Insulin degludec in a flexible daily dosing regimen provides similar glycaemic control without increasing rates of hypoglycaemia compared to dosing the same time daily in type 2 diabetes

Abstract

Background and aims: Current basal insulin preparations should be injected at a consistent time to ensure optimal biologic action. Patients have difficulty adhering to strict dosing schedules for many reasons. Insulin degludec (IDeg), which forms soluble multi-hexamers upon s.c. injection resulting in an ultra-long and consistent action profile, may enable more flexible dosing intervals as an alternative to the recommended strict dose timing of currently available insulins. In this registration trial for IDeg, we investigated whether once-daily administration of IDeg in a flexible dosing regimen (IDeg Flex) provides comparable glycaemic control as administration at the same time daily with the evening meal (IDeg OD). Materials and methods: In this 26-week, open-label, treat-to-target trial, people with type 2 diabetes were randomised to IDeg Flex (n=229) and required to alternate the timing of insulin administration to morning and evening, in effect creating 8-40 h intervals between insulin doses, or to IDeg OD (n=228), where injections were given daily with the evening meal. Insulin was added to existing OAD therapy (if any) and titrated to FPG <5 mmol/l (90 mg/dl). Mean baseline characteristics such as age (56.2 vs. 56.5 yrs), HbA 1c (8.5 vs. 8.4%), diabetes duration (10.8 vs. 10.3 yrs) and BMI (29.3 vs. 29.4 kg/m 2) were comparable between the IDeg Flex and IDeg OD groups, respectively. Results: At 26 weeks, IDeg Flex and IDeg OD improved HbA 1c by 1.3 and 1.1 %-points, respectively (estimated treatment difference (ETD) IDeg Flex- IDeg OD: -0.13 %-points [95% CI: -0.29; 0.03]). Mean FPG was reduced from 9.0 to 5.8 mmol/l (IDeg Flex) and from 8.8 to 5.8 mmol/l (IDeg OD) (ETD: -0.05 mmol/l [-0.45; 0.35]). At Week 26, groups were similar in terms of fluctuations in 9-point self-measured plasma glucose (SMPG) (estimated treatment ratio (ETR) IDeg Flex/IDeg OD: 0.94 [0.86; 1.04]) and variation in prebreakfast SMPG (ETR: 1.04 [0.94; 1.14]). Rates of confirmed hypoglycaemia (PG <3.1 mmol/l (56 mg/dl) or severe) were 3.6 episodes/patient-yr in both groups (estimated rate ratio (ERR) IDeg Flex/IDeg OD: 1.10 [0.79; 1.52]); the rate of nocturnal confirmed hypoglycaemia was 0.6 episodes/patient-yr in both groups (ERR: 1.18 [0.66; 2.12]). Severe hypoglycaemia was rare (2 episodes/group). Conclusion: By using extreme dosing intervals of between 8 and 40 hours, the trial demonstrates that IDeg can be dosed flexibly at any time of the day and that changes in the injection time from day to day do not affect glycaemic control or risk of hypoglycaemia. The flexible dosing regimen made possible by IDeg will facilitate the integration of insulin therapy with daily activities and potentially improve adherence and acceptance of treatment.