Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Arne Gessner, Anna Gemeinhardt, Agnes Bosch, Dennis Kannenkeril, Christian Staerk, Andreas Mayr, Martin F Fromm, Roland E Schmieder, Renke Maas, Arne Gessner, Anna Gemeinhardt, Agnes Bosch, Dennis Kannenkeril, Christian Staerk, Andreas Mayr, Martin F Fromm, Roland E Schmieder, Renke Maas

Abstract

Background: In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on L-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported.

Methods: Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters.

Results: Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (- 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on L-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure.

Conclusions: Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registration http://www.clinicaltrials.gov : NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

Keywords: ADMA; Cardiovascular disease; Dapagliflozin; Empagliflozin; Homoarginine; SDMA; SGLT-2 inhibitor; Type 2 diabetes mellitus.

Conflict of interest statement

A. Gessner was involved in research projects at his institution by Boehringer Ingelheim. M.F. Fromm has received consultancy fees from Boehringer Ingelheim and lecture fees from Janssen-Cilag. He has received third-party funds for research projects at his institution by Boehringer Ingelheim, Dr. R. Pfleger GmbH, and Heidelberg Pharma Research GmbH.

R.E. Schmieder has received speaker fees and advisory board fees from Boehringer Ingelheim and AstraZeneca. The other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Intraindividual percentage ratios after treatment with empagliflozin or dapagliflozin in comparison to baseline values (Verum) and after placebo treatment in comparison to baseline values (Placebo) for plasma concentration of hArg, Arg, ADMA, SDMA, and creatinine. P-values calculated by two-sided paired t-tests; p-values refer to the percentage changes of biomarkers; adj. p-values computed based on the procedure of Benjamini and Hochberg

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Source: PubMed

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