Empagliflozin as adjunctive to insulin therapyin type 1 diabetes

The EASE trials

Julio Rosenstock, Jan Marquard, Lori M. Laffel, Dietmar Neubacher, Stefan Kaspers, David Z. Cherney, Bernard Zinman, Jay S Skyler, Jyothis George, Nima Soleymanlou, Bruce A. Perkins

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to £180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were 20.28% (95% CI 20.42, 20.15) for 2.5 mg, 20.54% (20.65, 20.42) for 10 mg, and 20.53% (20.65, 20.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by 21.8/23.0/23.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by 26.4/213.3/212.7% (all P < 0.0001); and decreased systolic blood pressure by 22.1/23.9/23.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

Original languageEnglish (US)
Pages (from-to)2560-2569
Number of pages10
JournalDiabetes Care
Volume41
Issue number12
DOIs
StatePublished - Dec 1 2018

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Type 1 Diabetes Mellitus
Insulin
Placebos
Hypoglycemia
Ketosis
Glycosylated Hemoglobin A
Blood Pressure
Weights and Measures
empagliflozin
Glucose
Diabetic Ketoacidosis
Therapeutics
Ketones
Type 2 Diabetes Mellitus
Research Design
Safety

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

Cite this

Rosenstock, J., Marquard, J., Laffel, L. M., Neubacher, D., Kaspers, S., Cherney, D. Z., ... Perkins, B. A. (2018). Empagliflozin as adjunctive to insulin therapyin type 1 diabetes: The EASE trials. Diabetes Care, 41(12), 2560-2569. https://doi.org/10.2337/dc18-1749

Empagliflozin as adjunctive to insulin therapyin type 1 diabetes : The EASE trials. / Rosenstock, Julio; Marquard, Jan; Laffel, Lori M.; Neubacher, Dietmar; Kaspers, Stefan; Cherney, David Z.; Zinman, Bernard; Skyler, Jay S; George, Jyothis; Soleymanlou, Nima; Perkins, Bruce A.

In: Diabetes Care, Vol. 41, No. 12, 01.12.2018, p. 2560-2569.

Research output: Contribution to journalArticle

Rosenstock, J, Marquard, J, Laffel, LM, Neubacher, D, Kaspers, S, Cherney, DZ, Zinman, B, Skyler, JS, George, J, Soleymanlou, N & Perkins, BA 2018, 'Empagliflozin as adjunctive to insulin therapyin type 1 diabetes: The EASE trials', Diabetes Care, vol. 41, no. 12, pp. 2560-2569. https://doi.org/10.2337/dc18-1749
Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ et al. Empagliflozin as adjunctive to insulin therapyin type 1 diabetes: The EASE trials. Diabetes Care. 2018 Dec 1;41(12):2560-2569. https://doi.org/10.2337/dc18-1749
Rosenstock, Julio ; Marquard, Jan ; Laffel, Lori M. ; Neubacher, Dietmar ; Kaspers, Stefan ; Cherney, David Z. ; Zinman, Bernard ; Skyler, Jay S ; George, Jyothis ; Soleymanlou, Nima ; Perkins, Bruce A. / Empagliflozin as adjunctive to insulin therapyin type 1 diabetes : The EASE trials. In: Diabetes Care. 2018 ; Vol. 41, No. 12. pp. 2560-2569.
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abstract = "OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to £180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were 20.28{\%} (95{\%} CI 20.42, 20.15) for 2.5 mg, 20.54{\%} (20.65, 20.42) for 10 mg, and 20.53{\%} (20.65, 20.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by 21.8/23.0/23.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by 26.4/213.3/212.7{\%} (all P < 0.0001); and decreased systolic blood pressure by 22.1/23.9/23.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3{\%}) and 25 mg (3.3{\%}) but was comparable between empagliflozin 2.5 mg (0.8{\%}) and placebo (1.2{\%}). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.",
author = "Julio Rosenstock and Jan Marquard and Laffel, {Lori M.} and Dietmar Neubacher and Stefan Kaspers and Cherney, {David Z.} and Bernard Zinman and Skyler, {Jay S} and Jyothis George and Nima Soleymanlou and Perkins, {Bruce A.}",
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T1 - Empagliflozin as adjunctive to insulin therapyin type 1 diabetes

T2 - The EASE trials

AU - Rosenstock, Julio

AU - Marquard, Jan

AU - Laffel, Lori M.

AU - Neubacher, Dietmar

AU - Kaspers, Stefan

AU - Cherney, David Z.

AU - Zinman, Bernard

AU - Skyler, Jay S

AU - George, Jyothis

AU - Soleymanlou, Nima

AU - Perkins, Bruce A.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to £180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were 20.28% (95% CI 20.42, 20.15) for 2.5 mg, 20.54% (20.65, 20.42) for 10 mg, and 20.53% (20.65, 20.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by 21.8/23.0/23.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by 26.4/213.3/212.7% (all P < 0.0001); and decreased systolic blood pressure by 22.1/23.9/23.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

AB - OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to £180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were 20.28% (95% CI 20.42, 20.15) for 2.5 mg, 20.54% (20.65, 20.42) for 10 mg, and 20.53% (20.65, 20.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by 21.8/23.0/23.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by 26.4/213.3/212.7% (all P < 0.0001); and decreased systolic blood pressure by 22.1/23.9/23.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

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