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

Abstract and Introduction


The prevalence of diabetes mellitus has grown to staggering numbers, and its incidence is expected to rise in the next 2 decades. The need for novel approaches to treat hyperglycemia cannot be ignored. Current agents have been shown to modestly improve glycemia and in some cases prevent complications of diabetes, but they become less effective over time and are often accompanied by undesirable adverse effects. Dapagliflozin is the lead agent in a new class of oral antidiabetic agents known as sodium-glucose cotransporter type 2 (SGLT2) inhibitors, which represent a novel approach to the management of type 2 diabetes mellitus. By selectively and reversibly blocking the SGLT2 receptor, dapagliflozin prevents the reabsorption of glucose at the renal proximal tubule. Phase II and III clinical trials have demonstrated that dapagliflozin is a safe and effective method for treating type 2 diabetes. Dapagliflozin produces a sustained, dose-dependent reduction in plasma glucose levels while simultaneously improving insulin secretion and sensitivity. Over 12–24 weeks, reductions in hemoglobin A1c ranged from 0.54–0.89% when dapagliflozin was administered once/day (either as monotherapy or add-on therapy to oral antidiabetic drugs with or without insulin) to patients with type 2 diabetes. Therapy with dapagliflozin also results in a mild osmotic-diuretic effect that may account for decreases in total body weight (~2–3 kg) and blood pressure (systolic 2–5 mm Hg, diastolic 1.5–3 mm Hg), and increases in hematocrit (1–2%). Dapagliflozin has a favorable safety profile, with the rates of hypoglycemia similar to those of placebo. Genital and urinary tract infections were more commonly reported in patients taking dapagliflozin (2–13%) than those taking placebo (0–8%). Dapagliflozin does not appear to cause electrolyte disturbances, hepatotoxicity, or nephrotoxicity. Results from clinical trials have been promising, and well-designed clinical programs that address the long-term safety and efficacy of dapagliflozin are under way.


There are an estimated 285 million adults with diabetes mellitus and impaired glucose tolerance worldwide, and the prevalence is expected to increase to 438 million by 2030.[1,2] In just 3 years (2007–2010), there was a 5.5% increase in the number of deaths attributable to diabetes.[1] Diabetes is quickly becoming a leading cause of death and disability globally. Type 2 diabetes mellitus, which accounts for more than 90% of all cases of diabetes, is defined as a defect in glucose homeostasis resulting from improper insulin secretion and insulin action.[3] Chronic elevations in plasma glucose levels lead to a debilitating menu of microvascular and macrovascular complications, including retinopathy, neuropathy, nephropathy, and vascular disease.[4–8] As a result, hyperglycemia has become a prime therapeutic target in the management of type 2 diabetes; yet, there remains a considerable proportion of patients with unmet glycemic control despite a full range of oral antidiabetic drugs (OADs).

Although OADs promote a modest improvement in glycemic control, they often lose effectiveness over time, leading to the progression of type 2 diabetes and its complications.[9,10] As insulin resistance worsens, the body signals additional insulin secretion from pancreatic β cells.[10] The burden that is placed on pancreatic β cells causes them to progressively lose function and mass until they fail to meet the body's insulin demands, yielding overt hyperglycemia, which further damages insulin secretion and insulin sensitivity (i.e., glucotoxicity).[11] Other theories suggest that prolonged hyperglycemia impairs insulin gene expression secondary to a reduction in the activity of pancreatic-duodenum homeobox-1 and the activator of insulin promoter element 3b1.[12] Consequently, OADs that primarily function through an insulin-dependent mechanism eventually lose their ability to maintain glycemic control.

The United Kindgdom Prospective Diabetes Study (UKPDS) found that only 50% of patients receiving monotherapy with a baseline hemoglobin A1c (A1C) of less than 7.0% were able to maintain control over 3 years, and only 25% of patients were able to maintain control over 9 years.[13] This may be explained by findings from the Belfast Diabetes Study, which demonstrated that up to 40–50% of β-cell function is lost approximately 15 years before the diagnosis of type 2 diabetes and continues to progressively deteriorate.[14] Conversely, thiazolidinediones, which promote insulin sensitivity through a β-cell–independent mechanism, have been shown to improve insulin resistance and β-cell function.[15] These agents were not included in the UKPDS protocol; however, results from A Diabetes Outcome Progression Trial (ADOPT) showed that initial treatment with rosiglitazone was associated with a more durable monotherapy response than either metformin or glyburide; although even the insulin sensitizer was subject to loss of efficacy over time.[16]

Furthermore, current OAD therapy is often complicated by weight gain, hypoglycemia, edema, and gastrointestinal adverse effects.[17–20] More recently, the cardiovascular safety of several classes of agents, including the thiazolidinediones, have been called into question. Agents that are able to overcome these limitations have continued to generate much interest in the management of type 2 diabetes.

Dapagliflozin (BMS-512148) is one such agent. It inhibits the sodium-glucose cotransporter type 2 (SGLT2) receptor and is being investigated by AstraZeneca and Bristol-Myers Squibb (Princeton, NJ) for the treatment of type 2 diabetes. Inhibition of SGLT2 promotes the excretion of glucose at the renal proximal tubule, thereby lowering plasma glucose levels in an insulin-independent manner. To date, there are no OADs that address glucose transport as a molecular target; however, several drugs that target the SGLT2 receptor are being investigated, including canagliflozin, remogliflozin, and sergliflozin. The emerging class of SGLT2 inhibitors represents a promising addition to existing treatments and harbors numerous possible advantages over current OADs such as weight loss and a reduction in serum uric acid, blood pressure, and lipid levels.

In this comprehensive review of dapagliflozin, we outline the phase II clinical trials and international phase III studies that investigated the utility of dapagliflozin. Based on the available data reviewed in this article, we attempt to forecast the potential role of dapagliflozin in the management of type 2 diabetes by spotlighting its efficacy, safety, tolerability, pharmacology, and pharmacokinetic profile.


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