Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcomes in type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD). A decrease in renal blood flow (RBF) with attenuation of glomerular hyperfiltration may contribute to this. We examined renal and systemic hemodynamic effects of SGLT2i in relevant patient categories. Methods: Using a double-blind placebo controlled cross-over design we randomized patients with DM2 and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m2 (n=16), patients with DM2 and eGFR 20-60 ml/min/1.73m2 (n=17) and patients with non-diabetic CKD and eGFR 20-60 ml/min/1.73m2 (n=16) to empagliflozin 10 mg daily or placebo for four weeks and crossed over to the opposite treatment after two-week washout. RBF was measured with 82Rubidium positron emission tomography/computed tomography (82Rb-PET/CT), GFR as plasma clearance of 99mTechnetium- diethylene-triamine-pentaacetate, while 24-hour blood pressure (BP) and total peripheral vascular resistance (TVR) were recorded using the commercially available Mobil-O-graph. Results: Compared to placebo empagliflozin reduced RBF by 6% in the DM2-CKD group (p<0.001), while there were non-significant decreases of 4% in the DM2 group and 1% in the CKD group (p=0.29 and 0.72). Empagliflozin reduced GFR, BP and TVR in all groups. Although total renal vascular resistance (RVR) remained unchanged, calculations based on Gomez? equations revealed a reduction of post-glomerular resistance in the DM2 and CKD groups. Conclusion: Short-term empagliflozin treatment reduced RBF in patients with DM2 and CKD, whereas GFR, BP and TVR were reduced in all groups. The lack of reduction in total RVR together with a decrease in post-glomerular resistance and systemic BP suggest SGLT2i protect the glomerulus due to relative pre-glomerular vasoconstriction and post-glomerular vasodilation.

SFN has disclosed travel expenses covered by AstraZeneca. FHM disclosed advisory board participation and speaker honoraria from Boehringer-Ingelheim and AstraZeneca. JBN disclosed advisory board participation for Bayer, Boehringer-Ingelheim and AstraZeneca. No other disclosures were reported.

EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50

https://pubmed.ncbi.nlm.nih.gov/38680116/

This project was funded by The Augustinus Foundation, The Research Foundation of the Central Denmark Region, The Medicine Fund of the Danish Regions, Gødstrup Hospital Research Fund and Boehringer-Ingelheim, who delivered the study medication. Boehringer-Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to a Boehringer-Ingelheim substance, as well as intellectual property considerations. Boehringer-Ingelheim had no role in the design, analysis, interpretation of the results or the writing of this manuscript.

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The studies were approved by The Central Denmark Region Committees on Health Research Ethics and the Danish Medicines Agency and were conducted in accordance with the Declaration of Helsinki 2013. The studies were monitored by the Good Clinical Practice (GCP) Unit of Aarhus and Aalborg Universities.

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