Sotagliflozin (SOTA) is a dual SGLT1 and SGLT2 inhibitor in development as adjunct therapy to insulin in T1D.

In this double-blind, 52-week North American trial, 793 adults with T1D treated with multiple daily insulin injections (40%) or pump (60%) were randomized 1:1:1 to placebo (n=268), SOTA 200 mg (n=263) or SOTA 400 mg (n=262) once daily after 6 weeks of insulin optimization. Primary endpoint was change from baseline in A1C at Week 24. Other endpoints included A1C, weight, bolus insulin and FPG changes at Week 52, patient (pt) reported outcomes and net clinical benefit (NCB), assessing the proportion of pts with A1C <7.0% without severe hypoglycemia (SH) or diabetic ketoacidosis (DKA).

Baseline characteristics were similar between groups. Compared with placebo, SOTA 200 and 400 mg improved A1C and pt satisfaction at Week 24 and reduced A1C, weight, bolus insulin, FPG and pt distress at Week 52. More pts achieved NCB with SOTA vs. placebo (each P<0.05; Table). The highest incidence of SH was in the placebo arm; more genital mycotic infections, diarrhea and DKA events (more with pump than MDI) were in the SOTA arms (Table).

Efficacy (mITT population) and Safety (safety population) Results 
 Placebo n=268 SOTA 200 mg n=263 SOTA 400 mg n=262 
Mean A1C at Baseline, after 6-week insulin optimization, % 7.54 7.61 7.56 
Outcomes at Week 24    
A1C LSM difference from placebo, % ± SE (P-value) - -0.36±0.05(<0.001) -0.41±0.(<0.001) 
Outcomes at Week 52    
A1C LSM difference from placebo, % ± SE (P-value) - -0.25±0.(P<0.001) -0.31±0.(P<0.001) 
FPG LSM difference from placebo, mmol/L ± SE - -0.68±0.31 (P=0.028) -1.08±0.31 (P<0.001) 
Body weight LSM difference from placebo, kg ± SE (P-value) - -3.14±0.34 (P<0.001) -4.32±0.35 (P<0.001) 
Mean daily bolus insulin dose at Baseline, IU 31.7 30.3 30.8 
Bolus insulin dose mean change from Baseline, % ± SE 7.01±3.40 -1.48±3.40 -8.63±3.42 
Bolus insulin dose LSM difference from placebo, % ± SE (P-value) - -5.53±4.59 (P=0.23) -15.63±4.60 (P<0.001) 
Net clinical benefit at Week 52    
A1C <7.0% without SH and without DKA, n (%) 51 (19.0) 69 (26.2) 85 (32.4) 
Safety outcomes over 52 weeks 
Any TEAE, n (%) 216 (80.6) 215 (81.7) 209 (79.8) 
TEAEs leading to study discontinuation, n (%) 11 (4.1) 13 (4.9) 17 (6.5) 
Treatment-emergent serious adverse events, n (%) 20 (7.5) 27 (10.3) 29 (11.1) 
Death, n (%) 1 (0.4) 0 0 
DKA, n (%)1 1 (0.4) 9 (3.4) 11 (4.2) 
Severe hypoglycemia, n (%)1 26 (9.7) 17 (6.5) 17 (6.5) 
Diarrhea2, n (%) 18 (6.7) 22 (8.4) 27 (10.3) 
Genital mycotic infection, n (%) 9 (3.4) 24 (9.1) 34 (13.0) 
Patient reported outcomes 
DTSQ score LSM difference from placebo at Week 24 ± SE (P-value) - 2.5±0.40 (P<0.001) 2.5±0.40 (P<0.001) 
DDS2 score LSM difference from placebo at Week 52 ± SE (P-value) - -0.4±0.15 (P=0.003) -0.5±0.15 (P<0.001) 
Efficacy (mITT population) and Safety (safety population) Results 
 Placebo n=268 SOTA 200 mg n=263 SOTA 400 mg n=262 
Mean A1C at Baseline, after 6-week insulin optimization, % 7.54 7.61 7.56 
Outcomes at Week 24    
A1C LSM difference from placebo, % ± SE (P-value) - -0.36±0.05(<0.001) -0.41±0.(<0.001) 
Outcomes at Week 52    
A1C LSM difference from placebo, % ± SE (P-value) - -0.25±0.(P<0.001) -0.31±0.(P<0.001) 
FPG LSM difference from placebo, mmol/L ± SE - -0.68±0.31 (P=0.028) -1.08±0.31 (P<0.001) 
Body weight LSM difference from placebo, kg ± SE (P-value) - -3.14±0.34 (P<0.001) -4.32±0.35 (P<0.001) 
Mean daily bolus insulin dose at Baseline, IU 31.7 30.3 30.8 
Bolus insulin dose mean change from Baseline, % ± SE 7.01±3.40 -1.48±3.40 -8.63±3.42 
Bolus insulin dose LSM difference from placebo, % ± SE (P-value) - -5.53±4.59 (P=0.23) -15.63±4.60 (P<0.001) 
Net clinical benefit at Week 52    
A1C <7.0% without SH and without DKA, n (%) 51 (19.0) 69 (26.2) 85 (32.4) 
Safety outcomes over 52 weeks 
Any TEAE, n (%) 216 (80.6) 215 (81.7) 209 (79.8) 
TEAEs leading to study discontinuation, n (%) 11 (4.1) 13 (4.9) 17 (6.5) 
Treatment-emergent serious adverse events, n (%) 20 (7.5) 27 (10.3) 29 (11.1) 
Death, n (%) 1 (0.4) 0 0 
DKA, n (%)1 1 (0.4) 9 (3.4) 11 (4.2) 
Severe hypoglycemia, n (%)1 26 (9.7) 17 (6.5) 17 (6.5) 
Diarrhea2, n (%) 18 (6.7) 22 (8.4) 27 (10.3) 
Genital mycotic infection, n (%) 9 (3.4) 24 (9.1) 34 (13.0) 
Patient reported outcomes 
DTSQ score LSM difference from placebo at Week 24 ± SE (P-value) - 2.5±0.40 (P<0.001) 2.5±0.40 (P<0.001) 
DDS2 score LSM difference from placebo at Week 52 ± SE (P-value) - -0.4±0.15 (P=0.003) -0.5±0.15 (P<0.001) 

DDS2, two-item Diabetes Distress Screening Scale (positive scores indicate improvement); DKA, diabetic ketoacidosis; DTSQ, diabetes treatment satisfaction questionnaire; FPG, fasting plasma glucose; LSM, least squares mean; mITT, modified intent-to-treat; SD, standard deviation; SE, standard error; SH, severe hypoglycemia; SOTA, sotagliflozin; TEAE, treatment emergent adverse events. 1Positively-adjudicated events (defined as an adjudicator assessment of yes/certainly or yes/probably); 2Discontinuation of drug due to diarrhea was: 0.4% placebo, 0% SOTA 200 mg, and 0.4% SOTA 400 mg.

View Large

In conclusion, SOTA 200 and 400 mg were associated with statistically significant A1C reductions that were sustained (P<0.05) at Week 52, with an increased (but low) rate of DKA, and a lower incidence of SH, when compared with placebo.

Disclosure

J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. T. Danne: Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Dexcom, Inc.. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; DreaMed Diabetes, Ltd.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Menarini Group. J.A. Kushner: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; KNOW Foods, Inc. W. Lane: Advisory Panel; Self; Novo Nordisk A/S, Insulet Corporation, Intarcia Therapeutics, Inc., Sanofi. Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Sanofi, Dexcom, Inc.. Speaker's Bureau; Self; Novo Nordisk A/S, Insulet Corporation. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc., Merck & Co., Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC.. J.H. Reed: None. S. Sawhney: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc., AstraZeneca, Pfizer Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation. P. Strumph: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.. Board Member; Self; College Diabetes Network.

© 2018 by the American Diabetes Association.
2018
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.