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.