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.