Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic β cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes.

Targeted intestinal delivery of incretin secretagogues—towards new diabetes and obesity therapies

“…Inhibitors of the renal glucose transporter SGLT2 are now widely used in clinical practice, and mostly have limited efficacy on SGLT1. Canagliflozin and sotagliflozin, however, are mixed SGLT1/2 inhibitors that reduce intestinal as well as renal glucose absorption [28] . Both drugs have been associated with elevated post-prandial GLP-1 and PYY levels in human subjects [29] , [30] .…”

Pharmacological evaluation of HM41322, a novel SGLT1/2 dual inhibitor, in vitro and in vivo

“…Dapagliflozin has been known as a selective SGLT2 inhibitor. However, dapagliflozin also has a relatively weak inhibitory activity for SGLT1, and its selectivity for SGLT2 is weaker than other SGLT2 inhibitors such as empagliflozin and tofogliflozin, which are highly selective SGLT2 inhibitors [1431]. More interestingly, empagliflozin, a highly selective SGLT2 inhibitor, has also recently been shown to increase circulating GLP-1 [32], although the effect was relatively mild.…”

SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?

“…Regarding selectivity for SGLT-2, empagliflozin is the most selective of the 3, followed by dapagliflozin, with canagliflozin being the least selective [46][47][48]. Note that SGLT-2i with low SGLT-2/ SGLT-1 selectivity elevate the level of circulating glucagon-like peptide-1 [49], which may contribute to a pleiotropic effect.…”