Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives

Abstract

Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

“…However, at the same dose, when serum glucose was slightly higher in women than men, UGE was lower in women than men; when serum glucose was slightly lower in women than men, UGE was obviously lower in women than men. Considering the mechanism of SGLT2 inhibitors, we speculate that the response to rongliflozin was less potent in women compared with men . The glucose‐lowering effect of SGLT2 inhibitors is accompanied by the loss of calories and circulation fluid through the urine, potentially resulting in weight loss, as well as decreases in lipid levels and blood pressure.…”

“…Considering the mechanism of SGLT2 inhibitors, we speculate that the response to rongliflozin was less potent in women compared with men. 32,33 The glucose-lowering effect of SGLT2 inhibitors is accompanied by the loss of calories and circulation fluid through the urine, potentially resulting in weight loss, as well as decreases in lipid levels and blood pressure. Because the duration of treatment in these studies was relatively short, it was not possible to investigate such issues in depth.…”

Sodium–glucose cotransporters: Functional properties and pharmaceutical potential

“…As a concerning point, in the small intestine, the SGLT1 inhibitor is considered to induce gastrointestinal side‐effects, including diarrhea, but no serious gastrointestinal side‐effects were observed in the treatment of selective SGLT1 inhibitors, GSK‐1614235 and KGA‐2727, or a dual SGLT1/SGLT2 inhibitor, sotagliflozin 83,84,134 .…”

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

“…The currently marketed SGLT2 inhibitors are selective for SGLT2 over SGLT1 to different extent, of which canagliflozin is capable of slightly inhibiting SGLT1 in the small intestine at clinically relevant doses [25,26]. In fact, dual SGLT1/2 inhibitors have been developed to reduce postprandial glucose absorption via blockade of SGLT1 in the small intestine, while at the same time preserving the beneficial renal glucosuric effect by SGLT2 inhibition [27]. Individuals carrying loss-of-function mutations in the SGLT1 gene are estimated to have lower risk for developing HF, driven by mitigation of postprandial hyperglycemic episodes [28].…”