What is the comparative effect on blood sugar and A1C lowering with empagliflozin at doses 10 mg, 12.5 mg, and 25 mg?

Comment by InpharmD Researcher

Available evidence suggests that empagliflozin provides clinically meaningful reductions in blood glucose and HbA1c at doses of 10 mg and 25 mg, with most analyses demonstrating similar glycemic efficacy between these doses and only small, inconsistent numerical differences favoring 25 mg (Tables 1-11). HbA1c reductions are generally in the range of approximately 0.6–0.8% with both doses, and fasting plasma glucose lowering follows a comparable pattern, indicating a limited dose–response effect beyond 10 mg for glycemic outcomes. Data on a 12.5 mg dose is limited but also indicates HbA1c lowering comparable to both 10 mg and 25 mg, without a clear incremental glycemic benefit.

Pubmed: empagliflozin 10 mg, 12.5 mg, and 25 mg

Background

A 2021 network meta-analysis evaluated the efficacy and safety of empagliflozin at various dosages in patients with type 2 diabetes mellitus (T2DM). The analysis incorporated data from 23 randomized controlled trials involving 10,518 patients. The study aimed to discern the optimal dosing strategy for empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, widely used for its cardiovascular benefits and hypoglycemic effects. The comprehensive search spanned eight databases, filtering for studies that compared at least two empagliflozin doses and reported pharmacodynamic and adverse event outcomes. The meta-analysis demonstrated that higher daily doses (10, 25, 50 mg) of empagliflozin were significantly superior in lowering hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) compared to lower doses (1, 2.5, 5 mg). The 25 mg dose emerged as the most effective in balancing efficacy and safety, particularly after 12 weeks of treatment. The study also highlighted a dose-response relationship where adverse effects increased with higher doses. Despite these findings, empagliflozin was well-tolerated overall, with the most common adverse events being hypoglycemia and urogenital infections. The analysis concluded that while higher doses of empagliflozin offer enhanced glycemic control, careful monitoring for adverse effects is necessary, especially at the higher end of the dosing spectrum. [1]

Previously, a 2018 meta-analysis of 15 randomized controlled studies (N= 7,891) compared empagliflozin 10 and 25 mg for various efficacy outcomes in patients with type 2 diabetes mellitus. The weighted mean difference (WMD) HbA1c change from baseline was similar between dosing groups with a reduction of -0.61% for empagliflozin 10 mg (95% confidence interval [CI] -0.66 to -0.55) and reduction of -0.63% (95% CI -0.69 to -0.57) (p= 0.59). Other efficacy outcomes were also similar, including HbA1c reduction in patients with HbA1c <7%, reduction in fasting plasma glucose, reduction in body weight, reduction in systolic/diastolic blood pressure, and the percentage of patients who achieve controlled blood pressure. [2]

References: [1] Wu Q, Liu M, Fang Z, et al. Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials. J Clin Pharm Ther. 2022;47(3):270-286. doi:10.1111/jcpt.13521
[2] Zhang YJ, Han SL, Sun XF, et al. Efficacy and safety of empagliflozin for type 2 diabetes mellitus: Meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018;97(43):e12843. doi:10.1097/MD.0000000000012843
Literature Review

A search of the published medical literature revealed 11 studies investigating the researchable question:

What is the comparative effect on blood sugar and A1C lowering with empagliflozin at doses 10 mg, 12.5 mg, and 25 mg?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-11 for your response.

 

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

 63.2 ± 8.8 63.0 ± 8.6 63.2 ± 8.6  

Male

72% 70.5% 71.9%  

White

 71.9% 72.8% 72.4%  

Hgb A1c, %

 8.08% ± 0.84 8.07% ± 0.86 8.06% ± 0.84  

BMI, kg/m²

 30.7 ± 5.2 30.6 ± 5.2 30.6 ± 5.3  

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

 12.1% 10.4% 10.5% 0.04*

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

 14.3% 12.8% 12.8% 0.08*

All-cause mortality

 8.3% 5.8% 5.6% <0.001
*for superiority

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.



References:
[1] Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

 

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)

 Empagliflozin 25 mg (n = 155)  

Age, years

 58.1 ± 9.4 58.6 ± 9.8 59.9 ± 10.5  

Female

47% 45% 40%  

White

 66% 70% 72%  

BMI, kg/m²

 31.8 ± 6.0 32.1 ± 5.8 32.7 ± 5.9  

HbA1c, %

 8.2 ± 0.8 8.3 ± 0.8 8.3 ± 0.8  

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

 0.0% ± 0.1 -0.6% ± 0.1 -0.7% ± 0.1 <0.001

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. 



References:
[1] Rosenstock J, Jelaska A, Zeller C, et al. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2015;17(10):936-948. doi:10.1111/dom.12503

 

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

 To evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM)

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

 52 weeks

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

 In Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c.

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.



References:
[1] Araki E, Tanizawa Y, Tanaka Y, et al. Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17(7):665-674. doi:10.1111/dom.12464

 

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

 To investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks

Study Groups

Placebo (n= 228)

Empagliflozin 10 mg (n= 224)

Empagliflozin 25 mg (n= 224)

Sitagliptin (n= 223)

Inclusion Criteria

 Age ≥ 18 years (≥ 20 in Japan), previously untreated type 2 diabetes, BMI ≤ 45 kg/m2, insufficient glycemic control despite diet and exercise, > 10.0% HbA1c for the open-label treatment group

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

 24 weeks

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)

 Empagliflozin 25 mg (n= 224) Sitagliptin (n= 223) Open-label empagliflozin 25 mg (n= 87)

Age, years

 54.9 ± 10.9 56.2 ± 11.6 53.8 ± 11.6 55.1 ± 9.9 50.2 ± 11.3

Female

46% 37% 35% 37% 26%

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)

 Open-label empagliflozon 25 mg (n= 87)

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)

 0.65 (0.44 to 0.87) -1.08 (-1.29 to -0.87) -1.36 (-1.57 to -1.14) -0.38 (-0.60 to -0.17) -4.86 (-5.55 to -4.16)

Change from baseline in body weight, kg

 -0.33 (-0.67 to 0.00) -2.26 (-2.60 to -1.92) -2.48 (-2.82 to -2.14) 0.18 (-0.16 to 0.52) -2.43 (-3.50 to -1.37)

Patients who experienced one or more drug-related adverse events

 7% 12% 17% 9% 13%

One or more serious adverse event

 3% 4% 2% 3% 3%

Hypoglycemia

 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 0

Study Author Conclusions

 Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment.

InpharmD Researcher Critique

 A formal analysis between empagliflozin 10 and 25 mg was not performed to determine significance. Although the 25 mg seems to reduce HbA1c at a slightly higher rate, the results need to be verified. Compared to other studies, 24 weeks of therapy may be a shorter follow-up period to measure long-term efficacy and safety between the two doses of empagliflozin 10 mg and 25 mg.



References:
[1] Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208-219. doi:10.1016/S2213-8587(13)70084-6

Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial
Design

Randomized, placebo-controlled trial

N=983
Objective To compare the efficacy and safety of twice-daily versus once-daily regimens of empagliflozin as add-on to metformin in patients with type 2 diabetes mellitus (T2DM)
Study Groups

Empagliflozin 12.5 mg twice daily (n=219)

Empagliflozin 25 mg once daily (n=218)

Empagliflozin 5 mg twice daily (n=219)

Empagliflozin 10 mg once daily (n=220)

Placebo (n=107)
Inclusion Criteria Adults with T2DM, BMI ≤45 kg/m2, HbA1c level of ≥7 and ≤10%, on stable dose of metformin IR (≥1500 mg/day) for ≥12 weeks before randomization
Exclusion Criteria Uncontrolled hyperglycaemia, renal impairment or indication of liver disease at screening or during the placebo run-in, acute coronary syndrome, stroke, or a transient ischaemic attack within 3 months prior to consent, received anti-obesity drugs within 3 months of consent, undergone bariatric surgery within 2 years, any uncontrolled endocrine disorder except T2DM, or received any antidiabetes agent other than metformin IR in the 12 weeks prior to consent
Methods Patients were randomized to receive different doses of empagliflozin or placebo as add-on to metformin IR for 16 weeks. Randomization was stratified by region, HbA1c, and estimated glomerular filtration rate. Visits were scheduled at baseline and weeks 4, 10, and 16. Rescue medication could be initiated if plasma glucose level >13.3 mmol/l. 
Duration 16 weeks
Outcome Measures Change from baseline in HbA1c at week 16, change from baseline in fasting plasma glucose (FPG) at week 16
Baseline Characteristics   Empagliflozin 12.5 mg twice daily (n=215) Empagliflozin 25 mg once daily (n=214) Empagliflozin 5 mg twice daily (n=215) Empagliflozin 10 mg once daily (n=214) Placebo (n=107)
HbA1c at baseline, % 7.78 ± 0.05 7.73 ± 0.05 7.79 ± 0.06 7.83 ± 0.05 7.69 ± 0.07
FPG at baseline, mmol/l 8.7 ± 0.1 8.7 ± 0.1 9.0 ± 0.2 8.9 ± 0.2 8.9 ± 0.2
Weight at baseline, kg 89.42 ± 1.30 88.72 ± 1.27 88.30 ± 1.19 89.10 ± 1.30 90.10 ± 1.78
SBP at baseline, mmHg 130.2 ± 1.0 131.0 ± 1.0 132.4 ± 1.0 131.6 ± 1.0 131.5 ± 1.4
DBP at baseline, mmHg 78.5 ± 0.6 79.1 ± 0.6 78.5 ± 0.6 78.6 ± 0.6 78.3 ± 0.9
Results   Empagliflozin 12.5 mg twice daily (n=215) Empagliflozin 25 mg once daily (n=214) Empagliflozin 5 mg twice daily (n=215) Empagliflozin 10 mg once daily (n=214) Placebo (n=107)
Change in HbA1c from baseline, % -0.83 ± 0.05 -0.72 ± 0.05 -0.66 ± 0.05 -0.64 ± 0.05 -0.22 ± 0.07
Change in FPG from baseline, mmol/l -1.5 ± 0.1 -1.3 ± 0.1 -1.2 ± 0.1 -1.0 ± 0.1 0.0 ± 0.2
Weight change from baseline, kg -3.20 ± 0.18 -2.89 ± 0.18 -2.93 ± 0.18 -2.71 ± 0.18 -0.97 ± 0.25
Change in SBP from baseline, mmHg -4.1 ± 0.7 -3.8 ± 0.7 -4.2 ± 0.7 -2.5 ± 0.8 1.6 ± 1.1
Change in DBP from baseline, mmHg -2.1 ± 0.5 -2.6 ± 0.5 -1.6 ± 0.5 -0.8 ± 0.5 0.4 ± 0.6
Adverse Events Confirmed hypoglycaemic AEs were rare and reported in 1 patient in every group except empagliflozin 12.5 mg twice-daily group (none). Events consistent with increased urination were reported in 2.7% to 2.3% of patients across empagliflozin groups and 1.9% in placebo. Volume depletion events were reported in 1 patient on empagliflozin 12.5 mg twice daily and 2 patients on empagliflozin 10 mg once daily.
Study Author Conclusions The therapeutic effect of empagliflozin twice-daily and once-daily regimens can be considered equivalent when used as add-on to metformin IR in patients with T2DM. Empagliflozin regimens were well tolerated and showed potential for use as a fixed dose combination with metformin IR as a second-line therapy.
Critique The study was well-designed as a randomized, placebo-controlled trial, providing robust evidence for the non-inferiority of twice-daily versus once-daily empagliflozin regimens. However, the study's short duration of 16 weeks may not capture long-term efficacy and safety outcomes. Additionally, the exclusion criteria and stratification by region and HbA1c may limit the generalizability of the findings to broader populations. 
References:
[1] Ross S, Thamer C, Cescutti J, Meinicke T, Woerle HJ, Broedl UC. Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2015;17(7):699-702. doi:10.1111/dom.12469

Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes
Design

Phase III, randomized, double-blind, parallel-group study

N= 1,364
Objective To compare the efficacy and safety of initial combinations of empagliflozin and metformin with empagliflozin and metformin monotherapy in patients with type 2 diabetes
Study Groups

Empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. (n= 169)

Empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d. (n= 165)

Empagliflozin 5 mg b.i.d. + metformin 1,000 mg b.i.d. (n= 167)

Empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d. (n= 161)

Empagliflozin 25 mg q.d. (n= 164)

Empagliflozin 10 mg q.d. (n= 169)

Metformin 1,000 mg b.i.d. (n= 164)

Metformin 500 mg b.i.d. (n= 168)

Open-label empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. (n= 53)
Inclusion Criteria Adults with type 2 diabetes, BMI ≤45 kg/m2, drug-naïve (no oral antidiabetes therapy, glucagon-like peptide-1 analog, or insulin for ≥12 weeks before randomization), HbA1c >7.5% to ≤12% at screening
Exclusion Criteria Uncontrolled hyperglycemia (plasma glucose >240 mg/dL after an overnight fast), contraindication to metformin, renal impairment (estimated creatinine clearance rate <60 mL/min), indication of liver disease, treatment with anti-obesity drugs within 3 months before, uncontrolled endocrine disorder except type 2 diabetes
Methods Randomized patients received empagliflozin and metformin in various dosages for 24 weeks. Safety was assessed through adverse events and laboratory parameters. 
Duration October 2012 to December 2014
Outcome Measures Change from baseline in HbA1c at week 24
Baseline Characteristics   Empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. (n = 169) Empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d. (n = 165) Empagliflozin 5 mg b.i.d. + metformin 1,000 mg b.i.d. (n = 167) Empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d. (n = 161) Empagliflozin 25 mg q.d. (n = 164) Empagliflozin 10 mg q.d. (n = 169) Metformin 1,000 mg b.i.d. (n = 164) Metformin 500 mg b.i.d. (n = 168) Open-label empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d. (n = 53)
Female 81 (47.9%) 60 (36.4%) 68 (40.7%) 64 (39.8%) 81 (49.4%) 72 (42.6%) 72 (43.9%) 82 (48.8%) 12 (22.6%)
Age, years 53.6 ± 10.7 51.0 ± 10.7 52.3 ± 11.3 52.2 ± 11.7 53.3 ± 10.7 53.1 ± 10.7 51.6 ± 10.8 53.4 ± 10.9 50.3 ± 10.0
Weight, kg 83.8 ± 19.8 82.9 ± 18.7 83.0 ± 19.1 82.3 ± 19.2 83.1 ± 20.3 83.8 ± 19.8 83.7 ± 20.1 82.7 ± 21.2 93.7 ± 18.9
BMI, kg/m2 30.4 ± 5.3 30.2 ± 5.2 30.5 ± 5.0 30.1 ± 5.3 30.6 ± 5.9 30.3 ± 5.2 30.5 ± 5.9 30.3 ± 5.8 31.7 ± 5.5
HbA1c, % 8.66 ± 1.14 8.84 ± 1.31 8.65 ± 1.23 8.68 ± 1.26 8.86 ± 1.29 8.62 ± 1.24 8.58 ± 1.13 8.69 ± 1.04 11.46 ± 1.57
Results   Empagliflozin + Metformin b.i.d. Empagliflozin q.d. Metformin b.i.d. p-value
Reduction in HbA1c, % -1.9 to -2.1 -1.4 -1.2 to -1.8 <0.001 vs. Empagliflozin q.d., <0.01 vs. Metformin b.i.d.
Reduction in weight, kg -2.8 to -3.8 - -0.5 to -1.3 <0.001 vs. Metformin b.i.d.
Adverse Events Adverse event rates were similar across groups (56.7–66.3%). No hypoglycemic adverse events required assistance. Events consistent with urinary tract infection (5.9–12.4%) and genital infection (1.8–6.4%) were reported. No episodes of diabetic ketoacidosis. 
Study Author Conclusions Initial combinations of empagliflozin and metformin for 24 weeks significantly reduced HbA1c versus empagliflozin once daily and metformin twice daily, without increased hypoglycemia, reduced weight versus metformin twice daily, and were well tolerated. 
Critique The study was well-designed with a large sample size and robust methodology, providing strong evidence for the efficacy of empagliflozin and metformin combination therapy. However, the lack of a placebo group limits the ability to assess the additive effects of the combination therapy. Additionally, the study's duration was relatively short, and long-term effects were not evaluated. 
References:
[1] Hadjadj S, Rosenstock J, Meinicke T, Woerle HJ, Broedl UC. Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes. Diabetes Care. 2016;39(10):1718-1728. doi:10.2337/dc16-0522

 

A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes
Design

Phase IIb, randomized, double-blind, placebo-controlled trial

N= 408
Objective To evaluate the efficacy, safety, tolerability, and pharmacokinetics of empagliflozin in patients with type 2 diabetes
Study Groups

Placebo (n= 82)

5 mg empagliflozin (n= 81)

10 mg empagliflozin (n= 81)

25 mg empagliflozin (n= 82)

Open-label metformin (n= 80)
Inclusion Criteria Men and women aged ≥18 and ≤79 years with type 2 diabetes, treatment-naïve or on one antidiabetic drug (except thiazolidinediones, GLP-1 analogues, or insulin) at a stable dose for ≥10 weeks prior to screening, HbA1c ≥6.5 to ≤9.0% for patients treated with one other antidiabetic drug, or HbA1c >7.0 to ≤10.0% for treatment-naïve patients, BMI ≤40 kg/m2
Exclusion Criteria Myocardial infarction, stroke or transient ischaemic attack ≤6 months prior to informed consent; impaired hepatic function; renal insufficiency; unstable or acute congestive heart failure; acute or chronic acidosis; psychiatric disorders; chronic or clinically relevant acute infections; current or chronic urogenital tract infection; dehydration; intolerance to metformin; treatment with thiazolidinediones, GLP-1 analogues or insulin ≤3 months prior to informed consent; treatment with antiobesity drugs; alcohol abuse; pregnancy, breastfeeding
Methods Patients were randomized to receive empagliflozin 5, 10, or 25 mg once daily, placebo, or open-label metformin for 12 weeks. Safety and tolerability were assessed through adverse events reporting
Duration 12 weeks
Outcome Measures Change in HbA1c from baseline to week 12, change in fasting plasma glucose (FPG) from baseline to week 12
Baseline Characteristics   Placebo (n= 82) 5 mg empagliflozin (n= 81) 10 mg empagliflozin (n= 81) 25 mg empagliflozin (n= 82) Open-label metformin (n= 80)
Female 37 (45.1%) 35 (43.2%) 41 (50.6%) 41 (50.0%) 41 (51.3%)

Ethnicity

White

Asian

 

54 (65.9%)

28 (34.1%)

 

51 (63.0%)

29 (35.8%)

 

52 (64.2%)

28 (34.6%)

 

54 (65.9%)

27 (32.9%)

 

48 (60.0%)

28 (35.0%)
Age, years 58.0 (28–80) 59.0 (37–78) 58.0 (30–76) 57.0 (30–79) 58.0 (34–73)
BMI, kg/m2 28.8 (20.7–39.6) 28.5 (20.5–38.8) 28.1 (21.5–39.3) 28.3 (20.1–38.8) 28.6 (18.7–40.6)
Results   Placebo (n= 82) 5 mg empagliflozin (n= 81) 10 mg empagliflozin (n= 81) 25 mg empagliflozin (n= 82) Open-label metformin (n= 80)
Mean change HbA1c (%) +0.1 −0.4* −0.5* −0.6* −0.7*
Mean change FPG (mmol/l) +0.04 −1.29* −1.61* −1.72* −1.66*
* p<0.0001 vs. placebo
Adverse Events The incidence of adverse events was similar between placebo (32.9%) and empagliflozin (29.1%) groups. Common adverse events included pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo), and nasopharyngitis (2.0% vs. 1.2% for placebo). Urinary tract infections were reported in 1.6% of empagliflozin patients vs. 1.2% on placebo. Genital infections were reported in 2% of empagliflozin patients vs. 0% on placebo. 
Study Author Conclusions Empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile. 
Critique The study was well-designed with a robust sample size and clear endpoints. However, the short duration of 12 weeks limits the understanding of long-term efficacy and safety. The exclusion of patients with certain comorbidities may limit the generalizability of the findings to a broader diabetic population. Additionally, the study did not compare empagliflozin with other SGLT2 inhibitors, which could provide more context on its relative efficacy and safety. 
References:
[1] Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(8):721-728. doi:10.1111/dom.12081

Treatment Outcomes of Graded Dose of Empagliflozin in Type‑2 Diabetes: A Real World Study
Design

Retrospective study

N= 599
Objective To compare real world weight loss and glycaemic outcomes of 10 mg versus 12.5 mg versus 25 mg of empagliflozin (EMPA)
Study Groups

EMPA 10 mg/day (n=184)

EMPA 12.5 mg/day (n=239)

EMPA 25 mg/day (n=176)
Inclusion Criteria Patients >35 years with T2DM on EMPA as part of standard pharmacotherapy, with >6 months follow-up data available
Exclusion Criteria Coronary artery disease, chronic kidney disease (GFR<60ml/min), chronic lung disease, hospital admission in the last 6 months, autoimmune disorders, psychiatric problems on antipsychotic medications, chronic infections, organ transplant, follow-up duration less than 6 months
Methods Data retrospectively captured from records of 2 centers for patients >35 years with T2DM on EMPA. Patients were divided into 3 groups based on EMPA dosage: 10 mg/day, 12.5 mg/day, and 25 mg/day. Primary endpoints were glycaemic efficacy and weight-loss. Data on anthropometry, glycemia, lipid parameters, and adverse drug reactions were collected
Duration January 2018 to April 2019
Outcome Measures Primary: Glycaemic efficacy, weight-loss Secondary: Fraction achieving HbA1c < 5.7%
Baseline Characteristics   EMPA 10 mg/day (n=184) EMPA 12.5 mg/day (n=239) EMPA 25 mg/day (n=176)
Age, years 49.37±13.27 49.01±14.2 57.91±9.92
Sex (male:female) 94:90 123:116 105:71
Duration of diagnosis, years 4 (3–6) 3 (2–5) 5 (3–9)
BMI, kg/m2 29.66±5.07 30.52±5.6 27.97±4.6
Results   EMPA 10 mg/day (n=184) EMPA 12.5 mg/day (n=239) EMPA 25 mg/day (n=176) p-value
Change in HbA1c, % −0.9 (−1.9–0.0) −1.0 (−1.8–−0.5) −1.0 (−1.5–−0.22) 0.363
Weight loss, kg −0.3 (−2.4–1.32) −1.2 (−3.0–0.7) −1.7 (−3.47–−0.22) 0.083
Percent weight loss at 6 months, % −0.44 (−3.11–1.39) −1.63 (−4.02–0.89) −2.6 (−4.77–0.37) 0.070
HbA1c <5.7% at 6 months 0 (0.0) 11 (4.60%) 1 (0.01%) 0.012
Adverse Events 3 reports of severe hypoglycemia, 41 reports of mild self-limiting hypoglycemia, 27 reports of mild lower genital infection, 2 reports of upper urinary tract infection. 
Study Author Conclusions Half EMPA-25 is the most cost-effective way of using EMPA in clinical practice, with comparable glycaemic efficacy to full tablet EMPA-10 and EMPA-25, and better weight loss profile than EMPA-10.
Critique The study's retrospective design and lack of baseline matching for age and body weight are limitations. The short study period of 6 months limits the assessment of long-term outcomes. However, the study provides valuable real-world data on the cost-effectiveness and efficacy of half-tablet EMPA-25. 
References:
[1] Dutta D, Sharma M, Aggarwal S, Agarwal A, Dhall A. Treatment outcomes of graded dose of empagliflozin in type-2 diabetes: A real world study. Ann Afr Med. 2022;21(1):26-33. doi:10.4103/aam.aam_69_20

The effect of low and high dose empagliflozin on HbA1c and lipid profile in type 2 diabetes mellitus: A real-world data
Design

Retrospective study

N= 60
Objective To evaluate the efficacy and safety of the addition of 10 or 25 mg of empagliflozin to patients with type 2 diabetes mellitus using a maximum tolerable dose of metformin and gliclazide
Study Groups

10 mg empagliflozin (n=32)

25 mg empagliflozin (n=28)
Inclusion Criteria Patients aged ≥18 years with T2DM receiving gliclazide (60 mg/day) and metformin (2000 mg/day)
Exclusion Criteria Patients with acute coronary syndrome, cerebrovascular event, pregnancy, heart failure, chronic liver disease, renal function test abnormality, pregnancy, cancer, treatments impairing glucose metabolism, alcohol addiction, and illegal drug use
Methods Patients were divided into two groups: Group 1 received 10 mg empagliflozin, and Group 2 received 25 mg empagliflozin, added to metformin and gliclazide. Biochemical results, weight, and blood pressure changes were evaluated before and after 12 weeks of treatment. Incidence of urinary tract and genital infections was recorded
Duration January 2018 to December 2018
Outcome Measures Change in HbA1c 
Baseline Characteristics   10 mg empagliflozin (n=32) 25 mg empagliflozin (n=28)
Mean age, years  53.16±8.8 52.5±7.5
male/female 13 (40.6%)/19 (59.4%) 13 (59%)/9 (41%)
Duration of diabetes, years 15.4±7.1 14.6±6.8
HbA1c, % 10.3±2.5 9.6±1.7
FPG, mg/dl  206.5±91.3 217.1±75.5
Weight, kg  81.6±9.8 82.8±13.1
SBP, mmHg  136.2±8.2 137.2±8.6
DBP, mmHg  85.5±7.5 86.3±7.7
Results   10 mg empagliflozin (n=32) 25 mg empagliflozin (n=28) p-value
Δ HbA1c, % -1.54±2.14 -1.18±1.5 0.935
Δ FPG, mg/dl -39.0±94.1 -36.7±81.1 0.739
Δ Weight, kg -2.6±1.2 -3.8±2.0 0.021
Δ SBP, mmHg -6.8±5.1 -9.6±7.5 0.032
Δ DBP, mmHg -4.6±4.0 -6.7±4.6 0.005
Adverse Events Although there was a numerical increase in urinary tract and genital infections in both groups after empagliflozin treatment, there was no statistically significant difference compared to the pre-treatment period (p>0.05).
Study Author Conclusions Two doses of empagliflozin added to the present treatments showed a dose-independent improvement in glycemic control and a neutral effect on lipid metabolism. 
Critique The study's retrospective design and short follow-up duration of 12 weeks are limitations. The small sample size and potential selection bias due to its retrospective nature may affect the generalizability of the findings. Additionally, the use of different antihypertensive agents among patients could have influenced the results. 
References:
[1] Ozcelik S, Celik M, Vural A, Aydin B. The effect of low and high dose empagliflozin on HbA1c and lipid profile in type 2 diabetes mellitus: A real-world data. North Clin Istanb. 2019;7(2):167-173. Published 2019 Dec 2. doi:10.14744/nci.2019.22697

Empagliflozin as Add-On to Metformin in Patients With Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial
Design

Randomized, double-blind, placebo-controlled trial

N= 637
Objective To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes
Study Groups

Empagliflozin 10 mg (n= 217)

Empagliflozin 25 mg (n= 213)

Placebo (n= 207)
Inclusion Criteria Patients with HbA1c levels of ≥7% to ≤10% while receiving metformin (≥1,500 mg/day)
Exclusion Criteria Uncontrolled hyperglycemia (glucose level >13.3 mmol/L) after an overnight fast; acute coronary syndrome, stroke, or transient ischemic attack within 3 months prior to informed consent; indication of liver disease; impaired kidney function (eGFR <30 mL/min/1.73 m2); contraindications to metformin; bariatric surgery or other gastrointestinal surgeries that induce chronic malabsorption; medical history of cancer within the last 5 years; blood dyscrasias or any disorders causing hemolysis or unstable erythrocytes; treatment with antiobesity drugs 3 months prior to consent; use of any treatment at screening leading to unstable body weight; treatment with systemic steroids at the time of consent; change in the dosage of thyroid hormones within 6 weeks prior to consent; alcohol or drug abuse within 3 months of consent; investigational drug intake in another trial within 30 days prior to the current trial
Methods Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks as an add-on to metformin therapy. 
Duration 24 weeks
Outcome Measures Change in HbA1c level from baseline at week 24, changes in weight, mean daily glucose (MDG)
Baseline Characteristics   Placebo (n= 207) Empagliflozin 10 mg (n= 217) Empagliflozin 25 mg (n= 213)
Age, years 56.0 ± 9.7 55.5 ± 9.9 55.6 ± 10.2
Male 116 (56%) 125 (58%) 120 (56%)
BMI, kg/m2 28.7 ± 5.2 29.1 ± 5.5 29.7 ± 5.7
HbA1c, % 7.90 ± 0.88 7.94 ± 0.79 7.86 ± 0.87
Results   Placebo Empagliflozin 10 mg Empagliflozin 25 mg p-value
Change in HbA1c, % -0.13 ± 0.05 -0.70 ± 0.05 -0.77 ± 0.05 <0.001
Change in weight, kg -0.45 ± 0.17 -2.08 ± 0.17 -2.46 ± 0.17 <0.001
Change in MDG, mmol/L -0.11 ± 0.11 -0.54 ± 0.10 -0.80 ± 0.10 <0.001
Adverse Events Adverse events were similar across groups: placebo 58.7%; empagliflozin 49.5–57.1%. Confirmed hypoglycemic events were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively.
Study Author Conclusions Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated.
Critique The study demonstrated significant improvements in glycemic control, weight, and blood pressure with empagliflozin as an add-on to metformin. However, the trial's duration was relatively short, and the long-term effects and safety of empagliflozin require further investigation. Additionally, the study was funded by pharmaceutical companies, which may introduce potential bias. 
References:
[1] Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014;37(6):1650-1659. doi:10.2337/dc13-2105

 

Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial
Design

Double-blind extension of a Phase III randomized controlled trial

N= 615
Objective To investigate the long-term efficacy and safety of empagliflozin monotherapy compared with placebo and sitagliptin in drug-naïve patients with type 2 diabetes mellitus
Study Groups

Empagliflozin 10 mg (n= 224)

Empagliflozin 25 mg (n= 224)

Placebo (n= 228)

Sitagliptin 100 mg (n= 223)
Inclusion Criteria Drug-naïve patients with T2DM with insufficient glycaemic control despite a diet and exercise regimen (HbA1c ≥7 to ≤10 %, or HbA1c ≥7 to ≤9 % in Germany) and BMI ≤45 kg/m2
Exclusion Criteria Uncontrolled hyperglycaemia (glucose concentration >13.3 mmol/l following an overnight fast), eGFR <50 ml/min/1.73 m2, indication of liver disease, and contraindications to sitagliptin
Methods Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, sitagliptin 100 mg, or placebo once daily for 24 weeks, with a double-blind extension for ≥52 weeks. 
Duration

Initial study: 24 weeks

Extension study: ≥52 weeks

Total: ≥76 weeks
Outcome Measures

Primary: Change from baseline in HbA1c at week 24

Secondary: Change from baseline in HbA1c, fasting plasma glucose (FPG), body weight, SBP, and DBP at week 52 and week 76
Baseline Characteristics   Placebo (n= 228) Empagliflozin 10 mg (n= 224) Empagliflozin 25 mg (n= 224) Sitagliptin 100 mg (n= 223)
Male 123 (53.9%) 142 (63.4%) 145 (64.7%) 141 (63.2%)
Age, years 54.9 ± 10.9 56.2 ± 11.6 53.8 ± 11.6 55.1 ± 9.9

Race

Asian

White

 

146 (64.0%)

76 (33.3%)

 

143 (63.8%)

77 (34.4%)

 

144 (64.3%)

73 (32.6%)

 

143 (64.1%)

76 (34.1%)
Body weight, kg 78.2 ± 19.9 78.4 ± 18.7 77.8 ± 18.0 79.3 ± 20.4
Body mass index, kg/m2 28.7 ± 6.2 28.3 ± 5.5 28.2 ± 5.5 28.2 ± 5.2
HbA1c, % 7.91 ± 0.78 7.87 ± 0.88 7.86 ± 0.85 7.85 ± 0.79
Results   Placebo (n= 228) Empagliflozin 10 mg (n= 224) Empagliflozin 25 mg (n= 224) Sitagliptin 100 mg (n= 223)
HbA1c at week 76, % 8.01 ± 0.06 7.22 ± 0.06 7.12 ± 0.06 7.34 ± 0.06
Change from baseline in HbA1c 0.13 ± 0.06 -0.65 ± 0.06 -0.76 ± 0.06 -0.53 ± 0.06
FPG at week 76, mmol/l 9.2 ± 0.1 7.5 ± 0.1 7.3 ± 0.1 8.3 ± 0.1
Change from baseline in FPG 0.8 ± 0.1 -1.0 ± 0.1 -1.1 ± 0.1 -0.1 ± 0.1
Body weight at week 76, kg 78.0 ± 0.2 76.2 ± 0.2 76.0 ± 0.2 78.5 ± 0.2
Change from baseline in body weight -0.4 ± 0.2 -2.2 ± 0.2 -2.5 ± 0.2 0.1 ± 0.2
SBP at week 76 (mmHg) 130.7 ± 0.8 127.3 ± 0.8 127.3 ± 0.8 131.1 ± 0.8
Change from baseline in SBP -0.7 ± 0.8 -4.1 ± 0.8 -4.2 ± 0.8 -0.3 ± 0.8
Adverse Events Adverse events were reported in 76.8% of patients on empagliflozin 10 mg, 78.0% on empagliflozin 25 mg, 76.4% on placebo, and 72.2% on sitagliptin. Confirmed hypoglycaemic events were reported in two patients (0.9%) per treatment group. Events consistent with genital infection were more common in empagliflozin groups (5.8% and 6.3%) than placebo and sitagliptin (1.7% and 0.9%). 
Study Author Conclusions Empagliflozin monotherapy for ≥76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo.
Critique The study's long duration and double-blind design are strengths, providing robust data on the long-term effects of empagliflozin. However, the lack of a primary endpoint for the extension study and the high amount of missing data, with 51.4% of HbA1c data at week 76 imputed, are limitations. The results may not be generalizable to all T2DM patients, as two-thirds of participants were Asian. 
References:
[1] Roden M, Merker L, Christiansen AV, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial. Cardiovasc Diabetol. 2015;14:154. Published 2015 Dec 23. doi:10.1186/s12933-015-0314-0