TY - JOUR
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.
N1 - Funding Information:
Acknowledgments. The authors sincerely thank the EASE phase 3 patients who generously volunteered their invaluable time toward this research, all of the EASE-2 and EASE-3 investigators and site research professionals and staff who took part in the conduct of these trials, Dr. Ona Kinduryte and Elke Schüler for their supportduringthereviewofthismanuscript,and Dr. Jens Eilbracht and Ros Swallow along with the sponsor’s clinical trial teams for their diligent oversight of the operational conduct of these trials. Duality of Interest. The EASE-2 and EASE-3 clinical trials were supported by Boehringer Ingelheim and Eli Lilly and Company. J.R. has served on scientific advisory boards and received honoraria or consulting fees from Eli Lilly, Novo Nordisk, Sanofi, Janssen, Boehringer Ingelheim, and Intarcia and has received grants/research supportfromMerck,Pfizer,Sanofi,NovoNordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Boehringer Ingelheim, Intarcia, and Lexicon. L.M.L. has been a consultant for Johnson & Johnson, Eli Lilly, Sanofi, Novo Nordisk, MannKind, Merck, Bristol-Myers Squibb, AstraZeneca, Roche, Dexcom, Unomedical-ConvaTec, Insulet, and Boehringer Ingelhein and has received grant support from the National Institutes of Health, JDRF, the American Diabetes Association, Helmsley Charitable Trust, Dexcom, Insulet, Boehringer Ingelheim, Sanofi, and Novo Nordisk. D.Z.C. has received honoraria from Boehringer Ingelheim, Eli Lilly, Merck, AstraZeneca, Sanofi, Merck, Mitsubishi Tanabe, AbbVie, Janssen, Bayer, and Prometic and has received operational funding for clinical trials from Boehringer Ingelheim, Eli Lilly, Merck, Janssen, Sanofi, and AstraZeneca. B.Z. has received consulting fees and honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi.J.S.S.has actedasan advisor to Adocia, Applied Therapeutics, As-traZeneca, Boehringer Ingelheim, DalCor, Dance Biopharm, Diavacs, Duologics, Elcelyx, Eli Lilly, Esperion, Geneuro, Ideal Life, Immu-nomolecular Therapeutics, Intarcia, Intrexon/ ActoBio, Kamada, Merck, Orgenesis, Sanofi, Servier, Tolerion, vTv, Valeritas, Viacyte, and Zafgen; he has research funding from the National Institutes of Health, JDRF, and the Diabetes Research Institute Foundation; and he chairs the Strategic Advisory Board of the EU INNODIA consortium and has served as a member of the board of directors of Dexcom, Intarcia, and Moerae Matrix. B.A.P. has received speaker honoraria from Medtronic, Johnson & Johnson, Dexcom, Insulet, Novo Nordisk, AstraZeneca, Abbott, and Sanofi; has received research grant support from Boehringer Ingelheim, Medtronic, Novo Nordisk, and the Bank of Montreal; and has served as a consultant for Boehringer Ingelheim, Novo Nordisk, Insulet, Sanofi, Abbott, and Neuro-Metrix. J.M., D.N., S.K., J.G., and N.S. are employees of Boehringer Ingelheim. Author Contributions. B.A.P. and J.R. were the global coordinating investigators of EASE-2 and EASE-3 clinical trials, respectively. All authors took part in the analysis and interpretation of data as well as the drafting and critical revision of the manuscript. All authors had access to the data included in this publication and had the ultimate responsibility for the decision to publish this work. J.R. and B.A.P. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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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U2 - 10.2337/dc18-1749
DO - 10.2337/dc18-1749
M3 - Article
C2 - 30287422
AN - SCOPUS:85056803685
VL - 41
SP - 2560
EP - 2569
JO - Diabetes Care
JF - Diabetes Care
SN - 1935-5548
IS - 12
ER -