Molecular regulation of the renin–angiotensin system by sodium–glucose cotransporter 2 inhibition in type 1 diabetes mellitus

  • Chantal KopeckyEmail author
  • Yuliya Lytvyn
  • Oliver Domenig
  • Marlies Antlanger
  • Johannes J. Kovarik
  • Christopher C. Kaltenecker
  • Marko Poglitsch
  • Bruce A. Perkins
  • Kerry-Anne Rye
  • David Z. I. Cherney
  • Marcus D. Säemann
Research Letter

To the Editor: Sodium–glucose cotransporter-2 (SGLT-2) inhibitors are a highly promising class of glucose-lowering therapies and have been found to reduce cardiovascular and kidney disease risk in patients with type 2 diabetes [1, 2, 3]. The mechanisms underlying these cardio- and renoprotective effects of SGLT-2 inhibition are, however, incompletely understood and it is not known if these beneficial effects are also evident in people with type 1 diabetes.

Hyperglycaemia triggers renal haemodynamic abnormalities in diabetes, which increases glomerular pressure and can lead to hyperfiltration and subsequent renal injury [4]. We have previously shown that empagliflozin increases distal tubular sodium delivery in people with type 1 diabetes, which enhances an autoregulatory mechanism in the kidneys (tubuloglomerular feedback [TGF]) that lowers glomerular pressure and attenuates hyperfiltration [5]. Although these renal haemodynamic effects in response to SGLT-2 inhibition resemble those...


Angiotensins Diabetes mellitus Empagliflozin Renin–angiotensin system activation SGLT-2 inhibition 





Chronic kidney disease


Lower limit of quantification


Renin–angiotensin system


Sodium–glucose cotransporter 2


Tubuloglomerular feedback



Some of the data were presented as an abstract at the 45th ÖDG Annual Conference in 2017.

Contribution statement

CK devised the study, analysed the data, wrote the manuscript and reviewed and edited the manuscript. DZIC and BAP conducted the original study, provided patient samples and contributed to data interpretation. MP and OD performed mass spectrometry analyses and YL acquired epidemiological data of the patient cohort and performed correlation analysis. All named authors contributed to data interpretation, discussion, helped revise the manuscript providing critical intellectual content and approved it for publication. CK is the guarantor and takes full responsibility of the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.


DZIC is supported by funding from the Canadian Institutes of Health Research, the JDRF and the Banting and Best Diabetes Centre at the University of Toronto. DZIC is supported in part by a University of Toronto Merit Award, and his trainees are supported by the Canadian Diabetes Association (Diabetes Canada) Postdoctoral Fellowship, the University Health Network CaRE Fellowship Program. YL is supported by the Canadian Diabetes Association (Diabetes Care) Postdoctoral Fellowship. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sector.

The study sponsor for the original study (NCT01392560) was not involved with the study design, analysis and interpretation of data, writing or decision to submit the work for publication for this present post hoc analysis.

Duality of interest

DZIC has acted as a consultant and received honoraria from Boehringer Ingelheim, Lilly, Merck, Janssen, Sanofi, AbbVie, Mitsubishi-Tanabe Pharma and AstraZeneca and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, Merck, AstraZeneca and Janssen. BAP has received grants to his research institute and served on the advisory board for Boehringer Ingelheim. All other authors declare that they have no duality of interest associated with their contribution to this manuscript.

Supplementary material

125_2019_4871_MOESM1_ESM.pdf (132 kb)
ESM (PDF 131 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Chantal Kopecky
    • 1
    • 2
    Email author
  • Yuliya Lytvyn
    • 3
  • Oliver Domenig
    • 4
  • Marlies Antlanger
    • 2
  • Johannes J. Kovarik
    • 2
  • Christopher C. Kaltenecker
    • 2
  • Marko Poglitsch
    • 4
  • Bruce A. Perkins
    • 5
  • Kerry-Anne Rye
    • 6
  • David Z. I. Cherney
    • 3
  • Marcus D. Säemann
    • 7
    • 8
  1. 1.School of Medical Sciences, Faculty of MedicineUNSW SydneySydneyAustralia
  2. 2.Department of Internal Medicine III, Division of Nephrology and DialysisMedical University of ViennaViennaAustria
  3. 3.Department of Medicine, Division of Nephrology, Toronto General HospitalUniversity of TorontoTorontoCanada
  4. 4.Attoquant DiagnosticsViennaAustria
  5. 5.Mount Sinai HospitalUniversity of TorontoTorontoCanada
  6. 6.School of Medical SciencesFaculty of Medicine, UNSW SydneySydneyAustralia
  7. 7.6th Medical Department for Nephrology and DialysisWilhelminenhospitalViennaAustria
  8. 8.Sigmund Freud Private UniversityViennaAustria

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