Discussion
bone loss, Cushing’s phenotype, Cushing’s syndrome, ’s syndrome, glucocorticoid-induced suppression, effects.11β-HSD1, peritonitis, dysglycaemia
LUNG INFLAMMATION, BONE LOSS, ADVERSE EFFECTS, INSULIN RESISTANCE, PERITONITIS, JOINT INFLAMMATION
This is a randomised, double-blind, placebo-controlled study, to show that inhibition of 11β-HSD1 using AZD4017 in male participants has the potential to limit the adverse metabolic and bone effects of oral prednisolone treatment. Although this is a small, proof-of-concept study, it highlights the role of 11β-HSD1 to regulate the action of exogenous GCs in clinical practice. In addition, it suggests that there is a critical role of tissue-specific GC metabolism (inactivation and regeneration), over and above circulating levels in the blood, in controlling the biological impact of GCs. Prednisolone metabolism (inactivation and reactivation) occurs intracellularly, within key target organs and therefore circulating levels do not provide an accurate reflection of tissue- and cell-specific exposure to active/inactive glucocorticoids. We did not observe alterations in circulating prednisolone or prednisone levels, but these measurements are not able to identify the precise balance of prednisone/prednisolone to which a specific cell or tissue is exposed, and our data would suggest that it is this which is critical to the development of adverse effects.Previous studies with selective 11β-HSD1 inhibitors, including AZD4017, have shown activation of the HPA axis with increased ACTH as a consequence of decreased peripheral cortisol generationThe metabolic effects of 11β-HSD1 deficiency or inhibition have been extensively investigated in animal models. 11β-HSD1 KO mice have reduced visceral adipose tissue accumulation on a high fat diet and resist the development of insulin resistance and T2DCushing’s syndrome as a result of excess exogenous GC therapy is a significant clinical and economic burden. The use of prescribed glucocorticoids is widespread, particularly amongst the elderly who may be more susceptible to their adverse effects, and is associated with increased cardiovascular and cerebrovascular morbidity and mortalityTo date, the potential to modulate the adverse effects of prescribed GCs through manipulation of 11β-HSD1 activity and expression has only been examined in rodent models. 11β-HSD1 KO mice fail to develop a classical Cushing’s phenotype following corticosterone (the predominant circulating GC in rodents) administration; this was critically dependent upon adipose tissue (but not liver) 11β-HSD1 expressionThe expression and activity of 11β-HSD1 in human bone along with its potential role in bone biology are extensively described in the literatureOverall, the data from this study would support the concept that 11β-HSD1 inhibition may have potential as a therapy to limit GC-induced bone loss. However, larger studies incorporating more detailed bone phenotyping to confirm and endorse these data are now warranted.GCs are most commonly prescribed for their immune-suppressive and anti-inflammatory actions. 11β-HSD1 is highly expressed in the liver and adipose tissue, but is only expressed at very low levels in T-cells and other immune-inflammatory response cells. It has been suggested that 11β-HSD1 may have a role in controlling the endogenous anti-inflammatory response; 11β-HSD1 KO mice develop a greater inflammatory reaction in response to joint inflammation, peritonitis and lung inflammation and have a slower recoveryThe OX40 assay is used in clinical laboratories to assess immune (T-cell) function and relies upon the flow cytometric detection of the upregulation of CD25 and OX40 (CD134) on the cell surface following incubation with antigen. The OX40 assay was selected on a proof-of-principle basis as there is evidence of glucocorticoid-induced suppression of activity (endorsed by Fig. A small number of clinical studies have tried to address the issue of protection from the adverse metabolic effects of prescribed GCs, most commonly using established anti-diabetic agents. Glucagon-like peptide 1 (GLP-1) analogues appear to limit dysglycaemia associated with prednisolone use as well as improving pancreatic islet cell functionMore recently, Pernicova et al. examined the impact of metformin in patients already prescribed glucocorticoid therapyA key strength of the study is that the impact of a selective 11β-HSD1 inhibitor to treat iatrogenic Cushing’s syndrome has not been explored before. Additional strengths include the study design and the use of state-of-the-art metabolic phenotyping. There are however some significant limitations; the sample size is modest, although the trial was designed as an early phase II, proof-of-concept study. As a consequence of the small sample size, subtle, non-significant differences in baseline characteristics could potentially impact outcome. To correct for this, the statistical models used in the analysis adjust for any differences in baseline variables between groups. In addition, the study was only conducted in healthy male volunteers and over a relatively short duration. We can therefore not draw conclusions with regards to the potential benefits in women (although the drug has subsequently been administered to women for up to 12 weeks, and was well tolerated)The variability in Gd at baseline was higher than we had anticipated and higher than the values that we have used to inform our power and sample size estimates. This higher-than-anticipated variability in Gd may possibly explain why we were unable to detect significant differences in Gd between the two arms of the study despite having performed appropriate sample size and power calculations. Therefore, we cannot draw any robust conclusions as to the ability of AZD4017 to mitigate the adverse effects of prednisolone on glucose metabolism (although the patterns observed with regards to M/I-value, Gd as well as endogenous glucose production rates are all consistent). Further studies, in larger populations, perhaps using alternative measures of glucose metabolism, with adequate power are undoubtedly warranted. Importantly, the participants in this study did not have underlying immune or inflammatory conditions and therefore, the next step would be to conduct a larger, more prolonged trial in patients with underlying inflammatory conditions who are initiated on glucocorticoid therapy and who are more likely to suffer the long-term adverse side effects.11β-HSD1 inhibition appears to convey multiple metabolic benefits; we propose that this results from the specific targeting of a critical component of the tissue-specific action of GCs, whereby their impact in metabolic tissues is amplified (as a result of high 11β-HSD1 expression and active GC regeneration) leading to unwanted adverse side effects. We have demonstrated, that 11β-HSD1 inhibition, using AZD4017, has the potential to limit the adverse metabolic and bone side effects of prednisolone in healthy male participants. In the future, it may be that 11β-HSD1 inhibitors could prove to be an important protective adjunctive therapy alongside prescribed GCs and in addition may also offer another treatment strategy for patients with endogenous GC excess.