Ipragliflozin L-Proline

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase urine volume with glucosuria and natriuresis. We recently reported that osmotic diuresis by the SGLT2 inhibitor ipragliflozin induces fluid homeostatic action via the stimulation of fluid intake and vasopressin-induced water reabsorption in euvolemic rats. However, the effects of SGLT2 inhibitors on these parameters in hypervolemic animals remain unclear. In this study, Dahl salt-sensitive hypertensive rats, a hypervolemic rat model, were fed a low-salt (0.3%) or high-salt (8%) diet for 14 days, then divided into vehicle or ipragliflozin (0.01%) groups. During 7 days of treatment, the high-salt diet groups significantly increased fluid intake and urine volume. In the ipragliflozin groups, fluid intake and urine volume increased by 63% and 235%, respectively, in rats fed a normal-salt diet and by 46% and 72%, respectively, in rats fed a high-salt diet. Ipragliflozin increased urinary vasopressin by 200% and solute-free water reabsorption by 196% in the normal-salt group but by only 44% and 38%, respectively, in the high-salt group. A high-salt diet significantly increased fluid balance (fluid intake - urine volume) and Na⁺ balance (Na⁺ intake - urinary Na⁺), but ipragliflozin did not change fluid and Na⁺ balance in normal- or high-salt groups. A high-salt diet significantly increased systolic blood pressure, but ipragliflozin did not significantly change systolic blood pressure in normal- or high-salt groups. In conclusion, SGLT2 inhibitor ipragliflozin did not change fluid and Na⁺ balance regardless of basal fluid retention, suggesting the potential of SGLT2 inhibitors to maintain body water and Na⁺.

We hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function.

To investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF.

Differences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively).

Ipragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function.