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Diabetes Care. 2018 Dec;41(12):2560-2569. doi: 10.2337/dc18-1749. Epub 2018 Oct 4.

Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials.

Author information

1
Dallas Diabetes Research Center at Medical City, Dallas, TX juliorosenstock@dallasdiabetes.com bruce.perkins@sinaihealthsystem.ca.
2
Boehringer Ingelheim International GmbH, Ingelheim, Germany.
3
Joslin Diabetes Center, Harvard Medical School, Boston, MA.
4
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
5
Division of Nephrology, Department of Medicine, and Department of Physiology, Toronto General Hospital, University of Toronto, Toronto, Canada.
6
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada.
7
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL.
8
Boehringer Ingelheim (Canada) Ltd./Ltée, Burlington, Canada.
9
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada juliorosenstock@dallasdiabetes.com bruce.perkins@sinaihealthsystem.ca.

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 -0.28% (95% CI -0.42, -0.15) for 2.5 mg, -0.54% (-0.65, -0.42) for 10 mg, and -0.53% (-0.65, -0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by -1.8/-3.0/-3.4 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 -6.4/-13.3/-12.7% (all P < 0.0001); and decreased systolic blood pressure by -2.1/-3.9/-3.7 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02414958 NCT02580591.

PMID:
30287422
DOI:
10.2337/dc18-1749

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