Xigduo XR Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: XIGDUO XR combines two anti-hyperglycaemic 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, a SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.
Dapagliflozin: Dapagliflozin is a reversible competitive inhibitor of sodium glucose co-transporter 2 (SGLT2) with nanomolar potency that improves glycaemic control in patients with type 2 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. 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.
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. Dapagliflozin improves both fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. 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 blood glucose and/or low GFR, dapagliflozin has a low propensity to cause hypoglycaemia, as the amount of glucose filtrated is small and can be reabsorbed by SGLT1 and unblocked SGLT2 transporters. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. 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 the weight reduction was 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.
Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is approximately 1000-3000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption.
Metformin hydrochloride: Metformin is an antihyperglycaemic 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 utilisation. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Precautions) and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
In humans, independently of its action on glycaemia metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
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. 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. 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 18.3 to 48.3 μmol/L.
Cardiac Electrophysiology: Dapagliflozin: 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 trials: There have been no clinical efficacy studies conducted with XIGDUO XR; however, bioequivalence of XIGDUO XR with coadministered dapagliflozin and metformin hydrochloride extended release tablets was demonstrated.
Addition of dapagliflozin to metformin: The coadministration of dapagliflozin and metformin has been studied in patients with type 2 diabetes inadequately controlled on metformin alone or in combination with a sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor or insulin, in treatment-naive patients inadequately controlled on diet and exercise alone, and compared with a sulfonylurea in combination with metformin in patients with inadequate glycaemic control on metformin alone. Additionally, dapagliflozin 10 mg or placebo were studied in patients with type 2 diabetes with cardiovascular disease (approximately 37% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin alone [with or without insulin]) and patients with type 2 diabetes with hypertension (approximately 90% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin).
Initial combination therapy with metformin: 641 patients were randomised 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 the maximum and median dose achieved being 2000 mg. The patients were treatment-naïve, defined as either never having received diabetes medication or having had such for less than 24 weeks since the diagnosis of diabetes, not for more than 14 days during the 12 weeks prior to enrolment, and not at all during the 4 weeks prior to enrolment.
The combination treatment of dapagliflozin 10 mg plus metformin provided significant improvements in haemoglobin A1c (HbA_1c) and FPG, compared with either of the monotherapy treatments and significant improvements in body weight compared with metformin alone (Table 1). Dapagliflozin 10 mg as monotherapy also provided significant improvements in FPG and body weight compared with metformin alone and was non-inferior to metformin monotherapy in lowering HbA_1c. The proportion of patients who were rescued or discontinued for lack of glycaemic control during the 24 week double-blind treatment period (adjusted for baseline HbA_1c) was higher on treatment with metformin plus placebo (13.5%) than on dapagliflozin 10 mg plus placebo and dapagliflozin 10 mg plus metformin (7.8%, and 1.4%). (See Table 1.)

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Add-on to metformin: As add-on treatment to metformin, dapagliflozin 10 mg provided significant improvements in HbA_1c at Week 24 (Table 2). (See Table 2 and Figure 1.)

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Active glipizide controlled study add-on to metformin: In a 52 week, active-controlled non-inferiority study (with 52 week and 104 week extension periods), dapagliflozin was evaluated as add on therapy to metformin compared with a sulfonylurea (glipizide) as add on therapy to metformin in subjects with inadequate glycaemic control (HbA_1c >6.5% and ≤10%). The results showed a similar mean reduction in HbA_1c from baseline to Week 52, compared to glipizide, thus demonstrating non-inferiority (Table 3). At Week 104, adjusted mean change from baseline in HbA_1c was -0.32% for dapagliflozin and -0.14% for glipizide. At Week 208, the secondary endpoint of adjusted mean change from baseline in HbA_1c was 0.10% for FORXIGA and 0.20% for glipizide (see Figure 2). At 52, 104 and 208 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5%, 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia compared to the group treated with glipizide (40.8%, 47.0% and 50.0%, respectively). The proportions of subjects remaining in the study at Week 104 and Week 208 were 56.2% and 39% respectively for the group treated with dapagliflozin and 50.0% and 34.6% respectively for the group treated with glipizide. (See Table 3 and Figure 2.)

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Combination therapy with other anti-hyperglycaemic agents: Dapagliflozin as an add on with either sitagliptin (with or without metformin), metformin with a sulfonylurea, or insulin, resulted in statistically significant reductions in HbA_1c at 24 weeks compared with subjects receiving placebo (p<0.0001; see Tables 4, 5 and 6).

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The reductions in HbA_1c observed at Week 24 were sustained in add on combination studies and up to 104 week data (insulin, see Figure 3). At Week 48 when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for dapagliflozin 10 mg and placebo was -0.30% and 0.38%, respectively. For the add on to metformin study, HbA_1c reductions were sustained through Week 102 (-0.78% and 0.02% adjusted mean change from baseline for 10 mg and placebo, respectively, see also Figure 3). At Week 104 for insulin (with or without additional oral glucose lowering medicinal products), the HbA_1c reductions were -0.71% and -0.06% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively. At Weeks 48 and 104, the insulin dose remained stable compared to baseline in subjects treated with dapagliflozin 10 mg at an average dose of 76 IU/day (see Figure 4). In the placebo group there was a mean increase of 10.5 IU/day and 18.3 IU/day from baseline at Weeks 48 and 104, respectively. The proportion of subjects remaining in the study at Week 104 was 72.4% for the group treated with dapagliflozin 10 mg and 54.8% for the placebo group. (See Figures 3 and 4.)

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Fasting plasma glucose: Treatment with dapagliflozin 10 mg as an add on to either metformin, metformin and a sulfonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in fasting plasma glucose (-1.90 to -1.20 mmol/L) compared to placebo (-0.33 to 0.21 mmol/L) at 24 weeks. This effect was observed at Week 1 of treatment and maintained in studies extended through Week 104.
Concomitant Initiation of Dapagliflozin and Extended Release Exenatide in Patients Inadequately Controlled on Metformin: A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥ 8.0 and ≤ 12.0%) on metformin alone (≥ 1,500 mg/day) participated in this 28-week randomised, double-blind, active-controlled trial to compare the concomitant initiation of dapagliflozin 10 mg once daily and extended release exenatide 2 mg once weekly on a background of metformin versus extended release exenatide 2 mg once weekly (GLP-1 receptor agonist) alone and dapagliflozin 10 mg once daily alone when added to metformin. Following a 1-week placebo lead-in period, patients were randomised equally to one of three double-blind treatment groups to receive either dapagliflozin 10 mg and extended release exenatide, dapagliflozin 10 mg and placebo or extended release exenatide and placebo. During the treatment period, patients continued on the same type and dose of metformin as when they entered the study. At baseline, patients had a mean age of 54.2 years and a BMI of 32.73 kg/m². Randomisation was stratified by HbA_1c at baseline (<9.0% or ≥9.0%) and patients were regularly monitored every 4 weeks in this study.
The primary endpoint was the change in HbA_1c from baseline to Week 28 (Figure 5). Compared to dapagliflozin 10 mg alone and extended release exenatide alone, concomitant initiation of dapagliflozin 10 mg and extended release exenatide resulted in statistically significant reductions in HbA_1c from baseline at Week 28 (Table 7). (See Figure 5 and Table 7.)

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Postprandial glucose: Treatment with dapagliflozin 10 mg as an add on to sitagliptin (with or without metformin) resulted in reductions in 2 hour postprandial glucose at 24 weeks that were maintained up to Week 48.
Body weight: Dapagliflozin 10 mg as an add on to metformin, metformin and a sulfonylurea, sitagliptin (with metformin) or insulin resulted in a statistically significant body weight reduction at 24 weeks (Tables 2, 4, 5 and 6) with placebo-corrected reductions of 1.97 kg (2.43%), 2.07 kg (2.25%), 1.87 kg (2.08%) and 1.68 kg (1.83%), respectively. These effects were sustained in longer-term trials (see Figure 6 for add-on to insulin). At 48 weeks, the difference for dapagliflozin as add on to sitagliptin (with or without metformin) compared to placebo was -2.22 kg. At 102 weeks, the differences for dapagliflozin as add on to metformin compared to placebo, or as add on to insulin (at 104 weeks) compared to placebo were -2.14 kg and -2.88 kg, respectively.
As an add on therapy to metformin in an active controlled non inferiority study, dapagliflozin resulted in a statistically significant body weight reduction compared with glipizide of 4.65 kg at 52 weeks (Table 3) compared to glipizide, that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg respectively) (see Figures 6 and 7).

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Cardiovascular outcomes: Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international multicentre, randomized, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on cardiovascular (CV) and renal outcomes when added to current background therapy. All patient 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).
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 HbA_1c 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 <60 mL/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 an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (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 Figure 8. (See Figure 8.)

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Hospitalisation for 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 (HR 0.83 [95% CI 0.73, 0.95]; p=0.005) (Figure 9).
Explanatory 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 8 and Figure 10), with no clear difference in CV death (HR 0.98 [95% CI 0.82 to 1.17]). (See Figures 9 and 10.)

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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).
Nephropathy: The composite of confirmed sustained eGFR decrease, ESKD, renal or CV death was a secondary variable in the DECLARE study. Because confirmatory testing stopped before the secondary variables were assessed, the analyses of the secondary variables should be considered exploratory.
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] Figure 11). The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESKD and renal death (Figure 8), and was observed both in patients with and without CV disease. (See Figure 11.)

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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], 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], 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]).
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 patients with diabetes: Due to the mechanism of action of dapagliflozin a study was done to evaluate body composition and bone mineral density. Dapagliflozin 10 mg added on to metformin in 182 patients with type 2 diabetes 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 (change from baseline -322.6 cm³ vs. -8.7 cm³) in an MRI substudy. In an ongoing extension of this study to week 50, there was no important change in bone mineral density for the lumbar spine, femoral neck or total hip seen in either treatment group (mean change from baseline for all anatomical regions <0.5%, 7/89 dapagliflozin and 4/91 comparator subjects showed a decrease of 5% or more). These effects were sustained in a further extension of the study to 102 weeks where no important changes in BMD for the lumbar spine, femoral neck or total hip in either treatment group were observed.
Special Populations: Blood pressure: In the pre-specified pooled analysis of 13 placebo-controlled studies (see Adverse Reactions), treatment with dapagliflozin 10 mg resulted in a systolic blood pressure change from baseline of -3.7 mmHg and diastolic blood pressure of -1.8 mmHg versus -0.5 mmHg systolic and 0.5 mmHg diastolic blood pressure for the placebo group at Week 24. Similar reductions were observed up to 104 weeks.
In two 12-week, placebo-controlled studies a total of 1,062 patients with inadequately controlled type 2 diabetes and hypertension (despite pre-existing stable treatment with an ACE-I or ARB in one study and an ACE-I or ARB plus one additional antihypertensive treatment in another study) were treated with dapagliflozin 10 mg or placebo. At Week 12 for both studies, dapagliflozin 10 mg plus usual antidiabetic treatment provided improvement in HbA_1c and decreased the placebo-corrected systolic blood pressure on average by 3.1 and 4.3 mmHg, respectively.
Heart failure with reduced ejection fraction: 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. In each treatment group, 42% 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, totaling to 1075 patients in the dapagliflozin group and 1064 in the placebo group. Of the patients with type 2 diabetes mellitus, 48% were treated with metformin at baseline.
The mean age of the type 2 diabetes mellitus population was 67 years, 78% were male, 70% White, 6% Black or African-American and 23% Asian. At baseline, 64% patients were classified as NYHA class II, 35% class III and 1% class IV, median LVEF was 32%.
Patients were on standard of care therapy; 93% of type 2 diabetes mellitus patients were treated with ACEi, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 97% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 95% with diuretic and 27% 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 in type 2 diabetes patients was 63 mL/min/1.73 m², 46% of patients had eGFR <60 mL/min/1.73 m².
The treatment benefits of dapagliflozin over placebo observed in heart failure patients were consistent in the overall study population and the type 2 diabetes mellitus sub-population.
In the patients with type 2 diabetes mellitus, dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (HR 0.75 [95% CI 0.63, 0.90], nominal p=0.0018). All three components of the primary composite endpoint individually contributed to the treatment effect (Table 8). There were few urgent heart failure visits. (See Table 8.)

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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 328 events in the type 2 diabetes mellitus group treated with dapagliflozin versus 415 events in the placebo group (Rate Ratio 0.77 [95% CI 0.63, 0.94], nominal p=0.0109).
In patients with type 2 diabetes mellitus, the treatment effect of dapagliflozin over placebo on the primary endpoint was consistent across key subgroups, including heart failure severity, concomitant heart failure therapy, renal function (eGFR), age, gender, race and region.
Chronic kidney disease: 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. At baseline, 67.5% of the patients had type 2 diabetes mellitus, and 43% of these patients were treated with metformin. In patients with type 2 diabetes mellitus, mean eGFR was 44 mL/min/1.73 m² and median UACR was 1017 mg/g, 43% had eGFR 30 to <45 mL/min/1.73 m² and 14% had eGFR <30 mL/min/1.73 m². Treatment with dapagliflozin 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.
The mean age of the type 2 diabetes mellitus study population was 64 years, 67% were male, 53% White, 5% Black or African-American and 32% Asian. Patients were on standard of care therapy; 97% of patients were treated with an ACEi or ARB.
The treatment benefits of dapagliflozin observed in CKD patients with type 2 diabetes mellitus were consistent with the results seen in the overall study population.
In patients with type 2 diabetes mellitus, dapagliflozin reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, reaching ESKD, CV or renal death (HR 0.64 [95% CI 0.52, 0.79]; nominal p<0.0001). All four components of the primary composite endpoint individually contributed to the treatment effect (Table 9). (See Table 9.)

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In patients with type 2 diabetes mellitus, the treatment benefit of dapagliflozin over placebo on the primary endpoint was consistent across key subgroups, including renal function (eGFR), albuminuria (UACR) levels, age, gender, race and region.
Use in patients with type 2 diabetes and renal impairment: Dapagliflozin: Patients with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²): 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 (HbA_1c) and the placebo-corrected mean HbA_1c 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 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 HbA_1c, FPG, Body Weight and SBP compared with placebo (n=161) (Table 10). The mean change from baseline in HbA_1c and the placebo-corrected mean HbA_1c 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 10.)

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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 HbA_1c and the placebo-corrected mean HbA_1c 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 HbA_1c 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 HbA_1c 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).
Pharmacokinetics: The results of bioequivalence studies in healthy subjects demonstrated that XIGDUO XR combination tablets are bioequivalent to coadministration of corresponding doses of dapagliflozin and metformin hydrochloride modified-release as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of XIGDUO XR.
Absorption: Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. The C_max and AUC values increased proportional 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 did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Metformin hydrochloride: Following a single oral dose of metformin extended-release, C_max is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and C_max are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 μg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on C_max and T_max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release.
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g., 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 averaged 654 ± 358 L. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. 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 extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does 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.
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.
Excretion: Dapagliflozin: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After oral administration of 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug. The mean plasma terminal half-life (t_½) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects.
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. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Special populations: Renal impairment: Dapagliflozin: 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-h 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 haemodialysis on dapagliflozin exposure is not known.
Metformin hydrochloride: In patients with renal impairment function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged in proportion to the decrease in renal function.
Hepatic impairment: Dapagliflozin: 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 hepatic impairment groups or 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 (see Precautions).
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Age: Dapagliflozin: No dosage adjustment for dapagliflozin 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%]. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
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.
Paediatric and adolescent: Dapagliflozin: Pharmacokinetics in the paediatric 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 paediatric 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 AUC_ss 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 analysed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycaemic 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 [African descent] 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 (African descent) 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 antihyperglycaemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Body weight: Dapagliflozin: No dose adjustment 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 patients with type 2 diabetes mellitus with low body weight (<50 kg) is recommended.
Toxicology: Preclinical Safety Data: Genotoxicity: Dapagliflozin: Dapagliflozin was positive in an in vitro clastogenicity assay in the presence of metabolic activation. However, dapagliflozin was negative in the Ames mutagenicity assay and in a series of in vivo clastogenicity studies evaluating micronuclei or DNA repair in rats at exposure multiples at least 2100 times the human exposure at the MRHD. The weight of evidence from these studies, along with the absence of tumour findings in the rat and mouse carcinogenicity studies, support that dapagliflozin is not genotoxic.
Metformin hydrochloride: 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.
Carcinogenicity: Dapagliflozin: Dapagliflozin did not induce tumours in two-year carcinogenicity studies in mice or rats at oral doses up to 40 mg/kg/day and 10 mg/kg/day, respectively. These doses correspond to AUC exposure levels at least 78 times the human AUC at the MRHD of 10 mg/day.
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.