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Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial

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Janaka Karalliedde, Nikos Fountoulakis, Dimitra Stathi, Antonella Corcillo, Maria Flaquer, Angeliki Panagiotou, Giuseppe Maltese, Anastasios Mangelis, Salma Ayis, Luigi Gnudi

Original languageEnglish
Article number992327
JournalFrontiers in Cardiovascular Medicine
Early online date30 Sep 2022
Accepted/In press11 Aug 2022
E-pub ahead of print30 Sep 2022
Published30 Sep 2022

Bibliographical note

Funding Information: This work was an investigator sponsored/led research study and was supported by a grant from Astra Zeneca. SA was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Center based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the research nurses and participants who assisted in this work. Funding Information: This work was funded by a research grant from Astra Zeneca. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Publisher Copyright: Copyright © 2022 Karalliedde, Fountoulakis, Stathi, Corcillo, Flaquer, Panagiotou, Maltese, Mangelis, Ayis and Gnudi.

King's Authors


Objective: The mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.

Design/Setting: A 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.

Results: In total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.

Conclusions: The combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.

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