JARDIANCE DUO®
Efficacy
JARDIANCE DUO® glycemic control studies
In patients with type 2 diabetes, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo. Reductions in HbA1c were observed across subgroups including age, gender, race, and baseline body mass index (BMI).
Empagliflozin add-on combination therapy with metformin
Patients with type 2 diabetes inadequately controlled on at least 1,500 mg of metformin hydrochloride 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, empagliflozin 10 mg, or empagliflozin 25 mg.
At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (Table 1).
Table 1. Results at week 24 from a placebo-controlled study for empagliflozin used in combination with metformin
| Empagliflozin 10 mg + Metformin N=217 |
Empagliflozin 25 mg + Metformin N=213 |
Placebo + Metformin N=207 |
|
|---|---|---|---|
| HbA1c (%)* | |||
| 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) | -0.6† (-0.7, -0.4) | -0.6† (-0.8, -0.5) | -- |
| Patients [n (%)] achieving HbA1c <7% | 75 (38%) | 74 (39%) | 23 (13%) |
| FPG (mg/dL)‡ | |||
| 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) | -2.0† (-2.6, -1.4) | -2.5† (-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 empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.
Empagliflozin initial combination therapy with metformin
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: empagliflozin 10 mg or 25 mg; metformin hydrochloride 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin hydrochloride; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin hydrochloride.
At Week 24, initial therapy of empagliflozin in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01), compared to the individual components.
Table 2. Glycemic parameters at 24 weeks in a study comparing empagliflozin and metformin to the individual components as initial therapy
| Empagliflozin 10 mg Metformin 1,000 mg§ N=161 |
Empagliflozin 10 mg + Metformin 2,000 mg§ N=167 |
Empagliflozin 25 mg + Metformin 1,000 mg§ N=165 |
Empagliflozin 25 mg + Metformin 2,000 mg§ N=169 |
Empagliflozin 10 mg N=169 |
Empagliflozin 25 mg N=163 |
Metformin 1,000 mga N=167 |
Metformin 2,000 mga N=162 |
|
|---|---|---|---|---|---|---|---|---|
| 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 empagliflozin (adjusted mean) (95% CI) | -0.6¶ (-0.9, -0.4) | -0.7¶ (-1.0, -0.5) | -0.6|| (-0.8, -0.3) | -0.7|| (-1.0, -0.5) | -- | -- | -- | -- |
| Comparison vs metformin (adjusted mean) (95% CI) | -0.8¶ (-1.0, -0.6) | -0.3¶ (-0.6, -0.1) | -0.8|| (-1.0, -0.5) | -0.3|| (-0.6, -0.1) | -- | -- | -- | -- |
| Patients [n (%)] achieving HbA1c <7% | 96 (63%) | 112 (70%) | 91 (57%) | 111 (68%) | 69 (43%) | 51 (32%) | 63 (38%) | 92 (58%) |
Empagliflozin add-on combination therapy with metformin and sulfonylurea
Patients with inadequately controlled type 2 diabetes on at least 1,500 mg per day of metformin hydrochloride 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, empagliflozin 10 mg, or empagliflozin 25 mg.
Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (Table 3).
Table 3. Results at week 24 from a placebo-Controlled Study for empagliflozin in combination with metformin and sulfonylurea (SU)
| Empagliflozin 10 mg + metformin + SU N=225 |
Empagliflozin 25 mg + metformin + SU N=216 |
Placebo + metformin + SU N=225 |
|
|---|---|---|---|
| HbA1c (%)** | |||
| 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) | -0.6†† (-0.8, -0.5) | -0.6†† (-0.7, -0.4) | - |
| Patients [n (%)] achieving HbA1c <7% | 55 (26%) | 65 (32%) | 20 (9%) |
| FPG (mg/dL)‡‡ | |||
| 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) | -2.4†† (-3.0, -1.8) | -2.7†† (-3.3, -2.1) | - |
Active-controlled study vs glimepiride in combination with metformin
Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2-week run-in period were randomized to glimepiride or empagliflozin 25 mg.1
At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG. The difference in observed effect size between empagliflozin 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.1
Table 4. Results at week 52 from an active-controlled study comparing empagliflozin to glimepiride as add-on therapy in patients inadequately controlled on metformin
| Empagliflozin 25 mg + Metformin (N=765) |
Glimepiride + Metformin (N=780) |
||
|---|---|---|---|
| HbA1c (%)§§ | |||
| Baseline (mean) | 7.9 | 7.9 | |
| Change from baseline (adjusted mean) | -0.7 | -0.7 | |
| Difference from glimepiride (adjusted mean) (97.5% CI) | -0.07¶¶ (-0.15, 0.01) | -- | |
| FPG (mg/dL)*** | |||
| Baseline (mean) | 150 | 156 | |
| 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) | -5.9|||| (-6.3, -5.5) | -- | |
Figure 1. Adjusted mean hba1c change at each time point (completers) and at week 52 (mitt population) - last observation on study (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).
Empagliflozin cardiovascular outcome study in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease
Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of JARDIANCE DUO® on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease has not been established. The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease.
Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (hazard ratio [HR]: 0.86; 95% CI 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of cardiovascular 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. Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.
Table 5. Treatment effect for the primary composite endpoint, and its component†††
| Placebo N=2,333 |
Empagliflozin N=4,687 |
Hazard ratio vs placebo (95% CI) |
|
|---|---|---|---|
| Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)‡‡‡ | 282 (12.1%) | 490 (10.5%) | 0.86 (0.74, 0.99) |
| Non-fatal myocardial infarction§§§ | 121 (5.2%) | 213 (4.5%) | 0.87 (0.70, 1.09) |
| Non-fatal stroke§§§ | 60 (2.6%) | 150 (3.2%) | 1.24 (0.92, 1.67) |
| Cardiovascular death§§§ | 137 (5.9%) | 172 (3.7%) | 0.62 (0.49, 0.77) |
Figure 2. Estimated cumulative incidence of first major adverse cardiovascular event (MACE)
Figure 3. Estimated cumulative incidence of cardiovascular death
The efficacy of empagliflozin on cardiovascular death was generally consistent across major demographic and disease subgroups, including patients with an eGFR of 30 to <45 ml/min/1.73 m2 (381 patients treated with JARDIANCE; 189 patients treated with placebo).
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 cardiovascular deaths. The non-cardiovascular deaths were only a small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).
Footnotes:
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BMI, body mass index; HR, hazard ratio; LOCF, last observation on study; SU, sulfonylurea; MACE, major adverse cardiovascular event.
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*
Modified intent to treat population. 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 empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
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†
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.)
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‡
FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207
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§
Metformin hydrochloride total daily dose, administered in two equally divided doses per day.
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¶
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).
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||
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).
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**
Metformin hydrochloride total daily dose, administered in two equally divided doses per day.
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††
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).
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‡‡
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).
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§§
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 empagliflozin 25 mg and glimepiride, respectively.
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¶¶
Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region)
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ANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
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***
FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779
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†††
Treated set (patients who had received at least one dose of study drug)
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‡‡‡
p−value for superiority (2−sided) 0.04
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§§§
Total number of events
Reference:
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JARDIANCE DUO® approved package insert. Updated in December 2020 and approved in June 2021.