Sotagliflozin sustains HbA1c reductions, improves outcomes over 1 year in T1D
Combining the dual sodium glucose cotransporter (SGLT) 1 and 2 inhibitor sotagliflozin with optimized insulin therapy led to sustained reductions in HbA1c levels over 1 year in adults with type 1 diabetes (T1D), according to a study presented at ADA 2018.
“Despite recent advances, the challenges of T1D management, specifically hypoglycaemia or fear of hypoglycaemia, weight gain, glucose variability, and patient burden, prevent many patients from reaching their treatment goals,” said study lead investigator Professor John Buse from the University of North Carolina School of Medicine in Chapel Hill, North Carolina, US.
“The profile of sotagliflozin to improve glucose control beyond what can be achieved with intensified insulin alone while addressing these challenges has the potential to improve the lives of people with T1D,” said Buse.
Participants in the phase III inTandem1* study were 793 adults with inadequately controlled T1D (HbA1c 7–11 percent for ≥1 year) from 75 centres in North America who, following 6 weeks of treatment with optimized insulin (via pump or multiple injections), were randomized to receive once-daily oral sotagliflozin 200 mg (n=263), sotagliflozin 400 mg (n=262), or placebo (n=268) in addition to insulin for 52 weeks. Mean HbA1c at baseline was 7.57 percent.
Patients on sotagliflozin 200 mg and 400 mg experienced a significant reduction in HbA1c levels compared with placebo at 52 weeks (adjusted least squares mean [LSM], -0.25 percent and -0.31 percent, respectively; p<0.001 for each vs placebo). [ADA 2018, abstract 212-OR; Diabetes Care 2018;doi:10.2337/dc18-0343]
These findings were similar to those demonstrated at 24 weeks (LSM, -0.36 percent and -0.41 percent in patients on sotagliflozin 200 mg and 400 mg, respectively; p<0.001 for each vs placebo). [ADA 2017, abstract 69-OR]
Among patients with a baseline HbA1c of ≥7.0 percent, a greater proportion of those who received sotagliflozin achieved HbA1c <7.0 percent compared with those on placebo at 24 weeks (27.2 and 40.3 percent of those on sotagliflozin 200 and 400 mg, respectively, vs 15.7 percent; p≤0.003 vs placebo) and at 52 weeks (27.7 and 35.4 percent vs 18.4 percent).
At 52 weeks, more patients on sotagliflozin 200 mg and 400 mg also achieved HbA1c <7.0 percent without severe hypoglycaemia or diabetic ketoacidosis compared with placebo (26.2 percent and 32.4 percent vs 19.0 percent; p=0.05 and p<0.001, respectively). Patients on sotagliflozin 400 mg also required a lower bolus insulin dose compared with those on placebo (-15.63 percent; p<0.001), and demonstrated a significant reduction in BMI (LSM, -4.32 kg; p<0.001) and fasting plasma glucose levels (-1.08 mmol/L; p<0.001).
Overall rate of adverse events (AEs) was comparable between patients on sotagliflozin 200 and 400 mg and placebo (81.7, 79.8, and 80.6 percent, respectively). AEs that occurred more frequently among sotagliflozin vs placebo users were genital mycotic infections (9.1 and 13.0 percent [sotagliflozin 200 and 400 mg, respectively] vs 3.4 percent), diarrhoea (8.4 and 10.3 percent vs 6.7 percent), and diabetic ketoacidosis (3.4 and 4.2 percent vs 0.4 percent). However, severe hypoglycaemia was more frequent among placebo users (9.7 percent) than sotagliflozin users (6.5 percent of each treatment arm).
The widespread use of continuous subcutaneous insulin infusion (CSII; 75 percent of sotagliflozin users who experienced diabetic ketoacidosis) may have contributed to the higher incidence of diabetic ketoacidosis in sotagliflozin vs placebo users, said the researchers, citing the potential for increased diabetic ketoacidosis risk in CSII users due to “operational or mechanical failures”.
“The small but increased risk of diabetic ketoacidosis can be potentially mitigated with proper education and ketone monitoring,” said Buse.
“The beneficial effects on HbA1c, glycaemic variability, and weight with less hypoglycaemia outweigh this risk and support the combination of SGLT inhibitors with insulin as a therapeutic approach for T1D,” said Buse and co-authors.