A Novel Sodium-glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Niren K. Shah, Pharm.D.; Wasim E. Deeb, M.D.; Rushab Choksi, Pharm.D.; Benjamin J. Epstein, Pharm.D.


Pharmacotherapy. 2012;32(1):80-94. 

In This Article

Controversies and Therapeutic Concerns

Diabetes is associated with a 1.21–2.2 increase in the relative risk for UTI, and it has been suggested that glucosuria is responsible for increasing UTI risk.[57–61] However, the mechanism by which patients with diabetes experience a greater frequency of urogenital infections has yet to be fully elucidated. In fact, no direct relationship linking urinary glucose and UTI frequency has been identified. A prospective trial conducted in 636 women with diabetes found that glucosuria was not associated with a risk of developing asymptomatic bacteriuria or UTI.[62] Similarly, another study assessed 528 women with type 1 diabetes and found no correlation between A1C values and prevalence of cystitis.[63] The occurrence of UTI and genital fungal infections in dapagliflozin studies has been variable, highlighting the urgency for long-term studies that address UTI and genital fungal infection frequency in both male and female subjects treated with various antidiabetic regimens.

Long-term safety and efficacy data for dapagliflozin are still lacking. However, SGLT2 inhibition is not a novel concept and previous investigations may forecast the dapagliflozin experience. Perhaps the best insight into the long-term safety profile of SGLT2 inhibition comes from examining patients with familial renal glycosuria. These patients lose approximately 50–100 g/day of glucose in urine due to a genetic mutation on the SLC5A2 gene that encodes for SGLT2; yet, no increased risk of urogenital infections can be ascribed to the mutation.[64,65] Furthermore, it is anticipated that patients with this mutation are expected to have normal life expectancies and are not expected to manifest renal dysfunction, increased liver glucose production, or electrolyte disturbances.[28,66]

The efficacy profile of SGLT2 inhibition may be best described by the use of a substance isolated from the bark of fruit trees called phlorizin.[67] When studied in the 19th century, phlorizin was noted to produce glucosuria, polyuria, and weight loss in an animal model, but was associated with a high frequency of diarrhea. In the late 20th century, it was discovered that phlorizin inhibits the active transport of glucose reabsorption at the renal proximal tubule by blocking the activity of SGLT1 and SGLT2, and at the mucosa of the small intestine.[68] When given to partially pancreatectomized diabetic rats, phlorizin resulted in normoglycemia, improved insulin sensitivity, and improved residual pancreatic β-cell functioning without affecting insulin concentrations.[69] The results are consistent with a short-term study (24 days), which showed that dapagliflozin therapy results in improved insulin sensitivity and improvements in islet cell morphology in female Zucker diabetic fatty rats.[44] Although these results are promising, their clinical significance in type 2 diabetes remains to be explored.

Both contemporary and historical studies have illuminated a possible increase in the risk of cardiovascular disease with OADs.[70,71] Most recently, rosiglitazone was shown to increase the risk of myocardial infarction and death from other cardiovascular causes in patients with type 2 diabetes.[72,73] As a consequence, the United States Food and Drug Administration has mandated that robust cardiovascular studies be undertaken for new OADs approaching the market, in order to demonstrate that they do not result in an increased risk of cardiovascular events. Clinical data with dapagliflozin have not revealed any evidence of an increased risk of cardiovascular events. However, given that dapagliflozin exerts a favorable effect on blood pressure, body weight, and the metabolic milieu (i.e., serum uric acid, triglyceride, and HDL levels), it is possible that dapagliflozin might emerge as a preferred agent for patients at high risk for cardiovascular events, and long-term clinical data are under way to assess its cardiovascular effects.


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