Development of SGLT1 and SGLT2 inhibitors

Abstract

Sodium-glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.

Keywords: Chronic kidney disease; Drug development; Heart failure; Inhibitor; Intestinal glucose transport; Renal glucose transport; Review; Sodium–glucose cotransporter; Type 1 diabetes; Type 2 diabetes.

Fig. 1

Role of renal SGLT2 and SGLT1 in glucose reabsorption under normoglycaemic conditions and when SGLT2 is inhibited. SGLT2 and SGLT1 are expressed in the luminal membrane of the early (S1 and S2 segment) and late proximal tubule (S3 segment), respectively. They reabsorb ~97% (SGLT2) and ~3% (SGLT1) of filtered glucose under normoglycaemic conditions. A significant capacity of SGLT1 to reabsorb glucose is unmasked by SGLT2 inhibition and during hyperglycaemia (~40–50% reabsorption), which both enhance glucose delivery to the late proximal tubule. As a consequence, diabetes-induced hyperglycaemia or SGLT2 inhibition increase the SGLT1 inhibition-induced rise in glucose excretion, the latter providing the renal rationale for dual SGLT1/2 inhibition. Adapted with permission from [4]. This figure is available as part of a downloadable slideset

Fig. 2

Role and regulation of intestinal SGLT1 for glucose uptake and potential therapeutic applications of SGLT1 inhibitors. In the small intestine, luminal SGLT1 mediates glucose/galactose absorption. SGLT1 expression is regulated by multiple signalling cascades and is upregulated in diabetes and downregulated by leptin [43]. SGLT1 in L cells in the proximal intestine sense dietary glucose, which subsequently triggers the ‘acute’ release of GLP-1. SGLT1 inhibition in the early intestine reduces glucose absorption and thereby increases glucose delivery to the more distal portions of the small intestine, where glucose is used by the microbiome to form SCFAs. SCFAs enter the distal L cells by free fatty acid receptors (FFAR2/3) and trigger a ‘sustained’ release in GLP-1. Adapted with permission from [4]. This figure is available as part of a downloadable slideset