Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

Angé, Marine; Poortere, Julien De; Ginion, Audrey; Battault, Sylvain; Dechamps, Mélanie; Muccioli, Giulio G.; Roumain, Martin; Morelle, Johann; Druart, Sébastien; Mathivet, Thomas; Bertrand, Luc; Castanares-Zapatero, Diego; Horman, Sandrine; Beauloye, Christophe

doi:10.1038/s41598-021-93156-1

Cited by 13 publications

(11 citation statements)

References 57 publications

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“…improving intestinal barrier function have also been demonstrated in animal models (30,31). The beneficial effects of SGLT2 inhibitors were observed across all categories of ICU admission but were most evident in reducing nonoperative ICU admissions, which in our cohort referred to emergency admissions due to nonsurgical causes.…”

Section: Discussionsupporting

confidence: 57%

Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study

et al. 2023

Critical Care Medicine

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OBJECTIVES: The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined. DESIGN: Retrospective observational study. SETTING: Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System). PATIENTS: All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69–0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38–0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively). CONCLUSIONS: In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories.

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Section: Discussionsupporting

confidence: 57%

Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study

et al. 2023

Critical Care Medicine

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“…This class of drug may exert "off-target" cardiovascular benefits by modulating vascular endothelial cell activation and alleviating endothelial cell dysfunction. This is also supported by the work of Ange et al, who recently showed that CANA activates the alpha-1 AMPK-dependent pathway in human endothelial cells exposed to human septic plasma [32]. Furthermore, Behnammanesh et al have demonstrated that CANA stimulates the expression of heme-oxygenase (HO)-1, a highly inducible antioxidant, in vascular smooth muscle cells.…”

Section: Mechanisms Underlying Protective Effects Of Cana Against Iri In Vasculaturementioning

confidence: 67%

The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

Korkmaz‐Icöz

Kocer

Sayour

et al. 2021

IJMS

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Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

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“… Acting on the α1AMPK-dependent pathway. [ 152 ] Abbreviations : SGLT2, sodium-glucose cotransporter-2; LPS, lipopolysaccharides; UCP2, uncoupling protein 2; CLP, cecal ligation and puncture; AMPK, adenosine monophosphate-activated protein kinase. …”

Section: Introductionmentioning

confidence: 99%

Anti-Hyperglycemic Agents in the Adjuvant Treatment of Sepsis: Improving Intestinal Barrier Function

Wang¹,

Li²,

Wang³

et al. 2022

DDDT

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Intestinal barrier injury and hyperglycemia are common in patients with sepsis. Bacteria translocation and systemic inflammatory response caused by intestinal barrier injury play a significant role in sepsis occurrence and deterioration, while hyperglycemia is linked to adverse outcomes in sepsis. Previous studies have shown that hyperglycemia is an independent risk factor for intestinal barrier injury. Concurrently, increasing evidence has indicated that some anti-hyperglycemic agents not only improve intestinal barrier function but are also beneficial in managing sepsis-induced organ dysfunction. Therefore, we assume that these agents can block or reduce the severity of sepsis by improving intestinal barrier function. Accordingly, we explicated the connection between sepsis, intestinal barrier, and hyperglycemia, overviewed the evidence on improving intestinal barrier function and alleviating sepsis-induced organ dysfunction by anti-hyperglycemic agents (eg, metformin, peroxisome proliferators activated receptor-γ agonists, berberine, and curcumin), and summarized some common characteristics of these agents to provide a new perspective in the adjuvant treatment of sepsis.

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Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

Cited by 13 publications

References 57 publications

Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study

Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study

The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

Anti-Hyperglycemic Agents in the Adjuvant Treatment of Sepsis: Improving Intestinal Barrier Function

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