Targeting Iatrogenic Cushing's Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition
Status:
Completed
Trial end date:
2020-08-01
Target enrollment:
Participant gender:
Summary
Currently, 2-3% of the population of the United Kingdom and United States of America receive
glucocorticoid therapy. Significant adverse effects are not confined to chronic use;
recurrent short-course administration is associated with increased morbidity and mortality.
The adverse metabolic features associated with glucocorticoid use include obesity, skeletal
muscle myopathy, hypertension, insulin resistance and diabetes and are collectively termed
'iatrogenic Cushing's syndrome'. The efficacy of glucocorticoid therapy is not in doubt, but
there are no interventions to reduce their metabolic consequences. Within metabolic tissues
(liver, skeletal muscle, adipose), 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
regenerates active glucocorticoid and therefore is able to tightly control the availability
of glucocorticoids to activate the glucocorticoid receptor. In preclinical studies, the
investigators have shown that 11β-HSD1 is critical in regulating the development of the
adverse features associated with circulating glucocorticoid excess, endorsing our
observations in a patient with Cushing's disease, who was protected from a classical
phenotype due to a functional deficit in 11β-HSD1.
This study is the first clinical evaluation of the impact of the selective 11β-HSD1
inhibitor, AZD4017, in healthy volunteers taking exogenous glucocorticoids (prednisolone).
The investigators propose that in tissues expressing high levels of 11β-HSD1, prednisolone
action will be amplified, driving adverse effects within these tissues and have hypothesized
that AZD4017 in humans will reduce the adverse metabolic consequences of Prednisolone
administration without compromise to its anti-inflammatory action.
Our specific research objectives are:
1. To demonstrate the beneficial effect of the selective 11β-HSD1 inhibitor, AZD4017, upon
the prednisolone-induced deterioration in metabolic phenotype, including glucose
disposal and endogenous glucose production rates.
2. To determine the impact of AZD4017 on the anti-inflammatory actions of Prednisolone.
3. To identify the tissue-specific (skeletal muscle, adipose) mechanisms underpinning the
response to Prednisolone therapy administered in conjunction with AZD4017.
The investigators will perform a randomized, double-blind placebo controlled study to
determine if co-administration of the selective 11β-HSD1 inhibitor, AZD4017, limits the
adverse effects of short-course exogenous glucocorticoid administration. 32 healthy male
volunteers will have detailed metabolic investigations including 2-step hyperinsulinaemic
euglycaemic clamps (with stable isotope measurements of lipid and carbohydrate metabolism),
as well as assessment of skeletal muscle forearm glucose uptake. All volunteers will then be
treated with Prednisolone (20mg daily) and randomized to the co-administration of placebo or
AZD4017. After 1 week of therapy, all investigations will be repeated. Our hypothesis is that
the adverse metabolic effects of Prednisolone will be reduced by co-administration of
AZD4017.