Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study
Article Figures & Tables
Figures
- Figure 1
Study design. After a 2-week screening period, insulin therapy was optimized for 6 weeks prior to randomization (R), and optimized insulin continued until the study conclusion at week 52. After a 2-week placebo run-in, patients were randomly assigned to double-blind (DB) treatment with sotagliflozin 200 or 400 mg or placebo for 52 weeks. Insulin optimization refers to the adjustment of insulin to meet standard-of-care glycemic targets starting 6 weeks prior to randomization, which continued for the entire study. An IDMC assessed standard-of-care adherence and provided feedback to the principal investigator if deviations from standard of care were observed prior to week 24; HbA1c was masked to study staff during this period. Between week 24 and 52, insulin optimization continued without input from the IDMC, and HbA1c values were unmasked. Safety was monitored for 30 days after the last dose of study medication.
- Figure 2
Primary and other selected end points. Error bars represent SEM. A: LSM change from baseline in HbA1c over 52 weeks. Data between week −6 to week 0 depict arithmetic mean differences between screening and baseline HbA1c values to illustrate effect of insulin optimization. During the 24-week double-blind (DB) core treatment (CT) period, HbA1c levels were masked to study staff and an IDMC reviewed investigators’ insulin titration decisions and provided feedback. During the 28-week double-blind extension (EXT), HbA1c was unmasked and the IDMC did not review insulin titration. B: LSM percent change from baseline in total daily insulin dose (TDD) over 52 weeks. C: LSM change from baseline in weight over 52 weeks. PBO, placebo.
- Figure 3
Sotagliflozin inTandem1 interstitial glucose. 24-h CGM tracing consisting of interstitial glucose readings collected every 5 min. Solid lines represent mean values from each treatment group (light purple, placebo [n = 45]; light blue, sotagliflozin 200 mg [n = 44]; dark blue, sotagliflozin 400 mg [n = 47]); shaded areas represent ± 1 SEM. The figure shows data collected from midnight. Actual start time for 24-h readings may vary for each subject. Top of target CGM range = 10.0 mmol/L (180 mg/dL).
Tables
- Table 1
Summary of adverse events and events of special interest, overall treatment period (baseline to 52 weeks)
Placebo (n = 268) Sotagliflozin 200 mg (n = 263) Sotagliflozin 400 mg (n = 262) Any adverse event 216 (80.6) 215 (81.7) 209 (79.8) Serious adverse event 20 (7.5) 27 (10.3) 29 (11.1) Severe adverse event 7 (2.6) 12 (4.6) 12 (4.6) Death 1 (0.4)* 0 0 Positively adjudicated adverse events ≥1 severe hypoglycemia event† 26 (9.7) 17 (6.5) 17 (6.5) ≥1 severe nocturnal hypoglycemia event†** 10 (3.7) 10 (3.8) 2 (0.8) ≥1 DKA event 1 (0.4) 9 (3.4) 11 (4.2) ≥1 DKA event among CSII users 1/160 (0.6) 8/156 (5.1) 7/157 (4.5) ≥1 DKA event among MDI users 0/108 1/107 (0.9) 4/105 (3.8) Major adverse cardiovascular events Myocardial infarction or hospitalization for unstable angina 3 (1.1) 4 (1.5) 0 Stroke 1 (0.4) 0 1 (0.4) Heart failure hospitalization 0 0 0 Coronary revascularization 2 (0.7) 2 (0.8) 0 Drug-induced liver injury 0 0 2 (0.8) Events of special interest Any 266 (99.3) 260 (98.9) 259 (98.9) Genital mycotic infection 9 (3.4) 24 (9.1) 34 (13.0) Diarrhea‡ 18 (6.7) 22 (8.4) 27 (10.3) Urinary tract infection 19 (7.1) 26 (9.9) 11 (4.2) Bone fracture 10 (3.7) 9 (3.4) 5 (1.9) Renal event§ 5 (1.9) 7 (2.7) 4 (1.5) Volume depletion|| 4 (1.5) 8 (3.0) 4 (1.5) Malignancies of special interest¶ 0 2 (0.8) 2 (0.8) Amputation 0 0 1 (0.4) Pancreatitis 0 0 0 Venous thrombotic event 0 0 0 Any documented hypoglycemia# (SMBG ≤3.9 mmol/L [≤70 mg/dL]) 266 (99.3) 260 (98.9) 258 (98.5) Any nocturnal documented hypoglycemia** 247 (92.2) 239 (90.9) 238 (90.8) Any SMBG value ≤3.0 mmol/L (≤55 mg/dL) 248 (92.5) 250 (95.1) 244 (93.1) Any adverse event leading to discontinuation 11 (4.1) 13 (4.9) 17 (6.5) Any event of special interest leading to discontinuation†† 7 (2.6) 8 (3.0) 12 (4.6) Aortic valve incompetence 1 (0.4) 0 0 Diarrhea 1 (0.4) 0 1 (0.4) Hepatitis 0 0 1 (0.4) Urinary tract infection 0 1 (0.4) 0 Cystitis glandularis 1 (0.4) 0 0 Vulvovaginal events‡‡ 1 (0.4) 0 2 (0.8) Blood creatinine increased 0 0 1 (0.4) Hepatic enzymes increased 0 1 (0.4) 1 (0.4) DKA (positively adjudicated) 0 4 (1.5) 4 (1.5) Acetonemia§§ 0 1 (0.4) 1 (0.4) Hypoglycemia 3 (1.1) 1 (0.4) 0 Severe hypoglycemia (positively adjudicated) 2 (0.7) 1 (0.4) 0 Data are n or n (%) and include patients who received at least one dose of a study drug and include events that occurred up to 30 days after the last dose of double-blind study treatment.
↵*Death due to endocarditis, judged not related to study drug.
↵†Severe hypoglycemia was defined as any event that required assistance from another person or during which the patient lost consciousness or had a seizure. Hypoglycemia events include all those that occurred between first and last dose of study drug during the 52-week double-blind treatment period.
↵‡Diarrhea was mostly mild to moderate and transient.
↵§Renal events are listed in Supplementary Data.
||Volume depletion events are listed in Supplementary Data.
↵¶Included two breast cancer cases, one thyroid cancer, and one melanoma.
↵#Documented hypoglycemia was defined as a blood glucose level of ≤3.9 mmol/L (≤70 mg/dL) with or without hypoglycemia symptoms. In the sotagliflozin development program, hypoglycemia is considered an event of special interest, with a specialized case report form. Because analysis for hypoglycemia was based on data recorded in the case report form, investigators were asked to not submit hypoglycemic events on the adverse event case report form unless the episode met criteria for a serious adverse event.
↵**Nocturnal hypoglycemia was defined as positively adjudicated severe hypoglycemia or investigator-reported documented hypoglycemia (blood glucose level of ≤3.9 mmol/L [≤70 mg/dL] with or without hypoglycemia symptoms) that occurred between midnight and 5:59 a.m., regardless of whether the patient was awake during the event.
↵††All events of special interest leading to discontinuation were investigator reported except for DKA and severe hypoglycemia, which were positively adjudicated.
↵‡‡Vulvovaginal mycotic infection, vulvovaginits, and vulvovaginal pruritus.
↵§§Both cases of acetonemia were negatively adjudicated for DKA.
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