Uses
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Diabetes Mellitus
Empagliflozin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Empagliflozin is also used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione], a dipeptidylpeptidase-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.
Empagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
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Empagliflozin Monotherapy
When given as monotherapy for the management of type 2 diabetes mellitus, empagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting plasma glucose concentrations, and also reduces body weight. Efficacy of empagliflozin as monotherapy for the management of type 2 diabetes mellitus has been established in a phase 3, double-blind, placebo-controlled study of 24 weeks' duration in 986 adults with previously untreated type 2 diabetes mellitus (defined as receiving no oral or injected antidiabetic agents for 12 weeks prior to randomization or initiation of open-label treatment). Empagliflozin (10 mg or 25 mg once daily) improved glycemic control as evidenced by reductions in HbA1c, fasting plasma glucose concentrations, and body weight. Patients with HbA1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily with no placebo run-in phase. Patients with HbA1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled received empagliflozin 10 mg once daily, empagliflozin 25 mg once daily, sitagliptin 100 mg once daily, or placebo. The primary end point of the study was change from baseline in HbA1c at week 24. At 24 weeks, reductions (adjusted mean) in HbA1c were 0.7, 0.8, or 0.7% in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily, respectively; an increase (adjusted mean) in HbA1c of 0.1% was observed in patients who received placebo. Also, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentrations was 19 or 25 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, respectively, compared with an increase of 12 mg/dL in those receiving placebo. Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily had reductions (adjusted mean) in body weight of 2.8, 3.2, or 0.4%, respectively, at week 24; systolic blood pressure was reduced by 2.6 mm Hg in patients who received empagliflozin 10 mg once daily and by 3.4 mm Hg in those who received empagliflozin 25 mg once daily compared with that in placebo recipients.
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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, empagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure. In a 24-week phase 3, randomized, double-blind, placebo-controlled study in 637 adults with inadequately controlled type 2 diabetes mellitus who were receiving metformin hydrochloride (at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage), addition of empagliflozin 10 or 25 mg once daily resulted in reductions of HbA1c compared with placebo. Patients with HbA1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily without a placebo run-in phase. Patients with HbA1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled following the run-in phase received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks. The primary end point of the study was change from baseline in HbA1c at week 24. Following 24 weeks of therapy, the addition of empagliflozin to current metformin treatment resulted in reductions (adjusted mean) in HbA1c of 0.7, 0.8, and 0.1% in patients who received empagliflozin 10 mg once daily, empagliflozin 25 mg once daily, and placebo, respectively. In addition, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentration was 20 or 22 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, respectively, compared with an increase of 6 mg/dL in those receiving placebo. Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo experienced reductions (adjusted mean) in body weight of 2.5, 2.9, or 0.5%, respectively, at week 24; systolic blood pressure was reduced compared with placebo by 4.1 mm Hg in patients who received empagliflozin 10 mg and by 4.8 mm Hg in those who received empagliflozin 25 mg.
Efficacy and safety of the combination of empagliflozin and metformin hydrochloride as initial therapy in treatment-naive patients with type 2 diabetes mellitus is supported by results of a 24-week, randomized, double-blind trial. In this trial, concurrent therapy with empagliflozin (10 or 25 mg once daily) and metformin hydrochloride (1 or 2 g daily) substantially improved glycemic control (as evidenced by reductions in HbA1c), compared with empagliflozin or metformin hydrochloride monotherapy. Reductions in HbA1c were 2 or 2.1% with 1 or 2 g daily, respectively, of metformin hydrochloride plus empagliflozin 10 mg once daily; 1.9 or 2.1% with 1 or 2 g daily, respectively, of metformin hydrochloride plus empagliflozin 25 mg once daily; 1.2 or 1.8% with 1 or 2 g daily, respectively, of metformin hydrochloride; and 1.4% with empagliflozin 10 or 25 mg once daily.
Efficacy of empagliflozin 10 or 25 mg once daily in combination with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage) plus a sulfonylurea was established in 666 adults with type 2 diabetes mellitus in an international 24-week, phase 3, randomized, double-blind, placebo-controlled study. Patients with HbA1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg. Patients with HbA1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily. The primary end point of the study was change from baseline in HbA1c at week 24. Following 24 weeks of therapy, add-on therapy with empagliflozin reduced HbA1c by 0.8, 0.8, or 0.2% (adjusted mean values) in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively. Also, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentrations was 23 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, compared with an increase of 6 mg/dL in those receiving placebo. Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily had reductions (adjusted mean) in body weight of 2.9, 3.2, or 0.5%, respectively, at week 24.
Efficacy of empagliflozin 25 mg in combination with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage) in an international phase 3, randomized, double-blind study was established in 1545 adults with type 2 diabetes mellitus. Patients with inadequately controlled type 2 diabetes mellitus (HbA1c concentration of 7-10%) received empagliflozin 25 mg once daily or glimepiride 1-4 mg once daily (mean daily dosage of 2.7 mg) following a 2-week run-in period. The primary end point was change from baseline in HbA1c concentrations at weeks 52 and 104. At week 52, add-on therapy with empagliflozin 25 mg or glimepiride 1-4 mg in patients receiving metformin resulted in a reduction in HbA1c concentration of 0.7% for both drugs. At week 52, add-on therapy with empagliflozin 25 mg or glimepiride 1-4 mg reduced fasting plasma glucose concentrations by 19 or 9 mg/dL, respectively. Body weight was reduced by 3.9 or increased by 2% in those who received empagliflozin 25 mg or glimepiride 1-4 mg, respectively, plus metformin at week 52. At week 52, the reduction in systolic blood pressure in patients who received empagliflozin (3.6 mm Hg) was not appreciably different from that in patients who received glimepiride (2.2 mm Hg). Empagliflozin demonstrated noninferiority to glimepiride in glycemic control at weeks 52 and 104; the reduction (adjusted mean) in HbA1c with empagliflozin was 0.11% greater than that with glimepiride at week 104.
In a 24-week, double-blind, placebo-controlled study in 498 adults with type 2 diabetes mellitus receiving pioglitazone (dosage of at least 30 mg daily, or maximum tolerated dosage, or maximum labeled dosage) with or without metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage), addition of empagliflozin 10 or 25 mg once daily reduced HbA1c, fasting plasma glucose concentrations, and body weight. Following an open-label placebo run-in period of 2 weeks, patients with inadequate glycemic control (HbA1c concentrations of 7-10%) received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, in addition to existing antidiabetic therapy with pioglitazone with or without metformin. The primary end point was change from baseline in HbA1c concentrations at week 24. Addition of empagliflozin 10 or 25 mg to existing antidiabetic therapy resulted in reductions (adjusted mean) in HbA1c of 0.6 or 0.7%, respectively, at week 24 compared with a reduction of 0.1% in patients receiving placebo. Patients receiving empagliflozin 10 or 25 mg had reductions (adjusted mean) in fasting plasma glucose concentrations of 17 or 22 mg/dL, respectively, at week 24 compared with an increase of 7 mg/dL with placebo. Reductions in body weight were 2.0, 1.8, or 0.6% in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively.
In an international, phase 3, randomized, double-blind trial, add-on therapy with empagliflozin and linagliptin in fixed combination was more effective in reducing HbA1c and fasting plasma glucose concentrations than add-on empagliflozin or linagliptin monotherapy in 686 adults with type 2 diabetes mellitus inadequately controlled with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage). At 24 weeks, reduction in mean HbA1c from baseline was 1.19% with empagliflozin 25 mg/linagliptin 5 mg, 1.08% with empagliflozin 10 mg/linagliptin 5 mg, 0.62% with empagliflozin 25 mg, 0.66% with empagliflozin 10 mg, and 0.7% with linagliptin 5 mg. Glycemic efficacy (HbA1c reductions) with the fixed combinations of empagliflozin/linagliptin was maintained at week 52. The fixed combinations of empagliflozin and linagliptin also were associated with reductions from baseline in systolic blood pressure compared with linagliptin monotherapy. Body weight was reduced in patients receiving the fixed combinations of empagliflozin/linagliptin compared with linagliptin but not empagliflozin monotherapy.
In a double-blind, placebo-controlled study in 494 adults with inadequately controlled type 2 diabetes mellitus while receiving insulin with or without metformin and/or a sulfonylurea, add-on therapy with empagliflozin 10 or 25 mg once daily reduced HbA1c, fasting plasma glucose concentrations, and body weight after 18 and 78 weeks of treatment. Following a 2-week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or sulfonylurea therapy, patients received empagliflozin 10 or 25 mg or placebo once daily in addition to existing antidiabetic therapy. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment; for the remaining 60 weeks, adjustment of insulin dosage was permitted. Mean total daily insulin dosages at baseline for patients receiving empagliflozin 10 mg, empagliflozin 25 mg, or placebo were 45, 48, or 48 units, respectively. At 18 weeks, add-on therapy with empagliflozin 10 or 25 mg reduced HbA1c concentration by 0.6 or 0.7% (adjusted mean values), respectively, compared with no change in HbA1c concentration in patients who received placebo. Also, at 78 weeks, addition of empagliflozin 10 or 25 mg reduced HbA1c concentration by 0.4 or 0.6% (adjusted mean values), respectively, compared with an increase of 0.1% in patients who received placebo. Following 18 weeks of treatment, the reduction in fasting plasma glucose concentrations in patients who received empagliflozin 10 or 25 mg plus existing antidiabetic therapy was 17.9 or 19.1 mg/dL, compared with an increase of 10.4 mg/dL in those who received placebo; at 78 weeks, the reduction in fasting plasma glucose concentrations in patients who received empagliflozin 10 or 25 mg was 10.1 or 15.2 mg/dL, compared with an increase of 2.8 mg/dL in those receiving placebo. Furthermore, reductions in body weight at 18 weeks in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo were 1.8, 1.4, or 0.1%, respectively; at 78 weeks, patients who received empagliflozin 10 or 25 mg had reductions of 2.4% in body weight, while those receiving placebo had an increase of 0.7% in body weight.
In a randomized, double-blind, placebo-controlled, international study in 563 obese patients (body mass index [BMI] of 30-45 kg/m) with inadequately controlled type 2 diabetes mellitus (HbA1c concentrations 7.5-10%) despite multiple daily injections of insulin with or without metformin, add-on therapy with empagliflozin reduced HbA1c and body weight. Following a 2-week, open-label, placebo run-in period, patients received empagliflozin 10 or 25 mg or placebo once daily as add-on therapy to insulin, with or without metformin hydrochloride (dosage of at least 1.5 g daily, maximum tolerated dosage, or maximum labeled dosage), for 52 weeks. The total daily dosage of insulin was adjusted to achieve a preprandial glucose target of less than 100 mg/dL and a postprandial glucose target of less than 140 mg/dL, except during the first 18 weeks (adjusted to be within 10% of prescribed dosage at randomization) and during weeks 41-52 (adjusted to be within 10% of the prescribed dosage at week 40 except for safety reasons). Metformin hydrochloride dosage was not adjusted during the study, although rescue therapy (e.g., metformin, insulin) could be initiated at any time during treatment if patients experienced clinically important hyperglycemia. The primary end point of the study was change from baseline in HbA1c at week 18. At week 18, the reduction in HbA1c was 0.94 or 1.02% in patients who received empagliflozin 10 or 25 mg once daily, respectively, as add-on therapy, compared with a reduction of 0.5% in patients who received placebo. At week 52, insulin titration resulted in additional reductions in HbA1c of 1.18, 1.27, or 0.81% in those who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively. Also, at week 52, patients who received empagliflozin 10 or 25 mg once daily experienced reductions in body weight of 1.95 or 2.04 kg, respectively, compared with an increase in body weight of 0.44 kg in patients receiving placebo.
Efficacy and safety of empagliflozin in 738 adults with inadequately controlled type 2 diabetes mellitus (HbA1c concentrations of 7-10%) and renal impairment were established in a phase 3, randomized, double-blind, placebo-controlled study. Patients with an estimated glomerular filtration rate (eGFR) of 60-89 mL/minute per 1.73 m (mild renal impairment) received empagliflozin 10 or 25 mg or placebo once daily in addition to existing antidiabetic therapy. Patients with an eGFR of 30-59 mL/minute per 1.73 m (moderate renal impairment) or 15-29 mL/minute per 1.73 m (severe renal impairment) received empagliflozin 25 mg once daily or placebo. The primary end point was change from baseline in HbA1c at week 24. At 24 weeks, empagliflozin 25 mg reduced HbA1c concentration by 0.5% in the combined group of patients with mild or moderate renal impairment. Empagliflozin 25 mg also reduced HbA1c concentration in patients with either mild (0.7% reduction) or moderate (0.4% reduction) renal impairment, and empagliflozin 10 mg reduced HbA1c concentration by 0.5% in patients with mild renal impairment. Antihyperglycemic efficacy of empagliflozin 25 mg was reduced with decreasing level of renal function in the mild to moderate range. Mean reductions in HbA1c at 24 weeks were 0.6, 0.5, and 0.2% for those with a baseline eGFR of 60-89 mL/minute per 1.73 m, 45-59 mL/minute per 1.73 m, and 30-44 mL/minute per 1.73 m , respectively, for patients receiving empagliflozin 25 mg. In contrast, mean HbA1c at 24 weeks increased by 0.1 or 0.2% in patients with a baseline eGFR of 60-89 mL/minute per 1.73 m or 30-44 mL/minute per 1.73 m, respectively, and decreased by 0.1% in patients with a baseline eGFR of 45-59 mL/minute per 1.73 m for patients receiving placebo. For patients with severe renal impairment, the analyses of changes in HbA1c and fasting plasma glucose concentrations showed no discernible treatment effect of empagliflozin 25 mg compared with placebo.
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