TY - JOUR
T1 - HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes
T2 - The European in Tandem2 study
AU - Danne, Thomas
AU - Cariou, Bertrand
AU - Banks, Phillip
AU - Brandle, Michael
AU - Brath, Helmut
AU - Franek, Edward
AU - Kushner, Jake A.
AU - Lapuerta, Pablo
AU - McGuire, Darren K
AU - Peters, Anne L.
AU - Sawhney, Sangeeta
AU - Strumph, Paul
N1 - Funding Information:
Acknowledgments. The authors thank the inTandem2 trial investigators, staff, and patients for their participation and the following contributors for reviewing the manuscript: John Buse, MD, PhD; Roger Davies, MPhil; Diane Gesty-Palmer, MD, PhD; David Powell, MD; and Kristi Boehm, MS, ELS. Amanda Justice provided medical writing and editorial support, which was funded by Lexicon Pharmaceuticals, Inc. The authors thank Covance Inc. (Princeton, NJ) for operationally executing and performing medical monitoring of this study and Cenduit, LLC (Durham, NC) for providing visualizations of CGM data. Funding. This study was supported and conducted by Lexicon Pharmaceuticals, Inc. Lexicon Pharmaceuticals, Inc., and Sanofi entered a license agreement effective November 2015 and are collaborating on the development and commercialization of sotagliflozin. Duality of Interest. T.D. has acted as consultant, advisoryboardmember,steeringcommitteemem-ber,orspeakerforAbbottLaboratories,Medtronic, Roche, Lexicon Pharmaceuticals, Inc., Menarini Group,BoehringerIngelheim,AstraZeneca,Novo Nordisk, Sanofi, Dexcom, Inc., and Eli Lilly and Company and has received research grants from Abbott Laboratories, AstraZeneca, Novo Nordisk, Medtronic, and Sanofi. B.C. has received research funding and personal fees from Sanofi and Regeneron Pharmaceuticals, Inc.; research funding from Pfizer; and honoraria from Amgen, AstraZeneca, Genfit SA, Pierre Fabre Group, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, and Sanofi. P.B., P.L., S.S., and P.S. are employed by Lexicon Pharmaceuticals, Inc., and S.S. holds stock in Lexicon Pharmaceuticals, Inc. M.B. has acted as consultant, advisory board member, or speaker for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, and Merck Sharp & Dohme. H.B. has acted as speaker or advisory board member for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme, Mylan N.V., Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi, and ServierLaboratories.E.F.hasreceivedlecturer’s fees from AstraZeneca, Bioton, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Polfa Tarchomin S.A., Servier Laboratories, and Sanofi and has received consulting fees for serving on advisory boards for Boehringer Ingelheim and Novo Nordisk. J.A.K. serves on the type 1 diabetes steering committee for Lexicon Pharmaceuticals, Inc., and as an advisor for Sanofi and Know Foods. D.K.M. has received consulting fees and fees for serving on a clinical trial executive committee from Boehringer Ingelheim, Sanofi US, Novo Nordisk, and AstraZeneca; consulting fees from Lilly USA LLC; advisory board fees and fees for serving on a clinical trial executive committee from Merck Sharp & Dohme; fees for serving on a data monitoring committee from Janssen Research and Development, LLC, and GlaxoSmithKline; fees for chairing steering committees from Lexicon Pharmaceuticals, Inc.; and fees for serving on a clinical trial executive or steering committee from Eisai Co., Ltd., and Esperion Therapeutics. A.L.P. has participated on advisory boards for Abbott Diabetes Care, Becton, Dickinson and Company, Bigfoot Biomedical, Boehringer Ingelheim, Eli Lilly and Company, Medscape, Merck & Company, Novo Nordisk, Omada Health, and Sanofi; chairs the type 1 diabetes steering committee at Lexicon Pharmaceuticals, Inc.; has consulted for Science 37; has spoken for and received research supplies from Dexcom, Inc.; and has participated in a speaker’s bureau for Novo Nordisk. Author Contributions. T.D., J.A.K., P.L., D.K.M., A.L.P., S.S., and P.S. conceived and conducted the study and acquired, analyzed, and interpreted data. B.C., M.B., H.B., and E.F. conducted the study and acquired, analyzed, and interpreted data. P.B. contributed to the statistical design, analyzed and interpreted data, and oversaw the statistical analyses conducted by the independent statistician. P.B., P.L., and P.S. approved the protocol and its amendments. P.B., P.L., S.S., and P.S. reviewed the data quality before locking the database. P.L. provided safety oversight for monthly safety reviews. T.D., B.C., P.B., M.B., H.B., E.F., J.A.K., P.L., D.K.M., A.L.P., S.S., and P.S. drafted and critically revised the manuscript. T.D., B.C., P.B., M.B., H.B., E.F., J.A.K., P.L., D.K.M., A.L.P., S.S., and P.S. had full access to the data in the study and had final responsibility for the decision to publish. T.D. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. The inTandem2 24-week results were presented at the European Association for the Study of Diabetes (EASD) Annual Meeting, Lisbon, Portugal, 11–15 September 2017. The inTandem2 52-week results were presented at the 78th Scientific Sessions of the American Diabetes Association in Orlando, FL, 22–26 June 2018.
Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of the dual sodiumglucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS: At24weeks, placebo-adjusted changesin HbA1c from baseline (7.8%) were 20.37% and 20.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (20.87 mmol/L; P = 0.008), weight (22.92 kg; P < 0.001), and total daily insulin dose (28.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypogly-cemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS: In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).
AB - OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of the dual sodiumglucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS: At24weeks, placebo-adjusted changesin HbA1c from baseline (7.8%) were 20.37% and 20.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (20.87 mmol/L; P = 0.008), weight (22.92 kg; P < 0.001), and total daily insulin dose (28.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypogly-cemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS: In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).
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U2 - 10.2337/dc18-0342
DO - 10.2337/dc18-0342
M3 - Article
C2 - 29937431
AN - SCOPUS:85052747420
SN - 0149-5992
VL - 41
SP - 1981
EP - 1990
JO - Diabetes care
JF - Diabetes care
IS - 9
ER -