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Cited by 1,329Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesDiabetes Management and Research

Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus

Cherney, David Z.I., Perkins, Bruce A., Soleymanlou, Nima, Maione, Maria, Lai, Vesta, Lee, Alana, Fagan, Nora M., Woerle, Hans J. +3 more·2014·Circulation
DOI 10.1161/circulationaha.113.005081
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Abstract

Background—: The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks’ sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). Methods and Results—: Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m 2 , n=27) or normal GFR (T1D-N, GFR 90–134 mL/min/1.73m 2 , n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4–6 mmol/L) and hyperglycemic (9–11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 mL/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23–139±25 mL/min/1.73 m 2 , P <0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P <0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group ( P ≤0.04). Conclusions—: In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01392560.

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Crossref · 10.1161/circulationaha.113.005081

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  • SGLT2 inhibitors reduce kidney tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow GFR loss through mechanisms that appear independent of glycemia.

    “For example, SGLT2 inhibitors reduce kidney tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow GFR loss through mechanisms that appear independent of glycemia (31,(97)(98)(99)(100)(101).”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [97]

    The Discussion reports reduced tubular glucose reabsorption, body weight, blood pressure, and hyperfiltration after SGLT2 inhibition; it treats reduced intraglomerular pressure as an inferred mechanism. It cites a reduction in proteinuria in patients with type 2 diabetes, but does not establish reduced albuminuria in its own participants. Crucially, the Discussion says long-term renal protection is not yet known, so this paper does not support the claim that SGLT2 inhibitors slow GFR loss; it also does not establish that all the listed effects are independent of glycemia. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Blocking sodium reuptake in the proximal tubule restores delivery of sodium to the macula densa, leading to afferent arteriolar constriction and a reduction in intraglomerular pressure.

    “Blocking sodium reuptake in the proximal tubule has been suggested to restore delivery of sodium to the macula densa, leading to afferent arteriolar constriction and a reduction in intraglomerular pressure.36”

    From SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis (2019) · cites this paper as [36]

  • SGLT-2i has special potency such as reducing blood glucose, reducing oxidative stress, losing weight, reducing uric acid, controlling blood pressure and improving renal ultrafiltration and hypoxia.

    “As for the morbidity, renal outcome and HHF, it was clear that SGLT-2i had more significant impact than finerenone, which might be explained by the special potency of SGLT-2i such as reducing blood glucose, reducing oxidative stress, losing weight, reducing uric acid, controlling blood pressure and improving renal ultrafiltration and hypoxia [65, 71–79].”

    From Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease (2022) · cites this paper as [78]

  • Empagliflozin reduced kidney blood flow and increased vascular resistance in hyperglycemic patients with type 1 diabetes through afferent arteriolar vasoconstriction.

    “Consistent with this concept, SGLT2 inhibition by empagliflozin was observed to reduce kidney blood flow and increase vascular resistance in hyperglycemic patients with T1DM through afferent arteriolar vasoconstriction (23).”

    From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [23]

  • SGLT2 inhibitors reduce intraglomerular pressure, which may preserve long-term kidney function.

    “In type 1 and type 2 diabetes, clinical studies have shown that early and reversible reductions in eGFR occurred on initiation of SGLT2 inhibitor therapy, including in those participants with good glycemic control, 13 -15 suggesting that SGLT2 inhibitors reduce intraglomerular pressure, which may preserve long-term kidney function.”

    From A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy (2021) · cites this paper as [14]

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Authors
Cherney, D. Z. I., Perkins, B. A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., Fagan, N. M., Woerle, H. J., Johansen, O. E., Broedl, U. C., & von Eynatten, M.
Affiliations
  • Boehringer Ingelheim (Germany) (DE)
  • From the Department of Medicine, Division of Nephrology (D.Z.I.C., M.M., V.L., A.L.) and the Department of Medicine, Division of Endocrinology (B.A.P.), Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Boehringer Ingelheim Canada Ltd./Ltée, Burlington, Ontario, Canada (N.S.); Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT (N.M.F., M.v.E.); and Boehringer Ingelheim Pharma GmbH &amp; Co.KG, Ingelheim, Germany (H.J.W., O.E.J., U.C.B.).
Corresponding author
  • Cherney, David Z.I.
  • Perkins, Bruce A.
  • Soleymanlou, Nima
  • Broedl, Uli C.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-02-04
Volume
129
Issue
5
Pages
587-597
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.113.005081
OpenAlex
W1990025047
Semantic Scholar
4f55cd3b00dd2059d3ab005922b610c4f89a64e9
Cited by
1,329
References
48
Citations by year
2026: 77 · 2025: 77 · 2024: 76 · 2023: 90 · 2022: 115 · 2021: 134 · 2020: 140 · 2019: 117 · 2018: 133 · 2017: 112 · 2016: 115 · 2015: 87 · 2014: 53 · 2013: 2
FWCI
67.01
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Funders
American Diabetes Association
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
empagliflozin, SGLT2 inhibitors, type 1 diabetes, renal hyperfiltration, glomerular filtration rate, renal hemodynamics, effective renal plasma flow, nitric oxide, hyperglycemia, renin-angiotensin-aldosterone system, renal vascular resistance, glycemic control
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Adult, Benzhydryl Compounds, Diabetes Mellitus, Type 1, Female, Glomerular Filtration Rate, Glucosides, Hemodynamics, Humans, Kidney, Male, Glucose Clamp Technique, Treatment Outcome, Sodium-Glucose Transporter 2, Young Adult

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