Trial to Investigate the Effect of Dapagliflozin on Ischemia Reperfusion Induced Endothelial Dysfunction

Reperfusion Injury Clinical Trial

Official title:

A Randomized, Double - Blind, Placebo - Controlled Trial to Investigate the Effect of Dapagliflozin on Ischemia Reperfusion Induced Endothelial Dysfunction of the Forearm Vasculature in Healthy Male Subjects

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05217654
• Other study ID #: FBF-SGLT2
• Status: Recruiting
• Phase: Phase 1
• Start date: February 18, 2022
• Est. completion date: August 1, 2023

Study information

• Verified date: February 2022
• Source: Medical University of Vienna
• Contact: Martin Lutnik, M.D.
• Phone: +43 1 40400
• Email: martin.lutnik[@]meduniwien.ac.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to investigate the effect of dapagliflozin or placebo on acetylcholine (Ach)- or nitroglycerin (GTN)-induced vasodilation of the forearm resistance vasculature, as determined by FBF measurement before and 10 minutes after 20 minutes of forearm ischemia.

Description:

The aim is to test the effect of dapagliflozin or placebo on ACh-induced vasodilatation of the forearm resistance vasculature as assessed by FBF measurement before and 10 min after a 20 min forearm ischemia as well as after a 14 day treatment period. The area under the dose-effect curve (AUC) of different ACh doses will be calculated and compared between treatment groups (dapagliflozin vs. placebo) and different time points (pre-ischemia vs. post-ischemia). FBF measurements will be made in response to increasing intra-arterial doses of ACh (25, 50, 100 nmol/min) to assess endothelial function or GTN (4, 8, 16 nmol/min) to test vascular smooth muscle vasodilator function.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 32
• Est. completion date: August 1, 2023
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Healthy male subjects; 18 - 40 years of age

• Body mass index between 18 and 27 kg/m2

• Written informed consent

• Normal findings in medical history

• Non-smoking

Exclusion Criteria:

• Regular intake of any medication including OTC drugs and herbals within 2 weeks before IMP administration

• History of occlusive vascular diseases

• History of vascular anomalies

• History of coagulation disorders

• History of diabetes mellitus (Type 1&2) or pre-diabetes (i.e. HbA1c = 5,7 %)

• History of kidney disease

• History of ketoacidosis

• Impaired liver function (AST, ALT, gGT, bilirubin >3 x ULN)

• Impaired renal function (serum creatinine > 1.3 mg/dl)

• Any other relevant deviation from the normal range in clinical chemistry, haematology or urine analysis

• HIV-1/2-Ab, HbsAg or HCV-Ab positive serology

• Systolic blood pressure above 145 mmHg, diastolic blood pressure above 95 mmHg

• Known allergy against any test agent under study and/or lactose intolerance

• Regular daily consumption of more than on litre of xanthine-containing beverages or more than 40g alcohol

• Participation in another clinical trial during the preceding 3 weeks

Related Conditions & MeSH terms

• Ischemia
• Reperfusion Injury
• Vascular Complications

Intervention

Drug:
• Dapagliflozin 10mg
Daily orally administration of 10mg dapagliflozin
• Placebo
Daily orally administration of 10mg dapagliflozin-placebo

Locations

Country	Name	City	State
Austria	Medical University of Vienna	Vienna

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Vienna

Country where clinical trial is conducted

Austria, 

References & Publications (17)

Barcroft H, Edholm OG. The effect of temperature on blood flow and deep temperature in the human forearm. J Physiol. 1943 Jun 30;102(1):5-20. — View Citation

Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension. 1995 May;25(5):918-23. — View Citation

Chen X, Li X, Zhang W, He J, Xu B, Lei B, Wang Z, Cates C, Rousselle T, Li J. Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-?B pathway. Metabolism. 2018 Jun;83:256-270. doi: 10.1016/j.metabol.2018.03.004. Epub 2018 Mar 9. — View Citation

Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med. 2011 Nov 7;17(11):1391-401. doi: 10.1038/nm.2507. Review. — View Citation

Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017 Jun 8;376(23):2300-2302. doi: 10.1056/NEJMc1701990. — View Citation

He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes. 2013 Apr;62(4):1270-81. doi: 10.2337/db12-0533. Epub 2012 Dec 7. — View Citation

Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001 Mar 27;103(12):1624-30. — View Citation

Khemais-Benkhiat S, Belcastro E, Idris-Khodja N, Park SH, Amoura L, Abbas M, Auger C, Kessler L, Mayoux E, Toti F, Schini-Kerth VB. Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence. J Cell Mol Med. 2020 Feb;24(3):2109-2122. doi: 10.1111/jcmm.14233. Epub 2019 Mar 30. — View Citation

Korkmaz-Icöz S, Kocer C, Sayour AA, Kraft P, Benker MI, Abulizi S, Georgevici AI, Brlecic P, Radovits T, Loganathan S, Karck M, Szabó G. The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats. Int J Mol Sci. 2021 Jul 21;22(15). pii: 7774. doi: 10.3390/ijms22157774. — View Citation

Liem DA, Verdouw PD, Duncker DJ. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2003 Jun 24;107(24):e218-9; author reply e218-9. — View Citation

Lu Q, Liu J, Li X, Sun X, Zhang J, Ren D, Tong N, Li J. Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway. Mol Cell Endocrinol. 2020 Feb 5;501:110642. doi: 10.1016/j.mce.2019.110642. Epub 2019 Nov 21. — View Citation

Pleiner J, Schaller G, Mittermayer F, Marsik C, MacAllister RJ, Kapiotis S, Ziegler S, Ferlitsch A, Wolzt M. Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion. Atherosclerosis. 2008 Mar;197(1):383-91. Epub 2007 Jul 23. — View Citation

Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, Dugi K. Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects. Clin Pharmacol Drug Dev. 2013 Apr;2(2):152-61. doi: 10.1002/cpdd.16. Epub 2013 Mar 27. — View Citation

Szabó C. The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. Shock. 1996 Aug;6(2):79-88. Review. — View Citation

Tsai KL, Hsieh PL, Chou WC, Cheng HC, Huang YT, Chan SH. Dapagliflozin attenuates hypoxia/reoxygenation-caused cardiac dysfunction and oxidative damage through modulation of AMPK. Cell Biosci. 2021 Feb 26;11(1):44. doi: 10.1186/s13578-021-00547-y. — View Citation

Weisshaar S, Litschauer B, Eipeldauer M, Hobl EL, Wolzt M. Ticagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males - a randomized, single-blinded study. Br J Clin Pharmacol. 2017 Dec;83(12):2651-2660. doi: 10.1111/bcp.13378. Epub 2017 Aug 22. — View Citation

Weisshaar S, Litschauer B, Kerbel T, Wolzt M. Atorvastatin combined with ticagrelor prevent ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males - A randomized, placebo-controlled, double-blinded study. Int J Cardiol. 2018 Mar 15;255:1-7. doi: 10.1016/j.ijcard.2017.12.067. Epub 2017 Dec 24. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Acetylcholine - Area under the curve forearm blood flow measurement	effect of dapagliflozin after a two weeks period of regular intake on forearm blood flow (FBF) reactivity in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (GTN; endothelium-independent vasodilator)	14 days
Primary	Acetylcholine - Area under the curve forearm blood flow measurement	acute effect of dapagliflozin on forearm blood flow (FBF) reactivity in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (GTN; endothelium-independent vasodilator) 10 min before (baseline) and after 20 min forearm ischemia, respectively.	30 min