Sotagliflozin: Two Birds with One Stone?

Abstract

Purpose: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as antidiabetic agents, have become a cornerstone in the treatment of heart failure (HF) due to their well-established cardio-renal benefits. Clinical trials with SGLT2i have shown a reduction in major adverse cardiovascular events (MACE) across a broad range of patients with no effect on atherothrombotic cardiovascular events such as myocardial infarction (MI) or stroke. On the other hand, sotagliflozin, the first of a new class of dual SLGT1-2 inhibitor (SGLT1-2i), reduces MACE, with independent reductions in MI and stroke, an effect not seen with SGLT2 inhibition alone.

Method: A comprehensive literature review was conducted using PubMed and Scopus, focusing on publications from the last 5 years. Articles were selected based on relevance, methodological rigor, and citation impact.

Results: SGLT1 and SGLT2 work complimentarily in urinary glucose reabsorption, while SGlT1 also regulates dietary glucose in the intestine. However, its function in other organs remains undefined. SGLT1 is overexpressed in the failing heart and has been associated with increased oxidative stress, cardiomyocyte hypertrophy, and fibrosis. Additionally, SGLT1 also plays an important role in platelet activation and thrombus formation. Experimental studies suggest that sotagliflozin, by inhibiting SGLT1, reverses the metabolic derangements associated with SGLT1 overexpression.

Conclusion: These observations suggest that dual SGLT1-2 inhibition may offer additional benefits over single SGLT2-i. Further comparative and mechanistic studies are required to understand and differentiate the clinical impact of SGLT2i vs. SGLT1-2i, particularly in non-diabetic HF patients.

Keywords: Diabetes; Heart failure; SGLT1-2 inhibitors; SGLT2 inhibitors; Sotagliflozin; Thrombosis.