Dapagliflozin prevents vascular ischemia-reperfusion injury in healthy young males: a randomized, placebo-controlled, double-blinded trial

Ischemia-reperfusion injury (IRI) causes vascular endothelial dysfunction. Preclinical data suggest that the SGLT2 inhibitor dapagliflozin may protect against vascular IRI. This trial has investigated if oral treatment with dapagliflozin can mitigate the transient impairment of IRI-induced-endothelial dysfunction in the forearm resistance vasculature. 32 healthy males (n = 16 per group, age: 27 ± 4 yrs) were studied in this randomized, placebo-controlled, parallel-group, double-blinded trial. Acetylcholine (ACh; endothelium-dependent vasodilator) and glyceryltrinitrate (GTN; endothelium-independent vasodilator) were administered into the brachial artery of the non-dominant arm. The response to stepwise increasing doses on forearm blood flow (FBF) was assessed. FBF was measured before and after a cuff-induced 20-minute forearm ischemia at pre-dose and following daily intake of 10 mg dapagliflozin or placebo over 15 days. IRI reduced endothelium-dependent vasodilatation by 29% (p < 0.001, paired t-test). After a 15-day treatment period, IRI-induced endothelial dysfunction was abrogated in participants receiving dapagliflozin (FBF AChAUC ratios post- vs. pre-ischemia: dapagliflozin: 0.93; 95% CI: 0.80–1.29) but unchanged with placebo (0.81; 95% CI: 0.68–0.92; p = 0.015 vs. pre-ischemia). GTN-induced vasodilation was not altered by IRI or treatment. Dapagliflozin treatment at standard clinical doses over 15 days prevents IRI-induced vascular endothelial dysfunction in the forearm resistance vasculature of healthy young males. The underlying mechanism and the potential clinical impact remain to be demonstrated. Clinical trial registration https://clinicaltrials.gov/study/NCT05217654 NCT05217654; EudraCT number: 2021-005002-95 Date of registration: 20/01/2022.