A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation

Chorlton, Jamie; Hollowood, Zoe; Dyer, Carlene; Lockhart, Donna; Boekman, Pascal; McCafferty, Kieran; Coffey, Peter; Marelli‐Berg, Federica M.; Martin, John F.

doi:10.1016/j.eclinm.2022.101604

Cited by 4 publications

(2 citation statements)

References 29 publications

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“…In this study we used the Gckr:P446L mouse and a model of transcriptional Gckr deficiency (Gckr del/wt ) to test the hypothesis that compromised GKRP function or expression affects the response to chronic GKA treatment. Using AZD1656, a GKA with an established safety record [36,37] that has been extensively trialled in man [6,11,12], we show that compromised GKRP function (Gckr:P446L) or expression (Gckr del/wt ) affect chronic blood glucose lowering efficacy and lipid accumulation in liver.…”

Section: Introductionmentioning

confidence: 99%

“…Several classes of GK activator drugs (GKAs) were developed with good acute efficacy in lowering blood glucose [3]. However, few have been approved for T2D therapy or are still in development [4][5][6][7][8][9]. Key challenges encountered were risks of hypoglycaemia by excessive insulin secretion and a chronic decline in glucose-lowering efficacy [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Compromised chronic efficacy of a Glucokinase Activator AZD1656 in mouse models for common humanGCKRvariants

Ford,

Chachra,

Alshawi

et al. 2024

Preprint

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Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.

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