11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse
effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates
active glucocorticoid, we investigated whether 11β-HSD1 inhibition with
AZD4017 could mitigate adverse glucocorticoid effectswithout compromising
their anti-inflammatory actions. We conducted a proof-of-concept, randomized,
double-blind, placebo-controlled study at Research Unit, Churchill
Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized
to AZD4017 or placebo, alongside prednisolone treatment. Although
the primary endpoint of the study (change in glucose disposal during a twostep
hyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulin
sensitivity worsened in the placebo-treated but not in the AZD4017-treated
group. Protective effects of AZD4017 onmarkers of lipid metabolism and bone
turnover were observed. Night-time blood pressure was higher in the placebotreated
but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio
was lower in the AZD4017-treated but remained the same in the placebotreated
group. Most anti-inflammatory actions of prednisolone persisted with
AZD4017 co-treatment. Four adverse events were reported with AZD4017 and
no serious adverse events. Here we show that co-administration of AZD4017
with prednisolone in men is a potential strategy to limit adverse glucocorticoid
effects.