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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. [ABSTRACT FROM AUTHOR]

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.

The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response. [ABSTRACT FROM AUTHOR]

To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cl) and the Cl/Cl ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Cl, which was accompanied by an increase in Cl from 57.5±32, and 60.7±27.3 (duplicate measurements) to 103.9±55.4 ( p<0.01) and 103.8±46.5 ml min ( p<0.01). Cl/Cl rose from 0.60±0.24 and 0.61±0.16 to 0.91±0.31 and 0.91±0.21, respectively (both p<0.005). Serum digoxin concentration declined from 1.24±0.35 and 1.19±0.40 to 1.02±0.35 and 0.97±0.32 µg/l (both p<0.01) during the high sodium diet. In the furosemide - induced natriuresis (6 patients), changes in Na excretion and V were a multiple of those caused by Na loading, but the Cl/Cl ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) plays an important role in regulating body fluids and blood pressure. However, inappropriate activation of the RAS contributes to the pathogenesis of cardiovascular and renal diseases. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used as anti-diabetic agents. SGLT2 inhibitors induce glycosuria and improve hyperglycemia by inhibiting urinary reabsorption of glucose. However, in the early stages of treatment, these inhibitors frequently cause polyuria and natriuresis, which potentially activate the RAS. Nevertheless, the effects of SGLT2 inhibitors on RAS activity are not straightforward. Available data indicate that treatment with SGLT2 inhibitors transiently activates the systemic RAS in type 2 diabetic patients, but not the intrarenal RAS. In this review article, we summarize current evidence of the diuretic effects of SGLT2 inhibitors and their influence on RAS activity. [ABSTRACT FROM AUTHOR]