Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, Sodium glucose co-transporter (SGLT-2) inhibitors ATC code: A10BK01

Mechanism of action
Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2.

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 haematocrit and reduction in body weight. The cardiac and renal benefits of dapagliflozin are not solely dependent on the blood glucoselowering effect and not limited to patients with diabetes as demonstrated in the DAPA-HF and DAPA-CKD studies
Dapagliflozin improves both fasting and post-prandial 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 subjects with normal blood glucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin.


The SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

Pharmacodynamic effects

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects 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 subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects 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 in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects 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 sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from -48.3 to -18.3 micromoles/l (-0.87 to -0.33 mg/dl).

Clinical efficacy and safety
Type 2 diabetes mellitus
improvement of glycaemic control and reduction of cardiovascular and renal morbidity and mortality are integral parts of the treatment of type 2 diabetes.

Fourteen double-blind, randomised, controlled clinical studies were conducted with 7,056 subjects with type 2 diabetes to evaluate the glycaemic efficacy and safety of Forxiga; 4,737 subjects in these studies were treated with dapagliflozin. Twelve studies had a treatment period of 24 weeks duration, 8 with long-term extensions ranging from 24 to 80 weeks (up to a total study duration of 104 weeks), one study had a 28-week treatment period. and one study was 52 weeks in duration with long-term extensions of 52 and 104 weeks (total study duration of 208 weeks). Mean duration of diabetes ranged from 1.4 to 16.9 years. Fifty percent (50%) had mild renal impairment and 11% had moderate renal impairment. Fifty-one percent (51%) of the subjects were men, 84% were White, 8% were Asian, 4% were Black and 4% were of other racial groups. Eighty -one percent (81%) of the subjects had a body mass index (BMI) ≥ 27. Furthermore, two 12-week, placebo- controlled studies were conducted in patients with inadequately controlled type 2 diabetes and hypertension.
A cardiovascular outcome study (DECLARE) was conducted with dapagliflozin 10 mg compared with placebo in 17,160 patients with type 2 diabetes mellitus with or without established cardiovascular disease to evaluate the effect on cardiovascular and renal events.

Glycaemic control
Monotherapy
A double-blind, placebo-controlled study of 24-week duration (with an additional extension period) was conducted to evaluate the safety and efficacy of monotherapy with Forxiga in subjects with inadequately controlled type 2 diabetes mellitus. Once-daily treatment with dapagliflozin resulted in statistically significant (p < 0.0001) reductions in HbA1c compared to placebo (Table 2).

In the extension period, HbA1c reductions were sustained through Week 102 (-0.61%, and -0.17% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively).

Table 3 Results at Week 24 (LOCFa) of a placebo-controlled study of dapagliflozin as monotherapy
Monotherapy
Dapagliflozin                  Placebo
10 mg
Nb                                      70                          75 HbA1c (%)                              8.01                        7.79 Baseline (mean)                        -0.89                       -0.23 Change from baselinec                 -0.66*
Difference from placebo c
(-0.96, -0.36)
(95% CI)
Subjects (%) achieving:                50.8§                       31.6 HbA1c < 7%
Adjusted for baseline
Body weight (kg)                      94.13                        88.77 Baseline (mean)                        -3.16                       -2.19 
Change from baselinec                          -0.97
Difference from placeboc                   (-2.20, 0.25)
(95% CI)
aLOCF:  Last observation (prior to rescue for rescued subjects) carried forward bAllrandomised subjects who took at least one dose of double-blind study medication during the short-term double-blind period
cLeast squares mean adjusted for baseline value
*p-value < 0.0001 versus placebo
§ Not evaluated for statistical significance as a result of the sequential testing procedure for secondary end 
points

Add-on Combination therapy
In a 52-week, active-controlled non-inferiority study (with 52- and 104-week extension periods), Forxiga was evaluated as add-on therapy to metformin compared with a sulphonylurea (glipizide) as add-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 52, compared to glipizide, thus demonstrating non-inferiority (Table 4). At Week 104, adjusted mean change from baseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At Week 208, adjusted mean change from baseline in HbA1c was -0.10% for dapagliflozin and 0.20% for
glipizide. 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 proportion of subjects remaining in the study at Week 104 and Week 208 was 56.2% and 39.7% for the group treated with dapagliflozin and 50.0% and 34.6% for the group treated with glipizide.

Table 4. Results at Week 52 (LOCFa) in an active-controlled study comparing dapagliflozin to glipizide as add-on to metformin
Parameter                                Dapagliflozin +       Glipizide + metformin metformin
N b
400                      401
HbA1c (%)                                       7.69                     7.74 Baseline (mean)                                -0.52                    -0.52 Change from baselinec                          0.00d
Difference from glipizide +                (-0.11, 0.11)
metforminc
(95% CI)
Body weight (kg)                               88.44                   87.60 Baseline (mean)                                -3.22                     1.44 Change from baselinec                          -4.65*
Difference from glipizide +               (-5.14, -4.17)
metforminc
(95% CI)
aLOCF:  Last observation carried forward
bRandomised    and treated subjects with baseline and at least 1 post-baseline efficacy measurement cLeast squares mean adjusted for baseline value
dNon-inferior to glipizide + metformin
*p-value < 0.0001


Dapagliflozin as an add-on with either metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in HbA1c at 24 weeks compared with subjects receiving placebo (p < 0.0001; Tables 5, 6 and 7).

The reductions in HbA1c observed at Week 24 were sustained in add-on combination studies (glimepiride and insulin) with 48-week data (glimepiride) and up to 104-week data (insulin). 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, HbA1c reductions were sustained through Week 102 (-0.78% and 0.02% adjusted mean change from baseline for 10 mg and placebo, respectively). At Week 104 for insulin (with or without additional oral glucose-lowering medicinal products), the HbA1c 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. In the placebo group there was a mean increase of 10.5 IU/day and 18.3 IU/day from baseline (mean average dose of 84 and 92 IU/day) 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.

Table 5 Results of 24-week (LOCFa) placebo-controlled studies of dapagliflozin in add-on combination with metformin or sitagliptin (with or without metformin) Add-on combination
Metformin1
DPP-4 Inhibitor (sitagliptin2) ±
Metformin1
Dapagliflozin Placebo          Dapagliflozin            Placebo
10 mg                           10 mg
Nb                              135           137               223                 224 HbA1c (%)                       7.92          8.11              7.90                7.97 Baseline (mean)                -0.84         -0.30             -0.45                0.04 Change from baselinec         -0.54*                          -0.48*
Difference from placeboc  (-0.74, -0.34)                  (-0.62, -0.34) (95% CI)
Subjects (%) achieving:       40.6**          25.9
HbA1c < 7%
Adjusted for baseline
Body weight (kg)              86.28          87.74            91.02                89.23 Baseline (mean)                -2.86         -0.89             -2.14               -0.26 Change from baselinec         -1.97*                          -1.89*
Difference from placeboc  (-2.63, -1.31)                  (-2.37, -1.40) (95% CI)
1Metformin  ≥ 1500 mg/day; 2sitagliptin 100 mg/day
aLOCF:   Last observation (prior to rescue for rescued subjects) carried forward bAll randomised subjects who took at least one dose of double-blind study medicinal product during the 
short-term double-blind period
cLeast squares mean adjusted for baseline value
*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product **p-value < 0.05 versus placebo + oral glucose-lowering medicinal product 

Table 6. Results of 24-week placebo-controlled studies of dapagliflozin in add-on combination with sulphonylurea (glimepiride) or metformin and a sulphonylurea Add-on combination
Sulphonylurea (glimepiride1) Sulphonylurea + Metformin2
Dapagliflozin    Placebo      Dapagliflozin      Placebo
10 mg                        10 mg
Na                                151          145             108              108 HbA1c (%)   b
8.07          8.15            8.08             8.24
Baseline (mean)                  -0.82        -0.13           -0.86            -0.17 Change from Baselinec           -0.68*                       −0.69* Difference from Placebo c
(-0.86, -0.51)               (−0.89, −0.49)
(95% CI)
Subjects (%) achieving:          31.7*         13.0           31.8*             11.1 HbA1c < 7% (LOCF)    d


Adjusted for baseline
Body weight (kg) (LOCF)d              80.56                80.94          88.57               90.07 Baseline (mean)                       -2.26                -0.72          -2.65               -0.58 Change from Baselinec                 -1.54*                              −2.07* Difference from Placeboc          (-2.17, -0.92)                      (−2.79, −1.35) (95% CI)
1glimepiride 4 mg/day; 2Metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at least half maximum dose, of a sulphonylurea for at least 8 weeks prior to enrollment.
aRandomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.
bColumns 1 and 2, HbA1c analyzed using LOCF (see footnote d); Columns 3 and 4, HbA1c analyzed using 
LRM (see footnote e)
cLeast squares mean adjusted for baseline value
dLOCF: Last observation (prior to rescue for rescued subjects) carried forward eLRM: Longitudinal repeated measures analysis
*p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s) 

Table7. Results at Week 24 (LOCFa) in a placebo-controlled study of dapagliflozin in combination with insulin (alone or with oral glucose-lowering medicinal products) Parameter                        Dapagliflozin 10 mg + insulin ±    Placebo + insulin ± oral oral glucose-lowering medicinal glucose-lowering medicinal
products2                      products2
Nb                                             194                             193 HbA1c (%)                                      8.58                           8.46 Baseline (mean)                               -0.90                           -0.30 Change from baselinec                         -0.60*
Difference from placebo c
(-0.74, -0.45)
(95% CI)
Body weight (kg)                              94.63                           94.21 Baseline (mean)                               -1.67                           0.02 Change from baselinec                         -1.68*
Difference from placeboc                  (-2.19, -1.18)
(95% CI)
Mean daily insulin dose (IU)1                 77.96                           73.96 Baseline (mean)                               -1.16                           5.08 Change from baselinec                         -6.23*                          11.0 Difference from placebo c
(-8.84, -3.63)
(95% CI)                                      19.7**
Subjects with mean daily
insulin dose reduction of at
least 10% (%)
aLOCF:   Last observation (prior to or on the date of the first insulin up-titration, if needed) carried forward bAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-blind period
cLeast squares mean adjusted for baseline value and presence of oral glucose-lowering medicinal product *p-value < 0.0001 versus placebo + insulin ± oral glucose-lowering medicinal product **p-value < 0.05 versus placebo + insulin ± oral glucose-lowering medicinal product 1Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed if 
subjects met pre-defined FPG criteria.
2Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-lowering

medicinal product(s) in addition to insulin: Of this latter group, 80% were on metformin alone, 12% were on metformin plus sulphonylurea therapy, and the rest were on other oral glucose-lowering medicinal products.
In combination with metformin in drug-naive patients
A total of 1,236 drug-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 dapagliflozin (5 mg or 10 mg) in combination with metformin in drug-naive patients versus therapy with the monocomponents.

Treatment with dapagliflozin 10 mg in combination with metformin (up to 2000 mg per day) provided significant improvements in HbA1c compared to the individual components (Table 7), and led to greater reductions in fasting plasma glucose (FPG) (compared to the individual components) and body weight (compared to metformin).

Table 8: Results at Week 24 (LOCFa) in an active-controlled study of dapagliflozin and metformin combination therapy in drug-naive patients
Parameter              Dapagliflozin 10  Dapagliflozin 10     Metformin mg         mg
+
Metformin
Nb                           211b                219b               208b HbA1c (%)
Baseline (mean)               9.10                9.03               9.03 Change from                  -1.98               -1.45              -1.44 baselinec
Difference from             -0.53*
dapagliflozinc
(95% CI)                (−0.74, −0.32)
Difference from             −0.54*              −0.01
metforminc
(95% CI)                (−0.75, −0.33)       (−0.22, 0.20)
aLOCF:  last observation (prior to rescue for rescued patients) carried forward.
bAllrandomised patients who took at least one dose of double-blind study medication during the short-term double-blind period.
cLeast squares mean adjusted for baseline value.

*p-value <0.0001.

Combination therapy with prolonged-release exenatide
In a 28-week, double-blind, active comparator-controlled study, the combination of dapagliflozin and prolonged-release exenatide (a GLP-1 receptor agonist) was compared to dapagliflozin alone and prolonged-release exenatide alone in subjects with inadequate glycaemic control on metformin alone (HbA1c ≥ 8% and ≤ 12%). All treatment groups had a reduction in HbA1c compared to baseline. The combination treatment with dapagliflozin 10 mg and prolonged-release exenatide group showed superior reductions in HbA1c from baseline compared to dapagliflozin alone and prolonged-release exenatide alone (Table 9).

Table 9. Results of one 28-week study of dapagliflozin and prolonged-release exenatide versus dapagliflozin alone and prolonged-release exenatide alone, in combination with metformin (intent to treat patients)

Parameter                      Dapagliflozin 10       Dapagliflozin 10        Prolonged- mg                  mg QD+                release
QD +               Placebo QW           exenatide 2 mg
Prolonged-release                                  QW+
exenatide 2 mg                                Placebo QD
QW
N                                    228                    230                    227 HbA1c (%)
Baseline (mean)                      9.29                    9.25                  9.26 Change from baselinea                -1.98                  -1.39                 -1.60 Mean difference in                                         -0.59*                -0.38** change from baseline                                   (-0.84, -0.34)         (-0.63, -0.13) between combination

and single medicinal
product (95% CI)
Subjects (%) achieving               44.7                  19.1                  26.9 HbA1c < 7%
Body weight (kg)
Baseline (mean)                     92.13                  90.87                89.12 Change from baselinea               -3.55                   -2.22                -1.56 Mean difference in                                         -1.33*               -2.00* change from baseline                                   (-2.12, -0.55)       (-2.79, -1.20) between combination
and single medicinal
product (95% CI)
QD=once daily, QW=once weekly, N=number of patients, CI=confidence interval.
aAdjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline values
at Week 28 are modelled using a mixed model with repeated measures (MMRM) including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by week interaction as fixed factors, and baseline value as a covariate.
*p < 0.001, **p < 0.01.
P-values are all adjusted p-values for multiplicity.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study medicinal product.

Fasting plasma glucose
Treatment with dapagliflozin 10 mg as a monotherapy or as an add-on to either metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in FPG (-1.90 to -1.20 mmol/l [-34.2 to -21.7 mg/dl]) compared to placebo (-0.33 to 0.21 mmol/l [-6.0 to 3.8 mg/dl]). This effect was observed at Week 1 of treatment and maintained in studies extended through Week 104.


Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in significantly greater reductions in FPG at Week 28: -3.66 mmol/l (-65.8 mg/dl), compared to -2.73 mmol/l (-49.2 mg/dl) for dapagliflozin alone (p < 0.001) and -2.54 mmol/l (-45.8 mg/dl) for exenatide alone (p < 0.001).

In a dedicated study in diabetic patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2, treatment with dapagliflozin demonstrated reductions in FPG at Week 24: -1.19 mmol/L (-21.46 mg/dL) compared to -0.27 mmol/L (-4.87 mg/dL) for placebo (p=0.001).

Post-prandial glucose
Treatment with dapagliflozin 10 mg as an add-on to glimepiride resulted in statistically significant reductions in 2-hour post-prandial glucose at 24 weeks that were maintained up to Week 48.

Treatment with dapagliflozin 10 mg as an add-on to sitagliptin (with or without metformin) resulted in reductions in 2- hour post-prandial glucose at 24 weeks that were maintained up to Week 48.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in significantly greater reductions in 2-hour post-prandial glucose at Week 28 compared to either medicinal product alone.

Body weight
Dapagliflozin 10 mg as an add-on to metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant body weight reduction at 24 weeks (p < 0.0001, Tables 5 and 6). These effects were sustained in longer-term studies. At 48 weeks, the difference for dapagliflozin as add-on to sitagliptin (with or without metformin) compared with placebo was -2.22 kg. At 102 weeks, the difference for dapagliflozin as 

add-on to metformin compared with placebo, or as add-on to insulin compared with placebo was - 2.14 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 (p < 0.0001, Table 3) that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg, respectively).

The combination of dapagliflozin 10 mg and prolonged-release exenatide demonstrated significantly greater weight reductions compared to either medicinal product alone (Table 9).

A 24-week study in 182 diabetic subjects using dual energy X-ray absorptiometry (DXA) to evaluate body composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared with placebo plus metformin, respectively, in body weight and body fat mass as measured by DXA rather than lean tissue or fluid loss. Treatment with Forxiga plus metformin showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonance imaging substudy.

Blood pressure
In a pre-specified pooled analysis of 13 placebo-controlled studies, 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 placebo group at Week 24. Similar reductions were observed up to 104 weeks.

Combination therapy of dapagliflozin 10 mg and prolonged-release exenatide resulted in a significantly greater reduction in systolic blood pressure at Week 28 (-4.3 mmHg) compared to dapagliflozin alone (-1.8 mmHg, p < 0.05) and prolonged-release exenatide alone (-1.2 mmHg, p < 0.01).

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 HbA1c and decreased the placebo- corrected systolic blood pressure on average by 3.1 and 4.3 mmHg, respectively.

In a dedicated study in diabetic patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2, treatment with dapagliflozin demonstrated reductions in seated systolic blood pressure at Week 24: -4.8 mmHg compared to -1.7 mmHg for placebo (p < 0.05).

Glycaemic control in patients with Moderate renal impairment CKD 3A
(eGFR ≥ 45 to < 60 ml/min/1.73 m2)
The efficacy of dapagliflozin was assessed in a dedicated study in diabetic patients with an eGFR ≥ 45 to < 60 mL/min/1.73 m2 who had inadequate glycaemic control on usual care.
Treatment with dapagliflozin resulted in reductions in HbA1c and body weight compared with placebo
(Table 10).

Table 10. Results at Week 24 of a placebo-controlled study of dapagliflozin in diabetic patients
with an eGFR ≥ 45 to < 60 mL/min/1.73 m2



Dapagliflozina                     Placeboa
10 mg
Nb                                                               159                              161 HbA1c (%)
Baseline (mean)                                                    8.35                            8.03 Change from baselineb                                            -0.37                            -0.03 Difference from placebob                                          -0.34* (95% CI)                                                   (-0.53, -0.15) Body weight (kg)
Baseline (mean)                                                   92.51                          88.30 Percent change from baselinec                                     -3.42                          -2.02 Difference in percent change from placeboc                       -1.43* (95% CI)
(-2.15, -0.69)
a
Metformin or metformin hydrochloride were part of the usual care in 69.4% and 64.0% of the patients for the dapagliflozin and placebo groups, respectively.
b
Least squares mean adjusted for baseline value
c
Derived from least squares mean adjusted for baseline value
*
p<0.001

Patients with baseline HbA1c ≥ 9%
In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment with dapagliflozin 10 mg resulted in statistically significant reductions in HbA1c at Week 24 as a monotherapy (adjusted mean change from baseline: - 2.04% and 0.19% for dapagliflozin 10 mg and placebo, respectively) and as an add-on to metformin (adjusted mean change from baseline: -1.32% and -0.53% for dapagliflozin and placebo, respectively).
Cardiovascular and renal outcomes
Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicentre, randomised, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on cardiovascular outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular risk factors (age ≥ 55 years in men or ≥ 60 years in women and one or more of dyslipidaemia, hypertension or current tobacco use) or established cardiovascular disease.

Of 17,160 randomised patients, 6,974 (40.6%) had established cardiovascular disease and 10,186 (59.4%) did not have established cardiovascular disease. 8,582 patients were randomised 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 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 < 60 mL/min/1.73 m2, and 30.3% of patients had micro- or macroalbuminuria ( [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g, respectively).

Most patients (98%) used one or more diabetic medicinal products at baseline, including metformin (82%), insulin (41%) and sulfonylurea (43%),


The primary endpoints were time to first event of the composite of cardiovascular death, myocardial infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation for heart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint and all-cause mortality.

Major adverse cardiovascular events
Dapagliflozin 10 mg demonstrated non-inferiority versus placebo for the composite of cardiovascular death, myocardial infarction or ischaemic stroke (one-sided p < 0.001).

Heart failure or cardiovascular death
Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite of hospitalisation for heart failure or cardiovascular death (Figure 1). The difference in treatment effect was driven by hospitalisation for heart failure, with no difference in cardiovascular death (Figure 2).

The treatment benefit of dapagliflozin over placebo was observed both in patients with and without established cardiovascular disease, with and without heart failure at baseline, and was consistent across key subgroups, including age, gender, renal function (eGFR) and region.

Figure 1: Time to first occurrence of hospitalisation for heart failure or cardiovascular death 


Patients at risk is the number of patients at risk at the beginning of the period.
HR=Hazard ratio CI=Confidence interval.

Results on primary and secondary endpoints aredisplayed in Figure 2. 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.



Figure 2: Treatment effects for the primary composite endpoints and their components, and the secondary endpoints and components

Dapagliflozin    Placebo    Hazard Ratio        p-value
n (%)         n (%)      (95% CI)
(N=8582)      (N=8578)

Primary endpoints
Composite of hospitalisation for                                                               417 (4.9)     496 (5.8)   0.83 (0.73, 0.95)    0.005 heart failure/cardiovascular death

Composite of cardiovascular death/                                                             756 (8.8)     803 (9.4)   0.93 (0.84, 1.03)    0.172 myocardial infarction/ischaemic stroke


Components of the composite endpoints
Hospitalisation for heart failure                                                           212 (2.5)     286 (3.3)   0.73 (0.61, 0.88)    <0.001 Cardiovascular death                                                                        245 (2.9)     249 (2.9)   0.98 (0.82, 1.17)     0.830 Myocardial infarction                                                                       393 (4.6)     441 (5.1)   0.89 (0.77, 1.01)     0.080 Ischaemic stroke                                                                            235 (2.7)     231 (2.7)   1.01 (0.84, 1.21)     0.916 
Secondary endpoints
Renal composite endpoint
370 (4.3)     480 (5.6)   0.76 (0.67, 0.87)    <0.001
Renal components:
Sustained eGFR decrease                                                                     120 (1.4)     221 (2.6)   0.54 (0.43, 0.67)    <0.001 End-stage kidney disease                                                                     6 (<0.1)     19 (0.2)    0.31 (0.13, 0.79)     0.013 Renal death                                                                                  6 (<0.1)     10 (0.1)    0.60 (0.22, 1.65)     0.324 
All-cause mortality                                                                            529 (6.2)     570( 6.6)   0.93 (0.82, 1.04)    0.198 
Dapagliflozin Better               Placebo Better

0.2         0.4   0.6 0.8 1 1.2 1.6


Renal composite endpoint defined as: sustained confirmed ≥ 40% decrease in eGFR to eGFR <60 mL/min/1.73 m2 and/or end-stage kidney disease (dialysis ≥ 90 days or kidney transplantation, sustained confirmed eGFR < 15 mL/min/1.73 m2) and/or renal or cardiovascular death.
p-values are two-sided. p-values for the secondary endpoints and for single components are nominal. Time to first event was analysed in a Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint.
CI=confidence interval.

Nephropathy
Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, end-stage kidney disease, renal or cardiovascular death. The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, end-stage kidney disease and renal death (Figure 2).

The hazard ratio (HR) for time to nephropathy (sustained eGFR decrease, end-stage kidney 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 (HR 0.79 [95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (HR 1.82 [95% CI 1.51, 2.20]) compared with placebo

Heart Failure with Reduced Ejection Fraction

Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) 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% or less) to determine whether FORXIGA reduces the risk of cardiovascular death and worsening heart failure.
Of 4744 patients, 2373 were randomized to FORXIGA 10 mg and 2371 to placebo and were followed for a median of 18 months. The mean age of the study population was 66 years, 77% were male and 70% were White, 5% Black or African-American, and 24% Asian.
At baseline, 68% patients were classified as NYHA class II, 32% class III, and 1% class IV; median LVEF was 32%. History of type 2 diabetes mellitus was present in 42%, and an additional 3% had type 2 diabetes mellitus based on a HbA1c ≥6.5% at both enrollment and randomization.

At baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device.
FORXIGA reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (HR 0.74 [95% CI 0.65, 0.85]; p<0.0001). All three components of the primary composite endpoint individually contributed to the treatment effect. The FORXIGA and placebo event curves separated early and continued to diverge over the study period (Table 11, Figures 3A, 3B and 3C).

Table 11: Treatment Effect for the Primary Composite Endpoint*, its Components* and All-Cause Mortality in the DAPA-HF Study

Patients with events (event
rate)
Efficacy Variable                 FORXIGA 10 mg                  Placebo      Hazard ratio        p- (time to first occurrence)           N=2373                      N=2371        (95% CI)         value† Composite of Hospitalization for
502         0.74 (0.65,
Heart Failure, CV Death or          386 (11.6)                                                 <0.0001 (15.6)          0.85)
Urgent Heart Failure Visit
Composite of CV Death or                                           495         0.75 (0.65, 382 (11.4)                                                 <0.0001
Hospitalization for Heart Failure                                 (15.3)          0.85) Components of the composite endpoints‡
273        0.82 (0.69,
CV Death                                      227 (6.5)
(7.9)          0.98)
Hospitalization for Heart Failure                                  326        0.70 (0.59, 237 (7.1)
or Urgent Heart Failure Visit                                    (10.1)          0.83) 318        0.70 (0.59,
Hospitalization for Heart Failure             231 (6.9)
(9.8)          0.83)
0.43 (0.20,
Urgent Heart Failure Visit                    10 (0.3)          23 (0.7) 0.90)
276 (7.9)            329        0.83 (0.71,
All-Cause Mortality‡
(9.5)          0.97)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular.
* Full analysis set.
† Two-sided p-values.
NOTE: Time to first event was analyzed in a Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.



Figure 3: Kaplan-Meier Curves for the Primary Composite Endpoint (A), Cardiovascular Death (B), and Heart Failure Hospitalization (C) (DAPA-HF Study)
Figure 3A: Time to the First Occurrence of the Composite of Cardiovascular Death, Hospitalization for Heart Failure or Urgent Heart Failure Visit



NOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g. in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).
Patients at risk is the number of patients at risk at the beginning of the period.
HR=Hazard ratio, CI=Confidence interval.


Figure 3B: Time to the First Occurrence of Cardiovascular Death


Patients at risk is the number of patients at risk at the beginning of the period.
HR=Hazard ratio, CI=Confidence interval.


Figure 3C: Time to the First Occurrence of Heart Failure Hospitalization 


Patients at risk is the number of patients at risk at the beginning of the period.
HR=Hazard ratio, CI=Confidence interval.

FORXIGA reduced the total number of hospitalizations for heart failure (first and recurrent) events and CV death, with 567 and 742 total events in the FORXIGA-treated vs placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).
The results of the primary composite endpoint were consistent across the subgroups examined, including heart failure patients with and without type 2 diabetes mellitus (Figure 4).

Figure 4: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) Subgroup Analysis (DAPA-HF Study)



a   Hazard ratio estimates are not presented for subgroups with less than 15 events in total, both arms combined.
n/N# Number of subjects with event/number of subjects in the subgroup.
NT-proBNP = N-terminal pro b-type natriuretic peptide, HF = Heart failure, MRA = mineralocorticoid receptor antagonist, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate.
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.


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, NCT03036150) was an international, 
multicenter, randomized, double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria (urine albumin creatinine ratio [UACR] between 200 and 5000 mg/g) who were receiving standard of care background therapy, including a maximally tolerated, labeled daily dose of an angiotensin- converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding 6 months.

The primary objective was to determine whether FORXIGA reduces the incidence of the composite endpoint of ≥50% sustained decline in eGFR, progression to end-stage kidney disease (ESKD) (defined as sustained eGFR<15 mL/min/1.73 m2, initiation of chronic dialysis treatment or renal transplant), CV or renal death.

A total of 4304 patients were randomized equally to FORXIGA 10 mg or placebo and were followed for a median of 28.5 months.

The mean age of the study population was 62 years and 67% were male. The population was 53% White, 4% Black or African-American, and 34% Asian; 25% were of Hispanic or Latino ethnicity.

At baseline, mean eGFR was 43 mL/min/1.73 m2, 44% of patients had an eGFR 30 mL/min/1.73m2 to less than 45 mL/min/1.73m2, and 15% of patients had an eGFR less than 30 mL/min/1.73m2. Median UACR was 950 mg/g. A total of 68% of the patients had type 2 diabetes mellitus at randomization. The most common etiologies of CKD were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%).

At baseline, 97% of patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents, and 65% were on a statin.

FORXIGA reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, progression to ESKD, CV or renal death (HR 0.61 [95% CI 0.51,0.72]; p<0.0001). The FORXIGA and placebo event curves separate by Month 4 and continue to diverge over the study period. The treatment effect reflected a reduction in ≥50% sustained decline in eGFR, progression to ESKD, and CV death.
There were few renal deaths during the trial (Table 12, Figure 5).

FORXIGA also reduced the incidence of the composite endpoint of CV death or hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089) and all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035).


Table 12: Treatment Effect for the Primary Composite Endpoint, its Components, and Secondary Composite Endpoints, in the DAPA-CKD Study

Patients with events (event
rate)

Efficacy Variable                    FORXIGA 10 mg        Placebo       Hazard        p-value N=2152            N=2152         ratio
(time to first occurrence)                                             (95% CI) Composite of ≥50% sustained
0.61
eGFR decline, ESKD, CV or                197 (4.6)        312 (7.5)                   <0.0001 (0.51, 0.72)
renal death
0.53
≥50% sustained eGFR decline             112 (2.6)        201 (4.8)
(0.42, 0.67)


Table 12: Treatment Effect for the Primary Composite Endpoint, its Components, and Secondary Composite Endpoints, in the DAPA-CKD Study

Patients with events (event
rate)

Efficacy Variable                       FORXIGA 10 mg         Placebo        Hazard         p-value N=2152             N=2152           ratio
(time to first occurrence)                                                  (95% CI) 0.64
ESKD*                                      109 (2.5)         161 (3.8) (0.50, 0.82)
0.81
CV Death                                    65 (1.4)          80 (1.7) (0.58, 1.12)
Renal Death                                 2 (<0.1)          6 (0.3) ≥50% sustained eGFR decline,                                                   0.56 142 (3.3)         243 (5.8)                     <0.0001
ESKD or renal death                                                        (0.45, 0.68) CV death or Hospitalization for                                                0.71 100 (2.2)         138 (3.0)                      0.0089
Heart Failure                                                              (0.55, 0.92) 0.51
Hospitalization for Heart Failure           37 (0.8)          71 (1.6) (0.34, 0.76)
0.69
All-Cause Mortality                         101 (2.2)         146 (3.1)                      0.0035 (0.53, 0.88)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular, ESKD=End stage kidney disease.
* ESKD is defined as sustained eGFR<15 mL/min/1.73 m2, initiation of chronic dialysis treatment, or transplant.
NOTE: Time to first event was analyzed in a Cox proportional hazards model. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.
There were too few events of renal death to compute a reliable hazard ratio.



Figure 5: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Study)



Patients at risk is the number of subjects at risk at the beginning of the period. 1 month corresponds to 30 days. 2-sided p-value is displayed. HR, CI and p-value are from the Cox proportional hazard model.
HR=hazard ratio; CI=confidence interval; eGFR=estimated glomerular filtration rate; ESKD=end stage kidney disease; CV=cardiovascular; vs=versus.

The results of the primary composite endpoint were consistent across the subgroups examined, including CKD patients with and without type 2 diabetes mellitus, causes of CKD, age, biological sex, race, UACR, and eGFR.

DAPA-CKD enrolled a population with relatively advanced CKD at high risk of progression.
Exploratory analyses of a randomized, double-blind, placebo-controlled trial conducted to determine the effect of FORXIGA on CV outcomes (the DECLARE trial) support the conclusion that FORXIGA is also likely to be effective in patients with less advanced CKD.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax and AUC values following once daily 10 mg doses of dapagliflozin were 158 ng/ml and 628 ngh/ml, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high-fat meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by 
approximately 1 hour but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. Hence, Forxiga can be administered with or without food.

Distribution
Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 Liters.

Biotransformation
Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. 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 presents in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.

Elimination
The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 ml/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration of a 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in feces. In feces, approximately 15% of the dose was excreted as parent drug.

Linearity
Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.

Special populations
Renal impairment

At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin were 45%, 100% and 200% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type 2 diabetes.
Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment not result in a correspondingly higher 24-hour urinary glucose excretion.


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 subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of hemodialysis on dapagliflozin exposure is not known.


Hepatic impairment
In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax 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. In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.


Elderly (≥ 65 years)
There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. 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.


Paediatric population
Pharmacokinetics in the paediatric population have not been studied.

Gender
The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males.

Race
There were no clinically relevant differences in systemic exposures between White, Black or Asian races.

Body weight
Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.