Sodium-Glucose Cotransporters (SGLTs) are a family of membrane proteins involved in the transport of glucose, amino acids, vitamins, and ions. They are part of a complex system that the body uses to regulate glucose homeostasis. The primary functional SGLTs include SGLT2 and SGLT1:
SGLT2 is primarily expressed in the kidney (S1 and S2 segments of the early proximal tubule) where it reabsorbs 80-90% of filtered glucose. SGLT2 inhibitors block renal glucose reabsorption, resulting in increased glucose excretion in urine.
SGLT1 is primarily expressed in the small intestine and kidney (S3 segment of the late proximal tubule), with expression also found in the heart and brain. In the kidney, SGLT1 is responsible for the remaining 5-10% of filtered glucose reabsorption. In the small intestines, SGLT1 directly absorbs glucose from digested carbohydrates. SGLT1 inhibitors block both renal and intestinal glucose absorption, resulting in increased glucose and sodium excretion in urine and feces.
While SGLT2 is responsible for most of the filtered glucose reabsorption in the kidney, the capacity of SGLT1-mediated glucose reabsorption increases to 40-50% when SGLT2-mediated glucose reabsorption is overwhelmed or inhibited. Therefore, dual inhibition of SGLT1 and SGLT2 may serve as an important therapeutic target for a variety of diseases, including type 1 and 2 diabetes, diabetic kidney disease, and heart failure.
YG1699 is a dual, systemic SGLT1 and SGLT2 inhibitor with a potential best-in-class clinical profile. In clinical studies, YG1699 demonstrated acceptable gastrointestinal (GI) tolerability, superior post-prandial glucose (PPG) control, elevation in active GLP-1, and increased urinary glucose excretion (UGE) compared to selective SGLT2 inhibitors. YG1699 carries potential to be a superior next-generation SGLT inhibitor.