# SGLT2 Inhibitors, Loop Diuretics, and the Macula Densa

Andrew Bland, MD, FACP, FAAP · October 19, 2026

Both drugs can increase urinary salt loss, but they act at different sites. The distinction is between salt reaching the macula densa and salt entering its NKCC2 sensor. That difference changes the local feedback to the glomerulus.

![SGLT2 versus loop diuretic feedback](https://urinenephrology.org/2025_UDPA_Lectures_Live/assets/sglt2-loop-macula-densa-gfr-2026-10-19.png)

## SGLT2 inhibitor: delivery increases; sensing remains intact

Less proximal sodium–glucose reabsorption increases NaCl delivery downstream. NKCC2 in the macula densa can sense it. In the classic model, ATP/adenosine signaling through A1 receptors increases afferent arteriolar tone, reducing glomerular pressure and hyperfiltration. An early hemodynamic GFR dip can occur.

## Loop diuretic: block transport and the sensor

Loop diuretics inhibit NKCC2 in both the thick ascending limb and the macula densa. Salt can reach the sensor while uptake is blocked. The resulting feedback-mediated afferent constriction is blunted and renin release from juxtaglomerular granular cells is favored.

## Local feedback is only part of the GFR response

A loop diuretic does not invariably increase GFR: perfusion, volume loss, and relief of congestion affect the net response. SGLT2 vascular responses also vary; human type 2 diabetes studies support an efferent vasodilatory contribution. The diagram shows the classic feedback model, not a fixed GFR prediction for every patient.

## Sources

- [Schlatter et al. (1989): furosemide-sensitive macula-densa NaCl sensing](https://pubmed.ncbi.nlm.nih.gov/2780213/)
- [Cherney et al. (2014): empagliflozin and hyperfiltration in type 1 diabetes](https://pubmed.ncbi.nlm.nih.gov/24334175/)
- [van Bommel et al. (2020), RED trial: hemodynamics in type 2 diabetes](https://pubmed.ncbi.nlm.nih.gov/31791665/)

[Opening lecture](https://urinenephrology.org/2025_UDPA_Lectures_Live/case-based-lectures/opening-lecture.html#macula-densa)