Dapagliflozin: an evidence-based review of its potential in the treatment of type-2 diabetes

Abstract

Dapagliflozin is a sodium-glucose co-transporter-2 inhibitor that lowers plasma glucose by decreasing its renal reabsorption. The resulting excretion of glucose in the urine (glucosuria) has transformed what was once solely regarded as an adverse facet of diabetes into a potential novel therapeutic strategy. Glucosuria leads to weight loss, due to a reduction in calories, which is thought to rehabilitate insulin sensitivity, at least partially. By acting independently of insulin action or secretion, dapagliflozin appears to avert or minimize two key barriers to optimal glycemic control: hypoglycemia and weight gain. From the clinical studies conducted thus far in patients with type 2 diabetes, dapagliflozin significantly decreases HbA(1c) (by ~0.5%-1%, from a baseline of 8%-9%), as well as body weight (~2-3 kg), without increased risk of hypoglycemia. Dapagliflozin thus represents a paradigm shift in the treatment of diabetes. While long-term data on safety and efficacy are forthcoming, the results published to date suggest that this agent has the potential to be another option in the treatment of diabetes treatments. This article examines the evidence currently available on the efficacy and safety of dapagliflozin.

Keywords: SGLT2 inhibitors; dapagliflozin; kidney; type 2 diabetes mellitus.

Figures

Figure 1

Normal glucose homeostasis. Notes: This figure depicts the hormonal interactions that are key in normal glucose homeostasis. Normal fasting glucose homeostasis involves the regulation of glucose utilization and production, as well as the filtration and reabsorption of glucose by the kidney. Under basal conditions, glucose uptake by the tissues is matched by glucose production from the liver, which enables precise regulation of glucose at a very fixed level. Copyright © 2010, Nature Pub. Group. Adapted from DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131(4):281–303. Reproduced with permission from Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discovery. 2010;9(7):551–559.

Figure 2

Glucose regulation by the kidneys in a non-diabetic individual. Copyright © Nature Pub. Group. Adapted from Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol. 2001;280(1):F10–F18. Reproduced with permission from Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discovery. 2010;9(7):551–559.

Figure 3

SGLT2 mediates glucose reabsorption in the kidney and catalyzes the active transport of glucose (against a concentration gradient) across the luminal membrane, by coupling it with the downhill transport of Na+. Notes: The inward Na+ gradient across the luminal epithelium is maintained by active extrusion of Na+ across the basolateral surface into the intercellular fluid, which is in equilibrium with the blood. Glucose passively diffuses out of the cell, down a concentration gradient, via basolateral facilitative transporters, GLUT2 (and GLUT1) Copyright © 2010, Nature Pub. Group. Reproduced with permission from Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discovery. 2010;9(7):551–559.

Figure 4

Renal glucose handling before and following inhibition of SGLT2. Notes: With gradual infusion of glucose, as the plasma glucose concentration increases, the reabsorption progressively increases, following the line marked “Reabsorption” (in red). At plasma glucose concentrations <200 mg/dL, all the filtered glucose is reabsorbed, and there is no excretion. When glucose reaches a threshold, at −200–250 mg/dL, the maximum capacity of the renal tubule to reabsorb glucose – the Tmax – is exceeded. Once past this threshold, glucose begins to be excreted into the urine (green line, labeled “Excretion”). The breaking point, however, is not abrupt. Splay, which represents glucose excretion in the urine before saturation (Tmax), is fully attained and is explained by some nephrons releasing glucose at a slightly lower threshold (some a bit higher) and the relatively low affinity of the Na–glucose carriers. The dotted yellow lines depict renal glucose handling after SGLT2 inhibition. The SGLT2 inhibitors lower the Tmax of glucose, which in turn increases the excretion of glucose via the kidneys. Copyright © 2010, Nature Pub. Group. Reproduced with permission from Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discovery. 2010;9(7):551–559.