Physiology and Clinical Implications of SGLT-2 Inhibitors Use in Diabetes
David León-Jiménez, Vikas S. Sridhar, Manuel López-Mendoza, Rosalie A. Scholtes, Roland E. Schmieder, David Z.I. Cherney, Daniël H. van Raalte, Francisco J. Toro-Prieto, José Pablo Miramontes-González and Erik J.M. van Bommel
Kidney hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in diabetes: physiology and clinical implications. Clin Kidney J. 2024 Nov 27;18(1):sfae370.
Progressive loss of kidney function in diabetes is partly driven by glomerular hyperfiltration — a state of abnormally elevated filtration pressure that damages the kidney over time. Sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce glomerular filtration rate (GFR) and intraglomerular pressure, but the precise mechanisms underlying this effect have remained incompletely understood. This review, conducted by researchers from Amsterdam UMC, the University of Toronto, Friedrich-Alexander University Erlangen, and centres in Spain and the Netherlands, synthesises current evidence on the kidney hemodynamic effects of SGLT2 inhibitors in both type 1 diabetes (T1D) and type 2 diabetes (T2D), and discusses their clinical implications.
The review draws on data from several key mechanistic trials — including ATIRMA, RED, BETWEEN, RECOLAR, and ELMI — in which measured GFR, effective renal plasma flow (ERPF), and renal vascular resistance (RVR) were directly assessed in response to SGLT2 inhibition under controlled conditions.
Key findings:
- SGLT2 inhibitors reduce GFR through different mechanisms depending on the patient population: In people with T1D and glomerular hyperfiltration, the predominant mechanism is pre-glomerular vasoconstriction, mediated by restoration of tubuloglomerular feedback (TGF) via increased adenosine release. In people with T2D and those with T1D who are normofiltering, post-glomerular vasodilation appears to be the primary driver of GFR reduction.
- Baseline kidney hemodynamic function is a key determinant of response: Hyperfiltering individuals show a greater physiological response to SGLT2 inhibition — including greater glucosuria, sodium excretion, and urine output — compared to those with normal filtration. This appears to reflect more pronounced TGF activation and pre-glomerular vasoconstriction in this subgroup.
- Concomitant RAS blockade does not fully explain the differences: Although most T2D trials included patients on background renin-angiotensin system (RAS) inhibition, sensitivity analyses suggest that SGLT2 inhibition affects kidney hemodynamics independently of RAS blocker use.
- The acute GFR dip is not harmful and is associated with long-term kidney protection: Secondary analyses of major outcome trials (EMPA-REG OUTCOME, CREDENCE, VERTIS-CV) consistently confirm that the initial GFR decline with SGLT2 inhibition is not associated with adverse events or acute kidney injury. Patients with the largest acute GFR reductions tended to show the slowest subsequent loss of kidney function.
- Greater GFR reductions are linked to greater reductions in albuminuria: Larger acute declines in GFR have been associated with more pronounced reductions in albuminuria, which in turn independently predict lower risks of kidney, cardiovascular, and heart failure events.
- Findings support broader investigation of SGLT2 inhibition across high-risk populations: Ongoing mechanistic studies are examining SGLT2 inhibition in kidney transplant recipients, children with diabetes, adults with non-diabetic CKD, and patients with end-stage kidney disease — populations where kidney-protective effects may be similarly important.
This review provides a comprehensive synthesis of the hemodynamic mechanisms underlying the kidney-protective effects of SGLT2 inhibitors. While the specific arteriolar changes differ by population, the net outcome — a reduction in intraglomerular pressure and long-term preservation of kidney function — appears consistent across patient groups and irrespective of the underlying mechanism.
Concluding, the authors state
"Regardless of the responsible mechanisms, acute changes in GFR are associated with long-term kidney function preservation — a relationship that may reflect an underlying protective decline in glomerular hypertension."
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