Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes
Open Access
- 28 June 2011
- journal article
- review article
- Published by Springer Science and Business Media LLC in Diabetes Therapy
- Vol. 2 (3), 133-145
- https://doi.org/10.1007/s13300-011-0004-1
Abstract
There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances.Keywords
This publication has 54 references indexed in Scilit:
- Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitusBMC Pharmacology and Toxicology, 2013
- Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 InhibitorsJournal of Medicinal Chemistry, 2011
- SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic β-Cell FunctionDiabetes, 2011
- Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trialThe Lancet, 2010
- SGLT2 inhibition — a novel strategy for diabetes treatmentNature Reviews Drug Discovery, 2010
- Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agentsExpert Opinion on Therapeutic Patents, 2009
- A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin SensitizersDiabetes Care, 2009
- Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 DiabetesDiabetes Care, 2008
- Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki RatsLife Sciences, 2005
- Glucose transport in the kidneyBiochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1976