Xigduo XR Mechanism of Action

Pharmacology: Mechanism of action: XIGDUO XR combines two antihyperglycemic agents with complementary mechanisms of action to improve both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in patients with type 2 diabetes: dapagliflozin, an SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.
Dapagliflozin: Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium glucose co-transporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).
SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder, and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycemia in type 2 diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin reduces maximum tubular glucose transport by 55% and reduces renal glucose reabsorption such that glucose appears in the urine at normal plasma glucose levels. Thus, 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 healthy subjects with normal glucose, dapagliflozin has a low propensity to cause hypoglycemia. 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.
Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. 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. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis.
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.
Metformin hydrochloride: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics: General: Dapagliflozin: 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 (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: Clinical efficacy: Glycemic efficacy: The coadministration of dapagliflozin and metformin XR has been studied in treatment naive patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin IR or XR has been studied in patients with type 2 diabetes inadequately controlled on metformin, metformin plus a sulfonylurea. DPP4 inhibitors (with or without metformin), or insulin (with or without other oral antidiabetic therapy) and compared with a sulfonylurea in combination with metformin in patients with inadequate glycemic control on metformin alone.
Treatment with dapagliflozin plus metformin at all doses, produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c, and fasting plasma glucose (FPG) 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 and metformin 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.
Additionally, dapagliflozin 10 mg or placebo were studied in type 2 diabetes patients with cardiovascular disease (approximately 37% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin alone [with or without insulin]) and type 2 diabetes patients with hypertension (approximately 90% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin).
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 OADs 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.
Concomitant initiation of dapagliflozin therapy with saxagliptin has been studied in type 2 diabetes patients inadequately controlled on metformin, which produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c, compared to dapagliflozin added to metformin and saxagliptin added to metformin.
Initial combination therapy with dapagliflozin and 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 were randomized to one of three treatment arms following a 1-week lead-in period: 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 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 provided significant improvements in HbA1c and FPG, compared with either of the monotherapy treatments and significant reductions in body weight compared with metformin alone (Table 1, Figures 2 and 3). Dapagliflozin 10 mg as monotherapy also provided significant improvements in FPG and significant reduction in body weight compared with metformin alone and was non-inferior to metformin 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 plus placebo (13.5%) than for dapagliflozin 10 mg plus placebo and dapagliflozin 10 mg plus metformin (7.8% and 1.4%). (See Table 1, Figures 2 and 3.)

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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.
Addition of dapagliflozin 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, 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 2). At Week 102, adjusted mean change from baseline in HbA1c (Figure 4), 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. 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 2 and Figure 4.)

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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 non-inferiority 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 non-inferiority (Table 3). Dapagliflozin treatment led to a significant mean reduction in body weight from baseline to Week 52 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 3, Figures 5 and 6.)

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Add-on combination therapy of dapagliflozin to 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 4). 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 XIGDUO (10.1%). No patient was discontinued from study medication due to inadequate glycemic control. (See Table 4.)

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Add-on of dapagliflozin 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), were randomized 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 sitagliptin 100 mg once daily. Two-hundred-twenty-six (226) patients were analyzed in the sitagliptin with metformin stratum, 113 patients received dapagliflozin 10 mg plus sitagliptin and metformin, and 113 patients received placebo plus sitagliptin and metformin. Dose titration of dapagliflozin, sitagliptin or metformin was not permitted during the study.
For patients who received sitagliptin and 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 group at Week 24 (Table 5).
At Week 48, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline (unadjusted), FPG, PPG, and body weight were -0.44%, -1.05%, -23.7 mg/dL, -47.2 mg/dL, and -2.53 kg, respectively, for patients treated with dapagliflozin 10 mg plus sitagliptin with metformin, and 0.15%, -0.54%, 6.3 mg/dL, -18.6 mg/dL, and -0.45 kg for patients treated with placebo plus sitagliptin with metformin based on the longitudinal repeated measures analysis excluding data after rescue. (See Table 5.)

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Add-on combination therapy to insulin: A total of 808 patients with type 2 diabetes who had 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, 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 1 or 2 OADs in addition to insulin; of these, 80% were on metformin alone and 14% were on metformin plus another OAD. At Week 24, dapagliflozin 10 mg dose provided significant improvement in HbA1c, FPG, and mean insulin dose, and significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (Table 6); 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 -18.2mg/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 -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 0.91kg, respectively, for patients treated with placebo plus insulin (see Figure 7).
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%). At Weeks 48 and 104, the insulin dose remained stable compared to baseline in patients treated with dapagliflozin 10 mg at an average dose of 76 IU/day, but continued to increase (mean increase 10.5 IU/day and 18.3 IU/day, respectively, from baseline) in placebo-treated patients. By Weeks 48 and 104 (adjusted for baseline HbA1c), more patients treated with placebo (42.8% and 50.4%, respectively) required up-titration with insulin to maintain glycemic levels or discontinued due to lack of glycemic control than patients treated with dapagliflozin 10 mg (15.3% and 25.5%, respectively).
In a separate analysis of patients on insulin plus metformin IR alone, similar improvements to those seen in the total study population were seen in patients treated with dapagliflozin plus insulin with metformin in HbA1c, body weight, and mean insulin dose compared with placebo plus insulin with metformin at Week 24 (Table 6). (See Table 6 and Figure 7.)

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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 glycemic control (HbA1c ≥7% and ≤10.5%). Three hundred and twenty (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 saxagliptin plus dapagliflozin plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin plus metformin group 12.4% (95% [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.
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 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) or established CV disease.
Of 17,160 randomized patients, 6,974 (40.6%) had established CV disease and 10,186 (59.4%) did not have established CV disease. 8,582 patients were randomized to dapagliflozin 10 mg and 8,578 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. In total, 22.4% 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 ratio [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98%) used one or more diabetic medications at baseline, including metformin (82%), insulin (41%) and sulfonylurea (43%).
The primary endpoints were time to first event of the composite of CV death, myocardial infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalization for heart failure or CV death. The secondary endpoints were a renal composite endpoint and all-cause mortality.
Major Adverse Cardiovascular Events: Dapagliflozin 10mg demonstrated non-inferiority versus placebo for the composite of CV death, myocardial infarction or ischemic stroke (one-sided p <0.001).
Heart Failure or Cardiovascular Death: Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite of hospitalization for heart failure or CV death (Figure 8). The difference in treatment effect was driven by hospitalization for heart failure, with no difference in CV death (Figure 9).
The treatment benefit of dapagliflozin over placebo was observed both in patients with and without established CV disease, with and without heart failure at baseline, and was consistent across key subgroups, including age, gender, renal function (eGFR), and region. (See Figure 8.)

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Results on primary and secondary endpoints are displayed in Figure 9. Superiority of dapagliflozin over placebo was not demonstrated for MACE (p=0.172). The renal composite endpoint and all-cause mortality were therefore not tested as part of the confirmatory testing procedure. (See Figure 9.)

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Nephropathy: Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, ESRD, renal or CV death. The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESRD and renal death (Figure 9).
The hazard ratio for time to nephropathy (sustained eGFR decrease, end-stage renal disease and renal death) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin versus placebo.
In addition, dapagliflozin reduced the new onset of sustained albuminuria (hazard ratio 0.79 [95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82 [95% CI 1.51, 2.20]) compared with placebo.
Supportive efficacy studies: Dapagliflozin dual energy x-ray absorptiometry in 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 IR over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg vs -0.88 kg); waist circumference (mean change from baseline: -2.51 cm vs -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline -2.22 kg vs -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 (mean change from baseline: -322.6 cm³ vs -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 vs -2.03 kg; adjusted mean change from baseline at Week 102: -4.54 kg vs -2.12 kg), waist circumference (adjusted mean change from baseline at Week 50: -5.0 cm vs -3.0 cm; adjusted mean change from baseline at Week 102: -5.0 cm vs -2.9 cm), and body-fat mass as measured by DXA at Week 102 (mean change from baseline: -2.80 kg vs -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 vs 61.5 cm³; adjusted mean change from baseline at Week 102: -214.9 cm³ vs -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.
Metformin UKPDS study: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034; a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017; a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021); a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
Clinical safety - Dapagliflozin: Volume depletion: Events suggestive of volume depletion (including reports of dehydration, hypovolemia, or hypotension) were reported in 1.1% and 0.7% of patients who received dapagliflozin 10 mg and placebo, respectively, in the 13-study, short-term, placebo-controlled pool. Serious events occurred in ≤0.2% of patients across 21 active- and placebo-controlled studies (dapagliflozin as monotherapy or in combination with other antidiabetic therapies) and were balanced between dapagliflozin 10 mg and comparator.
In the CV outcomes study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and ACEi/ARB use. In patients with eGFR <60 mL/min/1.73 m² at baseline, there were 19 events of SAEs suggestive of volume depletion in the dapagliflozin group and 13 events in the placebo group.
Hypoglycemia: The incidence of hypoglycemia as seen in controlled clinical studies with dapagliflozin in different combinations is shown in Table 9. (See Table 9.)

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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 vs. -0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg vs. 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: Dapagliflozin: 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: Dapagliflozin: 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: Dapagliflozin: 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 pre-existing 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 (including metformin immediate- or extended-release) 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. Approximately 90% of patients treated with dapagliflozin 10 mg or placebo also received metformin immediate- or extended-release in addition to other OADs. 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 a significant reduction in seated systolic blood pressure compared with placebo plus usual treatment (see Table 10). 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 10.)

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Use in patients with type 2 diabetes and cardiovascular disease: Dapagliflozin: 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%) and stroke (20%). Approximately 19% of patients received loop diuretics at entry and 15% had congestive heart failure (2% had NYHA Class III). 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 systolic blood pressure (Table 11). Significant reductions in total body weight and seated systolic blood pressure were also seen in patients treated with dapagliflozin 10 mg compared with placebo.
In a separate analysis of patients on metformin alone (with or without insulin) in these two studies, similar improvements in HbA1c and percent body weight reduction to those seen in the total study population were seen in patients treated with dapagliflozin 10 mg plus metformin alone compared with placebo plus metformin alone at Week 24. A mean reduction in seated systolic blood pressure was observed, consistent with that seen in the total study population, in patients treated with dapagliflozin 10 mg plus metformin alone compared with placebo plus metformin alone at Week 24 in study 1, but not in study 2.
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 11.)

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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 systolic blood pressure 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.
Use in patients with type 2 diabetes and renal impairment: Dapagliflozin: Patients with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73m²): In the clinical trial program over 3000 patients with mild renal impairment were treated with dapagliflozin. Efficacy was assessed in a pooled analysis across 9 dapagliflozin 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 12). 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 12.)

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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. 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 an 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 diabetes: Dapagliflozin: A total of 2403 (26%) of the 9339 treated patients were 65 years and older and 327 (3.5%) patients were 75 years and older in the pool of 21 double-blind, controlled, clinical studies of dapagliflozin assessing the safety and efficacy of dapagliflozin in improving glycemic control, as monotherapy or in combination with other antidiabetic therapies. 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.
Metformin hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients.
Pharmacokinetics: XIGDUO XR tablets are considered to be bioequivalent to coadministration of corresponding doses of dapagliflozin and metformin hydrochloride (XR) administered together as individual tablets.
Interaction with food: The administration of XIGDUO XR in healthy subjects after a standard meal compared to the fasted state results in the same extent of exposure for both dapagliflozin and metformin XR. Compared to the fasted state, the standard meal results in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful.
The following statements reflect the pharmacokinetic properties of the individual active substances of XIGDUO XR.
Absorption: Dapagliflozin: 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 increase proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Metformin hydrochloride XR: After an oral dose of metformin extended-release 500 mg, metformin absorption is significantly delayed compared to the immediate-release tablet (T_max at 2.5 hours) with a T_max at 7 hours.
Following a single oral administration in the fed state of one tablet of metformin extended-release 1000 mg, a mean peak plasma concentration of 1214 ng/ml is achieved with a median time of 5 hours (range of 4 to 10 hours). Metformin extended-release 1000 mg was shown to be bioequivalent to metformin extended-release 500 mg at a 1000 mg dose with respect to C_max and AUC in healthy fed and fasted subjects.
At steady state, similar to the immediate-release formulation, C_max and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg metformin extended-release is similar to that observed after administration of 1000 mg metformin immediate-release twice daily.
Intrasubject variability of C_max and AUC of metformin extended-release is comparable to that observed with metformin immediate-release.
When 2 tablets of 500 mg metformin extended-release is administered in fed conditions the AUC is increased by approximately 70% (both C_max and T_max are only slightly increased).
When the 1000 mg extended-release tablet are administered in fed conditions the AUC is increased by 77% (C_max is increased by 26 % and T_max is slightly prolonged by about 1 hour).
Metformin absorption from the extended-release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000 mg metformin extended-release.
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (eg, renal or hepatic impairment).
Metformin hydrochloride: Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averages 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.
Metabolism: Dapagliflozin: 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 is 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 h]) 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 is a minor clearance pathway in humans.
Metformin hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination: Dapagliflozin: 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.
Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: Renal Impairment: Dapagliflozin: For dosing recommendations for patients with moderate to severe renal impairment see Dosage & Administration. 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 was 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.
Metformin hydrochloride: In patients with renal impairment, the plasma and blood half-life of metformin is prolonged in proportion to the decrease in renal function.
Hepatic Impairment: Dapagliflozin: For dosing recommendations for patients with moderate or severe hepatic impairment see 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. Dapagliflozin should not be used in patients with severe hepatic impairment.
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Age: Dapagliflozin: 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.
Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatric and Adolescent: Dapagliflozin: Pharmacokinetics in the pediatric and adolescent population have not been studied.
Metformin hydrochloride: After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin C_max and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
Gender: Dapagliflozin: 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 AUCs in females (n=619) was estimated to be 22% higher than in males (n=634), (90% CI: 117, 124).
Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race: Dapagliflozin: 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).
Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
Body Weight: No dose adjustments from the proposed dapagliflozin dose of 10 mg once daily is recommended 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: Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in two-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. These data strongly suggest 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.
Metformin hydrochloride: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body-surface-area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body-surface-area comparisons.
Teratogenicity and impairment of early development: Dapagliflozin: 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 pre-natal 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 centra, and duplicated manubria and sternal centra. Variations were primarily reduced ossifications.
Metformin hydrochloride: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Animal toxicology: A 3-month rat study was conducted with the combination of dapagliflozin and metformin. No toxicity was observed at AUC exposures 52 and 1.4 times the MRHD for dapagliflozin and metformin, respectively.
Dapagliflozin: 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.