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

Abstract

It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.

Keywords: 11β-hydroxysteroid dehydrogenase type 1 inhibition; SEGRA; adverse effects; chronopharmacology; steroid hormones.

Graphical Abstract

Figure 1.

Chemical structure of endogenous and commonly prescribed glucocorticoids.

Figure 2.

The side effect burden associated with prescribed glucocorticoids.

Figure 3.

Genomic effects of classic glucocorticoids (left) and Selective Glucocorticoid Receptor Agonists (SEGRAs, right).

Figure 4.

The 11β-hydroxysteroid dehydrogenases interconvert active and inactive glucocorticoids (A) and putatively have a critical role in regulating tissue-specific adverse effects that may be limited by 11β-HSD1 inhibition (B).