SGLT2 Inhibition: A Novel Prospective Strategy in Treatment of Diabetes Mellitus

Abstract

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.

Phlorizin ameliorates obesity-associated endotoxemia and insulin resistance in high-fat diet-fed mice by targeting the gut microbiota and intestinal barrier integrity

“…6 In other words, PHZ holds great potential for improving hyperglycemia (one of the symptoms of metabolic disorders (MDs), like obesity and type 2 diabetes mellitus (T2DM)), by directly decreasing the blood glucose concentration rather than targeting insulin resistance and impaired insulin secretion. 8,9 However, despite the fact that SGLT2 is regarded as a new class of therapeutic targets for managing MDs, 8,9 currently only few PHZ-based products are designed and available for such purpose mainly due to the extremely low bioavailability of PHZ. 9,10 Indeed, a large amount of ingested but unabsorbed PHZ will reach the gastrointestinal tract, and some of which will be hydrolyzed to PHT.…”

“…8,9 However, despite the fact that SGLT2 is regarded as a new class of therapeutic targets for managing MDs, 8,9 currently only few PHZ-based products are designed and available for such purpose mainly due to the extremely low bioavailability of PHZ. 9,10 Indeed, a large amount of ingested but unabsorbed PHZ will reach the gastrointestinal tract, and some of which will be hydrolyzed to PHT. 11 Gastrointestinal disorders induced by high-fat diet (HFD) are associated with MDs, including abnormal blood glucose metabolism, elevated triglycerides, and decreased high-density lipoproteins, contributing to the development of obesity, T2DM, and cardiovascular disease.…”

The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice

“…SGLT1 and SGLT2 knock out mouse studies determined that 97% of proximal tubular glucose transport is mediated via SGLT2 and only 3% by SGLT1 [ 16 , 17 ]. SGLT-2 inhibitors are a new class of antidiabetic drugs which inhibit renal glucose reabsorption [ 18 , 19 ]. Inhibition of SGLT2 results in a decrease in blood glucose due to increased renal glucose excretion.…”

Canagliflozin in der Monotherapie: Klinische Studiendaten bei Diabetes mellitus Typ 2

“…SGLT-2-Inhibitoren senken die Rückresorption von Glukose aus dem Primärharn durch Hemmung des Natrium-Glukose-Kotransporters Typ 2 (SGLT-2) im proximalen Tubulus der Niere und adressieren damit eine pathophysiologische Störung beim Typ-2-Diabetes: Die erhöhte Glukoserück-resorption im Nierentubulus durch Überexpres-sion von SGLT-2 [9]. Die SGLT-2-Inhibition mit Canagliflozin bewirkt, dass Glukose vermehrt mit dem Urin ausgeschieden wird, wodurch der Blutglukosespiegel und damit der HbA 1c -Wert sinkt [4]. Sekundäre Effekte sind ein Gewichtsverlust und eine moderate blutdrucksenkende Wirkung [4].…”

“…Die SGLT-2-Hemmung mit Canagliflozin adressiert die beim Typ-2-Diabetes pathologisch erhöhte Glukoserückresorption im proximalen Nierentubulus[9] und bietet damit eine neue weitere Therapieoption. Für den Einsatz von Canagliflozin in der Monotherapie sind folgende Charakteristika von praktischer Bedeutung: Canagliflozin 3 wirkt insulinunabhängig, 3 ist nicht mit einem intrinsischen Hypoglykämierisiko assoziiert und 3 wird in der Regel gut vertragen[4].Die blutzuckersenkende Wirkung einer Canagliflozin-Behandlung kann zusätzlich mit einer Gewichtsreduktion und einer moderaten Blutdrucksenkung einhergehen[16].Zu beachten sind die unter Canagliflozin häufiger beobachteten Harnwegsinfekte und Genitalmykosen. Hierbei ist das Infektrisiko des einzelnen Patienten abzuwägen.…”