Introduction
Sodium glucose co‐transporter 2 (SGLT2) inhibitors improve glycemic
control in people with type 2 diabetes by increasing urinary glucose
excretion; additional benefits are body weight loss and a low risk of
hypoglycemia (1). Furthermore, several large-scale clinical trials of
SGLT2 inhibitors have shown that these drugs have beneficial effects on
cardiovascular outcomes—including hospitalization for heart failure
and cardiovascular death—and renal outcomes in high-risk patients and
that these effects appear to be independent of the glucose-lowering
efficacy of these drugs (2-4).
SGLT2 inhibitors have been reported to increase plasma glucagon
concentration and endogenous glucose production (EGP) in patients with
type 2 diabetes (5, 6). Ferrannini et al demonstrated that acute dosing
(ie, a single tablet) of empagliflozin, an SGLT2 inhibitor, increases
both fasting and postprandial rates of EGP in patients with type 2
diabetes (5). The increase in EGP after treatment with SGLT2 inhibitors
may be attributed partly to an elevated plasma glucagon level. The
reduction in plasma glucose concentration expected with SGLT2 inhibitors
may be partially offset by a concomitant increase in EGP through a
compensatory mechanism caused by declining blood glucose or glucosuria
(5, 6).
In contrast, dipeptidyl peptidase (DPP)-4 inhibitors, incretin-based
drugs, suppress EGP by stimulating insulin secretion and inhibiting
glucagon secretion by enhancing glucagon-like peptide-1 (GLP-1) (7, 8).
DPP-4 inhibitors may antagonize the compensatory increase in EGP induced
by SGLT2 inhibitors. Therefore, we hypothesized that the increase in EGP
after administration of SGLT2 inhibitors may be attenuated in patients
receiving DPP-4 inhibitors and that, consequently, the glucose-lowering
effects of SGLT2 inhibitors may be stronger in patients receiving DPP-4
inhibitors than in those not receiving them. To study this hypothesis,
we investigated the acute effect of addition of tofogliflozin, an SGLT2
inhibitor, on 24-hour glucose levels and glycemic variability evaluated
by continuous glucose monitoring (CGM) in patients with type 2 diabetes
receiving or not receiving DPP-4 inhibitors.