Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

“…In this study, 2 weeks of empagliflozin therapy significantly reduced NHE3 activity in both normal and hypertensive Wistar rats 89 . Collectively, this evidence highly suggests that SGLT2 inhibitors are potent NHE3 inhibitors and decrease their activity 91,92 93 however, may represent another potential link between SGLT2 inhibition and acidosis.…”

“…89 Collectively, this evidence highly suggests that SGLT2 inhibitors are potent NHE3 inhibitors and decrease their activity. 91,92 Although this effect may be attenuated by inducing ammoniagenesis by SGLT2 inhibitors, 93 however, may represent another potential link between SGLT2 inhibition and acidosis.…”

Effect of dapagliflozin on 24-hour glycemic variables in Japanese patients with type 2 diabetes mellitus receiving basal insulin supported oral therapy (DBOT): a multicenter, randomized, open-label, parallel-group study

“… 7 Based on data from animal studies and clinical trials, the effects of SGLT2 inhibitors on urinary sodium excretion and diuresis appear to be transient. 22 The composition of body weight reduction in SGLT2 inhibitors therapy at ~16 weeks is body water 15%–35%, body fat 50%–75%, subcutaneous fat 25%–45%, and visceral fat ~25%. 23 Combined above, improvement in insulin sensitivity by reducing visceral fat 24 can be linked to decreased HbA1c in people treated with SGLT2 inhibitors.…”

“…The body weight reduction by SGLT2 inhibitors may influence decreases in HbA1c 7. Based on data from animal studies and clinical trials, the effects of SGLT2 inhibitors on urinary sodium excretion and diuresis appear to be transient 22. The composition of body weight reduction in SGLT2 inhibitors therapy at ~16 weeks is body water 15%–35%, body fat 50%–75%, subcutaneous fat 25%–45%, and visceral fat ~25% 23.…”

Effect of sodium-glucose cotransporter-2 inhibitors on aldosterone and renin levels in diabetes mellitus type 2 patients: a systematic review and meta-analysis

“…Apart from a glucosuric effect, SGLT2i can induce natriuresis and osmotic diuresis and can lead to reduced plasma volume and lower blood pressure. These effects can potentially lead to the renin–angiotensin–aldosterone system (RAAS) activation 7 . However, available data regarding the relationship between SGLT2i and RAAS activation are still inconclusive and contradictory.…”