Abstract

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.

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

What is new?

This is the first study of the hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in diabetic and non-diabetic chronic kidney disease.

We found that the sodium-glucose cotransporter 2 inhibitor empagliflozin reduced renal blood flow in patients with type 2 diabetes and chronic kidney disease.

Empagliflozin reduced blood pressure and total vascular resistance in patients with type 2 diabetes both with and without chronic kidney disease and in patients with non-diabetic chronic kidney disease.

What are the clinical implications?

This is the first time sodium-glucose cotransporter 2 inhibitors have been shown to decrease renal blood flow in patients with type 2 diabetes, corroborating the hypothesis that they exert clinical benefits through attenuation of hyperfiltration

Our findings suggest a combined pre- and post-glomerular hemodynamic response that may underlie the beneficial clinical effects.

The reduction in blood pressure and total peripheral resistance point to a novel vascular effect of empagliflozin that is present in both patients with and without type 2 diabetes or chronic kidney disease.

Competing Interest Statement

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.

Clinical Trial

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

Clinical Protocols

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

Funding Statement

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.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

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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Data Availability

All study data will be made available upon request.

Non-standard abbreviations and acronyms82Rb-PET/CT82Rubidium positron emission tomography/computed tomography99mTc-DTPA99mTechnetium-diethylene-triamne-pentaacetateAAabdominal aortaADPKDautosomal dominant polycystic kidney diseaseAEadverse eventBMIbody mass indexBPblood pressureCKDchronic kidney diseaseDM1type 1 diabetes mellitusDM2type 2 diabetes mellituseGFRestimated glomerular filtration rateERFPeffective renal plasma flowEVFerythrocyte volume fractionFFfiltration fractionGCPgood clinical practiceGFRglomerular filtration rateHbA1cglycated hemoglobinIQRinter quartile rangeMAPmean arteriel pressurePGLOintra glomerular pressureRaafferent glomerular arteriolar resistanceRBFrenal blood flowReefferent glomerular arteriolar resistanceRVRrenal vascular resistanceSAEserious adverse eventSDstandard deviationSGLT2isodium-glucose cotransporter 2 inhibitorsTGFtubulo-glomerular feedbackTVRtotal peripheral vascular resistanceuACRurinary albumin/creatinine ratioVOIvolume of interest