Abstract
The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by hyperglycemia resulting from insulin resistance and relative lack of insulin
sodium-dependent glucose cotransporter 2 (SGLT2) is a promising target for the treatment of T2DM because its inhibition could lower glucose levels without directly influencing insulin resistance or b-cell function
In a previous study, administration of SGLT2 inhibitors resulted in only 30–50% inhibition of glucose reabsorption in human subjects even at high doses, which was in contrast to the expected inhibition of 90% based on in vitro potency and plasma levels (Liu et al, 2012)
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by hyperglycemia resulting from insulin resistance and relative lack of insulin. Current therapies for T2DM primarily address endocrine pathogenesis of insulin resistance and b-cell dysfunction. In order to avoid direct influence on insulin resistance and b-cell dysfunction, T2DM can be treated with inhibition of glucose reabsorption. Glucose is reabsorbed to blood in the proximal tubules of the kidneys during the formation of primary urine. Where the reabsorption process is inhibited, glucose is excreted in urine and blood glucose concentration is reduced. Patients treated with inhibition of glucose reabsorption have a low risk of hypoglycemia because the mechanism of the treatment is independent of insulin release or endogenous glucose production (Misra, 2013). Sodium-dependent glucose cotransporter 2 (SGLT2) is thought to contribute to 90% of glucose reabsorption in kidneys (Liu et al, 2012), which makes it a promising target in T2DM therapy
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