Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Abstract

Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1-or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (K i ) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. 14 C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of a-methyl-D-glucopyranoside. Canagliflozin inhibited a-methyl-D-glucopyranoside-induced SGLT1-and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the K i value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The K i value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin.

Sotagliflozin: a dual sodium‐glucose co‐transporter‐1 and ‐2 inhibitor for the management of Type 1 and Type 2 diabetes mellitus

“…However, one recent meta‐analysis of data from 23 997 individuals with Type 2 diabetes from 38 randomized controlled trials, found that reductions in HbA 1c , fasting plasma glucose (FPG) and systolic blood pressure (SBP) relative to placebo were greater for canagliflozin 300 mg than for empagliflozin or dapagliflozin . This suggests that canagliflozin may be the agent to beat in terms of efficacy, potentially because of its additional SGLT1 inhibitory effect . However, heterogeneous study designs and variable participant characteristics mean that results should be interpreted with caution.…”

Effects of combination of mitiglinide with various oral antidiabetic drugs in streptozotocin‐nicotinamide‐induced type 2 diabetic rats and Zucker fatty rats

“…Thus, they increase urinary glucose excretion and correct hyperglycaemia. Canagliflozin weakly inhibits SGLT1 in addition to its inhibition of SGLT2 . The renal tubule SGLT1 plays a role glucose reabsorption, which is not reabsorbed by SGLT2 under hyperglycaemic conditions.…”

“…α‐GIs are used for patients with insulin‐independent postprandial hyperglycaemia who do not exhibit very high fasting blood glucose levels . Furthermore, SGLT2 inhibitors that also inhibit SGLT1 have been recently used . Mitiglinide is combined with these drugs in clinical practice because it is unlikely to negate their effects when used in combination …”

“…20,21 Furthermore, SGLT2 inhibitors that also inhibit SGLT1 have been recently used. 22 Mitiglinide is combined with these drugs in clinical practice because it is unlikely to negate their effects when used in combination. 23,24 In the present study, we aimed to investigate the combination effects of mitiglinide with insulin sensitizers, α-GIs, and SGLT2 inhibitors with SGLT1 inhibitory action.…”

Effects of canagliflozin on cardiovascular risk factors in patients with type 2 diabetes mellitus

“…Further reductions in postprandial glucose also occur through a non‐renal mechanism. While data indicate that canagliflozin does not have systemic effects on SGLT1 (eg, in the kidney, heart or skeletal muscle), the 300‐mg dose may provide transient, local inhibition of SGLT1 in the intestine. This intestinal SGLT1 inhibition may slow glucose absorption from the morning meal and delay the appearance of glucose in plasma .…”