Chadarevian, Rita, Eastell, R. (Richard), Ross, Richard J. M., Newell-Price, John and Randeva, Harpal S. (2013) Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study. PLoS One, Volume 8 (Number 4). e60984. doi:10.1371/journal.pone.0060984 ISSN 1932-6203.

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Abstract

Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly
population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of
patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an
independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their
insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we
examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to
determine whether their insulin resistance was reversible.
Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and
autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks
on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and
lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all
individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03),
lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in
insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by
the Helsinki heart study).
Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal
incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify
therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk.

Item Type:	Journal Article
Subjects:	R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Mifepristone, Insulin resistance -- Research, Hydrocortisone, Adrenal glands -- Tumors
Journal or Publication Title:	PLoS One
Publisher:	Public Library of Science
ISSN:	1932-6203
Official Date:	5 April 2013
Dates:	Date Event 5 April 2013 Published
Volume:	Volume 8
Number:	Number 4
Page Range:	e60984
DOI:	10.1371/journal.pone.0060984
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	24 December 2015
Date of first compliant Open Access:	24 December 2015
Funder:	HRA Pharma
Grant number:	R/123263

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