous thromboembolism, cognitive dysfunction, and infections. The severity of these effects is often dose- and duration-dependent, with even low doses (e.g., 5 mg prednisolone equivalent per day) associated with increased risks in some studies.

**Methods:** This is a comprehensive narrative review that synthesizes data from multiple epidemiological studies, randomized controlled trials, and observational cohorts. The authors summarize prevalence data from nine clinical studies across different populations (Sweden, US, Denmark, UK, France) and discuss the mechanisms of GC action via the glucocorticoid receptor (GR), including transactivation, transrepression, and nongenomic effects. They also review strategies to ameliorate adverse effects, including conventional comorbidity management (for hyperglycemia, hypertension, osteoporosis), selective GR agonists/modulators (SEGRAs), 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition, and chronopharmacology.

**Key Results:** The review reports that GC-induced diabetes occurs in 15% to 40% of patients depending on the underlying condition, with an odds ratio of 1.7 for new-onset diabetes in a meta-analysis of 6602 patients. Hypertension risk is doubled in GC users compared to placebo, with incidence rates from 3% to 30% in rheumatic conditions. Osteoporosis leads to fractures in up to 20% of patients within the first year of treatment, with vertebral fracture annual incidence of 5.1% in those initiating GCs. Mortality increases with doses above 5 mg prednisolone equivalent per day, with a 6% increase in all-cause mortality for each gram increase in cumulative dose. For SEGRAs, AZD9567 showed similar anti-inflammatory effects to prednisolone but with minimal impact on glucose tolerance, while fosdagrocorat demonstrated noninferior anti-inflammatory effects compared to prednisone 10 mg with nonsignificant improvements in glycemic control. 11β-HSD1 inhibition with AZD4017 combined with prednisolone 20 mg for 1 week reduced adverse effects on glucose handling, adipose tissue lipolysis, lipid profiles, and bone turnover markers in healthy volunteers.

**Clinical Implications:** The review highlights the urgent need for strategies to dissociate the therapeutic benefits of GCs from their adverse effects. Current approaches include careful dose minimization, use of bone-protective therapies (bisphosphonates, teriparatide, denosumab), and management of hyperglycemia and hypertension. Novel strategies such as SEGRAs and 11β-HSD1 inhibitors show promise in preclinical and early clinical studies, but further controlled trials are needed. Chronopharmacology, using modified-release formulations to better mimic circadian cortisol rhythms, has shown benefits in adrenal insufficiency and rheumatoid arthritis. The authors emphasize that despite progress, the development of effective strategies to separate the 'good' from the 'bad' effects of GCs remains a major unmet clinical need.