Rhea Dapagliflozin Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that improves glycemic control in patients with diabetes mellitus and provides cardio-renal benefits.
Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure. This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure, and lower preload and afterload, which may have beneficial effects on cardiac remodelling and preserve renal function. Other effects include an increase in hematocrit and reduction in body weight.
The cardio-renal benefits of dapagliflozin are not solely dependent on the blood glucose-lowering effect and not limited to patients with diabetes. In addition to the osmotic diuretic and related hemodynamic actions of SGLT2 inhibition, potential secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be mechanisms underlying the cardio-renal beneficial effects of dapagliflozin.
Dapagliflozin improves both fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood glucose and/or low GFR, dapagliflozin has a low propensity to cause hypoglycemia, as the amount of filtrated glucose is small and can be reabsorbed by SGLT1 and unblocked SGLT2 transporters. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta-cell function (HOMA-2) has been observed in clinical studies with dapagliflozin.
The majority of weight reduction is body-fat loss, including visceral fat, rather than lean tissue, or fluid loss as demonstrated by dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging.
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is greater than 1400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
General: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. This glucose elimination rate approached the maximum glucose excretion observed at 20 mg/day of dapagliflozin. Evidence of sustained glucose excretion was seen in patients with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume. Urinary volume increases in patients with type 2 diabetes mellitus treated with Dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from 0.33 mg/dL to 0.87 mg/dL. (See Figure 1.)

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Cardiac Electrophysiology: Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended dose) dapagliflozin in healthy subjects.
Clinical trial information - type 2 diabetes mellitus: More than 28000 patients have been included in 22 double blind controlled type 2 diabetes mellitus clinical studies conducted to evaluate the safety and efficacy of Dapagliflozin; more than 15000 patients in these studies were treated with Dapagliflozin.
Dapagliflozin has been studied as monotherapy and in combination with metformin (with or without a sulfonylurea), sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), sitagliptin (with or without metformin), saxagliptin and metformin, prolonged-release exenatide when initiated concomitantly with Dapagliflozin (on a background of metformin) or insulin (with or without other oral antidiabetic therapy).
Dedicated studies of the glycemic efficacy and safety of Dapagliflozin were performed in patients with type 2 diabetes and cardiovascular disease (CVD), with type 2 diabetes and hypertension and with type 2 diabetes and moderate renal impairment (see Pharmacology: Pharmacodynamics: Special populations as follows).
A large CV outcomes trial (DECLARE) assessed the effect of dapagliflozin on CV and renal outcomes in type 2 diabetes mellitus patients with or without established CV disease.
Clinical efficacy: Glycemic efficacy: Treatment with Dapagliflozin as monotherapy, as add-on combination therapy with metformin (with or without a sulfonylurea), sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), sitagliptin (with or without metformin), saxagliptin and metformin, insulin (with or without other oral antidiabetic therapy), or prolonged release exenatide when initiated concomitantly with dapagliflozin (on a background of metformin), produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 or week 28 (combination with exenatide study) in HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) (where measured), compared to control. Treatment with Dapagliflozin in concomitant initiation with saxagliptin as add-on to metformin produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control.
These clinically relevant glycemic effects were sustained in all long-term extensions up to 208 weeks. HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).
Additionally, at Week 24, clinically relevant and statistically significant reductions in mean changes from baseline in body weight were seen with Dapagliflozin combination treatments compared to control. Body-weight reductions were sustained in long-term extensions up to 208 weeks. In a dedicated clinical study, decrease in weight was mainly attributable to a reduction in body-fat mass as measured by DXA.
In two studies of Dapagliflozin 10 mg in type 2 diabetes patients with cardiovascular disease, statistically significant improvements in HbA1c and significant reductions in body weight and seated systolic blood pressure were seen at Week 24 in patients treated with Dapagliflozin 10 mg compared to those treated with placebo, and were sustained through Week 104.
In two studies of Dapagliflozin 10 mg in type 2 diabetes patients with hypertension, statistically significant reductions in mean seated systolic blood pressure were also seen in patients treated with Dapagliflozin 10 mg combined with other oral antidiabetic and antihypertensive treatments (an angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB] in one study and an ACEi or ARB plus one additional antihypertensive treatment in another study) compared to those treated with placebo at Week 12.
Dapagliflozin was evaluated at 10 mg once daily in 19 of 21 double-blind glycemic efficacy studies. Doses of dapagliflozin 2.5 mg and Dapagliflozin 5 mg were also evaluated in some of these studies; 2.5 mg was not consistently effective for glycemic control, and 10 mg had numerically better efficacy and comparable safety to Dapagliflozin 5 mg.
Monotherapy: A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes participated in two placebo-controlled studies to evaluate the efficacy and safety of monotherapy with Dapagliflozin.
In one monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study with a 78-week controlled, blinded, extension period. Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% to ≤10% were randomized to dapagliflozin 2.5 mg, Dapagliflozin 5 mg, or 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo in the morning only.
At Week 24, treatment with Dapagliflozin 10 mg QAM provided significant improvements in HbA1c and FPG compared with placebo (Table 1, Figure 2). Overall, the PM administration of Dapagliflozin had a comparable safety and efficacy profile to Dapagliflozin administered in the AM. Adjusted mean change from baseline in HbA1c and FPG was -0.61% and -27.0 mg/dL, respectively, at Week 102 in the QAM group for patients treated with Dapagliflozin 10 mg, and -0.17% and was -6.9 mg/dL, respectively, for patients treated with placebo based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients in the main cohort who were rescued or discontinued for lack of glycemic control at Week 24 (adjusted for baseline HbA1c) was higher for placebo (12.0%) than for Dapagliflozin 10 mg (0.0%). By Week 102 (adjusted for baseline HbA1c), more patients treated with placebo (44.0%) required rescue therapy than patients treated with Dapagliflozin 10 mg (35.0%). (See Table 1 and Figure 2.)

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Another 24-week study conducted evaluating dapagliflozin 1 mg, 2.5 mg and Dapagliflozin 5 mg monotherapy versus placebo also showed clinically relevant and statistically significant improvements in glycemic parameters and body weight.
Combination Therapy: Dapagliflozin was studied as initial combination with metformin, and as add-on to metformin, sulfonylurea (glimepiride), metformin plus a sulfonylurea, thiazolidinedione (pioglitazone), insulin (with or without other oral antidiabetic therapy), sitagliptin (with or without metformin), or saxagliptin plus metformin, and as concomitant initiation therapy with saxagliptin added to metformin, and as concomitant initiation therapy with exenatide added to metformin.
Combination therapy with metformin: Four studies were conducted in combination with metformin therapy. Two studies evaluated Dapagliflozin added to metformin as initial combination therapy, one study evaluated the effect of Dapagliflozin added to metformin in patients already on metformin, and one study evaluated the effect of Dapagliflozin added to metformin versus sulfonylurea added to metformin.
Initial Combination Therapy with Metformin: A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) participated in two active-controlled studies of 24-weeks duration to evaluate the efficacy and safety of initial therapy with Dapagliflozin 5 mg or 10 mg in combination with metformin extended-release formulation (XR).
In one study, 638 patients randomized to one of three treatment arms following a 1-week lead-in period received: Dapagliflozin 10 mg plus metformin XR (up to 2000 mg per day), Dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
The combination treatment of Dapagliflozin 10 mg plus metformin XR provided significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and significant reductions in body weight compared with metformin XR alone. (Table 2, Figures 3 and 4). Dapagliflozin 10 mg as monotherapy also provided significant improvements in FPG and significant reduction in body weight compared with metformin XR alone and was noninferior to metformin XR monotherapy in lowering HbA1c. The proportion of patients who were rescued or discontinued for lack of glycemic control during the 24-week double-blind treatment period (adjusted for baseline HbA1c) was higher for treatment with metformin XR plus placebo (13.5%) than for Dapagliflozin 10 mg plus placebo and Dapagliflozin 10 mg plus metformin XR (7.8%, and 1.4%, respectively). (See Table 2, Figures 3 and 4.)

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Another 24-week study evaluating Dapagliflozin 5 mg plus metformin XR showed clinically relevant and statistically significant improvements in glycemic parameters versus Dapagliflozin 5 mg monotherapy and metformin XR monotherapy.
Add-on to Metformin: A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study with a 78-week controlled, blinded extension period to evaluate Dapagliflozin in combination with metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 2.5 mg, Dapagliflozin 5 mg, or 10 mg, or placebo in addition to their current dose of metformin.
As add-on treatment to metformin, Dapagliflozin 10 mg provided significant improvements in HbA1c, and FPG, and significant reduction in body weight compared with placebo at Week 24 (Table 3). At Week 102, adjusted mean change from baseline in HbA1c (see Figure 5), FPG, and body weight was - 0.78%, -24.5 mg/dL, and -2.81 kg, respectively, for patients treated with Dapagliflozin 10 mg plus metformin and 0.02%, -10.4 mg/dL, and -0.67 kg for patients treated with placebo plus metformin based on the longitudinal repeated measures analysis excluding data after rescue (Figure 5). The proportion of patients who were rescued or discontinued for lack of glycemic control during the 24-week double-blind treatment period (adjusted for baseline HbA1c) was higher in the placebo plus metformin group (15.0%) than in the Dapagliflozin 10 mg plus metformin group (4.4%). By Week 102 (adjusted for baseline HbA1c), more patients treated with placebo plus metformin (60.1%) required rescue therapy than patients treated with Dapagliflozin 10 mg plus metformin (44.0%). (See Table 3 and Figure 5.)

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Active Glipizide-Controlled Study Add-on to Metformin: A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority study with a 156-week extension period to evaluate Dapagliflozin as add-on therapy to metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and Dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia. Rescue for lack of glycemic control was not available in this study through Week 104, but was available between Weeks 105 and 208.
At the end of the titration period, 87% of patients treated with Dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin led to a similar mean reduction in HbA1c from baseline to Week 52, compared with glipizide, thus demonstrating noninferiority (Table 4). Dapagliflozin treatment led to a significant mean reduction in body weight from baseline to week 52 (LOCF) compared with a mean increase in body weight in the glipizide group.
At Weeks 104 and 208, adjusted mean changes from baseline in HbA1c were -0.32% and -0.10%, and changes in body weight were -3.70 kg and -3.95 kg, respectively, for patients treated with Dapagliflozin; adjusted mean changes from baseline in HbA1c were -0.14% and 0.20%, respectively, and changes in body weight were 1.36 kg and 1.12 kg, respectively, for patients treated with glipizide based on the longitudinal repeated measures analysis (Figures 6 and 7). The percent of patients achieving weight loss of ≥5% (adjusted) at Weeks 104 and 208 were 23.8% and 51.0%, respectively, for patients treated with Dapagliflozin and 2.8% and 9.9%, respectively, for patients treated with glipizide.
By Weeks 52, 104, and 208, the proportion of patients who discontinued or were rescued for lack of glycemic control (adjusted for baseline HbA1c) were higher for glipizide plus metformin (3.6%, 21.6%, and 44.9%, respectively) than for Dapagliflozin plus metformin (0.2%, 14.5%, and 39.4%, respectively). At 52, 104, and 208 weeks, respectively, a significantly lower proportion of patients treated with Dapagliflozin (3.5%, 4.3%, and 5.0%) experienced at least one event of hypoglycemia, compared to glipizide (40.8%, 47.0%, and 50.0%). (See Table 4, Figures 6 and 7.)

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Add-on combination with other antidiabetic agents: Add-on Combination Therapy with a Sulfonylurea: A total of 597 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study with a 24-week extension period to evaluate Dapagliflozin in combination with glimepiride (a sulfonylurea).
Patients on at least half the maximum recommended dose of a glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to dapagliflozin 2.5 mg, Dapagliflozin 5 mg, or 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.
In combination with glimepiride, treatment with Dapagliflozin 10 mg provided significant improvement in HbA1c, FPG, 2-hour PPG, and significant reduction in body weight compared with placebo plus glimepiride at Week 24 (Table 5, Figure 8). At Week 48, adjusted mean change from baseline in HbA1c, FPG, and body weight were -0.73%, -28.8 mg/dL, and -2.41 kg, respectively, for patients treated with Dapagliflozin 10 mg plus glimepiride and -0.04%, 2.6 mg/dL, and -0.77 kg for patients treated with placebo plus glimepiride at Week 48 based on the longitudinal repeated measures analysis excluding data after rescue.
At Week 24, the proportion of patients who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher on placebo plus glimepiride (16.2%) than for Dapagliflozin 10 mg plus glimepiride (2.0%). By Week 48 (adjusted for baseline HbA1c), more patients on placebo plus glimepiride (52.1%) required rescue therapy than patients on Dapagliflozin 10 mg plus glimepiride (18.4%).
Add-on Combination Therapy with Metformin and a Sulfonylurea: A total of 218 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study with a 28-week extension period to evaluate Dapagliflozin in combination with metformin and a sulfonylurea. Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at least half maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to Dapagliflozin 10 mg or placebo. Dose-titration of Dapagliflozin or metformin was not permitted during the 24-week treatment period. Down-titration of sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted.
As add-on treatment to combined metformin and a sulfonylurea, treatment with Dapagliflozin 10 mg provided significant improvements in HbA1c and FPG and significant reductions in body weight compared with placebo at Week 24 (Table 5). Significant reduction in seated systolic blood pressure at Week 8 was also observed in patients treated with Dapagliflozin 10 mg compared to placebo. The effects in HbA1c, FPG and body weight observed at Week 24 were sustained at Week 52.
At Week 24, no patients treated with Dapagliflozin 10 mg combined with metformin and a sulfonylurea and 10 patients (9.3%) treated with placebo combined with metformin and a sulfonylurea were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c). By Week 52 (adjusted for baseline HbA1c) more patients on placebo combined with metformin and a sulfonylurea (42.7%) were rescued for lack of glycemic control than patients on Dapagliflozin (10.1%). No patient was discontinued from study medication due to inadequate glycemic control.
Add-on Combination Therapy with a Thiazolidinedione: A total of 420 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in this 24-week, placebo-controlled study with a 24-week extension period to evaluate Dapagliflozin in combination with pioglitazone (a thiazolidinedione) alone. Patients on a stable dose of pioglitazone of 45 mg/day (or 30 mg/day, if 45 mg/day not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 mg or 10 mg of Dapagliflozin or placebo in addition to their current dose of pioglitazone. Dose titration of Dapagliflozin or pioglitazone was not permitted during the study.
In combination with pioglitazone, treatment with Dapagliflozin 10 mg provided significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (Table 5, Figure 9) at Week 24. Treatment with Dapagliflozin 10 mg plus pioglitazone also led to a significant reduction in waist circumference compared with the placebo plus pioglitazone group. At Week 48, adjusted mean change from baseline in HbA1c, FPG, and body weight were -1.21%, -33.1 mg/dL, and 0.69 kg, respectively, for patients treated with Dapagliflozin 10 mg plus pioglitazone and - 0.54%, -13.1 mg/dL, and 2.99 kg for patients treated with placebo based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher in the placebo plus pioglitazone group (11.6%) than in the Dapagliflozin 10 mg plus pioglitazone group (3.7%) at Week 24. By Week 48 (adjusted for baseline), more patients treated with placebo plus pioglitazone (33.8%) required rescue therapy than patients treated with Dapagliflozin 10 mg plus pioglitazone (11.8%).
Add-on Combination Therapy with Insulin: A total of 808 patients with type 2 diabetes who have inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study with an 80-week extension period to evaluate Dapagliflozin as add-on therapy to insulin. Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior and on a maximum of two OADs including metformin, were randomized after completing a 2-week enrollment period to receive dapagliflozin 2.5 mg, Dapagliflozin 5 mg, or 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OADs were not allowed during the treatment phase, with the exception of decreasing OADs where there were concerns over hypoglycemia after cessation of insulin therapy.
In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, Dapagliflozin 10 mg dose provided significant improvement in HbA1c and mean insulin dose, and a significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (Table 5); the effect of Dapagliflozin on HbA1c was similar in patients on insulin alone and patients on insulin plus OADs.
At Weeks 48 and 104, adjusted mean changes from baseline in HbA1c were -0.93% and -0.71%, changes in FPG were -21.5 mg/dL and -18.2 mg/dL, and changes in body weight were -1.79 kg and -1.97 kg, respectively, for patients treated with Dapagliflozin 10 mg plus insulin; adjusted mean changes from baseline in HbA1c were and -0.43% and -0.06%, changes in FPG were -4.4 mg/dL and -11.2 mg/dL, and changes in body weight were -0.18 kg and 0.91 kg, respectively, for patients treated with placebo plus insulin (see Figure 10).
At Week 24, a significantly higher proportion of patients on Dapagliflozin 10 mg reduced their insulin dose by at least 10% compared to placebo. The proportion of patients who required up-titration of their insulin dose or discontinued due to lack of glycemic control (adjusted for baseline HbA1c) was higher for placebo plus insulin (29.2%) than for Dapagliflozin 10 mg plus insulin (9.7%). By Weeks 48 and 104, the insulin dose remained stable in patients treated with Dapagliflozin 10 mg at an average dose of 76 IU/day, but continued to increase (mean increase 10.5 IU and 18.3 IU, respectively, from baseline) in placebo-treated patients. By Weeks 48 and 104 (adjusted for baseline HbA1c), more patients on placebo treated with placebo required up-titration with insulin to maintain glycemic levels or discontinued due to lack of glycemic control (42.8% and 50.4%, respectively) compared with patients treated with Dapagliflozin 10 mg (15.3% and 25.5%, respectively). (See Tables 5a, 5b, Figures 8, 9 and 10.)

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Add-on to Sitagliptin Alone or in Combination with Metformin: A total of 452 patients with type 2 diabetes who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study with a 24-week extension period to evaluate Dapagliflozin in combination with sitagliptin (a DPP4 inhibitor) with or without metformin.
Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg/day) and within each stratum were randomized to either Dapagliflozin 10 mg plus sitagliptin 100 mg once daily or placebo plus sitaglipitin 100 mg once daily. Endpoints were tested for Dapagliflozin 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of Dapagliflozin, sitagliptin or metformin was not permitted during the study.
In combination with sitagliptin (with and without metformin), Dapagliflozin 10 mg provided significant improvements in HbA1c, HbA1c in patients with baseline HbA1c ≥8%, and FPG, and significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (Table 6). These improvements were also seen in the stratum of patients who received Dapagliflozin 10 mg plus sitagliptin alone (n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received Dapagliflozin 10 mg plus sitagliptin and metformin (n=113) compared with placebo plus sitagliptin with metformin (n=113) (Table 6).
At Week 48, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline, FPG, PPG, and body weight were -0.30%, -0.72%, -19.7 mg/dL, −43.0 mg/dL, and -2.03 kg, respectively, for patients treated with Dapagliflozin 10 mg plus sitagliptin with or without metformin, and 0.38%, 0.26%, 13.5 mg/dL,-12.1 mg/dL, and 0.18 kg for patients treated with placebo plus sitagliptin with or without metformin based on the longitudinal repeated measures analysis excluding data after rescue. At Week 48, for the stratum of patients without metformin, adjusted mean change from baseline in HbA1c for patients treated with Dapagliflozin 10 mg plus sitagliptin was 0.00% and placebo plus sitagliptin was 0.85%; and for the stratum of patients with metformin, adjusted mean change from baseline in HbA1c for patients treated with Dapagliflozin 10 mg plus sitagliptin was -0.44% and placebo plus sitagliptin was 0.15% based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients at Week 24 and Week 48 who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher for sitagliptin with or without metformin (40.5% and 56.5%, respectively) than for Dapagliflozin plus sitagliptin with or without metformin (19.5% and 32.6%, respectively). (See Table 6.)

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Concomitant Initiation of Saxagliptin and Dapagliflozin in Patients Inadequately Controlled on Metformin: A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycemic control on metformin alone (HbA1c ≥8% and ≤12%), participated in this 24-week randomized, double blind, active comparator-controlled superiority trial to compare the combination of saxagliptin and dapagliflozin added concurrently to metformin, versus saxagliptin (DPP4 inhibitor) or Dapagliflozin added to metformin. Patients were randomized to one of three double-blind treatment groups to receive saxagliptin 5 mg and Dapagliflozin 10 mg added to metformin XR, saxagliptin 5 mg and placebo added to metformin XR, or Dapagliflozin 10 mg and placebo added to metformin XR.
The saxagliptin and Dapagliflozin combination group achieved significantly greater reductions in HbA1c versus either saxagliptin group or Dapagliflozin group at 24 weeks. Forty-one percent (41%) of patients in the saxagliptin and Dapagliflozin combination group achieved HbA1c levels of less than 7% compared to 18% patients in the saxagliptin group and 22% patients in the Dapagliflozin group. (See Table 7.)

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The adjusted mean change in body weight at 24 weeks was -2.05 kg (95% CI [-2.52, -1.58]) in the saxagliptin and dapagliflozin plus metformin group and -2.39 kg (95% CI [-2.87, -1.91]) in the dapagliflozin plus metformin group. The adjusted mean change for body weight in the saxagliptin plus metformin group had no change 0.00 kg (95% CI [-0.48, 0.49]).
Add-on Therapy with Dapagliflozin in Patients Inadequately Controlled on Saxagliptin plus Metformin: A 24-week randomized, double-blind, placebo-controlled study compared the sequential addition of 10 mg Dapagliflozin to 5 mg saxagliptin and metformin to the addition of placebo to 5 mg saxagliptin (DPP4 inhibitor) and metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c ≥7% and ≤10.5%). 320 subjects were randomized equally into either the Dapagliflozin added to saxagliptin plus metformin treatment group or placebo plus saxagliptin plus metformin treatment group.
The group with Dapagliflozin sequentially added to saxagliptin and metformin achieved statistically significant (p-value <0.0001) greater reductions in HbA1c versus the group with placebo sequentially added to saxagliptin plus metformin group at 24 weeks (see Table 8).

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The proportion of patients achieving HbA1c <7.0% at Week 24 was higher in the Dapagliflozin plus saxagliptin plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin plus metformin group 12.4% (95% CI [7.0, 17.9]).
The adjusted changes from baseline at Week 24 in body weight were -1.91 kg (95% CI [-2.34, -1.48]), in the Dapagliflozin plus saxagliptin plus metformin group and -0.41 kg (95% CI [-0.86, -0.04]), in the placebo plus saxagliptin plus metformin group.
The effects in HbA1C, FPG and body weight observed at Week 24 were sustained at Week 52. Adjusted mean change from baseline in HbA1c, FPG, and body weight were -0.74% (95% CI [-0.90, -0.57]), -26.8 mg/dL (95% CI [-34.2, -19.4]) and -2.13 kg (95% CI [-2.70, -1.56]), respectively, for patients treated with Dapagliflozin 10 mg plus saxagliptin with metformin, and 0.07% (95% CI [-0.13, 0.27]), 10.2 mg/dL (95% CI [1.6, 18.8]) and -0.37 kg (95% CI [-1.01, 0.26]) for patients treated with placebo plus saxagliptin with metformin based on the longitudinal repeated measures analysis excluding data after rescue.
Concomitant Initiation of Dapagliflozin and Prolonged-Release Exenatide in Patients Inadequately Controlled on Metformin: A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥8.0 and ≤12.0%) on metformin alone (≥1,500 mg/day) participated in this 28-week randomized, double-blind, active-controlled trial to compare the concomitant initiation of Dapagliflozin 10 mg QD and prolonged-release exenatide 2 mg QW (GLP-1 receptor agonist) on a background of metformin, versus prolonged-release exenatide 2 mg QW alone and Dapagliflozin 10 mg QD alone, when added to metformin. Following a 1-week placebo lead-in period, patients were randomized equally to one of three double-blind treatment groups to receive either Dapagliflozin 10 mg and prolonged-release exenatide, Dapagliflozin 10 mg and placebo or prolonged-release exenatide and placebo. During the treatment period, patients continued on the same type and dose of metformin as when they entered the study. Randomization was stratified by glycated Hemoglobin A1c (HbA1c) at baseline (<9.0% or ≥9.0%).
The primary endpoint was the change in HbA1c from baseline to Week 28 (Figure 11). Compared to Dapagliflozin 10 mg alone and to prolonged-release exenatide alone, concomitant initiation of Dapagliflozin 10 mg and prolonged-release exenatide resulted in statistically significant reductions in HbA1c from baseline at Week 28 (Table 9). (See Figure 11 and Table 9.)

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Concomitant initiation therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in a greater proportion of patients achieving HbA1c ≤ 6.5% at Week 28 (30.3%) compared to dapagliflozin alone (10.4%) and prolonged-release exenatide alone (18.5%). The mean baseline HbA1c was 9.3%.
Cardiovascular and renal outcomes: Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicenter, randomized, double-blind, placebo-controlled clinical study conducted to determine the effect of Dapagliflozin compared with placebo on CV and renal outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension or current tobacco use) without having had a CV event at baseline (primary prevention) or established CV disease (secondary prevention). DECLARE was designed to ensure inclusion of a broad population.
Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. 8582 patients were randomized to Dapagliflozin 10 mg and 8578 to placebo and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female, 79.6% were White, 3.5% Black or African-American and 13.4% Asian. In total, 22.4% had had diabetes for ≤5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m².
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m², 7.4% of patients had eGFR <60mL/min/1.73 m² and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ration [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98.1%) used one or more diabetic medications at baseline, 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 agonist.
Approximately 81.3% of patients were treated with ACEi or ARB, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics and 10.5% with loop diuretics.
Results on primary and secondary endpoints are displayed in Figures 12 and 13. (See Figures 12 and 13.)

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Heart failure or cardiovascular death: Dapagliflozin 10 mg was superior to placebo in preventing the primary composite endpoint of hospitalization for heart failure or CV death (Hazard Ratio [HR] 0.83 [95% CI 0.73, 0.95]; p=0.005) (Figure 14).
Exploratory analyses of the single components suggest that the difference in treatment effect was driven by hospitalization for heart failure (HR 0.73 [95% CI 0.61, 0.88]) (Figure 12), with no clear difference in CV death (HR 0.98 [95% CI 0.82 to 1.17]).
The treatment benefit of Dapagliflozin over placebo was observed both in patients with and without established CV disease (Figure 13), with and without heart failure at baseline, and was consistent across key subgroups, including age, gender, renal function (eGFR), and region. (See Figure 14.)

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Major adverse cardiovascular events: Dapagliflozin demonstrated cardiovascular safety (tested as non-inferiority versus placebo for the composite of CV death, myocardial infarction or ischemic stroke [MACE]; one-sided p <0.001).
There were numerically fewer MACE events in the Dapagliflozin group compared with the placebo group (HR 0.93 [95% CI 0.84, 1.03]; p=0.172) (Figures 12 and 13).
Nephropathy Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, ESKD, renal or CV death (HR 0.76 [95% CI 0.67, 0.87]; nominal p<0.001, Figure 15). The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESKD and renal death (Figure 12), and was observed both in patients with and without CV disease (Figure 13). (See Figure 15.)

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When evaluating the renal components, there were 127 and 238 events of new or worsening nephropathy (sustained eGFR decrease, ESKD or renal death) in patients in the Dapagliflozin and placebo groups, respectively. The HR for time to nephropathy was 0.53 (95% CI 0.43, 0.66) for Dapagliflozin versus placebo.
Beneficial effects of Dapagliflozin on renal outcomes were also observed for albuminuria, e.g., In patients without pre-existing albuminuria, Dapagliflozin reduced the incidence of sustained albuminuria (UACR >30 mg/g) compared with placebo (HR 0.79 [95% CI 0.72, 0.87], nominal p<0.001).
In patients without pre-existing macroalbuminuria, new onset of macroalbuminuria (UACR >300 mg/g) was reduced in the Dapagliflozin group compared with the placebo group (HR 0.54 [95% CI 0.45, 0.65], nominal p<0.001).
In patients with pre-existing macroalbuminuria, regression of macroalbuminuria was greater in the Dapagliflozin group compared with the placebo group (HR 1.82 [95% CI 1.51, 2.20], nominal p<0.001).
The treatment benefit of Dapagliflozin over placebo was observed both in patients with and without existing renal impairment.
Supportive Studies: Dual Energy X-ray Absorptiometry in Type 2 Diabetic Patients: Due to the mechanism of action of Dapagliflozin, a study was done to evaluate body composition and bone mineral density in 182 patients with type 2 diabetes. Treatment with Dapagliflozin 10 mg added on to metformin over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg versus -0.88 kg); waist circumference (mean change from baseline: -2.51 cm versus -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline -2.22 kg versus -0.74 kg) rather than lean tissue or fluid loss. Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (change from baseline -322.6 cm³ versus -8.7 cm³) in an MRI substudy. Week 24 was analyzed using last observation carried forward (LOCF) analysis including data after rescue.
At Week 24, 2 patients (2.2%) in the placebo plus metformin group and no patients in the Dapagliflozin 10 mg plus metformin group were rescued for lack of glycemic control.
At Week 50 and Week 102, improvements were sustained in the Dapagliflozin 10 mg added on to metformin group compared with the placebo plus metformin group for body weight (adjusted mean change from baseline at Week 50: -4.39 kg versus -2.03 kg; adjusted mean change from baseline at Week 102: -4.54 kg versus -2.12 kg), waist circumference (adjusted mean change from baseline at Week 50: -5.0 cm versus -3.0 cm; adjusted mean change from baseline at Week 102: -5.0 cm versus -2.9 cm ), and body-fat mass as measured by DXA at Week 102 (mean change from baseline: -2.80 kg versus -1.46 kg) based on the longitudinal repeated measures analysis including data after rescue. In an MRI substudy at Weeks 50 and 102, Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (adjusted mean change from baseline at Week 50: -120.0 cm³ versus 61.5 cm³; adjusted mean change from baseline at Week 102: -214.9 cm³ versus -22.3 cm³).
The proportion of patients at Week 50 (unadjusted for baseline HbA1c) and Week 102 (adjusted for baseline HbA1c) who were rescued or discontinued for lack of glycemic control was higher in the placebo plus metformin group (6.6% and 33.2%, respectively) than in the Dapagliflozin 10 mg plus metformin group (2.2% and 13.5%, respectively).
In an extension of this study to Week 50, there was no change in bone mineral density (BMD) for the lumbar spine, femoral neck, or total hip seen in either treatment group (mean decrease from baseline for all anatomical regions <0.5%). There was also no change in BMD in either treatment group up to Week 102 (mean decrease from baseline for all anatomical regions <1.0%. There were no clinically meaningful changes in markers of bone resorption or bone formation.
Clinical safety: Hypoglycemia: The incidence of hypoglycemia as seen in controlled clinical studies with dapagliflozin in different combinations is shown in Table 10. (See Table 10.)

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Events Related to Decreased Renal Function: In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.041 mg/dL Dapagliflozin 10 mg versus -0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL Dapagliflozin 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the CV outcomes study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and UACR in the Dapagliflozin group compared with the placebo group. Fewer renal events (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the Dapagliflozin group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the Dapagliflozin group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the Dapagliflozin group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively.
Laboratory findings: Hematocrit: In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in Dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were 2.30% in the Dapagliflozin 10 mg group versus -0.33% in the placebo group. At Week 102, the mean changes were 2.68% versus -0.46%, respectively. By Week 24, hematocrit values >55% were reported in 1.3% of Dapagliflozin 10-mg-treated patients versus 0.4% of placebo-treated patients. Results were similar during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year).
Serum Inorganic Phosphorus: In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in Dapagliflozin 10-mg-treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL vs. -0.04 mg/dL, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in Dapagliflozin 10 mg group versus placebo at Week 24 (1.7% vs. 0.9%, respectively) and during the short-term plus long-term phase (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in Dapagliflozin-10-mg-treated patients compared with placebo-treated patients. Mean percent change from baseline at Week 24 for Dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; HDL cholesterol, 6.0% versus 2.7%; LDL cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. Mean percent change from baseline at Week 102 for Dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at Week 24.
In the CV outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.
Glycemic control in special populations: Use in Patients with Type 2 Diabetes and Hypertension: In two 12-week, placebo-controlled studies, a total of 1062 patients with inadequately controlled type 2 diabetes and hypertension were treated with Dapagliflozin 10 mg or placebo. Patients with inadequately controlled hypertension (seated systolic blood pressure ≥140 and <165 mmHg, seated diastolic blood pressure ≥85 and <105 mmHg, and a 24-hour mean blood pressure of ≥130/80 mmHg) despite preexisting stable treatment with an ACEi or ARB (alone [Study 1] or in combination with an additional antihypertensive [Study 2]) as well as inadequate glycemic control (HbA1c ≥7.0% and ≤10.5%) despite pre-existing stable treatment with OADs or insulin (alone or in combination) prior to entry, were eligible for these studies. During the studies, no adjustments in antidiabetic and antihypertensive medications were allowed. Across the 2 studies, 527 patients were treated with Dapagliflozin 10 mg and 535 with placebo. Patients treated with Dapagliflozin 10 mg or placebo also received the following medications for blood pressure control, which were balanced between treatment groups: ACEis (64%), ARBs (36%), thiazide diuretics (16%), calcium channel blockers (9%), and beta-blockers (6%).
At Week 12 for both studies, Dapagliflozin 10 mg plus usual treatment provided significant improvement in HbA1c and significant reduction in seated systolic blood pressure compared with placebo plus usual treatment (see Table 11). Consistent reductions were seen in mean 24-hour ambulatory systolic blood pressure in patients treated with Dapagliflozin 10 mg treatment compared with placebo. There was a small reduction in mean seated diastolic blood pressure in patients treated with Dapagliflozin 10 mg that was not statistically significant compared with placebo. (See Table 11.)

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Use in Patients with Type 2 Diabetes and Cardiovascular Disease: In two 24-week, placebo-controlled studies with 80-week extension periods, a total of 1887 patients with type 2 diabetes and CVD were treated with Dapagliflozin 10 mg or placebo. Patients with established CVD and inadequate glycemic control (HbA1c ≥7.0% and ≤10.0%), despite pre-existing, stable treatment with OADs or insulin (alone or in combination) prior to entry, were eligible for these studies and were stratified according to age (<65 years or ≥65 years), insulin use (no or yes), and time from most recent qualifying cardiovascular event (>1 year or <1 year prior to enrollment). Across the 2 studies, 942 patients were treated with Dapagliflozin 10 mg and 945 with placebo. Ninety-six percent (96%) of patients treated with Dapagliflozin 10 mg across the 2 studies had hypertension at entry, the majority for more than 10 years duration; the most common qualifying cardiovascular events were coronary heart disease (76%) or stroke (20%). Approximately 19% of patients received loop diuretics at entry and 15% had congestive heart failure (2% had NYHA Class III or higher). Approximately 37% of patients treated with Dapagliflozin 10 mg also received metformin plus one additional OAD (sulfonylurea, thiazolidinedione, DPP4-inhibitor, or other OAD with or without insulin at entry), 38% received insulin plus at least one OAD, and 18% received insulin alone.
At Week 24 for both studies, when added to pre-existing antidiabetic treatments, treatment with Dapagliflozin 10 mg provided significant improvement to coprimary endpoints of HbA1c and composite clinical benefit compared with placebo. Composite clinical benefit was defined as the proportion of patients with an absolute drop from baseline of 0.5% in HbA1c, and a relative drop from baseline of at least 3% in total body weight, and an absolute drop from baseline of at least 3 mmHg in seated SBP (Table 12). Significant reductions in total body weight and seated systolic blood pressure were also seen in patients treated with Dapagliflozin 10 mg compared with placebo.
At Week 52 and Week 104 for Study 1, adjusted mean change from baseline in HbA1c, seated systolic blood pressure, and adjusted percent change from baseline in body weight were -0.44% and -0.41%, -3.40 mmHg and -2.64 mmHg, and -2.89% and -3.53%, respectively, for patients treated with Dapagliflozin 10 mg plus usual treatment based on the longitudinal repeated measures analysis. Corresponding numbers for patients treated with placebo plus usual treatment were 0.22% and 0.50%, 0.18 mmHg and 1.54 mmHg, and -0.29% and -0.02%. At Week 52 and Week 104, percent composite clinical benefit was still higher in the Dapagliflozin 10 mg group (6.6% and 3.8%) than in the placebo group (0.7% and 0.5%).
At Week 24, Week 52, and Week 104 for Study 1, the proportion of patients who were rescued for lack of glycemic control (adjusted for baseline HbA1c) was higher in the placebo plus usual treatment group (24.0%, 51.8%, and 57.3%, respectively) than in the Dapagliflozin 10 mg plus usual treatment group (7.9%, 24.6%, and 31.8%, respectively).
At Week 52 and Week 104 for Study 2, adjusted mean change from baseline in HbA1c, seated systolic blood pressure, and adjusted percent change from baseline in body weight were -0.47% and -0.37%, -3.56 mmHg and -1.96 mmHg, and -3.20% and -3.51%, respectively, for patients treated with Dapagliflozin 10 mg plus usual treatment based on the longitudinal repeated measures analysis. Corresponding numbers for patients treated with placebo plus usual treatment were 0.03% and -0.18%, -0.91 mmHg and -0.37 mmHg, and -1.12% and -0.65%. At Week 52 and Week 104, percent composite clinical benefit was still higher in the Dapagliflozin 10 mg group (10.6% and 4.2%) than in the placebo group (3.1% and 1.1%).
At Week 24, Week 52, and Week 104 for Study 2, the proportion of patients who were rescued for lack of glycemic control (adjusted for baseline HbA1c) was higher in the placebo plus usual treatment group (22.3%, 43.6%, and 50.5%, respectively) than in the Dapagliflozin 10 mg plus usual treatment group (7.6%, 18.7%, and 27.5%, respectively). (See Table 12.)

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At Week 24, patients treated with Dapagliflozin 10 mg in the predefined age groups (<65 and ≥65 years of age) also showed significant improvements in the coprimary endpoints of HbA1c and composite clinical benefit compared with placebo in both studies. A significant reduction in total body weight was also seen in both age groups and a significant reduction of seated SBP in patients <65 years treated with Dapagliflozin 10 mg compared with placebo at Week 24. These effects were maintained at Week 52 and Week 104.
The safety profile of Dapagliflozin in these studies was consistent with that of Dapagliflozin in the general clinical study population through 104 weeks of treatment (see Adverse Reactions).
Use in Patients with Type 2 Diabetes and Renal Impairment: Patients with Mild Renal Impairment (eGFR ≥60 to <90 mL/min/1.73 m²): In the clinical trial program more than 3000 patients with mild renal impairment were treated with dapagliflozin. Efficacy was assessed in a pooled analysis across 9 clinical studies consisting of 2226 patients with mild renal impairment. The mean change from baseline in hemoglobin A1c (HbA1c) and the placebo-corrected mean HbA1c change at 24 weeks was -1.03% and -0.54%, respectively, for Dapagliflozin 10 mg (n=562). The safety profile in patients with mild renal impairment is similar to that in the overall population.
Patients with Moderate Renal Impairment (eGFR 30 to <60 mL/min/1.73 m²): The glycemic efficacy and safety of Dapagliflozin was evaluated in two dedicated studies of patients with moderate renal impairment and in two subgroup analyses of pooled clinical studies.
In a randomized, double blind, placebo-controlled trial a total of 321 adult patients with type 2 diabetes mellitus and eGFR ≥45 to <60 mL/min/1.73 m² (moderate renal impairment subgroup CKD 3A), with inadequate glycemic control on current treatment regimen, were treated with Dapagliflozin 10 mg or placebo. At Week 24, Dapagliflozin 10 mg (n=159) provided significant improvements in HbA1c, FPG, Body Weight and SBP compared with placebo (n=161) (Table 13). The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change was -0.37% and -0.34%, respectively. The mean change from baseline in FPG and the placebo-corrected mean FPG was -21.46 mg/dL and -16.59 mg/dL, respectively. The mean body weight reduction (percentage) and the placebo-corrected mean body weight reduction was -3.42% and -1.43%, respectively. The mean reduction in seated systolic blood pressure (SBP) and the placebo-corrected mean reduction in SBP was -4.8 mmHg and -3.1 mmHg, respectively. (See Table 13.)

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The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (Dapagliflozin: -3.39 mL/min/1.73 m² and placebo: -0.90 mL/min/1.73 m²). At 3 weeks after termination of Dapagliflozin, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (Dapagliflozin: 0.57 mL/min/1.73 m² and placebo: -0.04 mL/min/1.73 m²).
Efficacy in patients with moderate renal impairment was assessed in a pooled analysis across 9 clinical studies (366 patients, 87% with eGFR ≥45 to <60 mL/min/1.73 m²); this pool did not include the two dedicated studies of diabetic patients with moderate renal impairment. The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change at 24 weeks was -0.87% and -0.39%, respectively, for Dapagliflozin 10 mg (n=85).
Safety in patients with moderate renal impairment was assessed in a pooled analysis of 12 clinical studies (384 patients, 88% with eGFR ≥45 to <60 mL/min/1.73 m²); this pool did not include the two dedicated studies of diabetic patients with moderate renal impairment. At Week 24, safety was similar to that seen in the overall program of clinical studies except for a higher proportion of patients reporting at least one event related to renal impairment or failure (7.9% Dapagliflozin 10 mg versus 5.6% placebo). Of these events, increased serum creatinine was the most frequently reported (6.7% Dapagliflozin 10 mg versus 2.8% placebo). Increases in mean parathyroid hormone (PTH) and serum phosphorus observed with Dapagliflozin in the overall program of clinical studies were also seen in the pooled analysis. No imbalance in bone fractures was observed in this analysis. In the short-term plus long-term safety pool up to 102 weeks, the safety profile remained similar.
The efficacy and safety of Dapagliflozin was also assessed in a study of 252 diabetic patients with eGFR ≥30 to ≤60 mL/min/1.73 m² (moderate renal impairment subgroup CKD 3A and CKD 3B). Dapagliflozin treatment did not show a significant placebo corrected change in HbA1c in the overall study population (CKD 3A and CKD 3B combined) at 24 weeks. In additional analysis of the subgroup CKD 3A, Dapagliflozin 10 mg (n=32) provided a placebo-corrected mean HbA1c change at 24 weeks of -0.33%. At Week 52, Dapagliflozin was associated with changes from baseline in mean eGFR Dapagliflozin 10 mg -4.46 mL/min/1.73 m² and placebo -2.58 mL/min/1.73 m²). At Week 104, these changes persisted (eGFR: Dapagliflozin 10 mg -3.50 mL/min/1.73 m² and placebo -2.38 mL/min/1.73 m²). With Dapagliflozin 10 mg, this eGFR reduction were evident at Week 1 and remained stable through Week 104, while placebo-treated patients had a slow continuous decline through Week 52 that stabilized through Week 104.
At Week 52 and persisting through Week 104, greater increases in mean PTH and serum phosphorus were observed in this study with Dapagliflozin 10 mg compared to placebo, where baseline values of these analytes were higher. Elevations of potassium of ≥6 mEq/L were more common in patients treated with placebo (12.0%) than those treated with Dapagliflozin 5 mg and 10 mg (4.8% for both groups) during the cumulative 104-week treatment period. The proportion of patients discontinued for elevated potassium, adjusted for baseline potassium, was higher for the placebo group (14.3%) than for the Dapagliflozin groups (6.9% and 6.7% for the 5 mg and 10 mg groups, respectively).
Overall, there were 13 patients with an adverse event of bone fracture reported in this study up to Week 104 of which 8 occurred in the Dapagliflozin 10 mg group, 5 occurred in the Dapagliflozin 5 mg group, and none occurred in the placebo group. Eight (8) of these 13 fractures were in patients who had eGFR 30 to 45 mL/min/1.73 m² and 10 of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the site of fracture. No imbalance in bone fractures was observed in the safety analysis of the 12-study pool data and no bone fractures were reported in the dedicated study of patients with eGFR ≥45 to <60 mL/min/1.73 m² (CKD 3A).
Use in elderly patients with type 2 diabetes: A total of 2403 (26%) of 9339 treated patients with type 2 diabetes mellitus were 65 years and older and 327 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies of Dapagliflozin assessing the safety and efficacy of Dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), there was no conclusive evidence suggesting that age is an independent factor affecting efficacy. Overall, the proportion of patients reporting adverse events was consistent between those ≥65 and <65 years of age.
Clinical trial information - heart failure: Clinical efficacy: Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%) to determine the effect of dapagliflozin compared with placebo, when added to background standard of care therapy, on the incidence of CV death and worsening heart failure.
Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and followed for a median of 18 months. The mean age of the study population was 66 years, 77% were male, 70% White, 5% Black or African-American and 24% Asian.
At baseline, 67.5% patients were classified as NYHA class II, 31.6% class III and 0.9% class IV, median LVEF was 32%, 42% of the patients in each treatment group had a history of type 2 diabetes mellitus, and an additional 3% of the patients in each group were classified as having type 2 diabetes mellitus based on a HbA1c ≥6.5% at both enrollment and randomization.
Patients were on standard of care therapy; 94% of patients were treated with ACEi, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic and 26% had an implantable device (with defibrillator function).
Patients with eGFR ≥30 mL/min/1.73 m² at enrollment were included in the study. The mean eGFR was 66 mL/min/1.73 m², 41% of patients had eGFR <60mL/min/1.73 m² and 15% had eGFR <45 mL/min/1.73 m².
The DAPA-HF outcomes study compared dapagliflozin versus placebo in a population representative of that found in clinical practice. The overall study objective was to determine whether dapagliflozin prevents cardiovascular death and worsening heart failure, and if dapagliflozin improves heart failure symptoms.
Cardiovascular death and worsening heart failure: Dapagliflozin 10 mg was superior to placebo in preventing CV death and worsening heart failure, with consistent treatment effect on primary and secondary endpoints.
Dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (HR 0.74 [95% CI 0.65, 0.85]; p<0.0001). The number needed to treat per year was 26 (95% CI 18, 46). The dapagliflozin and placebo event curves separated early and continued to diverge over the study period (Figure 16). (See Figure 16.)

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All three components of the primary composite endpoint individually contributed to the treatment effect (Figure 17). There were few urgent heart failure visits. Dapagliflozin also reduced the incidence of cardiovascular death or hospitalization for heart failure (HR 0.75 [95% CI 0.65, 0.85], p<0.0001). (See Figure 17.)

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Dapagliflozin also reduced the total number of events of hospitalizations for heart failure (first and recurrent) and cardiovascular death; there were 567 events in the dapagliflozin group versus 742 events in the placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).
The treatment benefit of dapagliflozin was observed in heart failure patients both with type 2 diabetes mellitus and without diabetes (Figure 18). (See Figure 18.)

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The treatment benefit of dapagliflozin over placebo on the primary endpoint was also consistent across other key subgroups (Figure 19). (See Figure 19.)

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Patient reported outcome - heart failure symptoms: The treatment effect of dapagliflozin on heart failure symptoms was assessed by the Total Symptom Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), which quantifies heart failure symptom frequency and severity, including fatigue, peripheral edema, dyspnea and orthopnea. The score ranges from 0 to 100, with higher scores representing better health status.
Treatment with dapagliflozin resulted in a statistically significant and clinically meaningful benefit over placebo in heart failure symptoms, as measured by change from baseline to Month 8 in the KCCQ-TSS, (Win Ratio 1.18 [95% CI 1.11, 1.26]; p<0.0001). Both symptom frequency and symptom burden contributed to the results. Benefit was seen both in improving heart failure symptoms and in preventing deterioration of heart failure symptoms.
In responder analyses, the proportion of patients with a clinically meaningful improvement on the KCCQ-TSS from baseline at 8 months, defined as 5 points or more, was higher for the dapagliflozin treatment group compared with placebo. The proportion of patients with a clinically meaningful deterioration, defined as 5 points or more, was lower for the dapagliflozin treatment group compared to placebo. The benefits observed with dapagliflozin remained when applying more conservative cut-offs for larger clinically meaningful change (Table 14). (See Table 14.)

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Nephropathy: There were 28 and 39 events of the composite of confirmed sustained ≥50% eGFR decrease, ESKD, or renal death in patients in the dapagliflozin and placebo groups, respectively, (HR 0.71 [95% CI 0.44, 1.16]).
All-cause mortality: The incidence of all-cause mortality was lower in the dapagliflozin treatment group compared with placebo (HR 0.83; [95% CI 0.71, 0.97], Figure 17).
Clinical trial information - chronic kidney disease: Clinical efficacy: The Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD) was an international, multicenter, event-driven, randomized, double-blind, parallel-group, placebo-controlled study comparing dapagliflozin with placebo, when added to background standard of care therapy, in chronic kidney disease (CKD) patients with eGFR ≥25 to ≤75 mL/min/1.73 m² and albuminuria (urine albumin creatinine ratio [UACR] ≥200 and ≤5000 mg/g). The primary objective was to determine the effect of dapagliflozin compared with placebo in reducing the incidence of the composite endpoint of ≥50% sustained decline in eGFR, end stage kidney disease (ESKD) (defined as sustained eGFR <15 mL/min/1.73 m², chronic dialysis treatment or receiving a renal transplant), CV or renal death. A total of 4304 patients were randomised to dapagliflozin 10 mg (N=2152) or placebo (N=2152) once daily and followed for a median of 28.5 months. Treatment was continued if eGFR fell to levels below 25 mL/min/1.73 m² during the study and could be continued in cases when dialysis was needed.
At baseline, mean eGFR was 43.1 mL/min/1.73 m² and median UACR was 949.3 mg/g, 44.1% of patients had eGFR 30 to <45 mL/min/1.73 m² and 14.5% had eGFR <30 mL/min/1.73 m². 67.5% of the patients had type 2 diabetes mellitus.
Patients were on standard of care (SOC) therapy; 97.0% of patients were treated with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).
The mean age of the study population was 61.8 years, 66.9% were male, 53.2% White, 4.4% Black or African-American, and 34.1% Asian.
Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, reaching ESKD, CV or renal death (HR 0.61 [95% CI 0.51, 0.72]; p<0.0001). The number needed to treat per 27 months was 19 (95% CI 15, 27). Based on the Kaplan-Meier plot, the dapagliflozin and placebo event curves began to separate early (4 months) and continued to diverge over the study period (Figure 20). (See Figure 20.)

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All four components of the primary composite endpoint individually contributed to the treatment effect (Figure 21). Dapagliflozin also reduced the incidence of the composite endpoint of ≥50% sustained decline in eGFR, ESKD or renal death (HR 0.56 [95% CI 0.45, 0.68], p<0.0001), the composite endpoint of CV death and hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089), and all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035). (See Figure 21.)

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The treatment effect of dapagliflozin was consistent in chronic kidney disease patients with type 2 diabetes mellitus and without diabetes (Figure 22). (See Figure 22.)

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The treatment benefit of dapagliflozin over placebo on the primary composite endpoint was consistent across key subgroups (Figure 23). (See Figure 23.)

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The treatment benefit of dapagliflozin was also observed for exploratory endpoints; A greater reduction in UACR was demonstrated for dapagliflozin compared with placebo. The effect was observed as early as 14 days and was maintained throughout the study. At 36 months, the adjusted mean percent change from baseline in UACR (mg/g) was -41% in patients treated with dapagliflozin and -20% in patients treated with placebo, with a difference between treatment groups of -26.3% ([95% CI -36.8, -14.0], nominal p=0.0001).
The incidence of doubling of serum creatinine since the most recent laboratory measurement (an evaluation of acute worsening in kidney function), was reduced in the dapagliflozin group compared with the placebo group (HR 0.68 [95% CI 0.49, 0.94], nominal p=0.0187).
Pharmacokinetics: Absorption: Dapagliflozin is rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C_max) are usually attained within 2 hours after administration in the fasted state. The C_max and AUC values increased proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreased dapagliflozin C_max by up to 50% and prolonged T_max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (eg, renal or hepatic impairment).
Metabolism: Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to glucose by a carbon-carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t_1/2) for dapagliflozin was 12.9 hours following a single oral dose of Dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma, accounting for 42% (based on AUC [0-12 hour]) of total plasma radioactivity, similar to the 39% contribution by parent drug. Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.
Elimination: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After administration of 50 mg [14C]-dapagliflozin dose, 96% is recovered; 75% in urine and 21% in feces. In feces, approximately 15% of the dose is excreted as parent drug.
Special Populations: No dosage adjustments based on pharmacokinetic analyses are recommended for mild, moderate and severe renal impairment; mild, moderate and severe hepatic impairment; age; gender; race; and body weight.
Renal Impairment: At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes and mild, moderate, or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60%, and 87% higher, respectively, than those of patients with type 2 diabetes and normal renal function. At dapagliflozin 20 mg once-daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal-glucose clearance or 24-hour glucose excretion. The renal-glucose clearance and 24-hour glucose excretion were lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function, and 85, 52, 18, and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. The impact of hemodialysis on dapagliflozin exposure is not known. The effect of reduced renal function on systemic exposure was evaluated in a population pharmacokinetic model. Consistent with previous results, model predicted AUC was higher in patients with chronic kidney disease compared with patients with normal renal function, and was not meaningfully different in chronic kidney disease patients with type 2 diabetes mellitus and without diabetes.
Hepatic Impairment: For dosing recommendations for patients with moderate or severe hepatic impairment see Special Populations: Patients with Hepatic Impairment under Dosage & Administration. A single-dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between patients with hepatic impairment compared to healthy subjects. In patients with mild or moderate hepatic impairment, mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean C_max and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively. No dose adjustment is required for patients with severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population.
Age: No dosage adjustment for dapagliflozin from the dose of 10 mg once daily is recommended on the basis of age. The effect of age (young: ≥18 to <40 years [n=105] and elderly: ≥65 years [n=224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥40 to <65 years using data from healthy subject and patient studies). The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group (90% CI; 87.9, 92.2%) and 25% higher in elderly patients compared to the reference group (90% CI; 123, 129%). These differences in systemic exposure were considered to not be clinically meaningful.
Pediatric and adolescent patients: Pharmacokinetics in the pediatric and adolescent population have not been studied.
Gender: No dosage adjustment from the dose of 10 mg once daily is recommended for dapagliflozin on the basis of gender. Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUCss in females (n=619) was estimated to be 22% higher than in males (n=634) (90% CI; 117,124).
Race: No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (White, Black, or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to Whites (n=1147), Asian subjects (n=47) had no difference in estimated mean dapagliflozin systemic exposures (90% CI range; 3.7% lower, 1% higher). Compared to Whites, Black subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures (90% CI range; 7.7% lower, 3.7% lower).
Body Weight: No dose adjustments from the proposed dapagliflozin dose of 10 mg once daily is recommended in patients with diabetes mellitus or in patients without diabetes on the basis of weight.
In a population pharmacokinetic analysis using data from healthy subject and patient studies, systemic exposures in high-body-weight subjects (≥120 kg, n=91) were estimated to be 78.3% (90% CI; 78.2, 83.2%) of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥120 kg) is recommended.
Subjects with low body weights (<50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low-body-weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small, and based on these findings, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
Toxicology: Preclinical safety data: Carcinogenesis, mutagenesis, impairment of fertility: Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were equivalent to AUC exposure multiples of approximately 72× (males) and 105× (females) the human AUC at MRHD of 10 mg/day. In rats, AUC exposures were approximately 131× (males) and 186× (females) the human AUC at the MRHD.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in an in vitro clastogenicity assay, but only in the presence of S9 activation and at concentrations ≥100 μg/mL. Importantly, dapagliflozin was negative for clastogenicity in vivo in a series of studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100× the human exposure at the MRHD. These studies, along with the absence of tumor findings in the rat and mouse carcinogenicity studies, support that dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin-related gene transcription changes were evaluated in kidney, liver, adipose, and skeletal muscle of Zucker Diabetic Fatty (ZDF) rats treated daily with dapagliflozin for 5 weeks. These organs were specifically selected as they represent target organs in the treatment of diabetes. There was no evidence that dapagliflozin caused transcriptional changes that are predictive of tumor promoters.
Dapagliflozin and its primary human metabolite (3-O-glucuronide) did not enhance the in vitro growth of six human urinary bladder transitional cell carcinomas (TCC) cell lines at concentrations ≥100× human C_max at the MRHD. In a mouse xenograft study, dapagliflozin administered daily to male and female nude mice implanted with human TCC tumors did not significantly enhance the size of tumors at exposures up to 75× and up to 0.9× clinical exposures at the MRHD for dapagliflozin and its 3-O-glucuronide metabolite, respectively. These studies provide evidence that dapagliflozin and its primary human metabolite do not enhance urinary bladder tumor growth.
In a 15-month phenotyping study, there was no evidence of any difference in survival, body weights, clinical pathology parameters, or histopathologic findings observed between SGLT2 KO mice and their wild-type (WT) counterparts. SGLT2 KO mice had glucosuria, unlike the WT mice. Despite a lifetime of glucosuria, there was no evidence of any alteration of renal function or proliferative changes observed in the kidneys or urinary bladders of SGLT2 KO mice. This data strongly suggests that high levels of urinary glucose do not induce urinary tract tumors or accelerate age-related urinary tract pathology.
In a study of fertility and early embryonic development in rats, doses of 15, 75, or 300/210 mg/kg/day dapagliflozin were administered to males (the 300 mg/kg/day dose was lowered to 210 mg/kg/day after 4 days), and doses of 3, 15, or 75 mg/kg/day were administered to females. Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated males or females at any dose tested (at exposure multiples ≤1708× and 998× the MRHD in males and females, respectively). However, at 300/210 mg/kg/day, seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were low numbers of morphologically abnormal sperm.
Teratogenicity and impairment of early development: Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy and lactation (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥15× the MRHD. These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.
In a separate study of prenatal and postnatal development, maternal rats were dosed from gestation day (GD) 6 through PND 21 (also at 1, 15, or 75 mg/kg/day), and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal pelvic dilatation was again observed in adult offspring of treated dams, although only at 75 mg/kg/day (associated maternal and pup dapagliflozin exposures were 1415× and 137×, respectively, the human values at the MRHD). Additional developmental toxicity was limited to dose-related reductions in pup body weights and observed only at doses ≥15 mg/kg/day (associated with pup exposures that are ≥29× the human values at the MRHD). Maternal toxicity was evident only at 75 mg/kg/day, and limited to transient reductions in body weight and food consumption at dose initiation. The no-adverse-effect level (NOAEL) for developmental toxicity, 1 mg/kg/day, is associated with a maternal systemic exposure multiple that is approximately 19× the human value at the MRHD.
In additional studies of embryo-fetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested (20, 60, or 180 mg/kg/day); 180 mg/kg/day is associated with a systemic exposure multiple of approximately 1191× the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441× the MRHD). Doses ≥150 mg/kg/day (≥2344× the human values at the MRHD) were associated with both maternal and developmental toxicities. Maternal toxicity included mortality, adverse clinical signs, and decrements in body weight and food consumption. Developmental toxicity consisted of increased embryo-fetal lethality, increased incidences of fetal malformations and skeletal variations, and reduced fetal body weights. Malformations included a low incidence of great vessel malformations, fused ribs and vertebral centras, and duplicated manubria and sternal centra. Variations were primarily reduced ossifications.
Animal Toxicology: Most of the effects observed in pivotal repeat-dose toxicity studies in both rats and dogs were considered to be secondary to pharmacologically mediated increases in urinary glucose, and included decreases in body weights and/or body weight gains, increased food consumption, and increases in urine volumes due to osmotic diuresis. Dapagliflozin was well tolerated when given orally to rats for up to 6 months at doses of ≤25 mg/kg/day (≥346× the human exposures at the MRHD) and in dogs for up to 12 months at doses of ≤120 mg/kg/day (≥3200× the human exposures at the MRHD). Also, single-dose studies with dapagliflozin indicated that the dapagliflozin 3-O-glucuronide metabolite would have been formed in both rat and dog toxicity studies at exposure levels (AUCs) that are greater than, or approximately equal to, anticipated human dapagliflozin 3-O-glucuronide exposures following administration of dapagliflozin at the MRHD. In rats, the most noteworthy nonclinical toxicity finding of increased trabecular bone and tissue mineralization (associated with increased serum calcium) was only observed at high-exposure multiples (≥2100× based on human exposures at the MRHD). Despite achieving exposure multiples of ≥3200× the human exposure at the MRHD, there was no dose-limiting or target organ toxicities identified in the 12-month dog study.