Dapagliflozin: A Newly Approved SGLT2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a chronic disease in which a hyperglycemic state is induced by insulin resistance. While there are numerous treatment options available to manage T2DM, many patients require changes in therapy throughout treatment, as well as multiple medications. The sodium/glucose cotransporter 2 (SGLT2) inhibitors, canagliflozin and dapagliflozin, offer a therapeutic alternative in T2DM management through the utilization of a unique mechanism of action to provide intensified glycemic control. This article will evaluate the safety and efficacy of dapagliflozin in the management of T2DM. Introduction The recent introduction of the sodium/glucose cotransporter 2 (SGLT2) inhibitor drug class presents a novel treatment option in the type 2 diabetes mellitus (T2DM) therapeutic arsenal. Janssen Pharmaceuticals, Inc. manufactures the inaugural member of this class, canagliflozin (Invokana®), which gained U.S. Food and Drug Administration (FDA) approval in 2013.1 The introduction of dapagliflozin (Farxiga®) by Bristol-Myers Squibb, which was granted approval in early 2014, offers a second, “me too,” alternative to this novel class.2 Both canagliflozin and dapagliflozin are oral agents indicated to improve glycemic control in conjunction with dietary and exercise modifications in patients not adequately responding to current therapy.1,2 MOA/Pharmacology/Kinetics Reabsorption of glucose in the kidney is reliant on the mechanism of the SGLT2 protein, a low-affinity, highcapacity 1:1 sodium/glucose transporter.3 Its characterization as a low-affinity transporter indicates that a molecule of glucose attaches to the protein with less force and at an abbreviated time interval as compared to a high-affinity counterpart, sodium-glucose cotransporter 1 (SGLT1). Nearly the entire portion of the 144 grams of glucose filtered by the glomerulus on a 24 hour basis is reabsorbed in the renal tubules.4 The SGLT2 is highly expressed in the S1 segment of the proximal convoluted tubule and serves as the primary site for mammalian glucose reabsorption.3 A second sodium/ glucose cotransporter, SGLT1, is present in both the kidney and the intestine. The SGLT1 is characterized as high-affinity and possesses the additional capacity for galactose transport that is absent in SGLT2.3 The SGLT1 is located in the S3 segment of the proximal tubule to reabsorb any remaining glucose that escaped transport by SGLT2 from the lumen into the bloodstream (Figure 1). Inability to reach glycemic targets in addition to prevalent side effects of existing therapies has prompted researchers to investigate therapeutic alternatives. Selective inhibition of SGLT2 is a viable alternative in the treatment of T2DM.3 During hyperglycemia, SGLT2 is upregulated in an attempt to meet the demand of additional glucose reabsorption. Selective inhibition of these transporters in the hyperglycemic state of diabetic patients results in elevated urinary glucose levels and decreased blood glucose levels. Canagliflozin and dapagliflozin are both approved for use as adjuncts to diet and exercise in adult diabetic patients who are not adequately controlled on metformin or a sulfonylurea.2 Because of the novelty of this drug class and limited clinical experience with its members, trials directly comparing canagliflozin and dapagliflozin therapy have yet to be conducted. Dapagliflozin reaches maximum plasma concentration within two hours of fasting administration, and the oral bioavailability of a standard 10 mg dose is 78 percent.2 It can be taken without regard to meals. Dapagliflozin is 91 percent protein bound, and UGT1A1, an enzyme in the glucuronidation pathway, is responsible for the majority of its metabolism to an inactive metabolite, dapagliflozin 3-0-glucuronide. It is primarily eliminated through the kidneys with a mean plasma terminal half-life of 12.9 hours subsequent to a single 10 mg oral dose. In vitro, dapagliflozin did not significantly impact the pharmacokinetics of coadministered drugs, nor did the coadministered drugs significantly impact dapagliflozin. Therefore, no dosing adjustments need to be made during concurrent therapy with other oral medications based on This knowledge-based activity is targeted for all pharmacists and is acceptable for . 75 hour (.075 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions. ACPE Universal Activity Number (UAN): 0048-0000-14-174-H01-P