Low-dose empagliflozin as adjunct to hybrid closed-loop insulin therapy in sub-optimally controlled adults with type 1 diabetes: a randomized crossover controlled trial

Objective: To assess whether low doses of empagliflozin as adjunct to hybrid closed-loop therapy improve glycemia compared to placebo in adults with type 1 diabetes who are not able to achieve targets with the system alone. 

Research Design and Methods: A double-blind, crossover, randomized controlled trial was performed in sub-optimally controlled (HbA1c 7.0-10.5%) adults who were not able to achieve a target time-in-range (3.9-10.0 mmol/L) ≥ 70% after 14 days of hybrid closed-loop therapy.  Three 14-day interventions were performed with placebo, empagliflozin 2.5 mg, or empagliflozin 5 mg, as adjunct to the McGill Artificial Pancreas.  Participants were assigned in a 1:1:1:1:1:1 ratio with blocked randomization.  The primary outcome was time-in-range (3.9-10.0 mmol/L).  Analysis was by intention to treat and a p-value of less than 0.05 was regarded as significant.  This trial is registered, NCT04450563.

Results: 24 participants completed the study (50% male, age 33 ± 14 yrs, HbA1c 8.1 ± 0.5%). The time-in-range was 59.0 ± 9.0% for placebo, 71.6 ± 9.7% for empagliflozin 2.5 mg, and 70.2 ± 8.0% for empagliflozin 5 mg (p <0.0001 between empagliflozin 2.5 mg and placebo, and empagliflozin 5 mg and placebo).  Mean daily capillary ketone levels were not different between arms. There were no serious adverse events, diabetic ketoacidosis, or severe hypoglycemia in any intervention.

Conclusions: Empagliflozin 2.5 mg and 5 mg increased time-in-range on hybrid closed-loop therapy by 11–13 percentage points compared to placebo, in those who otherwise were unable to attain glycemic targets. Future studies are required to assess long-term efficacy and safety.