Fifty-Two-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (The European inTandem2 Study)

Abstract

Sotagliflozin (SOTA) is a dual SGLT1 and SGLT2 inhibitor in development as adjunct therapy to insulin in T1D. In this double-blind, 52-week study, 782 adults with T1D treated with multiple daily insulin injections or pump therapy were randomized 1:1:1 to placebo (n=258), SOTA 200 mg (n=261) or SOTA 400 mg (n=263) once daily after 6 weeks of insulin optimization. Primary endpoint was change from baseline in A1C at Week 24. Other endpoints included A1C, documented hypoglycemia (DH), weight and FPG change at Week 52, patient (pt) reported outcomes (PROs) 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, treatment with SOTA 200 or 400 mg improved A1C and pt satisfaction at Week 24 and reduced A1C, DH rate, weight, FPG and pt distress at Week 52 (Table). More pts achieved NCB in the SOTA arms vs. placebo (Table). Pts receiving SOTA 400 mg had the least SH events, but more genital mycotic infections, DKA and diarrhea than placebo. In conclusion, SOTA 200 and 400 mg were associated with statistically significant A1C reductions that were sustained (P<0.05) at Week 52, as well as improved DH and PROs. There was more DKA, but less SH, with SOTA 400 mg relative to placebo at Week 52. Efficacy (mITT population) and Safety (safety population) ResultsPlacebo n=258SOTA 200 mg n=261SOTA 400 mg n=263Mean A1C at Baseline, after 6-week insulin optimization, %7.797.747.71Outcomes at Week 24A1C LSM difference from placebo, % ± SE (P-value)--0.37±0.(P<0.001)-0.35±0.(P<0.001)Outcomes at Week 52A1C LSM difference from placebo, % ± SE (P-value)--0.21±0.07 (P=0.003)-0.32±0.07 (P<0.001)FPG LSM difference from placebo, mmol/L ± SE--0.27±0.33 (P=0.41)-0.87±0.33 (P=0.008)Daily insulin LSM difference from placebo, IU ± SE (P-value)--2.81±1.14 (P=0.014)-3.37±1.14 (P=0.003)DH ratea, LSM difference from placebo ± SE (P-value)-0.03±0.01 (P=0.017)-0.03±0.01 (P=0.006)Body weight LSM difference from placebo, kg ± SE (P-value)--2.18±0.36 (P<0.001)-2.92±0.36 (P<0.001)Mean daily bolus insulin dose at Baseline, IU32.131.131.9Bolus insulin dose mean change from Baseline, % ± SE4.21±3.25-3.48±3.24-7.94±3.23Bolus insulin LSM difference from placebo, % ± SE (P-value)--7.70±4.41 (P=0.08)-12.15±4.40 (P=0.006)Net clinical benefit at Week 52A1C <7.0% without SH and without DKA, n (%)37 (14.3)67 (25.7)70 (26.6)Safety outcomes over 52 weeksAny TEAE, n (%)158 (61.2)178 (68.2)181 (68.8)TEAEs leading to study discontinuation, n (%)9 (3.5)10 (3.8)18 (6.8)Treatment-emergent serious adverse events, n (%)17 (6.6)26 (10.0)21 (8.0)Death, n (%)2 (0.8)*00DKAb, n (%)06 (2.3)9 (3.4)Severe hypoglycemia, n (%)13 (5.0)13 (5.0)6 (2.3)Diarrheac, n (%)9 (3.5)12 (4.6)19 (7.2)Genital mycotic infection, n (%)6 (2.3)24 (9.2)29 (11.0)Patient reported outcomesDTSQ score LSM difference from placebo at Week 24 ± SE (P-value)-2.0±0.4 (P<0.001)1.7±0.4 (P<0.001)DDS2 score LSM difference from placebo at Week 52 ± SE (P-value)--0.2±0.2 (P=0.23)-0.3±0.2 (P=0.046)DDS2, two-item Diabetes Distress Screening Scale (negative scores indicate improvement); DH, documented hypoglycemia; DKA, diabetic ketoacidosis; DTSQ, diabetes treatment satisfaction questionnaire; FPG, fasting plasma glucose; LSM, least squares mean; mITT, modified intent-to-treat; SE, standard error; SH, severe hypoglycemia; SOTA, sotagliflozin; TEAE, treatment emergent adverse events. *One death was due to cardiopulmonary failure and the other to a malignant lung neoplasm.aevents per patient per day ≤3.0 mmol/L (≤55 mg/dL);bPositively-adjudicated events (defined as an adjudicator assessment of yes/certainly or yes/probably), discontinuation of drug due to DKA was: 0% placebo, 0% SOTA 200 mg, and 1.9% for SOTA 400 mg;cDiscontinuation of drug due to diarrhea was: 0.4% placebo, 0.8% SOTA 200 mg, and 0.8% SOTA 400 mg. Disclosure 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. B. Cariou: Board Member; Self; Amgen Inc.. Consultant; Self; Genfit. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Board Member; Self; Sanofi-Aventis, Regeneron Pharmaceuticals, Inc. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M. Brandle: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Novo Nordisk Foundation. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. H. Brath: Speaker's Bureau; Self; Abbott. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc.. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc., Pfizer Inc.. Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Self; Sanofi-Aventis Deutschland GmbH. Board Member; Self; Austrian Diabetes Association. E. Franek: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Bristol-Myers Squibb Company, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Servier. J.A. Kushner: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; KNOW Foods, Inc. 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. 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.