Discussion
In the present study, we found that tofogliflozin acutely decreased 24-hour mean glucose levels and postprandial glucose levels after each meal and increased time in range in patients with type 2 diabetes, irrespective of treatment with DPP-4 inhibitors. These findings are in agreement with previous studies, including ours (5, 9-11). In a previous study with CGM, we also demonstrated that acute dosing with a single tablet of canagliflozin, another SGLT2 inhibitor, caused a significant reduction in 24-hour mean glucose levels (10). Another study also found that an SGLT2 inhibitor lowered glucose levels from 2 hours after a single dose and improved glycemic variability within 1 week of treatment (11). The finding that tofogliflozin significantly reduced postprandial glucose after each meal is in accordance with other CGM studies on the SGLT2 inhibitor class (5, 9-12). In the present study, we could confirm by CGM that tofogliflozin rapidly lowers blood glucose levels.
This is the first study to compare the acute effects of a SGLT2 inhibitor on the 24-hour glucose profile and glycemic variability evaluated by CGM between patients receiving and those not receiving DPP-4 inhibitors. CGM revealed that the SD of 24-hour glucose levels, an index of glycemic variability, was significantly reduced in patients receiving DPP-4 inhibitors but was unchanged in those not receiving these drugs. Moreover, both MAGE and MPPGE, other indexes of glycemic variability, were significantly reduced only in patients receiving DPP-4 inhibitors. Thus, SGLT2 inhibitors may improve glycemic variability more strongly as an add-on treatment in patients receiving DPP-4 inhibitors than in patients not receiving DPP-4 inhibitors. Several studies reported that glucose fluctuations have a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia (13-14). We speculate that improvement of glycemic variability by tofogliflozin may suppress development of cardiovascular events in patients with type 2 diabetes, especially those receiving DPP-4 inhibitors.
The mechanisms by which add-on therapy with tofogliflozin reduces glycemic variability only in patents receiving DPP-4 inhibitors remains unclear. One possible explanation is that DPP-4 inhibitors, which inhibit glucagon secretion and promote insulin secretion by enhancing the effects of the incretin hormone GLP-1, may potentially attenuate the increase in hepatic glucose production induced by SGLT2 inhibitors (5, 6). In a previous study, we demonstrated that, during a meal test, plasma glucagon level was significantly reduced 30 minutes after treatment with teneligliptin (a DPP-4 inhibitor) compared with baseline (15). Enhancement of GLP-1 action by DPP-4 inhibitors may increase insulin secretion and suppress glucagon release in a glucose-dependent manner, leading to a decrease in postprandial glucose levels. Adding SGLT2 inhibitors to existing DPP-4 inhibitors could suppress EGP secondary to excess excretion of glucose into urine because treatment with DPP-4 inhibitors can offset SGLT2-induced EGP by inhibiting glucagon secretion and simulating insulin secretion. A previous study with CGM demonstrated that add-on therapy with canagliflozin did not increase fasting or postprandial plasma glucagon in patients with type 2 diabetes receiving teneligliptin (16). Taken together, the findings indicate that a combination of SGLT2 inhibitors and DPP‐4 inhibitors may be an effective treatment for patients with type 2 diabetes because of the complementary pharmacological effects of these drugs, ie, because of the opposite mechanisms of action of DPP-4 inhibitors and SGLT2 inhibitors on EGP, and because both medications have a fairly low risk of hypoglycemia (17).
The present study clearly has some limitations. First, the number of participants was small, so the results need to be confirmed in a larger study. Second, we did not measure plasma glucagon or insulin levels during CGM, so we could not prove that DPP-4 inhibitors counteract SGLT2-induced EGP by inhibiting glucagon secretion and simulating insulin secretion.
In conclusion, add-on therapy of tofogliflozin to DPP-4 inhibitors acutely reduces 24-hour mean glucose levels and improves glycemic variability in patients with type 2 diabetes.