Jardiance (Page 5 of 7)

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from a 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from a 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with a metabolic pathway predominantly present in the male mouse kidney.

Mutagenesis
Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.

Impairment of Fertility
Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

14  CLINICAL STUDIES

14.1 Glycemic Control

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 with mild or moderate renal impairment.

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

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

Treatment-naïve patients with inadequately controlled type 2 diabetes 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 4 and Figure 3).

Table 4 Results at Week 24 From a Placebo-Controlled Monotherapy Study of JARDIANCE
a Modified intent to treat population. Last observation on study (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.b ANCOVA 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.)c FPG (mg/dL); for JARDIANCE 10 mg, n=223, for JARDIANCE 25 mg, n=223, and for placebo, n=226
JARDIANCE10 mgN=224 JARDIANCE25 mgN=224 PlaceboN=228
HbA1c (%)a
Baseline (mean)7.97.97.9
Change from baseline (adjusted mean)-0.7-0.80.1
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)153153155
Change from baseline (adjusted mean)-19-2512
Difference from placebo (adjusted mean) (95% CI)-31 (-37, -26)-36 (-42, -31)
Body Weight
Baseline (mean) in kg787878
% 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

Figure 3
(click image for full-size original)

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 participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin.

Patients with type 2 diabetes inadequately controlled on at least 1500 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 5).

Table 5 Results at Week 24 From a Placebo-Controlled Study for JARDIANCE used in Combination with Metformin
a Modified intent to treat population. Last observation on study (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.b ANCOVA 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.)c FPG (mg/dL); for JARDIANCE 10 mg, n=216, for JARDIANCE 25 mg, n=213, and for placebo, n=207
JARDIANCE10 mg + MetforminN=217 JARDIANCE25 mg + MetforminN=213 Placebo + MetforminN=207
HbA1c (%)a
Baseline (mean)7.97.97.9
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)155149156
Change from baseline (adjusted mean)-20-226
Difference from placebo + metformin (adjusted mean)-26-29
Body Weight
Baseline mean in kg828280
% 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 1364 patients with type 2 diabetes participated in a double-blind, randomized, active-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes 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 1000 mg, or 2000 mg; JARDIANCE 10 mg in combination with 1000 mg or 2000 mg metformin; or JARDIANCE 25 mg in combination with 1000 mg or 2000 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 6).

Table 6 Glycemic Parameters at 24 Weeks in a Study Comparing JARDIANCE and Metformin to the Individual Components as Initial Therapy
a Metformin total daily dose, administered in two equally divided doses per day.b p-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).c p-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).
JARDIANCE10 mg +Metformin1000 mga N=161JARDIANCE10 mg +Metformin2000 mga N=167JARDIANCE25 mg +Metformin1000 mga N=165JARDIANCE25 mg +Metformin2000 mga N=169JARDIANCE10 mgN=169 JARDIANCE25 mgN=163 Metformin1000 mga N=167Metformin2000 mga N=162
HbA1c (%)
Baseline (mean)8.78.78.88.78.68.98.78.6
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 participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes on at least 1500 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 7).

Table 7 Results at Week 24 from a Placebo-Controlled Study for JARDIANCE in Combination with Metformin and Sulfonylurea
a Modified intent to treat population. Last observation on study (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.b ANCOVA 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.)c FPG (mg/dL); for JARDIANCE 10 mg, n=225, for JARDIANCE 25 mg, n=215, for placebo, n=224
JARDIANCE10 mg + Metformin+ SUN=225 JARDIANCE 25 mg + Metformin+ SUN=216 Placebo + Metformin + SUN=225
HbA1c (%)a
Baseline (mean)8.18.18.2
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)151156152
Change from baseline (adjusted mean)-23-236
Difference from placebo (adjusted mean)-29-29
Body Weight
Baseline mean in kg777876
% 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 participated in a double-blind, active-controlled study to evaluate the efficacy and safety of JARDIANCE 10 mg or 25 mg in combination with linagliptin 5 mg compared to the individual components.

Patients with type 2 diabetes inadequately controlled on at least 1500 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 Study versus Glimepiride in Combination with Metformin The efficacy of JARDIANCE was evaluated in a double-blind, glimepiride-controlled, study in 1545 patients with type 2 diabetes 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 8, 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 dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day.

Table 8 Results at Week 52 from an Active-Controlled Study Comparing JARDIANCE to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin
a Modified intent to treat population. Last observation on study (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.b Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region)c ANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)d FPG (mg/dL); for JARDIANCE 25 mg, n=764, for placebo, n=779
JARDIANCE 25 mg + MetforminN=765 Glimepiride + MetforminN=780
HbA1c (%)a
Baseline (mean)7.97.9
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)150150
Change from baseline (adjusted mean)-19-9
Difference from glimepiride (adjusted mean)-11
Body Weight
Baseline mean in kg82.583
% change from baseline (adjusted mean)-3.92.0
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

Figure 4
(click image for full-size original)

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 dose of glimepiride was 2.7 mg and the maximal approved dose 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 participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with pioglitazone, with or without metformin.

Patients with inadequately controlled type 2 diabetes on metformin at a dose of at least 1500 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 9).

Table 9 Results of Placebo-Controlled Study for JARDIANCE in Combination Therapy with Pioglitazone
a Modified intent to treat population. Last observation on study (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.b ANCOVA 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.)c FPG (mg/dL); for JARDIANCE 10 mg, n=163
JARDIANCE 10 mg +PioglitazoneN=165 JARDIANCE 25 mg +PioglitazoneN=168 Placebo + PioglitazoneN=165
HbA1c (%)a
Baseline (mean)8.18.18.2
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)152152152
Change from baseline (adjusted mean)-17-227
Difference from placebo + pioglitazone (adjusted mean) (97.5% CI)-23b (-31.8, -15.2)-28b (-36.7, -20.2)
Body Weight
Baseline mean in kg787978
% change from baseline (adjusted mean)-2.0-1.80.6
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 inadequately controlled on insulin, or insulin in combination with oral drugs participated in a double-blind, placebo-controlled study 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 10). JARDIANCE 10 mg or 25 mg daily also resulted in statistically significantly greater percent body weight reduction compared to placebo.

Table 10 Results at Week 18 and 78 for a Placebo-Controlled Study for JARDIANCE in Combination with Insulin
a Modified intent to treat population. Last observation on study (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.b ANCOVA 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.c p-value=0.0049d p-value=0.0052e p-value=0.0463
18 weeks(no insulin adjustment) 78 weeks(adjustable insulin dose after 18 weeks)
JARDIANCE10 mg +InsulinN=169 JARDIANCE25 mg +InsulinN=155 Placebo + InsulinN=170 JARDIANCE10 mg +InsulinN=169 JARDIANCE25 mg +InsulinN=155 Placebo + InsulinN=170
HbA1c (%)a
Baseline (mean)8.38.38.28.38.38.2
Change from baseline (adjusted mean)-0.6-0.70-0.4-0.60.1
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%18.019.55.512.017.56.7
FPG (mg/dL)
Baseline (mean)138146142138146142
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 kg929590929590
% change from baseline (adjusted mean)-1.8-1.4-0.1-2.4-2.40.7
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 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 study 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 11).

Table 11 Results at Week 18 for a Placebo-Controlled Study for JARDIANCE in Combination with Insulin and with or without Metformin
a Modified intent to treat population. Last observation on study (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. b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, geographical region, and background medication).
JARDIANCE 10 mg + Insulin +/- MetforminN=186 JARDIANCE 25 mg + Insulin +/- MetforminN=189 Placebo + Insulin +/- MetforminN=188
HbA1c (%)a
      Baseline (mean)8.48.38.3
      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 and a baseline eGFR less than 90 mL/min/1.73 m2 participated in a randomized, double-blind, placebo-controlled, parallel-group to evaluate the efficacy and safety of JARDIANCE in patients with type 2 diabetes 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 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 12). 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 Hb1Ac 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 12 Results at Week 24 (LOCF) of Placebo-Controlled Study for JARDIANCE in Patients with Type 2 Diabetes and Renal Impairment
a p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication)b eGFR 30 to less than 90 mL/min/1.73 m2 — Modified intent to treat population. Last observation on study (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.
Mild and Moderate Impairmentb
JARDIANCE 25 mg
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 Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

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