Sodium-glucose co-transporter 2 inhibitors: from apple tree to 'Sweet Pee'.
The sodium-glucose co-transporter 2 (SGLT2), located in the plasma membrane of cells lining the proximal tubule, facilitates the reabsorbtion of glucose in the kidney. Inhibition of SGLT2 has the potential to reduce blood glucose and represents an opportune target for managing blood glucose. By promoting the excretion of glucose, SGLT2 inhibitors are the first anti-diabetic treatment to target the removal rather than the metabolic redirection of glucose. Their mechanism of action is independent of that of endogenous insulin status and thus provides a means of managing plasma glucose irrespective of a patient's glycaemic status or treatments being used in combination. Several candidate SGLT2 inhibitors based on the core glucoside structure of phlorizin are currently being developed, of which, the metabolically more stable aromatic and heteroaromatic C-glucosides have demonstrated the most promising preclinical and clinical data. The inhibition of SGLT2 by messenger antisense technology is also being investigated. Current indications suggest that short-term benefits, in terms of HbA1(c) reductions, are modest and it remains to be seen whether encouraging exogenous glucose disposal will result in long term patient benefits in terms of returning metabolic balance or even weight loss. Indications are that clinical efficacy will be greater with molecules based on an O-glucoside structure. Concerns have been raised over the safety of these agents, particularly a possible predisposition to urinary tract infections, but these concerns have yet to be confirmed in clinical studies. Clinical development programs will need to establish those patients most likely to benefit from inhibition of SGLT2.
Consultant Chemical Pathologist St Thomas' Hospital, Lambeth Palace Road London SE1 7EH UK. Anthony.Wierzbicki@kcl.ac.uk
Timothy C
TC
Hardman
Peter
P
Rutherford
Simon W
SW
Dubrey
Anthony S
AS
Wierzbicki
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D010695:Phlorhizin / Q000494:pharmacology; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism / Q000502:physiology*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013347:Subcellular Fractions / Q000378:metabolism
D001786:Blood Glucose; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D010695:Phlorhizin