14 CLINICAL STUDIES

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

JARDIANCE has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, linagliptin, and insulin. JARDIANCE has also been studied in patients with type 2 diabetes mellitus with mild or moderate renal impairment.

In adult patients with type 2 diabetes mellitus, treatment with JARDIANCE reduced hemoglobin A1c (HbA1c), compared to placebo. The reduction in HbA1c for JARDIANCE compared with placebo was observed across subgroups including sex, race, geographic region, baseline BMI and duration of disease.

Monotherapy

A total of 986 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE monotherapy.

Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, JARDIANCE 10 mg, JARDIANCE 25 mg, or a reference comparator.

At Week 24, treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), fasting plasma glucose (FPG), and body weight compared with placebo (see Table 5 and Figure 3).

Table 5 Results at Week 24 From a Placebo-Controlled Monotherapy Trial of JARDIANCE
	JARDIANCE 10 mg N=224	JARDIANCE 25 mg N=224	Placebo N=228
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 9.4%, 9.4%, and 30.7% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA derived p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=223, for JARDIANCE 25 mg, n=223, and for placebo, n=226
HbA1c (%)a
Baseline (mean)	7.9	7.9	7.9
Change from baseline (adjusted mean)	-0.7	-0.8	0.1
Difference from placebo (adjusted mean) (97.5% CI)	-0.7b (-0.9, -0.6)	-0.9b (-1.0, -0.7)	--
Patients [n (%)] achieving HbA1c <7%	72 (35%)	88 (44%)	25 (12%)
FPG (mg/dL)c
Baseline (mean)	153	153	155
Change from baseline (adjusted mean)	-19	-25	12
Difference from placebo (adjusted mean) (95% CI)	-31 (-37, -26)	-36 (-42, -31)	--
Body Weight
Baseline (mean) in kg	78	78	78
% change from baseline (adjusted mean)	-2.8	-3.2	-0.4
Difference from placebo (adjusted mean) (95% CI)	-2.5b (-3.1, -1.9)	-2.8b (-3.4, -2.2)	--

Figure 3 Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT Population) - LOCF

At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -2.6 mmHg (placebo-adjusted, p-value=0.0231) in patients randomized to 10 mg of JARDIANCE and by -3.4 mmHg (placebo-corrected, p-value=0.0028) in patients randomized to 25 mg of JARDIANCE.

Add-On Combination Therapy with Metformin

A total of 637 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE in combination with metformin.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin per day entered an open-label 2-week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.

At Week 24, treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 6).

Table 6 Results at Week 24 From a Placebo-Controlled Trial for JARDIANCE used in Combination with Metformin
	JARDIANCE 10 mg N=217	JARDIANCE 25 mg N=213	Placebo N=207
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=216, for JARDIANCE 25 mg, n=213, and for placebo, n=207
HbA1c (%)a
Baseline (mean)	7.9	7.9	7.9
Change from baseline (adjusted mean)	-0.7	-0.8	-0.1
Difference from placebo + metformin (adjusted mean) (95% CI)	-0.6b (-0.7, -0.4)	-0.6b (-0.8, -0.5)	--
Patients [n (%)] achieving HbA1c <7%	75 (38%)	74 (39%)	23 (13%)
FPG (mg/dL)c
Baseline (mean)	155	149	156
Change from baseline (adjusted mean)	-20	-22	6
Difference from placebo + metformin (adjusted mean)	-26	-29	--
Body Weight
Baseline mean in kg	82	82	80
% change from baseline (adjusted mean)	-2.5	-2.9	-0.5
Difference from placebo (adjusted mean) (95% CI)	-2.0b (-2.6, -1.4)	-2.5b (-3.1, -1.9)	--

At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE 25 mg.

Initial Combination Therapy with Metformin

A total of 1,364 patients with type 2 diabetes mellitus participated in a double-blind, randomized, active-controlled trial to evaluate the efficacy of JARDIANCE in combination with metformin as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized to one of 8 active-treatment arms: JARDIANCE 10 mg or 25 mg; metformin 1,000 mg, or 2,000 mg; JARDIANCE 10 mg in combination with 1,000 mg or 2,000 mg metformin; or JARDIANCE 25 mg in combination with 1,000 mg or 2,000 mg metformin.

At Week 24, initial therapy of JARDIANCE in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 7).

Table 7 Glycemic Parameters at 24 Weeks in a Trial Comparing JARDIANCE and Metformin to the Individual Components as Initial Therapy
	JARDIANCE 10 mg + Metformin 1,000 mga N=161	JARDIANCE 10 mg + Metformin 2,000 mga N=167	JARDIANCE 25 mg + Metformin 1,000 mga N=165	JARDIANCE 25 mg + Metformin 2,000 mga N=169	JARDIANCE 10 mg N=169	JARDIANCE 25 mg N=163	Metformin 1,000 mga N=167	Metformin 2,000 mga N=162
aMetformin total daily dose, administered in two equally divided doses per day. bp-value ≤0.0062 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c). cp-value ≤0.0056 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).
HbA1c (%)
Baseline (mean)	8.7	8.7	8.8	8.7	8.6	8.9	8.7	8.6
Change from baseline (adjusted mean)	-2.0	-2.1	-1.9	-2.1	-1.4	-1.4	-1.2	-1.8
Comparison vs JARDIANCE (adjusted mean) (95% CI)	-0.6b (-0.9, -0.4)	-0.7b (-1.0, -0.5)	-0.6c (-0.8, -0.3)	-0.7c (-1.0, -0.5)	--	--	--	--
Comparison vs metformin (adjusted mean) (95% CI)	-0.8b (-1.0, -0.6)	-0.3b (-0.6, -0.1)	-0.8c (-1.0, -0.5)	-0.3c (-0.6, -0.1)	--	--	--	--

Add-On Combination Therapy with Metformin and Sulfonylurea

A total of 666 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes mellitus on at least 1,500 mg per day of metformin and on a sulfonylurea, entered a 2-week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.

Treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 8).

Table 8 Results at Week 24 from a Placebo-Controlled Trial for JARDIANCE in Combination with Metformin and Sulfonylurea
	JARDIANCE 10 mg N=225	JARDIANCE 25 mg N=216	Placebo N=225
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=225, for JARDIANCE 25 mg, n=215, for placebo, n=224
HbA1c (%)a
Baseline (mean)	8.1	8.1	8.2
Change from baseline (adjusted mean)	-0.8	-0.8	-0.2
Difference from placebo (adjusted mean) (95% CI)	-0.6b (-0.8, -0.5)	-0.6b (-0.7, -0.4)	--
Patients [n (%)] achieving HbA1c <7%	55 (26%)	65 (32%)	20 (9%)
FPG (mg/dL)c
Baseline (mean)	151	156	152
Change from baseline (adjusted mean)	-23	-23	6
Difference from placebo (adjusted mean)	-29	-29	--
Body Weight
Baseline mean in kg	77	78	76
% change from baseline (adjusted mean)	-2.9	-3.2	-0.5
Difference from placebo (adjusted mean) (95% CI)	-2.4b (-3.0, -1.8)	-2.7b (-3.3, -2.1)	--

In Combination with Linagliptin as Add-On to Metformin Therapy

A total of 686 patients with type 2 diabetes mellitus participated in a double-blind, active-controlled trial to evaluate the efficacy of JARDIANCE 10 mg or 25 mg in combination with linagliptin 5 mg compared to the individual components.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin per day entered a single-blind placebo run-in period for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized 1:1:1:1:1 to one of 5 active-treatment arms of JARDIANCE 10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with 10 mg or 25 mg JARDIANCE as a fixed-dose combination tablet.

At Week 24, JARDIANCE 10 mg or 25 mg used in combination with linagliptin 5 mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0.001) compared to the individual components in patients who had been inadequately controlled on metformin. Treatment with JARDIANCE/linagliptin 25 mg/5 mg or JARDIANCE/linagliptin 10 mg/5 mg daily also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg (p-value <0.0001). There was no statistically significant difference in body weight compared to JARDIANCE alone.

Active-Controlled Trial versus Glimepiride in Combination with Metformin

The efficacy of JARDIANCE was evaluated in a double-blind, glimepiride-controlled, trial in 1,545 patients with type 2 diabetes mellitus with insufficient glycemic control despite metformin therapy.

Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2-week run-in period were randomized to glimepiride or JARDIANCE 25 mg.

At Week 52, JARDIANCE 25 mg and glimepiride lowered HbA1c and FPG (see Table 9, Figure 4). The difference in observed effect size between JARDIANCE 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%. The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day.

Table 9 Results at Week 52 from an Active-Controlled Trial Comparing JARDIANCE to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin
	JARDIANCE 25 mg N=765	Glimepiride N=780
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to JARDIANCE 25 mg and glimepiride, respectively. bNon-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region) cANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) dFPG (mg/dL); for JARDIANCE 25 mg, n=764, for glimepiride, n=779
HbA1c (%)a
Baseline (mean)	7.9	7.9
Change from baseline (adjusted mean)	-0.7	-0.7
Difference from glimepiride (adjusted mean) (97.5% CI)	-0.07b (-0.15, 0.01)	--
FPG (mg/dL)d
Baseline (mean)	150	150
Change from baseline (adjusted mean)	-19	-9
Difference from glimepiride (adjusted mean)	-11	--
Body Weight
Baseline mean in kg	82.5	83
% change from baseline (adjusted mean)	-3.9	2.0
Difference from glimepiride (adjusted mean) (95% CI)	-5.9c (-6.3, -5.5)	--

Figure 4 Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) - LOCF

At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride. The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).

At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for JARDIANCE 25 mg and -0.66% for glimepiride. The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%. The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day. The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data. Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputed for JARDIANCE 25 mg and 12.9% for glimepiride.

At Week 104, JARDIANCE 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for JARDIANCE 25 mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).

Add-On Combination Therapy with Pioglitazone with or without Metformin

A total of 498 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE in combination with pioglitazone, with or without metformin.

Patients with inadequately controlled type 2 diabetes mellitus on metformin at a dose of at least 1,500 mg per day and pioglitazone at a dose of at least 30 mg per day were placed into an open-label placebo run-in for 2 weeks. Patients with inadequate glycemic control and an HbA1c between 7% and 10% after the run-in period were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.

Treatment with JARDIANCE 10 mg or 25 mg daily resulted in statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 10).

Table 10 Results of Placebo-Controlled Trial for JARDIANCE in Combination Therapy with Pioglitazone
	JARDIANCE 10 mg N=165	JARDIANCE 25 mg N=168	Placebo N=165
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 10.9%, 8.3%, and 20.6% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=163
HbA1c (%)a
Baseline (mean)	8.1	8.1	8.2
Change from baseline (adjusted mean)	-0.6	-0.7	-0.1
Difference from placebo + pioglitazone (adjusted mean) (95% CI)	-0.5b (-0.7, -0.3)	-0.6b (-0.8, -0.4)	--
Patients [n (%)] achieving HbA1c <7%	36 (24%)	48 (30%)	12 (8%)
FPG (mg/dL)c
Baseline (mean)	152	152	152
Change from baseline (adjusted mean)	-17	-22	7
Difference from placebo + pioglitazone (adjusted mean) (97.5% CI)	-23b (-31.8, -15.2)	-28b (-36.7, -20.2)	--
Body Weight
Baseline mean in kg	78	79	78
% change from baseline (adjusted mean)	-2.0	-1.8	0.6
Difference from placebo (adjusted mean) (95% CI)	-2.6b (-3.4, -1.8)	-2.4b (-3.2, -1.6)	--

Add-On Combination with Insulin with or without Metformin and/or Sulfonylureas

A total of 494 patients with type 2 diabetes mellitus inadequately controlled on insulin, or insulin in combination with oral drugs participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE as add-on therapy to insulin over 78 weeks.

Patients entered a 2-week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or sulfonylurea background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of JARDIANCE 10 mg, JARDIANCE 25 mg, or placebo. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment. For the remaining 60 weeks, insulin could be adjusted. The mean total daily insulin dose at baseline for JARDIANCE 10 mg, 25 mg, and placebo was 45 IU, 48 IU, and 48 IU, respectively.

JARDIANCE used in combination with insulin (with or without metformin and/or sulfonylurea) provided statistically significant reductions in HbA1c and FPG compared to placebo after both 18 and 78 weeks of treatment (see Table 11). JARDIANCE 10 mg or 25 mg daily also resulted in statistically significantly greater percent body weight reduction compared to placebo.

Table 11 Results at Week 18 and 78 for a Placebo-Controlled Trial for JARDIANCE in Combination with Insulin
	18 weeks (no insulin adjustment)			78 weeks (adjustable insulin dose after 18 weeks)
	JARDIANCE 10 mg N=169	JARDIANCE 25 mg N=155	Placebo N=170	JARDIANCE 10 mg N=169	JARDIANCE 25 mg N=155	Placebo N=170
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. At Week 78, 32.5%, 38.1% and 42.4% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, and region; FPG: MMRM model includes baseline FPG, baseline HbA1c, treatment, region, visit and visit by treatment interaction. Body weight: MMRM model includes baseline body weight, baseline HbA1c, treatment, region, visit and visit by treatment interaction. cp-value=0.0049 dp-value=0.0052 ep-value=0.0463
HbA1c (%)a
Baseline (mean)	8.3	8.3	8.2	8.3	8.3	8.2
Change from baseline (adjusted mean)	-0.6	-0.7	0	-0.4	-0.6	0.1
Difference from placebo (adjusted mean) (97.5% CI)	-0.6b (-0.8, -0.4)	-0.7b (-0.9, -0.5)	--	-0.5b (-0.7, -0.3)	-0.7b (-0.9, -0.5)	--
Patients (%) achieving HbA1c <7%	18.0	19.5	5.5	12.0	17.5	6.7
FPG (mg/dL)
Baseline (mean)	138	146	142	138	146	142
Change from baseline (adjusted mean, SE)	-17.9 (3.2)	-19.1 (3.3)	10.4 (3.1)	-10.1 (3.2)	-15.2 (3.4)	2.8 (3.2)
Difference from placebo (adjusted mean) (95% CI)	-28.2b (-37.0, -19.5)	-29.5b (-38.4, -20.6)	--	-12.9c (-21.9, 3.9)	-17.9b (-27.0, -8.8)	--
Body Weight
Baseline mean in kg	92	95	90	92	95	90
% change from baseline (adjusted mean)	-1.8	-1.4	-0.1	-2.4	-2.4	0.7
Difference from placebo (adjusted mean) (95% CI)	-1.7d (-3.0, -0.5)	-1.3e (-2.5, -0.0)	--	-3.0b (-4.4, -1.7)	-3.0b (-4.4, -1.6)	--

Add-on Combination with MDI Insulin with or without Metformin

A total of 563 patients with type 2 diabetes mellitus inadequately controlled on multiple daily injections (MDI) of insulin (total daily dose >60 IU), alone or in combination with metformin, participated in a double-blind, placebo-controlled trial to evaluate the efficacy of JARDIANCE as add-on therapy to MDI insulin over 18 weeks.

Patients entered a 2-week placebo run-in period on MDI insulin with or without metformin background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of JARDIANCE 10 mg, JARDIANCE 25 mg, or placebo. Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment. The mean total daily insulin dose at baseline for JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo was 88.6 IU, 90.4 IU, and 89.9 IU, respectively.

JARDIANCE 10 mg or 25 mg daily used in combination with MDI insulin (with or without metformin) provided statistically significant reductions in HbA1c compared to placebo after 18 weeks of treatment (see Table 12).

Table 12 Results at Week 18 for a Placebo-Controlled Trial for JARDIANCE in Combination with Insulin and with or without Metformin
	JARDIANCE 10 mg N=186	JARDIANCE 25 mg N=189	Placebo N=188
aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 18. At Week 18, 23.7%, 22.8% and 23.4% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, geographical region, and background medication).
HbA1c (%)a
Baseline (mean)	8.4	8.3	8.3
Change from baseline (adjusted mean)	-0.9	-1.0	-0.5
Difference from placebo (adjusted mean) (95% CI)	-0.4b (-0.6, -0.3)	-0.5b (-0.7, -0.4)	--

During an extension period with treatment for up to 52 weeks, insulin could be adjusted to achieve defined glucose target levels. The change from baseline in HbA1c was maintained from 18 to 52 weeks with both JARDIANCE 10 mg and 25 mg. After 52 weeks, JARDIANCE 10 mg or 25 mg daily resulted in statistically greater percent body weight reduction compared to placebo (p-value <0.0001). The mean change in body weight from baseline was -1.95 kg for JARDIANCE 10 mg, and -2.04 kg for JARDIANCE 25 mg.

Renal Impairment

A total of 738 patients with type 2 diabetes mellitus and a baseline eGFR less than 90 mL/min/1.73 m2 participated in a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of JARDIANCE in patients with type 2 diabetes mellitus and renal impairment. The trial population comprised of 290 patients with mild renal impairment (eGFR 60 to less than 90 mL/min/1.73 m2), 374 patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and 74 with severe renal impairment (eGFR less than 30 mL/min/1.73 m2). A total of 194 patients with moderate renal impairment had a baseline eGFR of 30 to less than 45 mL/min/1.73 m2 and 180 patients had a baseline eGFR of 45 to less than 60 mL/min/1.73 m2.

At Week 24, JARDIANCE 25 mg provided statistically significant reduction in HbA1c relative to placebo in patients with mild to moderate renal impairment (see Table 13). A statistically significant reduction relative to placebo was also observed with JARDIANCE 25 mg in patients with either mild [-0.7 (95% CI: -0.9, -0.5)] or moderate [-0.4 (95% CI: -0.6, -0.3)] renal impairment and with JARDIANCE 10 mg in patients with mild [-0.5 (95% CI: -0.7, -0.3)] renal impairment.

The glucose lowering efficacy of JARDIANCE 25 mg decreased with decreasing level of renal function in the mild to moderate range. Least square mean HbA1c changes at 24 weeks were -0.6%, -0.5%, and -0.2% for those with a baseline eGFR of 60 to less than 90 mL/min/1.73 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73 m2, respectively [see Dosage and Administration (2) and Use in Specific Populations (8.6)]. For placebo, least square mean HbA1c changes at 24 weeks were 0.1%, -0.1%, and 0.2% for patients with a baseline eGFR of 60 to less than 90 mL/min/1.73 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73 m2, respectively.

Table 13 Results at Week 24 (LOCF) of Placebo-Controlled Trial for JARDIANCE in Adults with Type 2 Diabetes Mellitus and Renal Impairment
	Mild and Moderate Impairmentb
	JARDIANCE 25 mg
ap-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication) beGFR 30 to less than 90 mL/min/1.73 m2 - Modified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 24.6% and 26.2% was imputed for patients randomized to JARDIANCE 25 mg and placebo, respectively.
HbA1c
Number of patients	n=284
Comparison vs placebo (adjusted mean) (95% CI)	-0.5a (-0.6, -0.4)

For patients with severe renal impairment, the analyses of changes in HbA1c and FPG showed no discernible treatment effect of JARDIANCE 25 mg compared to placebo [see Indications and Usage (1), Dosage and Administration (2.1, 2.2) and Use in Specific Populations (8.6)].

14.2 Glycemic Control Trial in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus

DINAMO (NCT03429543) was a 26-week, double-blind, randomized, placebo-controlled, parallel group trial, with a double-blind active treatment safety extension period up to 52 weeks to assess the efficacy of JARDIANCE. The trial enrolled pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c 6.5 to 10.5%). Patients treated with metformin (at least 1,000 mg daily or maximally tolerated dose), with or without insulin therapy, and those with a history of intolerance to metformin therapy were enrolled. Patients were randomized to 3 treatment arms (JARDIANCE 10 mg, a dipeptidyl peptidase-4 (DPP-4) inhibitor or placebo), over 26 weeks. Patients in the JARDIANCE 10 mg group who failed to achieve HbA1c <7.0% at Week 12 underwent a second randomization at Week 14 to remain on the 10 mg dose or increase to 25 mg. Patients on placebo were re-randomized at Week 26 to one of the JARDIANCE doses (10 mg or 25 mg) or a DPP-4 inhibitor.

A total of 157 patients were treated with either JARDIANCE (10 mg or 25 mg; N=52), a DPP-4 inhibitor (N=52), or placebo (N=53). Background therapies as adjunct to diet and exercise included metformin (51%), a combination of metformin and insulin (40.1%), insulin (3.2%), or none (5.7%). The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years. The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older. Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity. The mean BMI was 36.0 kg/m2 and mean BMI Z-score was 3.0. Patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled in the trial. Approximately 25% of the study population had microalbuminuria or macroalbuminuria.

At Week 26, treatment with JARDIANCE was superior in reducing HbA1c from baseline versus placebo (see Table 14).

Table 14 Results at Week 26 for a Placebo-Controlled Trial for JARDIANCE in Combination with Metformin and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitusa
	JARDIANCE 10 mg and 25 mg	Placebo
aModified intent-to-treat set (All randomized and treated patients with baseline measurement). bMultiple imputations using placebo wash-out approach with 500 iterations for missing data. Imputed for HbA1c (Jardiance N=5 (9.6 %), Placebo N=3 (5.7%)), for FPG (Jardiance N=4 (8.3%), Placebo N=2 (3.8%)). cLeast-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value and baseline age stratum (< 15 years vs 15 to < 18 years). dNot evaluated for statistical significance, not part of sequential testing procedure. ep-value=0.0116 (two-sided)
HbA1c (%)b
Number of patients	n=52	n=53
Baseline (mean)	8.0	8.1
Change from baselinec	-0.2	0.7
Difference from placeboc (95% CI)	-0.8e (-1.5, -0.2)	--
FPG (mg/dL)b,d
Number of patients	n=48	n=52
Baseline (mean)	154	159
Change from baselinec	-19	17
Difference from placeboc (95% CI)	-36 (-60.7, -10.7)	--

14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

The effect of JARDIANCE on cardiovascular (CV) risk in adult patients with type 2 diabetes mellitus and established, stable, atherosclerotic CV disease was evaluated in the EMPA-REG OUTCOME trial, a multicenter, multinational, randomized, double-blind parallel group trial. The trial compared the risk of experiencing a major adverse cardiovascular event (MACE) between JARDIANCE and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic CV disease. Concomitant antidiabetic medications were to be kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7,020 patients were treated (JARDIANCE 10 mg = 2,345; JARDIANCE 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years. Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.

All patients in the trial had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes mellitus for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators, respectively and the mean eGFR was 74 mL/min/1.73 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).

All patients had established atherosclerotic CV disease at baseline including one (82%) or more (18%) of the following: a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a CV death or a non-fatal myocardial infarction (MI) or a non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

JARDIANCE significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of CV death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 15 and Figures 5 and 6). Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dosage groups.

Table 15 Treatment Effect for the Primary Composite Endpoint and its Componentsa
	Placebo N=2,333	JARDIANCE N=4,687	Hazard ratio vs placebo (95% CI)
aTreated set (patients who had received at least one dose of trial drug) bp-value for superiority (2-sided) 0.04 cTotal number of events
Composite of CV death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b	282 (12.1%)	490 (10.5%)	0.86 (0.74, 0.99)
Non-fatal myocardial infarctionc	121 (5.2%)	213 (4.5%)	0.87 (0.70, 1.09)
Non-fatal strokec	60 (2.6%)	150 (3.2%)	1.24 (0.92, 1.67)
CV deathc	137 (5.9%)	172 (3.7%)	0.62 (0.49, 0.77)

Figure 5 Estimated Cumulative Incidence of First MACE

Figure 6 Estimated Cumulative Incidence of CV Death

The efficacy of JARDIANCE on CV death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as CV deaths. The non-CV deaths were only a small proportion of deaths and were balanced between the treatment groups (2.1% in patients treated with JARDIANCE, and 2.4% of patients treated with placebo).

14.4 Heart Failure Trials in Adults

EMPEROR-Reduced (NCT03057977) was a double-blind trial conducted in adults with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy of JARDIANCE as adjunct to standard of care heart failure therapy.

Of 3,730 patients, 1,863 were randomized to JARDIANCE 10 mg and 1,867 to placebo and were followed for a median of 16 months. The mean age of the trial population was 67 years (range: 25 to 94 years) and 76% were men, 24% were women, and 27% were 75 years of age or older. Approximately 71% of the trial population were White, 18% Asian, and 7% Black or African American. At baseline, 50% of the patients had type 2 diabetes mellitus.

At randomization, 75% of patients were NYHA class II, 24% were class III, and 0.5% were class IV. The mean LVEF was 28%. At baseline, the mean eGFR was 62 mL/min/1.73 m2 and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g. Approximately half of the patients (52%) had eGFR equal to or above 60 mL/min/1.73 m2, 24% had eGFR 45 to less than 60 mL/min/1.73 m2, 19% had eGFR 30 to less than 45 mL/min/1.73 m2, and 5% had eGFR 20 to less than 30 mL/min/1.73 m2.

At baseline, 88% of patients were treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or angiotensin receptor-neprilysin inhibitors (ARNI), 95% with beta-blockers, 71% with mineralocorticoid receptor antagonists (MRA), and 95% with diuretics.

The primary endpoint was the time to first event of either cardiovascular (CV) death or hospitalization for heart failure (HHF). First and recurrent HHF was assessed as a key secondary endpoint.

JARDIANCE was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalization for heart failure compared with placebo, mostly through a reduction in hospitalization for heart failure. JARDIANCE reduced the risk of first and recurrent HHF (see Table 16 and Figures 7 and 8).

Table 16 Treatment Effect for the Primary Composite Endpoint, its Components, and Key Secondary Endpoints
	Placebo N=1,867	JARDIANCE 10 mg N=1,863	Hazard ratio vs placebo (95% CI)	p-value
	Number of Patients (%)
	aTime to first event bIncludes deaths following hospitalization cJoint frailty model accounting for CV death
CV death or HHFa	462 (24.7%)	361 (19.4%)	0.75 (0.65, 0.86)	<0.0001
CV deatha,b	202 (10.8%)	187 (10.0%)	0.92 (0.75, 1.12)
HHFa	342 (18.3%)	246 (13.2%)	0.69 (0.59, 0.81)
	Number of Events
First and recurrent HHFc	553	388	0.70 (0.58, 0.85)	0.0003

Figure 7 Time to First Occurrence of the Primary Composite Endpoint of CV Death or Hospitalization for Heart Failure

Figure 8 Time to Event of Hospitalization for Heart Failure (First and Recurrent)

The results of the primary composite were generally consistent across the pre-specified subgroups (see Figure 9).

Figure 9 Treatment Effects for the Primary Composite Endpoint (CV Death and Hospitalization for Heart Failure) Subgroup Analysis (EMPEROR-Reduced)

LVEF >30%: Includes both above and below the median NT-proBNP. To be eligible for inclusion, patients with an LVEF >30% were required to meet a higher NT-proBNP threshold than those with LVEF ≤30%, unless they additionally had a history of HHF within the past 12 months.

EMPEROR-Preserved (NCT03057951) was a double-blind trial conducted in adults with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy of JARDIANCE as adjunct to standard of care therapy.

Of 5,988 patients, 2,997 were randomized to JARDIANCE 10 mg and 2,991 to placebo and were followed for a median of 26 months. The mean age of the trial population was 72 years (range: 22 to 100 years) and 55% were men, 45% were women, and 43% were 75 years of age or older. Approximately 76% of the trial population were White, 14% Asian, and 4% Black or African American.

At randomization, 82% of patients were NYHA class II, 18% were class III, and 0.3% were class IV. The EMPEROR-Preserved trial population included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%). At baseline, the mean eGFR was 61 mL/min/1.73 m2 and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g. Approximately half of the patients (50%) had eGFR equal to or above 60 mL/min/1.73 m2, 26% had eGFR 45 to less than 60 mL/min/1.73 m2, 19% had eGFR 30 to less than 45 mL/min/1.73 m2, and 5% had eGFR 20 to less than 30 mL/min/1.73 m2.

At baseline, 81% of patients were treated with ACE inhibitors, ARBs, or ARNI, 86% with beta-blockers, 38% with MRAs, and 86% with diuretics.

The primary endpoint was the time to first event of either CV death or HHF. First and recurrent HHF was assessed as a key secondary endpoint.

JARDIANCE was superior in reducing the risk of the primary composite endpoint compared with placebo, mostly through a reduction in hospitalization for heart failure. JARDIANCE reduced the risk of first and recurrent HHF (see Table 17 and Figures 10 and 11).

Table 17 Treatment Effect for the Primary Composite Endpoint, its Components, and Key Secondary Endpoints
	Placebo N=2,991	JARDIANCE 10 mg N=2,997	Hazard ratio vs placebo (95% CI)	p-value
	Number of Patients (%)
	aTime to first event bIncludes deaths following hospitalization cJoint frailty model accounting for CV death
CV death or HHFa	511 (17.1%)	415 (13.8%)	0.79 (0.69, 0.90)	0.0003
CV deatha,b	244 (8.2%)	219 (7.3%)	0.91 (0.76, 1.09)
HHFa	352 (11.8%)	259 (8.6%)	0.71 (0.60, 0.83)
	Number of Events
First and recurrent HHFc	541	407	0.73 (0.61, 0.88)	0.0009

Figure 10 Time to First Occurrence of the Primary Composite Endpoint of CV Death or Hospitalization for Heart Failure

Figure 11 Time to Event of Hospitalization for Heart Failure (First and Recurrent)

The results of the primary composite endpoint were consistent across the pre-specified subgroups (see Figure 12).

Figure 12 Treatment Effects for the Primary Composite Endpoint (CV Death or Hospitalization for Heart Failure) Subgroup Analysis (EMPEROR-Preserved)

14.5 Chronic Kidney Disease Trial in Adults

EMPA-KIDNEY (NCT03594110) was a randomized, double-blind, placebo-controlled trial conducted in adults with chronic kidney disease (eGFR ≥20 to <45 mL/min/1.73 m2; or eGFR ≥45 to <90 mL/min/1.73 m2 with urine albumin to creatinine ratio [UACR] ≥200 mg/g). The trial excluded patients with polycystic kidney disease or patients requiring intravenous immunosuppressive therapy in the preceding three months or >45 mg of prednisone (or equivalent) at the time of screening. The primary objective of the trial was to assess the effects of empagliflozin as an adjunct to standard of care therapy, including RAS-inhibitor therapy when appropriate, on time to kidney disease progression or cardiovascular death.

A total of 6,609 patients, were equally randomized to JARDIANCE 10 mg or placebo and were followed for a median of 24 months.

The mean age of the study population was 63 years (range: 18 to 94 years) and 67% were male. Approximately 58% of the study population were White, 36% Asian, and 4% Black or African American. Approximately 44% of the patients had type 2 diabetes mellitus.

At baseline, the mean eGFR was 37 mL/min/1.73 m2, 21% of patients had an eGFR equal to or above 45 mL/min/1.73 m2, 44% had an eGFR 30 to less than 45 mL/min/1.73 m2, and 35% had an eGFR less than 30 mL/min/1.73 m2. The median UACR was 329 mg/g, 20% of patients had a UACR <30 mg/g, 28% had a UACR 30 to ≤300mg/g, and 52% had a UACR >300 mg/g. Approximately 1% of patients had type 1 diabetes at baseline. The most common etiologies of CKD were diabetic nephropathy/diabetic kidney disease (31%), glomerular disease (25%), hypertensive/renovascular disease (22%) and other/unknown (22%).

At baseline, 85% of patients were treated with ACE inhibitor or ARB, 64% with statins, and 34% with antiplatelet agents.

JARDIANCE was superior to placebo in reducing the risk of the primary composite endpoint of sustained ≥40% eGFR decline, sustained eGFR <10 mL/min/1.73 m2, progression to end-stage kidney disease, or CV or renal death. The treatment effect reflected a reduction in a sustained ≥40% eGFR decline, sustained eGFR <10 mL/min/1.73 m2, progression to end-stage kidney disease, and CV death. There were few renal deaths during the trial. JARDIANCE also reduced the risk of first and recurrent hospitalization (see Table 18 and Figure 13); information collected on the reason for hospitalization was insufficient to further characterize the benefit.

Table 18 Treatment Effect for the Primary Composite Endpoint, its Components and Key Secondary Endpoints
	Placebo N=3,305	JARDIANCE 10 mg N=3,304	Hazard ratio vs placebo (95% CI)	p-value
CV=Cardiovascular, eGFR=Estimated glomerular filtration rate, ESKD=End-stage kidney disease
aESKD is defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
bThere were too few events of renal death to compute a reliable hazard ratio.
cInformation collected on the reason for hospitalization was insufficient to further characterize the benefit.
	Number of Patients (%)
Composite of sustained ≥40% eGFR decline, sustained eGFR <10 mL/min/1.73 m2, ESKDa, or CV or renal death (time to first occurrence)	558 (16.9)	432 (13.1)	0.72 (0.64, 0.82)	<0.0001
Sustained ≥40% eGFR decline	474 (14.3)	359 (10.9)	0.70 (0.61, 0.81)
ESKDa or sustained eGFR <10 mL/min/1.73 m2	221 (6.7)	157 (4.8)	0.69 (0.56, 0.84)
Renal deathb	4 (0.1)	4 (0.1)
CV death	69 (2.1)	59 (1.8)	0.84 (0.60, 1.19)
	Number of Events
First and recurrent hospitalization c	1,895	1,611	0.86 (0.78, 0.95)	0.0025

Figure 13 Time to First Occurrence of the Primary Composite Endpoint, Sustained ≥40% eGFR Decline, Sustained eGFR <10 mL/min/1.73 m2, ESKD or Renal Death, or CV Death

The results of the primary composite endpoint were generally consistent across the pre-specified subgroups examined, including eGFR categories, underlying cause of kidney disease, diabetes status, or background use of RAS inhibitors (see Figure 14). The treatment benefit with JARDIANCE on the primary composite endpoint was not evident in patients with very low levels of albuminuria, however there were few events in these patients.

Figure 14 Treatment Effects for the Primary Composite Endpoint (Sustained ≥40% eGFR Decline, Sustained eGFR <10 mL/min/1.73 m2, ESKD or Renal Death, or CV Death) Subgroup Analysis (EMPA-KIDNEY)

*=Trend test