Dapagliflozin

Abstract

Dapagliflozin (Forxiga®) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a reduction in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action. A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10 mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated haemoglobin values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycaemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clinical trials, dapagliflozin was associated with reductions in body weight that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to ≈2 years. Dapagliflozin was generally well tolerated in clinical trials of 24 or 52 weeks duration and in extension studies of up to ≈2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycaemia, especially when used alone or in combination with metformin, although the incidence of hypoglycaemic events reported with dapagliflozin in clinical trials varied depending on the background therapy. Longer-term tolerability/safety data with dapagliflozin are awaited with interest. In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addition to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy.