Dapagliflozin propanediol, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.1, 53, 55
Dapagliflozin propanediol is used as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus.1, 2, 3, 15, 32, 34 In clinical studies in adults, dapagliflozin was evaluated as monotherapy and in combination with other antidiabetic agents (e.g., metformin, sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 [DPP-4] inhibitor, glucagon-like peptide [GLP-1] receptor agonist, insulin).1, 4, 5, 6, 7, 8, 9, 10, 12, 13, 16, 52 In pediatric patients, dapagliflozin was evaluated as add-on therapy to metformin and/or insulin in patients with inadequately controlled type 2 diabetes mellitus.1
Dapagliflozin is commercially available as a single-entity preparation1 and also in fixed combination with extended-release metformin hydrochloride53 or saxagliptin for use in the management of type 2 diabetes mellitus.55 The fixed combination of dapagliflozin and extended-release metformin hydrochloride is indicated for use in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus, and the fixed combination of dapagliflozin and saxagliptin is indicated for use in adults only53, 55
Dapagliflozin and the fixed combination of dapagliflozin and metformin are also used to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.1, 53, 70, 707, 708
Dapagliflozin is not recommended to improve glycemic control in patients with type 2 diabetes mellitus and eGFR less than 45 mL/minute per 1.73 m2 because the drug is not expected to be effective in these patients based on its mechanism of action.1 Dapagliflozin and the fixed combinations of dapagliflozin with extended-release metformin or saxagliptin are not indicated for the treatment of type 1 diabetes mellitus.1, 53, 55
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.1, 2, 3
Efficacy of dapagliflozin for the management of type 2 diabetes mellitus in adult patients was 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%.1, 2, 3 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.1, 2 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.1, 2 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.3
Efficacy of dapagliflozin for the management of type 2 diabetes mellitus in pediatric patients 10 years of age and older was established in a 26-week, placebo-controlled, double-blind, randomized trial.1, 709 Patients with inadequately controlled type 2 diabetes mellitus (baseline HbA1c≥6.5% and ≤10.5%) were randomized to dapagliflozin 5 mg or placebo once daily as add-on therapy to either metformin, insulin, or the combination of metformin and insulin; at week 14, patients receiving dapagliflozin 5 mg once daily who had HbA1c≥7% were further randomized to either continue dapagliflozin 5 mg or titrate the dose to 10 mg once daily.1, 709 In the dapagliflozin group, the mean age was 14.4 years and the majority of patients were female (61%) and white (52%).1 In the placebo group, the mean age was 14.7 years; 58% of patients were female and 42% were white.1 The mean baseline HbA1cwas 8.2% and 8.0% in the dapagliflozin and placebo groups, respectively.1 At the end of the 26-week study period, dapagliflozin treatment resulted in a significant reduction in HbA1c compared to placebo (-0.6 versus 0.4%, respectively; treatment difference 1%).1 In patients with a baseline HbA1c≥7%, 26.6% of patients in the dapagliflozin group compared to 10% in the placebo group achieved an HbA1c<7%.1
Clinical trials evaluating the safety and efficacy of the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) in reducing HbA1c have not been conducted; unless otherwise specified, clinical trials of dapagliflozin in combination with metformin discussed in this monograph were conducted using concomitantly administered dapagliflozin and immediate- or extended-release metformin hydrochloride.53 Bioequivalence between the fixed combination of dapagliflozin and extended-release metformin hydrochloride and each agent (dapagliflozin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated.53 Safety and efficacy of the fixed combination of dapagliflozin and saxagliptin (Qtern®) have been established by clinical studies evaluating treatment with saxagliptin as add-on therapy to treatment with dapagliflozin and metformin hydrochloride or with dapagliflozin and saxagliptin as add-on therapy to treatment with metformin.55, 57
When given in combination with one or more oral antidiabetic agents (e.g., metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor) and/or insulin or a GLP-1 receptor agonist (e.g., exenatide), dapagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure.1, 4, 5, 6, 7, 8, 9, 10, 52 Dapagliflozin generally is well tolerated, although genital mycotic infections appear to be more common with dapagliflozin than with other antidiabetic therapy.1, 2, 3, 4, 5, 6, 7, 8, 9, 10
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, a GLP-1 receptor agonist, or insulin.1, 4, 5, 6, 7, 8, 9, 52 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.1, 4, 5, 6, 7, 8, 9, 52
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.1, 4 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.1, 4
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.1, 5 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.1, 5 In a 78-week extension of this study, add-on dapagliflozin was associated with sustained reductions in HbA1c, fasting plasma glucose, and body weight.12
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.1, 6 In addition, weight loss with add-on dapagliflozin therapy (3.2 kg) was superior to that with add-on glipizide therapy (1.4 kg).1, 6
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.1, 7 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.1, 8 Dapagliflozin also improved postprandial and fasting plasma glucose concentrations as well as reducing body weight and systolic blood pressure.1, 8 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.1, 9 Patients receiving dapagliflozin add-on therapy also showed improved fasting plasma glucose and reduced body weight.1, 9
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.1 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.1
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.14
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.1, 10 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.1, 10 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.1 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.10
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.16 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.16 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.16
Efficacy of the combination of dapagliflozin and saxagliptin with metformin hydrochloride for the management of type 2 diabetes mellitus is supported by several randomized, controlled clinical studies.55, 57, 72 In a 24-week study in patients with inadequate glycemic control (HbA1c concentration of 7.5-10%) despite treatment with metformin hydrochloride, the addition of dapagliflozin and saxagliptin to existing therapy with metformin hydrochloride substantially improved glycemic control.55, 57 Patients who received triple therapy with dapagliflozin, saxagliptin, and metformin hydrochloride had an HbA1c reduction of 1.02% compared with a reduction of 0.62 or 0.69% in those who received dual therapy with dapagliflozin and metformin hydrochloride or saxagliptin and metformin hydrochloride, respectively.55 Additionally, a larger proportion of patients who received triple therapy achieved HbA1c below 7% compared with those who received dual therapy.55
In another clinical study of 24 weeks' duration, adults with type 2 diabetes mellitus who had inadequate glycemic control on metformin alone (HbA1c 8-12%) received add-on therapy with 10 mg of dapagliflozin and 5 mg of saxagliptin, 10 mg of dapagliflozin, or 5 mg of saxagliptin.55 After 24 weeks, concomitant therapy with dapagliflozin and saxagliptin resulted in substantial decreases in HbA1c, and a greater proportion of patients receiving this therapy achieved an HbA1c below 7% compared with those receiving add-on therapy with dapagliflozin or saxagliptin.55
In a clinical study evaluating the efficacy of add-on therapy with saxagliptin in adults (mean age: 54.6 years, 52.7% female, 87.9% Caucasian) with type 2 diabetes mellitus (mean HbA1c: 7.9%) already receiving concomitant dapagliflozin and metformin therapy, the addition of saxagliptin resulted in substantial reductions in HbA1c.55, 72 The combination of the 3 agents was well tolerated, and patients receiving therapy with all 3 agents had a reduction in HbA1c of 0.5% compared with a reduction of 0.2% in patients receiving dapagliflozin and metformin therapy.55, 72
Efficacy of dapagliflozin in conjunction with extended-release exenatide as add-on therapy to metformin hydrochloride in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control (HbA1c concentration of 8 to less than 12%) with metformin hydrochloride is supported by results of a 28-week, randomized, active-controlled study.1, 52 In this study, addition of dapagliflozin (10 mg daily) and extended-release exenatide (2 mg subcutaneously every week) to existing stable therapy with metformin hydrochloride (at least 1.5 g daily) resulted in substantially greater improvements in HbA1c and fasting plasma glucose compared with dapagliflozin or extended-release exenatide alone.1, 52 In patients who received dapagliflozin 10 mg once daily and extended-release exenatide 2 mg once weekly as add-on to metformin hydrochloride therapy, addition of dapagliflozin and extended-release exenatide reduced HbA1c by 1.8% compared with a 1.3 or 1.4% reduction in those receiving add-on therapy with dapagliflozin or extended-release exenatide alone, respectively.1 More weight loss and greater reductions in systolic blood pressure also were observed among those who received add-on therapy with dapagliflozin and extended-release exenatide compared with add-on therapy with either drug alone.52
Reduction in Risk of Heart Failure-related Hospitalization
Dapagliflozin is used to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.1, 53, 707, 708, 710 In addition to lowering blood glucose, SGLT2 inhibitors such as dapagliflozin appear to modify several nonglycemic cardiovascular risk factors such as blood pressure, body weight, adiposity, and arterial stiffness.84, 85
In a randomized, placebo-controlled trial in adults with type 2 diabetes mellitus and established ASCVD or multiple (2 or more) ASCVD risk factors (DECLARE-TIMI 58), dapagliflozin demonstrated a beneficial effect specifically related to the risk of heart failure; a lower risk of major adverse cardiovascular events compared with placebo was not observed.1, 70 In this study, patients 40 years of age or older with type 2 diabetes mellitus who had or were at risk for ASCVD received dapagliflozin 10 mg once daily or placebo for a median of 4.2 years.1, 70 The use of other antidiabetic agents was at the discretion of the treating clinician.1, 70 Approximately 59% of patients had multiple risk factors for ASCVD (but not established ASCVD); 10% of patients had a history of heart failure.1, 70 The primary efficacy outcomes were major adverse cardiovascular events (e.g., cardiovascular death, myocardial infarction [MI], ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure.1, 70 Dapagliflozin was noninferior to placebo with regard to the risk of major adverse cardiovascular effects but did not significantly reduce or increase the risk of such events compared with placebo (event rate: 8.8 versus 9.4%, respectively).1, 70 However, dapagliflozin therapy was associated with a reduction in the risk of the composite outcome of cardiovascular death or hospitalization for heart failure, which was attributable to a 27% relative risk reduction in hospitalization for heart failure; there was no difference between placebo and dapagliflozin with regard to the risk of cardiovascular death.1, 70
For the treatment of patients with type 2 diabetes mellitus and established ASCVD (or high risk of ASCVD), current clinical practice guidelines generally recommend the use of an SGLT2 inhibitor with proven efficacy in cardiovascular outcome trials.707, 708
Beneficial Effects on Renal Function
SGLT2 inhibitors reduce renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow glomerular filtration rate (GFR) loss through mechanisms that appear to be independent of glucose-lowering effects.84 In several cardiovascular outcomes trials involving the use of SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function have been observed as a secondary outcome.84, 707
In the DECLARE-TIMI 58 study in adults with type 2 diabetes with ASCVD (or at high risk of ASCVD), dapagliflozin therapy was associated with a lower incidence of a secondary composite renal outcome (at least a 40% decrease in eGFR to less than 60 mL/minute per 1.73 m2, end-stage renal disease, or death from renal or cardiovascular causes), which occurred in 4.3% of dapagliflozin-treated patients versus 5.6% of those receiving placebo.70, 100
For the treatment of patients with type 2 diabetes mellitus and CKD, current clinical practice guidelines generally recommend the use of an SGLT2 inhibitor with proven benefit in reducing adverse renal outcomes.707, 708
The American Diabetes Association (ADA) publishes an annual guideline on diabetes management, which provides clinical practice recommendations for glucose-lowering therapies in patients with type 2 diabetes mellitus.707 The current 2024 guideline states that in adults with type 2 diabetes mellitus, pharmacologic strategies that provide sufficient effectiveness to achieve and maintain the intended treatment goals should be used and guided by a person-centered shared decision-making approach.707 In general, higher-efficacy approaches have a greater likelihood of achieving glycemic goals.707 Weight management should be included as a distinct treatment goal, and other healthy lifestyle behaviors should also be considered.707 When selecting an appropriate treatment regimen, clinicians should be guided by factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.707 In adults with type 2 diabetes mellitus and established/high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure, and/or chronic kidney disease, the treatment regimen should include agents that reduce cardiorenal risk, such as an SGLT2 inhibitor or a glucagon-like peptide 1 receptor agonist.707 The use of an SGLT2 inhibitor and/or a GLP-1 receptor agonist that has been demonstrated to have cardiovascular benefit is recommended.707
The American Association of Clinical Endocrinology (AACE) also publishes a guideline for the management of type 2 diabetes.708 The principles of diabetes management outlined in the guideline are similar to those recommended by the ADA.708 The AACE guideline states that in adult patients with type 2 diabetes mellitus and with ASCVD (or high risk of ASCVD), heart failure, and/or chronic kidney disease, an SGLT2 inhibitor or a GLP-1 receptor agonist with proven efficacy for the comorbid condition should be initiated as first-line therapy.708
ADA guidelines for the management of diabetes in children and adolescents recommend metformin as the initial pharmacologic treatment of choice in pediatric patients with type 2 diabetes mellitus with normal renal function.721 If glycemic goals are no longer met with metformin (with or without long-acting insulin), GLP-1 receptor agonist therapy and/or empagliflozin should be considered in children 10 years of age or older.721 Similar to adults, comprehensive lifestyle management should be included as part of the treatment plan.721 Dapagliflozin received FDA approval for the expanded indication in pediatric patients with type 2 diabetes mellitus after publication of these guidelines.1
Dapagliflozin is used to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure.1, 90, 711, 712, 713
The efficacy and safety of dapagliflozin were assessed in 2 double-blind, placebo-controlled studies in adult patients with heart failure.1 In the first study (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]), which was conducted in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction (left ventricular ejection fraction [LVEF] of 40% or less), dapagliflozin therapy reduced the risk of worsening heart failure or death from cardiovascular causes in patients with or without type 2 diabetes mellitus.1, 90 In this study, 4744 patients with chronic heart failure (68% NYHA class II, 32% class III, and 1% class IV) and reduced ejection fraction (median baseline LVEF: 32%) received dapagliflozin 10 mg orally once daily or placebo in conjunction with standard medical and medical device therapy for heart failure for a median duration of 18.2 months.1, 90 Initially, 42% of enrolled patients had a history of type 2 diabetes mellitus and an additional 3% of patients in each group received a diagnosis of type 2 diabetes mellitus (based on a HbA1c of at least 6.5%) during the enrollment process.1, 90 At baseline, most patients were receiving an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor antagonist, or angiotensin receptor-neprilysin inhibitor (ARNI); a β-adrenergic blocking agent (β-blocker); a mineralocorticoid receptor antagonist; and a diuretic; 26% had an implantable cardiac device.1, 90 The primary outcome was a composite of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit (i.e., urgent, unplanned clinician assessment requiring treatment for worsening heart failure).1, 90 Among patients who received dapagliflozin therapy, the incidence of the primary end point was reduced by 26%.1 All three components of the primary composite end point contributed individually to the treatment effect, and the results were applicable to all subgroups analyzed, including patients with or without type 2 diabetes mellitus.1, 90
In the second study (Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure [DELIVER]), patients ≥ 40 years of age with heart failure (NYHA II-IV) with LVEF >40% and evidence of structural heart disease were randomized to receive either dapagliflozin 10 mg or placebo.1, 711 A total of 6263 patients were enrolled; 10% were randomized during hospitalization for heart failure or within 30 days of hospital discharge.1, 711 At baseline, 77% of patients were treated with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI, 83% with a β-blocker, 43% with a mineralocorticoid receptor antagonist, and 98% with a diuretic.1 Among patients who received dapagliflozin, the composite endpoint of cardiovascular death, heart failure hospitalization for heart failure, or urgent heart failure visit was reduced by 18%.1 All three components of the primary composite end point contributed individually to the treatment effect and the results were applicable across the range of LVEF and irrespective of a diagnosis of type 2 diabetes mellitus.1, 711
Current American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines for heart failure recommend guideline-directed medical therapy with a combination of drug therapies to reduce morbidity and mortality, including angiotensin-converting enzyme (ACE) inhibitors, SGLT2 inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors (ARNIs), β-adrenergic blocking agents, and mineralocorticoid receptor antagonists.712, 713 Diuretics are recommended on an as-needed basis to improve symptoms of congestion and prevent worsening of disease in patients with fluid retention.712 Once guideline-directed medical therapy is optimized, additional therapies (e.g., ivabradine, vericiguat, digoxin, polyunsaturated fatty acids) may be considered based on patient-specific factors.712
SGLT2 inhibitors are recommended in all patients with heart failure (either reduced ejection fraction or preserved ejection fraction), irrespective of the presence of type 2 diabetes in the absence of contraindications.712, 713 The AHA/ACC/HFSA guidelines strongly recommend the use of SGLT2 inhibitors in patients with symptomatic (stage C) chronic heart failure with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40%) to reduce hospitalization for heart failure and cardiovascular mortality.712 In addition to an SGLT2 inhibitor, these patients should also be treated with an ARNI, an evidence-based beta-adrenergic blocking agent, and a mineralocorticoid antagonist.713 This 4-drug regimen is currently considered the standard of care in patients with HFrEF and should be initiated and titrated to target doses as soon as possible.713 In patients with heart failure with mildly reduced ejection fraction (LVEF 41-49%) or preserved ejection fraction (LVEF ≥50%), SGLT2 inhibitors can also be beneficial in decreasing heart failure hospitalizations and cardiovascular mortality and are recommended for use in these patients based on moderate quality evidence.712
Dapagliflozin is used to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.1, 714, 715
The efficacy of dapagliflozin in the management of chronic kidney disease was evaluated in a randomized, double-blind, placebo-controlled trial (DAPA-CKD) in adults with a history of chronic kidney disease (eGFR between 25 and 75 mL/minute per 1.73 m2) and albuminuria (urine albumin creatinine ratio between 200 and 5000 mg/g) who were receiving standard of care background therapy, including a maximally tolerated FDA-labeled daily dose of an ACE inhibitor or angiotensin II receptor antagonist.1, 715 The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding 6 months.1, 715 The primary objective was to determine whether dapagliflozin reduces the incidence of the composite endpoint of ≥50% sustained decline in eGFR, progression to end-stage kidney disease (defined as sustained eGFR <15 mL/minute per 1.73 m2, initiation of chronic hemodialysis, or renal transplant), or death from cardiovascular or renal causes.1, 715
A total of 4304 patients were randomized 1:1 to either dapagliflozin 10 mg or placebo.1, 715 The mean age of the study population was 62 years; the majority were male (67%) and white (53%).1 At baseline, the mean eGFR was 43 mL/minute per 1.73 m2, with 44% of patients having an eGFR 30 to less than 45 mL/minute per 1.73 m2 and 15% with an eGFR <30 mL/minute per 1.73 m2.1 The most common etiologies of chronic kidney disease were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and immunoglobulin A nephropathy (6%); 68% of patients had a diagnosis of type 2 diabetes mellitus at baseline.1 Nearly all (97%) patients were taking an ACE inhibitor or angiotensin II receptor antagonist at baseline.1 Dapagliflozin reduced the incidence of the primary endpoint of ≥50% sustained reduction in eGFR, progression to end-stage kidney disease, or cardiovascular or renal death (hazard ratio 0.61).1 Dapagliflozin also reduced the incidence of the composite endpoint of cardiovascular death or hospitalization for heart failure (hazard ratio 0.71) and all-cause mortality (hazard ratio 0.69).1 The results were consistent among patients with and without type 2 diabetes mellitus, cause of chronic kidney disease, biological sex, race, and eGFR.1
Dispensing and Administration Precautions
Dapagliflozin is administered orally once daily.1 Dapagliflozin is commercially available as single-entity tablets that may be administered with or without food.1 Dapagliflozin is also available in fixed combination with saxagliptin (Qtern®) or extended-release metformin hydrochloride (Xigduo® XR); the fixed-combination dapagliflozin/saxagliptin tablets should be administered orally once daily in the morning, with or without food, and the fixed combination dapagliflozin/metformin tablets should be administered once daily in the morning with food to reduce the adverse GI effects of the metformin component.1, 53, 55 See the full prescribing information for additional administration instructions for the combination products.53, 55
If a dose of dapagliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1 If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.1
Store dapagliflozin tablets at 20 to 25ºC (excursions permitted between 15 and 30ºC).1
Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.1
Glycemic Control in Type 2 Diabetes Mellitus
For adults and pediatric patients 10 years of age and older, the recommended starting dosage of dapagliflozin for glycemic control in type 2 diabetes mellitus is 5 mg orally once daily.1 For additional glycemic control, the dosage can be increased to 10 mg orally once daily.1
For adult patients with heart failure, the recommended dosage of dapagliflozin is 10 mg orally once daily.1
For adult patients with chronic kidney disease, the recommended dosage of dapagliflozin is 10 mg orally once daily.1
Dapagliflozin/Metformin Hydrochloride Fixed-combination Therapy
Glycemic Control in Type 2 Diabetes Mellitus
When the commercially available fixed-combination preparation containing dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) is used for glycemic control in patients with type 2 diabetes mellitus, the recommended initial dosage is based on the patient's current regimen of dapagliflozin and/or metformin hydrochloride.53 Patients who are already receiving extended-release metformin hydrochloride in the evening and are switching to the fixed combination of dapagliflozin and metformin hydrochloride should skip their last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.53
For adult and pediatric patients 10 years of age and older not currently receiving dapagliflozin, the recommended initial dosage of the dapagliflozin component is 5 mg once daily in the morning.53 Dosage should be titrated gradually based on effectiveness and tolerability, up to a maximum daily dosage of 10 mg of dapagliflozin and 2 g of extended-release metformin hydrochloride.53
When the commercially available fixed-combination preparation containing dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) is used for heart failure in adult patients, the recommended dosage of the dapagliflozin component is 10 mg orally once daily.53
When the commercially available fixed-combination preparation containing dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) is used for chronic kidney disease in adult patients, the recommended dosage of the dapagliflozin component is 10 mg orally once daily.53
Dapagliflozin/Saxagliptin Fixed-combination Therapy
Glycemic Control in Type 2 Diabetes Mellitus
In patients not already receiving dapagliflozin therapy, the recommended initial dosage of the fixed combination of dapagliflozin and saxagliptin (Qtern®) is 5 mg of dapagliflozin and 5 mg of saxagliptin once daily in the morning.55 In patients who tolerate the initial dosage and require additional glycemic control, the dosage of the fixed combination may be increased to 10 mg of dapagliflozin and 5 mg of saxagliptin once daily in the morning.55
The fixed combination of dapagliflozin and saxagliptin should not be used in patients receiving concomitant therapy with a potent cytochrome P-450 (CYP) 3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).55
No dosage adjustment of dapagliflozin or dapagliflozin in fixed combination with saxagliptin is recommended for patients with mild, moderate, or severe hepatic impairment.1, 55 However, the benefits versus risks of treatment should be individually assessed in patients with severe hepatic impairment since the safety and efficacy of dapagliflozin have not been specifically studied in this population.1, 55
The fixed combination of dapagliflozin and extended-release metformin hydrochloride is not recommended in patients with hepatic impairment, as metformin use in patients with hepatic impairment has been associated with some cases of lactic acidosis.53
When dapagliflozin is used for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors, dosage adjustments are not needed in patients with an estimated glomerular filtration rate (eGFR) ≥45 mL/minute per 1.73 m2.1 Dapagliflozin is not recommended in such patients who have an eGFR less than 45 mL/minute per 1.73 m2, as it is likely to be ineffective in improving glycemic control in this setting.1
When dapagliflozin is used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and heart failure-related hospitalization, dosage adjustments are not needed in patients with an eGFR ≥25 mL/minute per 1.73 m2.1 If the eGFR falls below 25 mL/minute per 1.73 m2, dapagliflozin may be continued in this patient population.1 Initiation of dapagliflozin is not recommended in patients with an eGFR less than 25 mL/minute per 1.73 m2.1
Initiation of the fixed combination of dapagliflozin and extended-release metformin hydrochloride is not recommended in patients with an eGFR between 30 and 45 mL/minute per 1.73 m2.53 Assess the benefits versus risks of continuing therapy if the eGFR falls persistently below this level; dapagliflozin is likely to be ineffective in improving glycemic control and metformin initiation is not recommended in patients with an eGFR <45 mL/minute per 1.73 m2.53 The fixed combination of dapagliflozin and metformin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2, end-stage kidney disease, or in those receiving hemodialysis due to the metformin component.53
No dosage adjustment of the fixed combination of dapagliflozin and saxagliptin is needed in patients with an eGFR ≥45 mL/minute per 1.73 m2.55 The fixed combination of dapagliflozin and saxagliptin is contraindicated in patients with an eGFR <45 mL/minute per 1.73 m2.55
No adjustment of dapagliflozin dosage is necessary based solely on age.1
Use of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes mellitus significantly increases the risk of life-threatening diabetic ketoacidosis (DKA).1, 40, 41, 42 In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to patients who received placebo.1 Dapagliflozin is not indicated for glycemic control in patients with type 1 diabetes mellitus.1 Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis.1 Fatal cases of ketoacidosis have been reported in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin, in the postmarketing setting.1
An FDA review of reports submitted to FAERS from March 2013 to May 2015 identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes mellitus treated with SGLT2 inhibitors.50 All patients required hospitalization or treatment in the emergency department.50 Treatment was delayed in some cases because ketoacidosis was not immediately recognized as blood glucose concentrations were below those typically expected for the condition.50 No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified.50 Potential factors for the development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake (due to illness or surgery), pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.1, 50
Prior to initiating therapy with an SGLT2 inhibitor, consider patient factors that may predispose the patient to ketoacidosis such as insulin deficiency from any cause, reduced caloric intake, acute febrile illness, ketogenic diet, surgery, volume depletion, and alcohol abuse.1, 50 Risk factors for the development of ketoacidosis should be resolved prior to restarting dapagliflozin therapy.1, 50 Educate all patients on the signs and symptoms of ketoacidosis and instruct them to discontinue dapagliflozin and seek medical attention immediately if signs and symptoms occur.1 Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath.1 Ketoacidosis and glucosuria may persist longer than typically expected.1 Urinary glucose excretion persists for 3 days after discontinuing dapagliflozin; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of an SGLT2 inhibitor.1
Consider monitoring ketones in patients with type 1 diabetes mellitus and other patients who may be at risk of ketoacidosis.1 Evaluate for the presence of ketoacidosis in patients experiencing signs and symptoms consistent with severe metabolic acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration.40, 50 If ketoacidosis is suspected, discontinue dapagliflozin and promptly treat the patient if confirmed; monitor the patient for resolution of ketoacidosis prior to restarting the drug.1
Withhold dapagliflozin therapy if possible in temporary clinical situations that may predispose patients to ketoacidosis and resume therapy once the patient is clinically stable and able to resume oral intake.1 For patients who undergo surgery or procedures associated with prolonged fasting, withhold dapagliflozin therapy for at least 3 days if possible.1
Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels, if indicated by the clinical situation.1, 40, 42, 50
Volume Depletion and Renal Effects
Dapagliflozin can cause intravascular volume depletion, which may manifest as symptomatic hypotension or acute transient changes in serum creatinine concentration.1, 51, 55 Patients with impaired renal function (estimated glomerular filtration rate [eGFR] less than 60 mL/minute per 1.73 m2), geriatric patients, and patients receiving loop diuretics may be at an increased risk for volume depletion or hypotension.1, 53
There have been post-marketing reports of acute kidney injury, sometimes requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin.1, 55 FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in the FDA Adverse Event Reporting System (FAERS) between March 2013 and October 2015.51 Hospitalization for evaluation and management of kidney injury was warranted in most cases, and some cases required admission to an intensive care unit and dialysis.1, 51 In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating dapagliflozin therapy, and most patients' kidney function improved after stopping the drug.51 However, kidney injury may not be fully reversible in some situations and has led to death in some patients.51
Prior to initiating dapagliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant medications (e.g., diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]).51 Intravascular volume status should be assessed and corrected prior to initiating dapagliflozin.1
Patients should be monitored for signs and symptoms of hypotension and effects on renal function as clinically indicated after initiating therapy with dapagliflozin.1
Dapagliflozin may increase the risk of serious urinary tract infections; urosepsis and pyelonephritis have been reported with SGLT2 inhibitors, including dapagliflozin.1
FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014.50 In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment.50 The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).50
Patients should be monitored for signs and symptoms of urinary tract infections and treatment instituted promptly, if indicated.1, 50
Hypoglycemia with Concomitant Therapy with Insulin or Insulin Secretagogues
When dapagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1, 53, 55 Therefore, patients receiving dapagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1, 53, 55
Necrotizing Fasciitis of the Perineum
Necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and life-threatening bacterial infection requiring urgent surgical intervention, has been reported during postmarketing surveillance in males and females with type 2 diabetes mellitus receiving an SGLT2 inhibitor, including dapagliflozin.1, 60 Permanent disfigurement, prolonged hospitalization, disability, and complications from sepsis all may be associated with Fournier gangrene.59 Although diabetes mellitus is a risk factor for developing Fournier gangrene, this condition is still rare among patients with diabetes mellitus.60
FDA identified 12 cases of Fournier gangrene in patients taking an SGLT2 inhibitor reported in FAERS and the medical literature between March 2013 and May 2018.60, 61, 62 Since FDA's review, additional cases of Fournier gangrene have been reported.59 In the initial cases reviewed by FDA, the average time to onset of infection was 9.2 months (range: 7 days to 25 months) after initiation of therapy with an SGLT2 inhibitor.60 Some experts speculate that the variation in time to diagnosis of Fournier gangrene might be due to fluctuating glycemic control, microvascular complications, or an inciting event associated with SGLT2 inhibitors (e.g., urinary tract infection, mycotic infection, skin or mucosal breakdown due to pruritus).59 In all reported cases, hospitalization and surgery were required.60 Among these cases, some patients required multiple disfiguring surgeries, some developed complications (e.g., diabetic ketoacidosis, acute kidney injury, septic shock), and 1 patient died.60 In a review of other antidiabetic drugs (e.g., insulin, biguanides, sulfonylureas, dipeptidyl peptidase-4 inhibitors) over a period of more than 30 years, only 6 cases of Fournier gangrene were identified; all of theses cases occurred in men.60
Patients receiving dapagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise, should be assessed for necrotizing fasciitis.1, 60 If Fournier gangrene is suspected, dapagliflozin should be discontinued and immediate treatment with broad-spectrum antibiotics should be initiated; surgical debridement should be performed if necessary.1, 60 Blood glucose concentrations should be closely monitored; alternative antidiabetic therapy should be initiated to maintain glycemic control.1, 60
Dapagliflozin may increase the risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection).1, 11, 37 In glycemic control clinical trials, patients with a history of genital mycotic infections were more likely to develop such infections.1, 37 Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.1
SGLT2 inhibitors, including dapagliflozin, increase urinary glucose excretion and will result in false-positive urine glucose tests.1 In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors.1 Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.1
Initiation of therapy with an SGLT2 inhibitor, including dapagliflozin, may cause small increases in serum creatinine concentration and decreases in eGFR.1, 53, 55 In patients with normal or mildly impaired renal function, these changes in serum creatinine and eGFR generally occur within weeks of starting dapagliflozin therapy and then stabilize.1 Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury.1 The acute effect on eGFR reverses after dapagliflozin discontinuation, suggesting that acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin.1
When dapagliflozin is used in fixed combination with metformin hydrochloride, saxagliptin, or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) must be considered in addition to those associated with dapagliflozin.1, 53, 55
There is insufficient evidence with dapagliflozin in pregnant women to evaluate a drug-associated risk of major birth defects or miscarriage.1 Based on the results of reproductive and developmental toxicity studies in animals, dapagliflozin use during pregnancy may affect renal development and maturation.1 Adverse renal pelvic and tubule dilatations that were not fully reversible were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy at all doses tested, the lowest of which provided an exposure 15 times the 10-mg clinical dosage.1
Poorly controlled diabetes mellitus and untreated heart failure also are associated with risks to the mother and fetus, including DKA, preeclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity.1 The manufacturer states that dapagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.1
There are no data on the presence of dapagliflozin in human milk, the effects on the breast-fed child, or the effects on milk production.1 Dapagliflozin is distributed into milk in rats.1 Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.1 Use of dapagliflozin in women who are breast-feeding is not recommended.1
The safety and effectiveness of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older.1, 709 Use of dapagliflozin for this indication is supported by a 26-week, placebo-controlled trial with a 26-week extension in 157 pediatric patients 10 to 17 years of age with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus.1 The safety profile observed in the placebo-controlled trial in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults.1 Safety and efficacy of dapagliflozin have not been established in pediatric patients younger than 10 years of age for glycemic control in type 2 diabetes mellitus.1
Safety and efficacy of dapagliflozin have not been established in pediatric patients for other indications.1
Among patients with type 2 diabetes mellitus in 21 clinical trials, 1424 (24%) were 65 years of age or older and 207 (3.5%) were 75 years of age or older.1 Efficacy of dapagliflozin was similar for patients younger than 65 years of age and those 65 years of age or older after controlling for renal function (eGFR).1 Geriatric patients receiving dapagliflozin for glycemic control were more likely to experience hypotension compared with patients treated with placebo.1
In the DAPA-CKD, DAPA-HF, and DELIVER trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65 years of age.1 In the DAPA-CKD study, 42% of patients were older than 65 years of age.1 In the DAPA-HF study, 57% of patients were older than 65 years.1 In the DELIVER study, 76% of patients were older than 65 years.1
The benefits versus risks of using dapagliflozin or the fixed combination of dapagliflozin and saxagliptin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of these preparations have not been established in this population.1, 22, 55
Compared with values in healthy individuals, values for peak plasma dapagliflozin concentration were increased by 40% in patients with severe hepatic impairment (Child-Pugh class C) following a single 10-mg dose of the drug.1, 22 The AUC of dapagliflozin was increased by 67% in patients with severe hepatic impairment compared with that in healthy individuals.1, 22 Differences in peak plasma concentration and AUC of the drug in patients with mild or moderate hepatic impairment were not considered clinically important.1
Use of the fixed-combination preparation containing dapagliflozin and extended-release metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment.53
Safety and efficacy of dapagliflozin were evaluated in 2 randomized, placebo-controlled studies that included patients with type 2 diabetes mellitus and moderate renal impairment (eGFR of 45 to less than 60 mL/minute per 1.73 m2 or eGFR of 30 to less than 60 mL/minute per 1.73 m2).1, 35, 55 Patients with an eGFR of 45 to less than 60 mL/minute per 1.73 m2 experienced adverse effects similar to those observed in patients without renal impairment.1, 55, 71 Additionally, these patients also experienced a substantial reduction in glycosylated hemoglobin (hemoglobin A1c; HbA1c) compared with placebo.1 Patients in this study who received dapagliflozin therapy had a greater reduction in eGFR compared with those who received placebo; however, renal function generally increased back to baseline values after discontinuing treatment with dapagliflozin.1, 71 Efficacy and safety trials with dapagliflozin did not enroll patients with an eGFR less than 25 mL/minute per 1.73 m2.1
In patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment, geometric mean systemic exposures of dapagliflozin at steady state (20 mg once daily for 7 days) were 45%, 2.04-fold, or 3.03-fold higher, respectively, compared with patients with type 2 diabetes mellitus and normal renal function.1 Higher systemic exposure of dapagliflozin did not result in a correspondingly higher 24-hour urinary glucose excretion.1
Patients with renal impairment receiving dapagliflozin may be more likely to experience hypotension and may be at an increased risk for acute kidney injury.1 The impact of hemodialysis on dapagliflozin exposure is not known.1
Renal function should be assessed prior to initiation of therapy and then as clinically indicated.1 The manufacturer states that dapagliflozin therapy is not recommended for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors who have an eGFR of less than 45 mL/minute per 1.73 m2.1
The fixed combination of dapagliflozin and metformin hydrochloride is not recommended in patients with an eGFR of less than 45 mL/minute per 1.73 m2 and is contraindicated in patients with severe renal impairment (eGFR of less than 30 mL/minute per 1.73 m2).53 The fixed combination of dapagliflozin and saxagliptin is contraindicated in patients with moderate to severe renal impairment (eGFR of less than 45 mL/minute per 1.73 m2).55
The most common adverse effects of dapagliflozin monotherapy (≥5% of patients) reported in clinical studies include female genital mycotic infections, nasopharyngitis, and urinary tract infections.1
The most common adverse effects of dapagliflozin in combination with extended-release metformin hydrochloride (>5% of patients) reported in clinical trials include female genital mycotic infections, nasopharyngitis, urinary tract infection, diarrhea, and headache.53
The most common adverse effects of dapagliflozin in combination with saxagliptin (≥5% of patients) reported in clinical trials include upper respiratory tract infection, urinary tract infection, and dyslipidemia.55
The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9; cytochrome P450 (CYP)-mediated metabolism is a minor clearance pathway.1, 20
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Dapagliflozin and dapagliflozin 3- O -glucuronide, an inactive metabolite of dapagliflozin, did not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 in in vitro studies.1, 19 Dapagliflozin also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.1, 19
Drugs Affecting Efflux Transport Systems
Dapagliflozin 3- O -glucuronide is a substrate of organic anion transport (OAT) 3.1 Dapagliflozin and dapagliflozin 3- O -glucuronide did not meaningfully inhibit OAT1 or OAT3 active transporters; pharmacokinetic interactions are unlikely with substrates of OAT1 or OAT3.1
Dapagliflozin and dapagliflozin 3- O -glucuronide did not meaningfully inhibit organic cation transporter (OCT) 2; pharmacokinetic interactions are unlikely with substrates of OCT2.1
Dapagliflozin is a weak P-glycoprotein substrate, but does not meaningfully inhibit P-glycoprotein.1 The manufacturer states that dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered P-glycoprotein substrates.1
Insulin and Insulin Secretagogues
When dapagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Patients receiving dapagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1
Administration of a single dose of glimepiride (4 mg) with a single dose of dapagliflozin (20 mg) increased glimepiride AUC by 13%; no dosage adjustment for either drug is necessary.1
Concomitant use of dapagliflozin with loop diuretics may increase the incidence of symptomatic hypotension.1 Prior to initiation of dapagliflozin, volume status should be assessed and corrected in patients receiving diuretics.1 Patients should be monitored for signs and symptoms of symptomatic hypotension following initiation of dapagliflozin therapy.1
Administration of a single dose of bumetanide (1 mg) to individuals receiving dapagliflozin (10 mg once daily for 7 days) increased bumetanide area under the concentration-time curve (AUC) and peak plasma concentrations by 13%.1 The manufacturer states that no adjustment of dapagliflozin or bumetanide dosage is necessary.1
Administration of a single dose of digoxin (0.25 mg) with dapagliflozin (20 mg loading dose, then 10 mg once daily for 7 days) did not have a clinically meaningful effect on the AUC or peak plasma concentration of digoxin.1, 20, 26 The manufacturer states that no adjustment of digoxin dosage is necessary.
Administration of a single dose of hydrochlorothiazide (25 mg) with a single dose of dapagliflozin (50 mg) did not have a clinically important effect on the pharmacokinetics of hydrochlorothiazide or dapagliflozin.1, 20 The manufacturer states that no adjustment of dapagliflozin or hydrochlorothiazide dosage is necessary.1
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.1 Monitor serum lithium concentration more frequently during dapagliflozin initiation and dosage changes.1
Concurrent use of mefenamic acid (loading dose of 500 mg, then 250 mg every 6 hours for 14 doses) and a single dose of dapagliflozin (10 mg) increased dapagliflozin peak plasma concentration and AUC by 13 and 51%, respectively.1, 20, 24 No adjustment of dapagliflozin dosage is necessary.24
Administration of a single dose of metformin (1 g) with a single dose of dapagliflozin (20 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin or metformin. 1, 20, 25 No dosage adjustment for either drug is necessary.1, 25
Administration of a single dose of pioglitazone (45 mg) with a single dose of dapagliflozin (50 mg) decreased pioglitazone peak plasma concentration by 7%.1, 20 No dosage adjustment for either drug is necessary.1, 25
Administration of rifampin (600 mg once daily for 6 days) with a single dose of dapagliflozin (10 mg) decreased dapagliflozin peak plasma concentration and AUC by 7 and 22%, respectively.1, 20, 24 No adjustment of dapagliflozin dosage is necessary.1, 24
Administration of a single dose of simvastatin (40 mg) with a single dose of dapagliflozin (20 mg) increased simvastatin AUC by 19%.1, 26 The manufacturer states that no adjustment of dapagliflozin or simvastatin dosage is necessary.1
Administration of a single dose of sitagliptin (100 mg) with a single dose of dapagliflozin (20 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin or sitagliptin. 1 No dosage adjustment for either drug is necessary.1, 25
Administration of a single dose of valsartan (320 mg) with a single dose of dapagliflozin (20 mg) decreased peak plasma concentrations of valsartan and dapagliflozin by 6 and 12%, respectively, and increased valsartan AUC by 5%.1, 20, 26 The manufacturer states that no adjustment of dapagliflozin or valsartan dosage is necessary.1
Administration of a single dose of warfarin (25 mg) in individuals receiving dapagliflozin (20 mg loading dose, then 10 mg once daily for 7 days) did not have a clinically meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin.1, 20, 26 No warfarin dosage adjustment is necessary.1, 20
Dapagliflozin propanediol is a potent, competitive, reversible and highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), a transporter that is expressed in the proximal renal tubules and is responsible for most of the reabsorption of filtered glucose from the tubular lumen.1, 20 Through inhibition of SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion;1, 17, 30, 31 increased glucose excretion is independent of insulin secretion.36 After discontinuation of a 10-mg dose of dapagliflozin, the elevation in urinary glucose excretion approaches baseline in an average of about 3 days for the 10-mg dose.1, 53 Reduction of plasma glucose with dapagliflozin to induce glucosuria improves sensitivity of muscle to insulin;28, 29 however, glucosuria induction appears to be associated with a paradoxical increase in endogenous glucose production.28 Following dapagliflozin treatment, endogenous glucose production increased, accompanied by an increase in fasting plasma glucagon concentration.28 Dapagliflozin also reduces sodium reabsorption and increases delivery of sodium to the distal renal tubule.1 These actions may influence several physiological functions, including, but not restricted to, lowering of preload and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure, which is thought to be mediated by increased tubuloglomerular feedback.1
Following oral administration of dapagliflozin in the fasting state, peak plasma concentration is usually attained within 2 hours.1, 18, 19, 20, 23, 30 Following administration of a 10-mg dose, the absolute oral bioavailability of the drug is 78%.1, 27 Administration of dapagliflozin with a high-fat meal decreased peak plasma concentration by up to 50% and prolonged time to peak plasma concentration by approximately 1 hour, but did not alter the AUC.1, 20, 21 These changes are not considered clinically meaningful and dapagliflozin can be administered with or without food.1, 20, 21 The metabolism of dapagliflozin is principally eliminated by UGT1A9 with CYP-mediated metabolism a minor clearance pathway.1 Dapagliflozin is approximately 91% protein bound.1, 19 Following administration of a single 50-mg radiolabeled dose of dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively, with less than 2% in urine as parent drug1, 19 and approximately 15% in feces as parent drug.1, 20 The mean terminal elimination half-life of dapagliflozin was approximately 12.9 hours following a single oral 10-mg dose.1
Bioequivalence between the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) and each agent (dapagliflozin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo® XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established.53 Metformin hydrochloride immediate-release and extended-release tablets have a similar extent of absorption (AUC), but peak plasma concentrations of metformin following administration of the drug as extended-release tablets are approximately 20% lower than peak concentrations following administration of the same dose as immediate-release tablets.53
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 5 mg (of dapagliflozin)* | Dapagliflozin Tablets | |
10 mg (of dapagliflozin)* | Dapagliflozin Tablets | |||
Farxiga® | AstraZeneca |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 2.5 mg (of dapagliflozin) with Extended-release Metformin Hydrochloride 1 g | Xigduo® XR | AstraZeneca |
5 mg (of dapagliflozin) with Extended-release Metformin Hydrochloride 500 mg | Xigduo® XR | AstraZeneca | ||
5 mg (of dapagliflozin) with Extended-release Metformin Hydrochloride 1 g* | Dapagliflozin and Extended-release Metformin Hydrochloride Tablets | |||
Xigduo® XR | AstraZeneca | |||
10 mg (of dapagliflozin) with Extended-release Metformin Hydrochloride 500 mg | Xigduo® XR | AstraZeneca | ||
10 mg (of dapagliflozin) with Extended-release Metformin Hydrochloride 1 g* | Dapagliflozin and Extended-release Metformin Hydrochloride Tablets | |||
Xigduo® XR | AstraZeneca | |||
Tablets, film-coated | 5 mg (of dapagliflozin) with Saxagliptin 5 mg | AstraZeneca | ||
10 mg (of dapagliflozin) with Saxagliptin 5 mg | Qtern® | AstraZeneca |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions February 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. AstraZeneca Pharmaceuticals. Farxiga® (dapagliflozin) tablets prescribing information. Wilmington, DE; 2024 Jun.
2. Ferrannini E1, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care . 2010 Oct; 33:2217-24.
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