Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin + MDI insulin

Rosenstock J, Jelaska A, Frappin G, et al; on behalf of the EMPA-REG MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014. DOI:10.2337/dc13-3055.

The EMPA-REG MDI trial looked at the investigational SGLT2 inhibitor, empagliflozin, and is the first trial to explore the efficacy and safety of an SGLT2 inhibitor in subjects who are obese and insulin resistant, and have inadequate glycemic control despite high-dose multiple daily injections (MDI) of insulin. Results showed that empagliflozin improved glycemic control and decreased weight with no increased risk of hypoglycemia and lower requirements for insulin dosing.

Subjects in this randomized, double-blind, placebo-controlled, parallel-group:

  • Type 2 diabetes
  • BMI ≥30 and ≤45 kg/m2  
  • A1C ≥7.5% to ≤10% despite diet and exercise counseling and MDI insulin alone or in combination with metformin*

Randomization was 1:1:1 for 52 weeks with diet and exercise counseling:

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=186)
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=189)
  • MDI insulin + placebo +/- metformin (n=188)

Insulin dosing was as follows:

  • Weeks 1-18: stable (within 10% of dose at randomization)
  • Weeks 19-40: adjusted to meet glucose targets <100 mg/dL preprandial; <140 mg/dL postprandial
  • Weeks 41-52: stable (within 10% of dose at Week 40)

A1C change from baseline to Week 18 was the primary endpoint. Secondary endpoints explored changes from baseline to Week 52 in insulin daily dose, body weight, and A1C.

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EMPA-REG MDI Design  
EMPA-REG MDI: Design 

A1C change from baseline
For the primary endpoint, change in A1C from baseline to Week 18:

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=186): -0.94 ± 0.05; % difference vs placebo, -0.44 ± 0.08 (95% CI, -0.59 to -0.29); P<0.001
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=189): -1.02 ± 0.05; % difference vs placebo, -0.52 ± 0.07 (95% CI, -0.67 to -0.37); P<0.001
  • MDI insulin + placebo +/- metformin (n=188): -0.50 ± 0.05

For the secondary endpoint of change in A1C from baseline to Week 52, further reductions in A1C were seen with insulin titration; insulin titration was lower in the empagliflozin groups vs the placebo group

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=119): -1.18 ± 0.08; % difference vs placebo, -0.38 ± 0.11 (95% CI, -0.59 to -0.16); P<0.001
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=118): -1.27 ± 0.08; % difference vs placebo, -0.46 ± 0.11 (95% CI, -0.67 to -0.25); P<0.001
  • MDI insulin + placebo +/- metformin (n=115): -0.81 ± 0.08

Among subjects with A1C ≥7% at baseline, at Week 52, 31.4% who received empagliflozin 10 mg and 41.7% who received empagliflozin 25 mg achieved A1C <7.0% vs 21.0% who received placebo (odds ratio for empagliflozin doses vs placebo: P<0.01). Baseline A1C was 8.3%.

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EMPA-REG MDI Percent Change in A1C from Baseline With Empagliflozin Vs Placebo  
EMPA-REG MDI: % Change in A1C from Baseline With Empagliflozin Vs Placebo 

Body weight change from baseline
Body weight decreased with empagliflozin treatment at Week 18. Changes in body weight at Week 18 (kg):

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=186): -0.97 ± 0.18; % difference vs placebo, -1.31 ± 0.26 (95% CI, -1.82 to -0.80); P<0.001
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=189): -1.54 ± 0.18; % difference vs placebo, -1.88 ± 0.26 (95% CI, -2.39 to -1.37); P<0.001
  • MDI insulin + placebo +/- metformin (n=188): +0.34 ± 0.18

For the secondary endpoint of change in body weight from baseline to Week 52 (kg):

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=119): -1.95 ± 0.36; % difference vs placebo, -2.39 ± 0.51 (95% CI, -3.40 to -1.39); P<0.001
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=118): -2.04 ± 0.36; % difference vs placebo, -2.48 ± 0.51 (95% CI, -3.48 to -1.47); P<0.001
  • MDI insulin + placebo +/- metformin (n=115): +0.44 ± 0.36

Baseline mean weight (kg) was 96.69 in the empagliflozin 10 mg group, 95.90 in the empagliflozin 25 mg group, and 95.49 in the placebo group.

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EMPA-REG MDI Change in Body Weight from Baseline With Empagliflozin Vs Placebo  
EMPA-REG MDI: Change in Body Weight from Baseline With Empagliflozin Vs Placebo  

Change in insulin dose from baseline to Week 52
Results for the secondary endpoint of change in insulin dose from baseline to Week 52:

  • MDI insulin + empagliflozin 10 mg qd +/- metformin (n=118): +1.3 ± 2.1; % difference vs placebo, -8.8 ± 3.1 (95% CI, -14.8 to -2.8); P=0.004
  • MDI insulin + empagliflozin 25 mg qd +/- metformin (n=119): -1.1 ± 2.1; % difference vs placebo, -11.2 ± 3.1 (95% CI, -17.2 to -5.2); P<0.001
  • MDI insulin + placebo +/- metformin (n=115): +10.2 ± 2.2

Baseline insulin dose was 92 international units/day.  

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EMPA-REG MDI Change in Insulin Dose from Baseline to Week 52 With Empagliflozin Vs Placebo  
EMPA-REG MDI: Change in Insulin Dose from Baseline to Week 52 With Empagliflozin Vs Placebo  

Adverse events (AEs)
AEs over the 52-week treatment period (empagliflozin 10-mg group [n=186], empagliflozin 25-mg group [n=189], and placebo group shown [n=188], respectively):

  • AEs, serious AEs, and AEs leading to discontinuation similar across treatment groups ~90% of patients reported mild or moderate AEs
  • Similar rates of hypoglycemic adverse events in all groups: confirmed hypoglycemic AEs: 51.1% (n=95), 57.7% (n=109), 58% (n=109); severe hypoglycemic AEs: 1.6% (n=3), 0.5% (n=1), 1.6% (n=3)
  • Similar proportion of subjects with UTIs§, which were more frequent among females: 15.6% (n=29), 15.3% (n=29), 15.4% (n=29)
  • More empagliflozin-treated subjects with genital infectionsǁ: 4.3% (n=8), 9.5% (n=18), 1.6% (n=3)  
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EMPA-REG MDI Adverse Events at Week 52 With Empagliflozin Vs Placebo  
EMPA-REG MDI: Adverse Events at Week 52 With Empagliflozin Vs Placebo 

 

*Total daily dose of insulin: >60 international units; metformin immediate or extended release ≥1,500 mg qd, max tolerated dose, or max dose according to local label. 
AEs consistent with hypoglycemia and with plasma glucose ≤70 mg/dL and/or requiring assistance
AEs consistent with hypoglycemia and with plasma glucose ≤70 mg/dL and requiring assistance
§Reports of UTI based on 70 preferred terms
ǁReports of genital infection based on 89 preferred terms

Empagliflozin is an investigational agent that is not FDA approved for the treatment of type 2 diabetes or weight loss. 

  

Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

June 2014 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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Last Modified: 8/4/2014