Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Free Radical Research |
| Vol/bind | 57 |
| Udgave nummer | 2 |
| Sider (fra-til) | 140-151 |
| ISSN | 1071-5762 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank the participants for their time and effort in making these trials possible. We thank senior laboratorian technician Lis K Hansen, laboratory technician Agnethe Mehlsen, and Lilli-Ann Starnov for their assistance with the conduction of the EMPOX trial. Further, we thank chemist Trine Henriksen, PhD, and laboratorian technician Katja R Christensen for analyzing urine concentration of 8-oxoGuo, 8-oxodG, and creatinine in both studies and Ricki Thaning for analyzing plasma MDA in the EMPOX trial. We also thank laboratorian technicians Berit R Nielsen, Tina R Juhl, Jessie A Herman, and Anne G Lundgaard for assistance with the conduction of the DapKid study. We are grateful to all that helped recruit participants. ELL has received a research grant from Copenhagen University Hospital, Bispebjerg Frederiksberg - ‘Bispebjerg Frederiksbergs Forskningsfond’ for completion of this study in relation to his Ph.D. thesis. We thank Servier Medical Art ( http://smart.servier.com/ ) for the images provided by the CC-BY license that has been modified and used in the graphical abstract.
Funding Information:
Both the EMPOX and the DapKid studies were investigator-initiated and funded by unrestricted research grants to the institutions by Boehringer-Ingelheim and AstraZeneca AB, respectively. The funders had no role in study design, analyses, interpretation of data, drafting of manuscript, or decision to submit the manuscript for publication. The funders were allowed to comment on the protocol and manuscript prior to submission; however, the final wording was in full discretion of the sponsor-investigator. Filip K. Knop has served on scientifc advisory panels and/or been part of speakers’ bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, and Zealand Pharma. Tina Vilsbøll has served on scientifc advisory panels, been part of speakers’ bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi, and Sun Pharmaceuticals. Jørgen Rungby has within last 3 years received consultancy fees from Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, and Abott. Peter Rossing has served as a consultant, on advisory boards, or as educator for AstraZeneca, Astellas, AbbVie, Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Merck, Bayer (all honoraria’s to institution), and has received research grants from Novo Nordisk and AstraZeneca. Frederik Persson has served as a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Mundipharma, MSD, Novartis, Amgen and has received research grants to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. Mie K Eickhoff has served as educator for AstraZeneca (all honoraria to institution). All other authors declare no additional conflict of interest associated with this manuscript.
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