Introduction

Dapagliflozin 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.¹

Figure 1 Characteristics of dapagliflozin

Pharmacological Properties

Dapagliflozin is a highly potent (inhibitory constant 0.55 nmol/L) and reversible SGLT2 inhibitor that is > 1400 times more selective for SGLT2 than SGLT1, the main transporter responsible for glucose absorption in the gut. Dapagliflozin increased the amount of glucose excreted in the urine and improved both fasting (FPG) and post-prandial plasma glucose levels in patients with T2D. Urinary glucose excretion (glucuresis) was seen after the first dose of dapagliflozin, was continuous during the 24 h dosing interval and maintained over the course of therapy. Dapagliflozin-induced glucuresis in patients with T2D was associated with caloric loss and a modest reduction in bodyweight, as well as mild osmotic diuresis and transient natriuresis. The loss in bodyweight with SGLT2 inhibitors is less than that calculated from calorie loss due to glucuresis, which may be because of compensatory mechanisms such as increased energy intake. A modest decrease in blood pressure (BP) was also seen with dapagliflozin, which may be explained by a decrease in circulating volume because of the diuretic/natriuretic properties of the drug.²

Therapeutic Efficacy

In a randomized, double-blind, multinational, phase 3 study in patients inadequately controlled with metformin (n = 182), add-on dapagliflozin reduced bodyweight largely by reducing fat mass relative to placebo, with fat mass accounting for approximately two-thirds of the total weight loss. At week 24, patients receiving add-on dapagliflozin 10 mg once daily had significantly lower total bodyweight (primary endpoint; difference from placebo ? 2.1 kg; baseline?≈ 92 kg; p < 0.0001), smaller waist circumference (? 1.5 cm; baseline?≈ 105 cm p = 0.0143) and less fat mass as assessed by dual X-ray absorptiometry (DXA) (? 1.5 kg; baseline?≈ 33 kg; p = 0.0001) than those receiving add-on placebo. A rapid decline in bodyweight was seen in the first few weeks of dapagliflozin treatment, with a gradual decline thereafter that had not plateaued at week 24. This change in bodyweight was reflected in the daily spot urinary glucose level, which showed an initial rapid increase and stable levels thereafter, supporting the DXA findings that the loss in bodyweight and fat mass with dapagliflozin was largely because of caloric loss from glucosuria. However, the initial rapid decline in bodyweight in dapagliflozin recipients may partly be because of fluid loss.

Additionally, the proportion of patients with a decrease in bodyweight of ≥ 5% was significantly higher in patients receiving dapagliflozin than those receiving placebo (31 vs. 4%; p < 0.0001). Moreover, magnetic resonance imaging in a substudy in 80 patients showed that both visceral and subcutaneous adipose tissues were reduced in dapagliflozin relative to placebo recipients (difference from placebo ? 258 and ? 185 cm3, respectively; both nominal p < 0.05). The reductions in bodyweight, fat mass and waist circumference with add-on dapagliflozin versus add-on placebo at week 24 were maintained over 102 weeks' therapy.²

References

1. Plosker G L. Dapagliflozin: a review of its use in type 2 diabetes mellitus[J]. Drugs, 2012, 72: 2289-2312.

2. Dhillon S. Dapagliflozin: a review in type 2 diabetes[J]. Drugs, 2019, 79(10): 1135-1146.