Combined SGLT1 and SGLT2 Inhibitors and Their Role in Diabetes Care

Abstract

The sodium–glucose cotransporter type 1 (SGLT1) is the primary transporter for absorption of glucose and galactose in the gastrointestinal tract. Inhibition blunts and delays postprandial glucose (PPG) excursion. Sodium–glucose cotransporter type 2 (SGLT2) is expressed in the kidney, where it reabsorbs 90% of filtered glucose. Thus, a dual SGLT1 and SGLT2 inhibition (compared with selective SGLT2 inhibition) could result in lower PPG and robust A1c reduction even in patients with reduced kidney function. Sotagliflozin is an oral potent dual inhibitor of the insulin-independent SGLT1 and SGLT2. Preliminary data released from phase 2 and 3 clinical studies in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) showed improved glycemic control, and met efficacy endpoints beyond A1c with a safety profile consistent with the SGLT class: significant reduction in body weight, systolic blood pressure, and efficacy maintained in lower estimated glomerular filtration rate levels with no increased hypoglycemia. Increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild-to-moderate glucose elevations (euglycemic DKA) is associated with the use of all the approved SGLT2 inhibitors. Factors that trigger DKA include insulin reductions, low caloric and fluid intake, intercurrent illness, and alcohol use. However, DKA is detectable and manageable with proper patient education. With sotagliflozin, DKA rates were not higher than the expected background rate in T1DM, but numerically higher than placebo. Sotagliflozin is the first oral SGLT1 and SGLT2 inhibitor developed for the treatment of adult patients with T1DM, in adjunct with insulin, and has the potential to address unmet needs for patients with T1DM and possibly T2DM, with a favorable benefit/risk profile.