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

Chiara Maria Assunta Cefalo, Francesca Cinti, Simona Moffa, Flavia Impronta, Gian Pio Sorice, Teresa Mezza, Alfredo Pontecorvi, Andrea Giaccari, Chiara Maria Assunta Cefalo, Francesca Cinti, Simona Moffa, Flavia Impronta, Gian Pio Sorice, Teresa Mezza, Alfredo Pontecorvi, Andrea Giaccari

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.

Keywords: Diabetes; Hypoglycemic therapy; SGLT2 inhibitors.

Figures

Fig. 1
Fig. 1
The chemical structure of sotagliflozin: (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol
Fig. 2
Fig. 2
Comparison of the effect of sotagliflozin on HbA1c (a) and fasting plasma glucose (b) in various clinical trials on type 2 diabetic patients
Fig. 3
Fig. 3
Intestinal effects of SGLT-1 inhibition by sotagliflozin. By inhibiting SGLT-1 sotagliflozin reduces PPG and improves glycemic control. Possible mechanisms are: (1) delayed glucose absorption in the distal small intestine; (2) consequent increased GLP-1 secretion by L cells, mostly located in the cecum, and (3) delayed glucose in the colon where it could promote changes in microbiota and increase production of SCFAs; the latter seems to independently increase GLP-1 secretion. G glucose, GIP gastric inhibitory peptide, GLP glucagon like peptide, SCFAs short chain fatty acids
Fig. 4
Fig. 4
Percent of patients reaching the primary end point (a) and reduction in glycated hemoglobin level (b) after 24 weeks of intervention in the sotagliflozin group compared to placebo group as reported in inTandem 3 trial
Fig. 5
Fig. 5
inTandem 1 and inTandem 2 clinical trials: study design (a) and percentage of patients that achieve composite endpoints (Hba1c < 7%, no weight gain, no severe hypoglycemic event or diabetic ketoacidosis) at week 52 (b). P# = sota 200 mg vs placebo; P* = sota 400 mg vs placebo

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Source: PubMed

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