Pharmacodynamics Efficacy and Safety of Sodium–Gl

Authors: André J Scheen

Publish Date: 2014/12/09

Volume: 75, Issue: 1, Pages: 33-59

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Abstract

Inhibitors of sodium–glucose cotransporter type 2 SGLT2 are proposed as a novel approach for the management of type 2 diabetes mellitus T2DM Several compounds are already available in many countries dapagliflozin canagliflozin empagliflozin and ipragliflozin and some others are in a late phase of development The available SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption a long elimination halflife allowing oncedaily administration an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites the absence of clinically relevant drug–drug interactions and a low renal elimination as parent drug SGLT2 cotransporters are responsible for reabsorption of most 90  of the glucose filtered by the kidneys The pharmacological inhibition of SGLT2 cotransporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate Results of numerous placebocontrolled randomised clinical trials of 12–104 weeks duration have shown significant reductions in glycated haemoglobin HbA1c resulting in a significant increase in the proportion of patients reaching HbA1c targets and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucoselowering therapies including insulin in patients with T2DM In headtohead trials of up to 2 years SGLT2 inhibitors exerted similar glucoselowering activity to metformin sulphonylureas or sitagliptin The durability of the glucoselowering effect of SGLT2 inhibitors appears to be better however this remains to be more extensively investigated The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin pioglitazone or sitagliptin Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucoselowering agents The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction Caution is also recommended in the elderly population because of a higher risk of renal impairment orthostatic hypotension and dehydration even if the absence of hypoglycaemia represents an obvious advantage in this population The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebocontrolled trials with cardiovascular outcomes The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention SGLT2 inhibitors are generally welltolerated The most frequently reported adverse events are female genital mycotic infections while urinary tract infections are less commonly observed and generally benign In conclusion with their unique mechanism of action that is independent of insulin secretion and action SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease Although SGLT2 inhibitors have already been extensively investigated further studies should even better delineate the best place of these new glucoselowering agents in the already rich armamentarium for the management of T2DM

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