Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Design

Randomized, double-blind, placebo-controlled trial 

N = 7,020

Objective

To assess the effect of once-daily empagliflozin (at a dose of either 10 mg or 25 mg) versus placebo on cardiovascular events in adults with type 2 diabetes at high cardiovascular risk agianst a background of standard care

Study Groups

Placebo (n = 2,333)

Empagliflozin 10 mg (n = 2,345)

Empagliflozin 25 mg (n = 2,342)

Inclusion Criteria

Adults (≥ 18 years of age) with type 2 diabetes (Hemoglobin [Hgb] A1c 7-10%), a body-mass index (BMI) ≤ 45 kg/m², estimated glomerular filtration rate (eGFR) of ≥ 30 mL/min/1.73m²

Exclusion Criteria

Uncontrolled hyperglycemia (fasting glucose >240 mg/dL), liver disease, planned cardiac surgery or angioplasty within 3 months, eGFR < 30mL/min/1.73m², recent gastrointestinal surgery that induces chronic malabsorption, blood dyscrasias, history of malignancy, treatment with anti-obesity drugs in the last 3 months, treatment with systemic steroids, any uncontrolled endocrine disorder except type 2 diabetes

Methods

Eligible patients underwent a 2-week, open-label, placebo run-in period in which background glucose-lowering therapy was unchanged. They were then randomized 1:1:1 to receive either empagliflozin 10 mg or 25 mg or placebo once daily. Background glucose-lowering therapy was to remain unchanged for the first 12 weeks after randomization, although intensification was permitted if the patient had a confirmed fasting glucose level of > 240 mg/dL.

After week 12, investigators were encouraged to adjust glucose-lowering therapy at their discretion to achieve glycemic control according to local guidelines. Throughout the trial, investigators were encouraged to treat other cardiovascular risk factors (including dyslipidemia and hypertension) to achieve the best available standard of care. Patients were instructed to attend the clinic at prespecified times, which included a follow-up visit 30 days after the end of treatment.

Duration

The trial continued until an adjudicated primary outcome event had occurred in at least 691 patients: 3 years

Outcome Measures

Primary: a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent myocardial infarction), or nonfatal stroke

Secondary: a composite of the primary outcome plus hospitalization for unstable angina

Baseline Characteristics

Placebo (n = 2,333)

Empagliflozin 10 mg (n = 2,345)

 Empagliflozin 25 mg (n = 2,342)

Age, years

Male

White

Hgb A1c, %

BMI, kg/m²

Antidiabetic therapy

Metformin

Insulin

Sulfonylurea

DPP-4 inhibitor

GLP-1 agonist

74.3%

48.6%

42.5%

11.4%

3%

73.7%

48.3%

42%

12%

12%2.9%

73.9%

47.8%

43.9%

10.5%

2.5%

Results

Placebo (n = 2,333)

Empagliflozin 10 mg (n = 2,345)

Empagliflozin 25 mg (n = 2,342)

p-value

Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina

All-cause mortality

Adverse Events

Hypoglycemic event (27.9% vs 28% vs 27.9%); urinary tract infection (1.8% vs 1.4% vs 2%); genial infection (1.8% vs 6.5% vs 6.3%); volume depletion (4.9% vs 4.9% vs 5.3%)

Serious Adverse Events: 42.3% vs. 37.4% vs. 39.0%

Percentage that Discontinued due to Adverse Events: 19.4% vs. 17.7% vs. 17.0%

Study Author Conclusions

In conclusion, patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had significantly lower rates of the primary composite cardiovascular outcome and of death from any cause than did those in the placebo group when the study drugs were added to standard care.

InpharmD Researcher Critique

Overall this study was conducted well, it provided strong data to support the long-term use of empagliflozin as well as strong evidence for a reduction in cardiovascular risk. This study also included analysis of smaller adverse events such as genital infections (more common in empagliflozin groups; specifically in females) and ruled out concern regarding renal safety.

Strengths include the large sample size, broad site involvement (42 countries), as well as multiple treatment groups. A weakness is the inclusion of patients may have differing regimens when it comes to insulin, statins, anti-coagulation, or anti-hypertensive therapy. This, alongside medication adherence, may have an influence on patient outcomes. Other weaknesses include the use of a composite endpoint that may have been misleading and a strict exclusion criteria.

Impact of empagliflozin Added on to Basal insulin in Type 2 Diabetes Inadequately Controlled on Basal insulin

Design

Randomized, double-blind, placebo-controlled phase IIb trial 

N = 494

Objective

To evaluate the efficacy, safety, and tolerability of add-on therapy with empagliflozin (10 and 25 mg once daily) versus placebo over 78 weeks in patients with type 2 diabetes inadequately controlled on basal insulin, with or without metformin and/or sulfonylureas

Study Groups

Placebo (n = 170)

Empagliflozin 10 mg (n = 169)

Empagliflozin 25 mg (n = 155)

Inclusion Criteria

Adults with a body mass index (BMI) ≤ 45 kg/m² and inadequately controlled type 2 diabetes (hemoglobin A1c [HbA1c] 7-10%), despite treatment with basal glargine or detemir insulin (≥ 20 units per day) or Neutral Protamine Hagedorn (NPH) insulin (≥ 14 units per day), with or without metformin and/or sulfonylurea (SU) use

Exclusion Criteria

Uncontrolled hyperglycemia (> 240 mg/dL) after an overnight fast, frequent hypoglycemic events on basal insulin therapy; myocardial infarction, stroke, or transient ischemic attack < 3 months before consent; estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m²; bariatric surgery; chronic short-acting insulin or glucagon-like peptide -1 receptor agonists within 3 months of consent

Methods

After a 2-week open-label placebo run-in period, eligible patients were randomized (1:1:1) to receive once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo, as an add-on to basal insulin, with or without metformin and/or sulfonylureas, for 78 weeks.

For the first 18 weeks, patients were to remain on a fixed dose of basal insulin; during the subsequent 60 weeks, the insulin dose was to be adjusted at the discretion of the investigator for any fasting plasma glucose level > 110 mg/dL. Metformin and/or sulfonylurea were to remain unchanged. Study visits were scheduled at screening; at the start of the placebo run-in period; and at weeks 0, 6, 12, 18, 30, 42, 54, 66, and 78 of treatment followed by a follow-up visit at week 82.

Duration

Treatment: 78 weeks

Follow-up: 82 weeks

Outcome Measures

Primary: change from baseline in HbA1c at week 18

Secondary: changes from baseline to week 78 in basal insulin dose and HbA1c, changes from baseline to weeks 18 and 78 in fasting blood glucose and body weight, and percentage of patients with HbA1c ≥ 7% at baseline who had HbA1c < 7% at weeks 18 and 78

Baseline Characteristics

Placebo (n = 170)

Empagliflozin 10mg (n = 169)

Age, years

Female

White

BMI, kg/m²

HbA1c, %

Antidiabetic medications

Insulin + metformin

Insulin + metformin + SU

Insulin only

Insulin + SU

36%

40%

14%

10%

41%

40%

9%

9%

45%

37%

7%

11%

Results

Placebo (n = 170)

Empagliflozin 10mg (n = 169)

Empagliflozin 25 mg (n = 155)

p-value*

Change from baseline in HbA1c

Changes from baseline to week 78 in:

Basal insulin dose, units

HbA1c, %

Fasting plasma glucose, mmol/L

Body weight, kg

5.5 ± 1.6

0.0 ± 0.1

0.2 ± 0.2

0.7 ± 0.5

-1.5 ± 1.5

-0.5 ± 0.1

-0.6 ± 0.2

-2.2 ± 0.5

-0.5 ± 1.6

-0.6 ± 0.1

-0.8 ± 0.2

-2.0 ± 0.5

0.002, 0.009

<0.001

0.005, <0.001

<0.001

Percentage of patients with HbA1c < 7%**

Week 18

Week 78

5.5%

6.7%

18.0%

12.0%

19.5%

17.5%

<0.001

0.099, 0.002

*versus placebo

**Of patients who had HbA1c ≥ 7% at baseline

Adverse Events

Common Adverse Events: Hypoglycemic events 33% vs 33% vs 35%

Serious Adverse Events: 16% vs 17% vs 18%

Percentage that Discontinued due to Adverse Events: 8% vs 11% vs 13%

Study Author Conclusions

In conclusion, in basal insulin-treated patients with type 2 diabetes with inadequate glycaemic control, empagliflozin 10 and 25 mg once daily for 78 weeks provided improvements in glycemic control, with a similar risk of hypoglycemia to placebo, and with reductions in body weight and blood pressure. Empagliflozin was well tolerated except for an increase in genitourinary side effects.

InpharmD Researcher Critique

Study limitations include no forced titration of insulin thus leading to insulin doses not being optimized as a whole, lack of a strict treat-to-target design which, as a result, the full impact of empagliflozin on glucose control and insulin dose could not be established, no control for changes in the use of antihypertensive drugs which may have influenced the effects observed on blood pressure, and lastly only three-quarters of the patients completed the 78-week treatment duration. 

Strengths of this study include, compared to prior studies, a more homogenous patient population in regard to only basal insulin being allowed. Further improvements include the acknowledgment of important findings such as a reduction of 0.7% HbA1c equating to 2kg weight loss (normally -1.0% = -2kg) and the theory that adding empagliflozin empirically to insulin regimens may improve adherence vs insulin-only regimens resulting in patients gaining weight and thus negatively impacting adherence. 

Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus

Design

Randomized, parallel-group, phase III study

N= 1,160

Objective

Study Groups

Empagliflozin 10 mg (n= 548)

Empagliflozin 25 mg (n= 549)

Open-label metformin (n= 63)

Inclusion Criteria

Age ≥ 20 years; body mass index (BMI) ≤ 45 kg/m² and HbA1c concentration ≥ 7.0 and ≤ 10.0% at screening despite treatment with an oral antidiabetic agent (sulfonylurea [SU], biguanide, thiazolidinedione [TZD], 𝛼-glucosidase inhibitor [AGI], dipeptidyl-peptidase-4 [DPP-4] inhibitor or glinide)

Exclusion Criteria

Uncontrolled hyperglycemia (> 240 mg/dL) after overnight fast; estimated glomerular filtration rate (eGFR) during screening or run-in < 60 mL/min/1.73 m² on biguanide or < 30 mL/min/1.73 m² on other therapies; on anti-obesity drugs < 12 weeks before enrollment; treated with systemic corticosteroids or change in thyroid dose hormone < 6 weeks before enrollment; patients on sulfonylurea contraindicated to metformin

Methods

After an initial 2-week placebo run-in period to determine compliance, patients were randomized to receive either empagliflozin 10 mg or 25 mg. The ratio of randomization was 1:1 for those on oral anti-diabetic medication other than sulfonylurea. Patients on sulfonylurea were randomized 2:2:1 to receive empagliflozin 10 mg, 25 mg, or open-label metformin immediate-release increased to > 1000 mg/day (max dose 2,250 mg/day).

Duration

Outcome Measures

Primary: safety as defined by reported adverse events and changes in vital signs and clinical laboratory values

Secondary: Change in baseline HbA1c at week 52, fasting plasma glucose (FPG)

Baseline Characteristics

Empagliflozin 10 mg (n= 548)

Empagliflozin 25 mg (n= 549)

Age, years

SU

Biguanide

TZD

AGI

DPP-4 inhibitor

Glinide

61.3 ± 9.9

56.9 ± 9.5

60.4 ± 10.1

63.5 ± 8.8

63.3 ± 9.9

59.2 ± 12.1

61.8 ± 9.6

57.3 ± 11.4

59.7 ± 9.9

61.9 ± 11.7

59.1 ± 10.3

57.7 ± 11.8

HbA1c

SU

Biguanide

TZD

AGI

DPP-4 inhibitor

Glinide

79.9% ± 0.73%

7.68% ± 0.74%

7.85% ± 0.74%

7.78% ± 0.68%

7.78% ± 0.68%

8.01% ± 0.85%

8.06% ± 0.76%

7.51% ± 0.73%

7.95% ± 0.84%

7.56% ± 0.59%

7.82% ± 0.74%

7.98% ± 0.84%

Fasting plasma glucose, mg/dL

SU

Biguanide

TZD

AGI

DPP-4 inhibitor

Glinide

150.6 ± 27.2

142.6 ± 27.7

149.6 ± 29.0

148.3 ± 26.1

146.1 ± 26.4

159.8 ± 31.5

155.7 ± 34.0

136.6 ± 28.7

150.9 ± 28.6

146.9 ± 22.4

145.0 ± 25.0

163.4 ± 31.8

Results

Empagliflozin 10 mg (n= 548)

Empagliflozin 25 mg (n= 549)

Drug-related adverse events

SU

Biguanide

TZD

AGI

DPP-4 inhibitor

Glinide

14.0%

19.1%

14.6%

10.1%

13.2%

12.9%

18.2%

13.8%

14.0%

7.1%

25.4%

12.9%

 Hypoglycemia

SU

Biguanide

TZD

AGI

DPP-4 inhibitor

Glinide

4.4%

0

1.5%

0

0

0

6.6%

1.5%

0.7%

0

1.4%

2.9%

Change from baseline in HbA1c, range between all groups

-0.77% ± 0.06% to -1.00% ± 0.06%

Change from baseline in fasting blood glucose, range between all groups, mg/dL

-16.4 ± 1.8 to -33.1 ± 2.2

Study Author Conclusions

InpharmD Researcher Critique

As the study was performed in Japan, the results may not be applicable to the U.S. population. The changes in HbA1c were not differentiated between the dosing groups, instead, primarily presented as graphs. There were instances where the 10 mg dose reduced HbA1c greater than the 20 mg group, particularly in those taking oral DPP-4 Inhibitor and AGI anti-diabetic medications; possibly implying comparative efficacy between the dosing groups. Yet this suggestion needs to be further investigated.

Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

Design

Multicenter, randomized, placebo-controlled, phase-3 trial

N= 899

Objective

Study Groups

Placebo (n= 228)

Empagliflozin 10 mg (n= 224)

Empagliflozin 25 mg (n= 224)

Sitagliptin (n= 223)

Inclusion Criteria

Exclusion Criteria

Uncontrolled hyperglycemia, estimated glomerular filtration rate < 50 mL/min/1.73m², treated with anti-obesity drugs in the past 3 months, treated with systemic steroids at the time of informed consent, change in thyroid hormone dose 6 weeks before consent, any other uncontrolled endocrine disorder aside from type 2 diabetes

Methods

Patients were randomized (1:1:1:1) to receive oral empagliflozin 10 mg, 25 mg, sitagliptin 100 mg, or placebo once daily. Patients with HbA1c > 10.0% were placed in the open-label empagliflozin 25 mg group without a placebo run-in. There were four visits throughout the study period.

Duration

Outcome Measures

Primary: change in HbA1c from baseline to week 24

Secondary: change in fasting plasma glucose, change from baseline in body weight at week 24

Baseline Characteristics

Placebo (n= 228)

Empagliflozin 10 mg (n= 224)

Age, years

Female

White

Asian

33%

64%

34%

64%

33%

64%

34%

64%

33%

61%

Body mass index, kg/m²

28.7

28.3

28.2

28.2

28.2

HbA1c

7.91%

7.87%

77.8%

79.3%

11.50%

Fasting plasma glucose, mmol/L

8.59

8.48

8.47

8.16

12.76

Systolic blood pressure, mm Hg

Diastolic blood pressure, mm Hg

130.4

78.9

133.0

79.2

129.9

78.3

132.5

80.1

129.5

81.0

Estimated glomerular filtration rate, mL/min/1.73m²

86.8

87.7

87.6

87.6

94.7

Results

Endpoint

Placebo (n= 228)

Empagliflozin 10 mg (n= 224)

Empagliflozin 25 mg (n= 224)

Sitagliptin (n= 223)

HbA1c at week 24 (95% confidence interval [CI])

Change from baseline (95% CI)

7.98% (7.84 to 8.12)

0.08% (-0.03 to 0.18)

7.21% (7.10 to 7.32)

-0.66 (-0.76 to -0.56)

7.09% (6.98 to 7.21)

-0.78% (-0.88 to -0.67)

7.20% (7.08 to 7.33)

-0.66% (-0.76 to -0.56)

7.55% (7.24 to 7.86)

-3.70% (-4.11 to -3.29)

Patients who reached HbA1c < 7.0% at week 24

Odds ratio vs placebo (95% CI; p-value)

Odds ratio vs sitagliptin (95% CI; p-value)

--

--

4.12 (2.44 to 6.97; p<0.0001)

0.87 (0.56 to 1.33; p=0.5138)

6.15 (3.65 to 10.36; p<0.0001)

1.29 (0.85 to 1.97; p=0.2349)

4.76 (2.81 to 8.06; p<0.0001)

--

--

--

Change from baseline in fasting plasma glucose, mmol/L (95% CI)

Change from baseline in body weight, kg

Patients who experienced one or more drug-related adverse events

One or more serious adverse event

Hypoglycemia

Study Author Conclusions

InpharmD Researcher Critique