Uses
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Diabetes Mellitus
Dapagliflozin propanediol is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Dapagliflozin is also used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione], a dipeptidyl peptidase-4 [DPP-4] inhibitor), or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.
Dapagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
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Dapagliflozin Monotherapy
When given as monotherapy for the management of type 2 diabetes mellitus, dapagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c) and in fasting and 2-hour postprandial plasma glucose concentrations. Efficacy of dapagliflozin as monotherapy has been established in 2 double-blind, placebo-controlled studies of 24-weeks' duration in 840 treatment-naive patients with type 2 diabetes mellitus and baseline HbA1c concentrations of 7-10%. In the first study, HbA1c was reduced by 0.8 or 0.9% in patients receiving dapagliflozin 5 or 10 mg once daily, respectively, compared with a decrease of 0.2% in those receiving placebo. In patients who received dapagliflozin 5 or 10 mg, approximately 44 or 51%, respectively, had HbA1c reductions to less than 7%, compared with approximately 32% of patients receiving placebo. In the second study, mean HbA1c reduction at week 24 was 0.68, 0.72, or 0.82% in patients receiving 1, 2.5, or 5 mg of dapagliflozin, respectively, compared with an increase of 0.02% in those receiving placebo.
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Combination Therapy
When given in combination with one or more oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione, a DPP-4 inhibitor) or insulin, dapagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure. Dapagliflozin generally is well tolerated, although genital mycotic infections appear to be more common with dapagliflozin than with other antidiabetic therapy.
Efficacy of dapagliflozin in combination with other antidiabetic agents for the management of type 2 diabetes mellitus is supported by results from several randomized, active- or placebo-controlled studies in patients receiving dapagliflozin with metformin, a sulfonylurea, metformin and a sulfonylurea, a thiazolidinedione, a DPP-4 inhibitor, or insulin. In these studies, initial combined therapy with dapagliflozin (5 or 10 mg once daily) and one or more antidiabetic drugs or addition of dapagliflozin to existing therapy improved glycemic control as evidenced by reductions in HbA1c, fasting plasma glucose, and 2-hour postprandial plasma glucose concentrations; combined therapy also had beneficial effects on weight reduction and blood pressure compared with placebo and/or monotherapy.
In two 24-week studies in treatment-naive patients with baseline mean HbA1c concentrations of 9-9.2%, the combination of extended-release metformin hydrochloride (up to 2 g daily) and dapagliflozin 5 or 10 mg once daily resulted in a reduction of 2.1 or 2%, respectively, in HbA1c compared with a reduction of 1.5, 1.2 or 1.4% in HbA1c with dapagliflozin 10 mg, dapagliflozin 5 mg, or extended-release metformin hydrochloride alone, respectively. Dapagliflozin 10 mg once daily was noninferior to metformin in reducing HbA1c, and superior in reducing fasting plasma glucose; dapagliflozin in this dosage also was associated with substantially greater weight loss than metformin monotherapy.
In a 24-week study in patients with HbA1c concentrations of 7-10% while receiving metformin hydrochloride (dosage of at least 1.5 g daily), the addition of dapagliflozin 5 or 10 mg resulted in a reduction of 0.7 or 0.8%, respectively, in HbA1c compared with a 0.3% HbA1c reduction with placebo. In these patients, add-on therapy with dapagliflozin 5 or 10 mg resulted in HbA1c reductions to less than 7% in 37.5 or 40.6% of patients, respectively, compared with 25.9% of patients receiving add-on placebo. In a 78-week extension of this study, add-on dapagliflozin was associated with sustained reductions in HbA1c, fasting plasma glucose, and body weight.
In a study in patients with HbA1c concentrations of approximately 6.5-10% while receiving metformin hydrochloride (dosage of at least 1.5 g daily), add-on therapy with dapagliflozin (titrated to 10 mg once daily) was noninferior to add-on glipizide (titrated to 20 mg once daily) in reducing HbA1c after 52 weeks of therapy. In addition, weight loss with add-on dapagliflozin therapy (3.2 kg) was superior to that with add-on glipizide therapy (1.4 kg).
In a 24-week study in patients who had inadequate glycemic control (HbA1c concentration of 7-10%) while receiving a sulfonylurea antidiabetic agent (glimepiride), add-on therapy with dapagliflozin 2.5, 5, or 10 mg once daily resulted in a reduction of approximately 0.6, 0.6, or 0.8%, respectively, in HbA1c compared with a reduction of approximately 0.1% with add-on placebo. In a 24-week study in patients who had inadequate glycemic control (HbA1c concentration of 7-10.5%) on pioglitazone (30 or 45 mg daily), the addition of dapagliflozin 5 or 10 mg resulted in a reduction of 0.8 or 1%, respectively, in HbA1c compared with a reduction of 0.4% with add-on placebo. Dapagliflozin also improved postprandial and fasting plasma glucose concentrations as well as reducing body weight and systolic blood pressure. In a 24-week study in patients who were treatment naive or who had inadequate glycemic control (HbA1c concentration of 7-10%) while receiving sitagliptin (100 mg once daily) with or without metformin hydrochloride (dosage of at least 1.5 g daily), addition of dapagliflozin 10 mg once daily reduced HbA1c by 0.45%, while patients receiving add-on placebo experienced no appreciable change. Patients receiving dapagliflozin add-on therapy also showed improved fasting plasma glucose and reduced body weight.
In a 24-week study in patients who had inadequate glycemic control (HbA1c concentration 7-10.5%) while receiving immediate- or extended-release metformin hydrochloride (at least 1.5 g daily) plus a sulfonylurea antidiabetic agent at the maximum tolerated dosage (and at least 50% of the maximum dosage), add-on therapy with dapagliflozin 10 mg once daily was associated with a 0.7% reduction in HbA1c compared with add-on placebo at 24 weeks. Add-on dapagliflozin therapy also was associated with reductions in fasting plasma glucose and body weight at week 24, and systolic blood pressure at week 8 compared with placebo.
In a 24-week study examining the effects of dapagliflozin on total body weight in patients with inadequate glycemic control on metformin hydrochloride, addition of dapagliflozin 10 mg once daily reduced total body weight by 2.96 kg compared with a reduction of 0.88 kg in those receiving add-on placebo.
Efficacy of dapagliflozin as add-on therapy to insulin in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control (HbA1c concentration of 7.5-10.5%) with insulin is supported by results of a 24-week, randomized, placebo-controlled study. In this study, addition of dapagliflozin (5 or 10 mg daily) to existing stable therapy with insulin (mean daily dosage of at least 30 units) with or without up to 2 additional oral antidiabetic agents resulted in improvements in HbA1c, fasting plasma glucose, 2-hour postprandial plasma glucose concentrations, and body weight. In patients who received dapagliflozin 5 or 10 mg as add-on to insulin therapy with or without 1 or 2 additional antidiabetic agents, addition of dapagliflozin 5 or 10 mg reduced HbA1c by 0.8 or 0.9%, respectively, compared with a 0.3% reduction in those receiving add-on placebo. During extended treatment and follow-up in this study, reductions in HbA1c, body weight, and insulin dosage were maintained for 104 weeks with dapagliflozin therapy.
In a 12-week randomized, double-blind study in patients receiving insulin with or without up to 2 oral antidiabetic agents, HbA1c was reduced by 0.7 or 0.78% with addition of dapagliflozin 10 or 20 mg once daily, respectively, to existing therapy compared with addition of placebo. The mean change from baseline in body weight at the end of the study was 4.5, 4.3, or 1.9 kg with dapagliflozin 10 mg, 20 mg, or placebo, respectively. Patients receiving add-on dapagliflozin 10 or 20 mg had mean reductions in insulin dosage from baseline of 1.4 and 0.8 units, respectively, at the end of the study compared with a mean increase from baseline of 1.7 units in those receiving add-on placebo.
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