Glucocorticoid activation by 11β‐hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross‐sectional study

Sagmeister, Michael; Taylor, Angela E.; Fenton, Anthony; Wall, Nadezhda A.; Chanouzas, Dimitrios; Nightingale, Peter; Ferro, Charles J.; Arlt, Wiebke; Cockwell, Paul; Hardy, Rowan; Harper, Lorraine

doi:10.1111/cen.13889

Cited by 30 publications

(30 citation statements)

References 47 publications

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“…However, preliminary proof-of-concept was demonstrated though a reduction in [THF+alloTHF]/THE ratios (the gold-standard measure of systemic 11β-HSD1 activity) and elevated DHEAS consistent with other selective 11β-HSD1 inhibitor trials, including AZD4017 ( 34, 36-39 ). As anticipated, 11β-HSD2 activity was unaffected ( 40, 41 ). The lack of peripheral inhibition was not due to a lack of exposure in situ as skin biopsy AZD4017 correlated with plasma levels, albeit at lower concentrations.…”

Section: Discussionsupporting

confidence: 73%

A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

Ajjan

Hensor

Shams

et al. 2021

Preprint

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Chronic wounds (e.g. diabetic foot ulcers) have a major impact on quality of life, yet treatments remain limited. Glucocorticoids impair wound healing; preclinical research suggests that blocking glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves wound repair. This investigator-initiated double-blind, randomised, placebo-controlled parallel-group phase 2b pilot trial investigated efficacy, safety and feasibility of 11β-HSD1 inhibition for 35 days by oral AZD4017 (AZD) treatment in adults with type 2 diabetes (n=14) compared to placebo (PCB, n=14) in a single-centre secondary care setting. Computer-generated 1:1 randomisation was pharmacy-administered. From 300 screening invitations, 36 attended, 28 were randomised. There was no proof-of-concept that AZD inhibited 24 hour skin 11β-HSD1 activity at day 28 (primary outcome: adjusted difference AZD-PCB 90% CI (diffCI)=-3.4,5.5) but systemic 11β-HSD1 activity (median urinary [THF+alloTHF]/THE ratio) was 87% lower with AZD at day 35 (PCB 1.00, AZD 0.13, diffCI=-1.04,-0.69). Mean wound gap diameter (mm) following baseline 2mm punch biopsy was 34% smaller at day 2 (PCB 1.51, AZD 0.98, diffCI=-0.95,-0.10) and 48% smaller after repeat wounding at day 30 (PCB 1.35, AZD 0.70, diffCI=-1.15,-0.16); results also suggested greater epidermal integrity but modestly impaired barrier function with AZD. AZD was well-tolerated with minimal side effects and comparable adverse events between treatments. Staff availability restricted recruitment (2.9/month); retention (27/28) and data completeness (95.3%) were excellent. These preliminary findings suggest that AZD may improve wound healing in patients with type 2 diabetes and warrant a fully-powered trial in patients with active ulcers. [Trial Registry: www.isrctn.com/ISRCTN74621291. Funding: MRC Confidence in Concept and NIHR Senior Investigator Award.]

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Section: Discussionsupporting

confidence: 73%

A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

Ajjan

Hensor

Shams

et al. 2021

Preprint

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“…The latter conversion is of importance for salt regulation, for cortisol has an equal affinity for the mineralocorticoid receptor and thus equal effect as aldosterone, whereas cortisone has no binding potential [25,43,44]. In line with prior research in adults and children, we found that 11β-HSD type 1 activity was negatively correlated with kidney function [45,46]. Also consistent with our data is literature that indicates that the functionality of 11β-HSD type 2 declines over the course of kidney disease [47,48], although some data indicate that this phenomenon might only occur at severely impaired kidney function [49].…”

Section: Discussionsupporting

confidence: 87%

“…The overall daily glucocorticoid production, as measured by the total 24 h urinary excretion of glucocorticoid compounds did not differ between the 2 groups (p = 0.32). In plasma, a significantly lower concentration of cortisone was found (41 vs. 55 [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] nmol/L, respectively, p < 0.001), but not of cortisol (see online suppl. , p = 0.03).…”

Section: Baseline Characteristicsmentioning

confidence: 99%

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism

et al. 2020

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Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. Methods: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. Results: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 μmol/24 h, p = 0.007, and 0.29 vs. 0.53 μmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 μmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. Conclusions: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

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“…Global 11β-HSD1 activity was evaluated through the quantification of 24-hour urinary glucocorticoid metabolites, by LC–MS/MS ( Sagmeister et al , 2018 ). 11β-HSD1 activity was inferred from the ratio of (5α-tetrahydrocortisol + tetrahydrocortisol):tetrahydrocortisone [(5α-tetrahydrocortisol + tetrahydrocortisol):tetrahydrocortisone] alongside a stable ratio of total urinary cortisol (F):total urinary cortisone (E) reflecting 11β-HSD2 activity ( Tomlinson and Stewart, 2001 ).…”

Section: Methodsmentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

Markey

Mitchell

Botfield

et al. 2020

Brain Communications

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Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

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Glucocorticoid activation by 11β‐hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross‐sectional study

Cited by 30 publications

References 47 publications

A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism

11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

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