BACKGROUND: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial.
METHODS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.
BACKGROUND: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.
BACKGROUND: NCT05772169.

BACKGROUND: Measuring cortisol during military training offers insights into physiological responses to stress. We attempted precisely timed, cortisol awakening response (CAR) and pre-sleep cortisol (PSC), and diurnal slope (peak morning minus evening cortisol), during a British Army exercise. We aimed to understand cortisol dynamics and evaluate the feasibility of CAR and PSC in this environment.
METHODS: Setting: high-intensity, 10-day infantry exercise. Participants: regular infantry soldiers exercising (EX, n=25) or headquarters-based (HQ, n=6). Participants undertook PSC and WAKE and WAKE+30 min samples after 1-2 days, 5-6 days and 9-10 days. Wrist-worn GENEActiv accelerometers were used to assess sleep duration in EX only. Samples taken ±15 min from prespecified time points were deemed adherent. Validated questionnaires were used to measure resilience and perceived stress. Cortisol and cortisone were measured simultaneously by liquid chromatography tandem mass spectrometry.
RESULTS: From adherent participants\' samples, CAR was positive and tended to decrease as the exercise progressed. From all available data, HQ demonstrated greater diurnal slope than EX (F=7.68, p=0.02), reflecting higher morning cortisol (F=4.72, p=0.038) and lower PSC (p=0.04). No differences were seen in cortisol:cortisone ratio. 26.1% of CAR samples were adherent, with moderately strong associations between adherence and stress (r=0.41, p=0.009) but no association between adherence and day of exercise (χ2=0.27, p=0.8), sleep duration (r=-0.112, p=0.43) or resilience (r=-0.79, p=0.75). Test-retest reliability ratings for CAR were Cronbach\'s α of 0.48, -11.7 and 0.34 for the beginning, middle and end of the exercise, respectively.
CONCLUSIONS: We observed a reduction in morning cortisol and decreased diurnal slope during a high-intensity military exercise, compared with the HQ comparator cohort in whom diurnal slope was preserved. A carefully timed CAR was not feasible in this setting.

We sought to understand the factors that influence a general practitioner\'s (GP\'s) experience of screening for primary aldosteronism (PA) in hypertensive patients.
A qualitative study, framed by phenomenology, using semistructured interviews that were audiorecorded, transcribed verbatim, entered into NVivo V.12.0 for coding and analysed for emerging themes.
Melbourne, Australia.
Eligible GPs had received education on PA as part of a previous study. We recruited a purposive sample of 16 GPs (6 females, 10 males) who varied in practice location, clinical experience and the number of patients screened for PA.
Although GPs had been educated about PA, they found it challenging to explain the condition to patients and were uncertain about how to screen patients who were already taking antihypertensive medications. Most viewed the screening process to be practical, inexpensive and, by and large, acceptable to their patients. However, they found it inconvenient to alter antihypertensive medications before screening to allow for easier interpretation of the aldosterone-renin ratio. They were also less enthused about screening patients whom they thought fitted a clinical picture of essential hypertension. Knowledge of the screening process, cost and convenience of performing the aldosterone-renin ratio, conceptualisation of risk related to PA, and a desire to improve clinical care were influencing factors that modified the GPs\' screening experience.
Our findings suggest that knowledge gaps, practical limitations of the aldosterone-renin ratio, and errors in diagnostic reasoning were challenges of routine PA screening. Most of these practical barriers could be addressed by relatively simple educational and practice modifications to increase PA screening rates and optimise detection for the most common cause of secondary hypertension in primary care.

OBJECTIVE: The short synacthen test (SST) is widely used across the UK to assess adrenal reserve. The main objective of our study was to determine the morning serum cortisol level that will predict adrenal insufficiency (AI) thus reducing our reliance on SST.
METHODS: This was a single centre retrospective study of 393 SST tests measuring 0 and 60 min cortisol levels after administration of 250 μg of synacthen (synthetic ACTH).
METHODS: All the SST tests for patients suspected of primary or secondary AI between April 2016 and October 2018 were included in this study. We used serum to determine circulating cortisol by a newer generation competitive electrochemiluminescence immunoassay (ECLIA) (Roche Diagnostics). A post-ACTH cortisol response of ≥420 nmol/L at 60 min was considered adequate to rule out AI. The data were analysed to ascertain the relationship between 0 min and 60 min serum cortisol.
RESULTS: A total of 393 SST results were included in this study. Overall, a total of 332 (84.5%) subjects achieved sufficient serum cortisol level at 60 min, while 61 subjects (15.5%) showed insufficient response. Using the logistic regression, we determined that a morning basal serum cortisol level of ≥354 nmol/L was able to predict normal adrenal function with 100% sensitivity. We were unable to find a lower cut-off value below which SST will not be required. By using this proposed cut-off point, approximately 37% of the SSTs tests could be avoided.
CONCLUSIONS: Basal morning serum cortisol can be safely used as a first step in the evaluation of patients with suspected AI. This will enhance the number of patients being screened for this condition.

Patients with adrenal insufficiency have impaired health-related quality of life (QoL). The dual-release hydrocortisone preparation, Plenadren, has been developed to mimic the physiological cortisol release more closely than conventional hydrocortisone treatment. Plenadren has been shown to improve QoL, in particular fatigue, in patients with primary adrenal insufficiency. However, the effect has not been investigated in patients with secondary adrenal insufficiency; furthermore, no study has taken the diurnal variation of fatigue into account. To assess diurnal variations, it is necessary to use repeated daily measurements, such as ecological momentary assessments (EMAs). This study aims to evaluate EMAs of fatigue as outcome in future large-scale randomised clinical trials.
The PlenadrEMA trial is an investigator-initiated open-label switch pilot trial of the effect of Plenadren versus conventional hydrocortisone on fatigue in patients with secondary adrenal insufficiency. The trial will include 30 participants. After 5 weeks on their usual hydrocortisone treatment, patients will be shifted to Plenadren for 16 weeks. Fatigue will be assessed using momentary versions of the Multidimensional Fatigue Inventory (MFI-20). Items will be administered to participants via a smartphone application four times daily during 20 days. Assessments will be performed before treatment shift and repeated after 12.5 weeks on Plenadren. The study will identify the best suited outcome for future randomised clinical trials, and in addition, estimate the variability and difference in fatigue between the two treatments to perform power calculations.
The trial will be conducted in accordance with the Declaration of Helsinki and has been approved by the Regional Scientific Ethical Committee in Copenhagen (ID: H-1-2014-073). All patients will receive written and verbal information about the trial and will give informed consent before enrolment. Findings will be published in peer-reviewed journals and presented at international conferences.
EudraCT201400203932.