Dapagliflozin Propanediol Oral

Type 2 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.^{[1][2][3][15][32][34]} Dapagliflozin also is used in combination with other antidiabetic agents (e.g., metformin and/or a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione], a dipeptidyl peptidase-4 [DPP-4] inhibitor, a glucagon-like peptide [GLP-1] receptor agonist, insulin) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with dapagliflozin monotherapy.^{[1][4][5][6][7][8][9][10][12][13][16][52]} Dapagliflozin is commercially available in fixed combination with extended-release metformin hydrochloride,^[53] saxagliptin,^[55] or both extended-release metformin hydrochloride and saxagliptin.^[101] The fixed combination of dapagliflozin and extended-release metformin hydrochloride, dapagliflozin and saxagliptin, or dapagliflozin, saxagliptin, and extended-release metformin hydrochloride is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{[53][55][101]} The manufacturer states that the fixed-combination preparation containing dapagliflozin, saxagliptin, and extended-release metformin hydrochloride is intended only for patients currently taking metformin hydrochloride.^[101]

Dapagliflozin also is used as monotherapy or in fixed combination with extended-release metformin hydrochloride 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][70][704][705]} In addition, dapagliflozin is used to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with heart failure (New York Heart Association [NYHA] class II-IV) and reduced ejection fraction.^[1][70]

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).^{[698][704][705]} (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 (GLP-1) receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.^[698][704] Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.^[698][704] In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic classes with complementary mechanisms of action.^[698]

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.^[698][704] Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.^[704] In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.^[704]

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.^{[698][704][705][706]} When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.^[704] While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.^[698] Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^[698][704] For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.^[704][705] (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.^[704] GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). ^{[698][704][706]} (See Beneficial Effects on Renal Function under Uses: Type 2 Diabetes Mellitus.) In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.^[704]

The manufacturer states that dapagliflozin or the fixed combinations of dapagliflozin with extended-release metformin hydrochloride, saxagliptin, or both extended-release metformin hydrochloride and saxagliptin are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.^{[1][53][55][101]}

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 A_1c; HbA_1c) and in fasting and 2-hour postprandial plasma glucose concentrations.^[1][2][3] 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 HbA_1c concentrations of 7-10%.^[1][2][3] In the first study, HbA_1c 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 HbA_1c reductions to less than 7%, compared with approximately 32% of patients receiving placebo.^[1][2] In the second study, mean HbA_1c 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]

Combination Therapy

Clinical trials evaluating the safety and efficacy of the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo^® XR) in reducing HbA_1c 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] (See Description.) 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, a sulfonylurea, a thiazolidinedione, a 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 HbA_1c, 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 HbA_1c 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 HbA_1c compared with a reduction of 1.5, 1.2 or 1.4% in HbA_1c 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 HbA_1c, 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 HbA_1c 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 HbA_1c compared with a 0.3% HbA_1c reduction with placebo.^[1][5] In these patients, add-on therapy with dapagliflozin 5 or 10 mg resulted in HbA_1c 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 HbA_1c, fasting plasma glucose, and body weight.^[12]

In a study in patients with HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c, 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 HbA_1c 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 HbA_1c, 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, HbA_1c 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 (HbA_1c 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 HbA_1c 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 HbA_1c 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 (HbA_1c 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 HbA_1c, and a greater proportion of patients receiving this therapy achieved an HbA_1c 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 HbA_1c: 7.9%) already receiving concomitant dapagliflozin and metformin therapy, the addition of saxagliptin resulted in substantial reductions in HbA_1c.^[55][72] The combination of the 3 agents was well tolerated, and patients receiving therapy with all 3 agents had a reduction in HbA_1c 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 (HbA_1c 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 HbA_1c 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 HbA_1c 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][70][698][699][704][705]} 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][704][705]} 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]

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][706] 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][704][706]} Some experts state that the use of an SGLT2 inhibitor should be considered to reduce the risk of CKD progression, cardiovascular events, or both in patients with type 2 diabetes mellitus and diabetic kidney disease with albuminuria^† (an eGFR of at least 30 mL/minute per 1.73 m² and urinary albumin exceeding 30 mg/g creatinine, particularly urinary albumin exceeding 300 mg/g creatinine).^[706]

In the DECLARE-TIMI 58 study, 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 (ESRD), or death from renal or cardiovascular causes), which occurred in 4.3% of dapagliflozin-treated patients versus 5.6% of those receiving placebo.^[70] In a clinical study evaluating the use of another SGLT2 inhibitor, canagliflozin, in patients with type 2 diabetes mellitus, CKD (eGFR 30-89 mL/minute per 1.73 m²; mean 56.2 mL/minute per 1.73 m²), and albuminuria (urine albumin:creatinine ratio exceeding 300 but less than 5000 mg/g), canagliflozin therapy reduced the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure.^[100]

Reduction in Risk of Cardiovascular Death and Heart Failure-Related Hospitalization

Dapagliflozin is used to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with heart failure (NYHA class II-IV) and reduced ejection fraction.^[1][90]

In a double-blind, placebo-controlled study (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]) 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, approximately 4700 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 HbA_1c 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]

General

Volume depletion should be corrected before initiating dapagliflozin.^[1] In addition, renal function should be assessed prior to treatment and then as clinically indicated.^[1] (See Dosage and Administration: Special Populations.)

Administration

Dapagliflozin or the fixed combination of dapagliflozin and saxagliptin is administered orally once daily in the morning, with or without food.^[1][55] The fixed combination of dapagliflozin and extended-release metformin hydrochloride or dapagliflozin, saxagliptin, and extended-release metformin hydrochloride is administered once daily in the morning with food to reduce the adverse GI effects of the metformin hydrochloride component.^[53][101]

The fixed-combination tablets of dapagliflozin and extended-release metformin hydrochloride, dapagliflozin and saxagliptin, or dapagliflozin, extended-release metformin hydrochloride, and saxagliptin should be swallowed whole; tablets should not be crushed, cut, or chewed.^{[53][55][101]} Occasionally, inactive ingredients in the fixed-combination tablets containing extended-release metformin hydrochloride may be eliminated in feces as a soft mass that may resemble the original tablet.^[53][101]

If a dose of dapagliflozin, the fixed combination of dapagliflozin and extended-release metformin hydrochloride, or the fixed-combination of dapagliflozin and saxagliptin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.^[1][53][55] 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][53][55] If a dose of the fixed combination of dapagliflozin, extended-release metformin hydrochloride, and saxagliptin is missed and it is 12 hours or more until the next dose, the dose should be taken.^[101] If a dose if missed and it is less than 12 hours until the next dose, the missed dose should be skipped and the next dose taken at the usual time; patients should be advised not to take 2 doses at the same time.^[101]

Dosage

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.^[1]

Type 2 Diabetes Mellitus

Glycemic Control

The recommended initial dosage of dapagliflozin as monotherapy for the management of type 2 diabetes mellitus in adults is 5 mg once daily in the morning.^[1] If well tolerated, the dosage may be increased to 10 mg once daily in the morning in patients who require additional glycemic control.^[1]

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] For patients 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] 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]

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] (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes, in Saxagliptin 68:20.05.)

When the fixed-combination preparation containing dapagliflozin, saxagliptin, and extended-release metformin hydrochloride (Qternmet^® XR) is used in patients with type 2 diabetes mellitus, the recommended initial dosage is based on the patient's current antidiabetic drug regimen.^[101] For patients not currently receiving dapagliflozin, the recommended initial total daily dosage of the fixed combination is dapagliflozin 5 mg, saxagliptin 5 mg, and extended-release metformin hydrochloride 1 or 2 g once daily in the morning.^[101] Dosage should be titrated gradually based on effectiveness and tolerability, up to a maximum daily dosage of 10 mg of dapagliflozin, 5 mg of saxagliptin, and 2 g of extended-release metformin hydrochloride.^[101] The manufacturer states that the fixed-combination preparation containing dapagliflozin, saxagliptin, and extended-release metformin is intended only for patients currently taking metformin.^[101]

The fixed combination of dapagliflozin, saxagliptin, and extended-release metformin 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).^[101] (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes, in Saxagliptin 68:20.05.)

Reduction in Heart Failure-Related Hospitalization in Type 2 Diabetes Mellitus

The recommended dosage of dapagliflozin for the reduction of heart failure-related hospitalization in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors is 10 mg once daily.^[1][53]

Reduction in Cardiovascular Death and Heart Failure-Related Hospitalization

The recommended dosage of dapagliflozin for reduction in cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) and reduced ejection fraction is 10 mg once daily.^[1]

Special Populations

Dosage adjustments for dapagliflozin or the fixed combination of dapagliflozin and saxagliptin are not necessary in patients with mild, moderate, or severe hepatic impairment.^[1][55] Use of the fixed-combination preparations containing dapagliflozin and extended-release metformin hydrochloride or dapagliflozin, saxagliptin, and extended-release metformin hydrochloride should be avoided in patients with hepatic impairment.^[101]

When dapagliflozin is used for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors, dosage adjustments are not needed if patients have an estimated glomerular filtration rate (eGFR) of at least 45 mL/minute per 1.73 m².^[1] Dapagliflozin is not recommended in such patients who have an eGFR of 30 to less than 45 mL/minute per 1.73 m², and the drug is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m²) and in those with end-stage renal disease (ESRD) or undergoing dialysis.^[1]

When dapagliflozin is used to reduce the risk of heart failure-related hospitalization in patients with type 2 diabetes mellitus and cardiovascular disease or multiple cardiovascular risk factors, dosage adjustments are not needed in patients with an eGFR of at least 45 mL/minute per 1.73 m².^[1] There are insufficient data to support a dapagliflozin dosage recommendation in patients with an eGFR less than 45 mL/minute per 1.73 m²; dapagliflozin is contraindicated in patients with ESRD or undergoing dialysis.^[1]

When dapagliflozin is used to reduce the risk of cardiovascular death or heart failure-related hospitalization in patients with or without type 2 diabetes mellitus who have heart failure and a reduced ejection fraction, no dosage adjustment is needed in patients with an eGFR of at least 30 mL/minute per 1.73 m².^[1] There are insufficient data to support a dosage recommendation in patients with an eGFR less than 30 mL/minute per 1.73 m², and dapagliflozin is contraindicated in patients with ESRD or undergoing dialysis.^[1]

Dosage adjustments for the fixed combination of dapagliflozin and extended-release metformin hydrochloride or the fixed combination of dapagliflozin and saxagliptin are not necessary in patients with an eGFR of at least 45 mL/minute per 1.73 m².^[53][55] The fixed combination of dapagliflozin and metformin hydrochloride should not be used in patients with an eGFR of less than 45 mL/minute per 1.73 m².^[53][55] Use of the fixed combination of dapagliflozin and metformin hydrochloride is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m².^[53] The fixed combination of dapagliflozin and saxagliptin is contraindicated in patients with an eGFR of less than 45 mL/minute per 1.73 m².^[55]

No adjustment of dapagliflozin dosage is necessary based solely on age.^[1] In addition, dosage adjustment is not recommended based solely on sex, race, or body weight.^[1]

Contraindications

History of serious hypersensitivity reaction to dapagliflozin or any ingredient in the formulation.^[1][53][55]

Dapagliflozin is contraindicated in patients receiving the drug for glycemic control who have severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m²) without established cardiovascular disease or multiple cardiovascular risk factors.^[1]

Dapagliflozin is contraindicated in patients with end-stage renal disease (ESRD) or undergoing dialysis.^[1]

Warnings/Precautions

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 (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] (See Drug Interactions: Diuretics.) Intravascular volume status should be assessed and corrected prior to initiating dapagliflozin.^[1]

Acute kidney injury, sometimes requiring hospitalization and dialysis, has been reported in patients with type 2 diabetes mellitus receiving canagliflozin or dapagliflozin.^[1][55] FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in 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] Clinicians should consider temporarily discontinuing dapagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).^[51] Patients should be monitored for signs and symptoms of hypotension and effects on renal function as clinically indicated after initiating therapy with dapagliflozin.^[1] If patients develop acute kidney injury, dapagliflozin should be discontinued and appropriate treatment initiated for such injury.^[51]

Ketoacidosis in Patients with Diabetes Mellitus

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization.^{[1][39][40][41][42][50]} Fatal cases of ketoacidosis have been reported in patients receiving dapagliflozin.^[1] Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).^{[1][39][40][41][42][50]}

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015.^[41][50] DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication for use was not specified.^[39][40][50] The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days).^[50] No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified.^[50] In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted.^[39][50] In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported.^[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, clinicians should consider patient factors that may predispose the patient to ketoacidosis such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse.^[1][50]

Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration.^[39][40][50] For patients who undergo scheduled surgery, temporary discontinuation of dapagliflozin for at least 3 days prior to surgery should be considered.^[1][55] Clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in other clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).^[1][50] If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately.^[39][40] In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis.^[39] Risk factors for the development of ketoacidosis should be resolved prior to restarting dapagliflozin therapy.^[1][55]

Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations.^{[1][40][42][50]} Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.^{[1][39][42][50][55]}

Urosepsis and Pyelonephritis

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]

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to serious urinary tract infections such as a history of difficulty urinating or infections of the bladder, kidneys, or urinary tract.^[50] Patients should be monitored for urinary tract infections and treatment instituted if indicated.^[1][50]

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][101]} 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][101]} (See Drug Interactions: Antidiabetic Agents.)

Necrotizing Fasciitis of the Perineum

Necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, has been reported during postmarketing surveillance in men and women 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 agents should be initiated to maintain glycemic control.^[1][60]

Genital Mycotic Infections

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]

Risk of Bone Fracture

An increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, has been observed in patients receiving another drug in the SGLT2 inhibitor class (canagliflozin).^[43] (See Risk of Bone Fracture under Cautions: Warnings/Precautions, in Canagliflozin 68:20.18.) In a clinical trial in patients with renal impairment (eGFR of 30 to less than 60 mL/minute per 1.73 m²), a greater incidence of bone fractures was observed in patients receiving dapagliflozin compared with those receiving placebo.^[1][35][55] FDA is continuing to evaluate the risk of bone fracture with SGLT2 inhibitors.^[43]

Laboratory Test Interferences

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][101]} 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] Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury.^[1] (See Warnings/Precautions: Volume Depletion and Renal Effects, under Cautions.) 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]

Use of Fixed Combinations

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][101]}

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity), some serious, have been reported with dapagliflozin treatment.^[1] If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.^[1]

Specific Populations

Pregnancy

Data are lacking on the use of dapagliflozin in pregnant women.^[1] Based on the results of reproductive and developmental toxicity studies in animals, dapagliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.^[1] Poorly controlled diabetes mellitus and untreated heart failure also are associated with risks to the mother and fetus.^[1] The manufacturer states that dapagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.^[1]

Lactation

Dapagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.^[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]

Pediatric Use

Safety and efficacy of dapagliflozin have not been established in pediatric patients younger than 18 years of age.^[1]

Geriatric Use

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-HF study, 57% of patients were older than 65 years of age; safety and efficacy in these patients were similar to those in patients younger than 65 years of age.^[1]

Hepatic Impairment

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 area under the concentration-time curve (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 preparations containing dapagliflozin and extended-release metformin or dapagliflozin, saxagliptin, and extended-release metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment.^[53][101]

Renal Impairment

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 A_1c; HbA_1c) 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] 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][55]

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]

The impact of hemodialysis on dapagliflozin exposure is not known.^[1] (See Cautions: Contraindications.)

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; the drug is contraindicated in patients with severe renal impairment (eGFR less than 30 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]

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving dapagliflozin in clinical trials and more commonly than with placebo include female genital mycotic infection,^{[1][2][3][4][6][7][8]} nasopharyngitis,^{[1][2][3][5][6][7][8]} urinary tract infection,^{[1][2][3][4][5][6][8][33]} back pain,^[1][5][8] increased urination,^[1] male genital mycotic infection,^{[1][2][3][4][5][7]} nausea,^[1][4] dyslipidemia,^[1][4][8] constipation,^[1] discomfort with urination,^[1] and pain in extremity.^[1][8]

Adverse effects reported in at least 2% of patients receiving dapagliflozin in combination with metformin hydrochloride and more commonly than with placebo in combination with metformin hydrochloride include female genital mycotic infection,^[53] nasopharyngitis,^[53] urinary tract infection,^[53] diarrhea,^[53] headache,^[53] male genital mycotic infection,^[53] influenza,^[53] nausea,^[53] back pain,^[53] dizziness,^[53] cough,^[53] constipation,^[53] dyslipidemia,^[53] pharyngitis,^[53] increased urination,^[53] and discomfort with urination.^[53]

Adverse effects reported in at least 2% of patients receiving dapagliflozin in combination with saxagliptin and metformin hydrochloride include upper respiratory tract infection,^[55][101] urinary tract infection,^[55][101] dyslipidemia,^[55][101] headache,^[55][101] diarrhea,^[55][101] back pain,^[55][101] genital infection,^[55][101] and arthralgia.^[55][101]

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.^[1][20]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Dapagliflozin and dapagliflozin 3-O-glucuronide, an inactive metabolite of dapagliflozin, did not inhibit cytochrome P-450 (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 Affected by Organic Anion Transporter

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]

Drugs Affected by Organic Cation Transporter

Dapagliflozin and dapagliflozin 3-O-glucuronide did not meaningfully inhibit organic cation transporter (OCT) 2; pharmacokinetic interactions are unlikely with substrates of OCT2.^[1]

Drugs Affected by P-glycoprotein Transport

Dapagliflozin is a weak P-glycoprotein substrate, but does not meaningfully inhibit P-glycoprotein.^[1][19][20] The manufacturer states that dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered P-glycoprotein substrates.^[1]

Antidiabetic Agents

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]

Diuretics

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]

Bumetanide

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] (See also Drug Interactions: Diuretics.)

Digoxin

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.^[1]

Glimepiride

Administration of a single dose of glimepiride (4 mg) with a single dose of dapagliflozin (20 mg) increased glimepiride AUC by 13%;^[1][20] no dosage adjustment for either drug is necessary.^[1][25]

Hydrochlorothiazide

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] (See also Drug Interactions: Diuretics.)

Mefenamic Acid

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]

Metformin

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]

Pioglitazone

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]

Rifampin

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]

Simvastatin

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]

Sitagliptin

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]

Valsartan

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]

Voglibose

Concomitant administration of voglibose (0.2 mg three times daily; not commercially available in the US) with a single dose of dapagliflozin (10 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin.^[1]

Warfarin

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]

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 area under the concentration-time curve (AUC).^[1][20][21] These changes are not considered clinically meaningful and dapagliflozin can be administered with or without food.^[1][20][21] 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 drug^[1][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] The overall pharmacokinetics of dapagliflozin, saxagliptin, and metformin were not affected in a clinically relevant manner when administered in fixed combination (as Qternmet^® XR).^[101]

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.^{[1][38][53][54][55][56]}

When dapagliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).^{[1][53][55][101]}

Importance of informing patients of the potential risks and benefits of dapagliflozin and of alternative therapies.^[1][38] Importance of not using dapagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.^[1][38]

Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with dapagliflozin therapy in patients with diabetes mellitus (sometimes associated with illness or surgery among other risk factors).^[1][38][55] Importance of informing patients receiving dapagliflozin and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and of instructing patients to discontinue dapagliflozin and seek medical advice immediately should they experience any such signs or symptoms.^{[1][39][42][50][55]} Advise patients to use a ketone dipstick to check for ketones in their urine (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated (e.g., less than 250 mg/dL).^{[1][38][50][55]}

Importance of informing patients that symptomatic hypotension may occur with dapagliflozin and advising patients to report such symptoms to their clinician.^[1][38][55] Inform patients that dapagliflozin-induced dehydration may increase the risk of hypotension and changes in kidney function and that they should maintain adequate fluid intake.^[1][38][55]

Importance of informing patients that acute kidney injury has been reported with dapagliflozin therapy.^{[1][38][51][55]} Advise patients to seek medical attention immediately if they experience decreased urine output, or swelling of the legs or feet.^[51][55] Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue dapagliflozin in those settings.^[1][51][55]

Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with diabetes mellitus.^[1][55][60] Advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, in addition to fever (above 38°C) or malaise.^[1][55][60]

Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).^[1][38][55] Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g., rash or redness of the glans or foreskin of the penis).^{[1][38][53][55]} Advise patients of treatment options and when to seek medical advice.^[1][38][55]

Importance of informing patients of the potential for urinary tract infections, which may be serious, with dapagliflozin therapy.^{[1][38][50][55]} Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician if such signs and symptoms occur.^[1][50][55]

Importance of informing patients that due to the mechanism of action of dapagliflozin, patients taking the drug will test positive for glucose in their urine.^[1][55] Importance of not using urine glucose tests to monitor glycemic status while taking dapagliflozin.^[1] (See Laboratory Test Interferences under Cautions: Warnings/Precautions.)

Risk of serious hypersensitivity reactions, such as urticaria and angioedema.^[1][38][55] If signs or symptoms of such a reaction or angioedema occur, importance of discontinuing dapagliflozin and promptly informing clinician.^[1][38][55]

Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.^[1][38]

Importance of promptly seeking medical advice during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.^[1][38][56]

Importance of taking dapagliflozin exactly as directed by clinician.^[1][38] (See Dosage and Administration: Administration.)

Importance of women informing their clinicians immediately if they are or plan to become pregnant or plan to breast-feed.^[1][38]

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., severe kidney disease).^[1][38]

Importance of informing patients of other important precautionary information.^[1][38] (See Cautions.)

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.

†Use is not currently included in the labeling approved by the US Food and Drug Administration.

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