TY - JOUR

T1 - Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation

T2 - two randomized, placebo-controlled trials

AU - Larsen, Emil List

AU - Andersen, Andreas

AU - Kjær, Laura K.

AU - Eickhoff, Mie K.

AU - Frimodt-Møller, Marie

AU - Persson, Frederik

AU - Rossing, Peter

AU - Lykkesfeldt, Jens

AU - Knop, Filip K.

AU - Vilsbøll, Tina

AU - Rungby, Jørgen

AU - Poulsen, Henrik E.

N1 - Publisher Copyright: © 2023 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2023

Y1 - 2023

N2 - Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (n = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (n = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: −4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: −4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by −0.17 nmol/mmol (95% CI: −0.29 to −0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: −0.02 to 0.22)) resulting in a significant between-group difference (p = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691.Highlights Plasma ferritin correlated with DNA and RNA oxidation in individuals with T2D. Twelve weeks dapagliflozin treatment decreased DNA oxidation. Dapagliflozin and empagliflozin treatment did not change RNA oxidation. Lipid peroxidation was unaffected by two weeks empagliflozin treatment.

AB - Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (n = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (n = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: −4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: −4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by −0.17 nmol/mmol (95% CI: −0.29 to −0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: −0.02 to 0.22)) resulting in a significant between-group difference (p = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691.Highlights Plasma ferritin correlated with DNA and RNA oxidation in individuals with T2D. Twelve weeks dapagliflozin treatment decreased DNA oxidation. Dapagliflozin and empagliflozin treatment did not change RNA oxidation. Lipid peroxidation was unaffected by two weeks empagliflozin treatment.

KW - 8-oxodG

KW - 8-oxoGuo

KW - dapagliflozin

KW - empagliflozin

KW - oxidative stress

U2 - 10.1080/10715762.2023.2213820

DO - 10.1080/10715762.2023.2213820

M3 - Journal article

C2 - 37171199

AN - SCOPUS:85159652939

VL - 57

SP - 140

EP - 151

JO - Free Radical Research

JF - Free Radical Research

SN - 1071-5762

IS - 2

ER -