Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction

Aim: To compare the pharmacokinetic (PK) [area under the curve (AUC₀(-)₂₄ (h), C(max))] and pharmacodynamic (PD) (AUC(GIR) ₀(-)₂₄ (h), GIR(max)) properties of single-dose insulin detemir in the presence or absence of steady-state liraglutide (1.8 mg dose) in subjects with type 2 diabetes to determine whether co-administration affected the PK and PD profiles of either therapeutic agent.

Methods: Following a 3-week washout of oral antidiabetic agents (OADs) other than metformin, PK and PD assessments during three euglycaemia clamps were conducted: day 1 following a single dose of insulin detemir alone (0.5 U/kg), day 22 after 3 weeks of once-daily liraglutide with weekly dose escalation to 1.8 mg daily, and day 36 after 2 weeks of steady-state liraglutide maintenance at the 1.8 mg dose following co-administration with a single dose of insulin detemir (0.5 U/kg).

Results: The study population (N = 33; age 49.6 (±8.5) years) had diabetes for an average of 6.5 (±4.1) years, BMI 33 (±6.4) kg/m², FPG 9.7 (±1.6) mmol/l and HbA1c 8.3% (±0.9). PK: The PK profiles of insulin detemir were similar with and without steady-state liraglutide. Liraglutide did not affect AUC or C(max) of insulin detemir and vice versa. The 90% confidence intervals (CIs) for ratios of insulin detemir AUC [1.03; CI (0.97, 1.09)] and C(max) [1.05; CI (0.98, 1.13)] and liraglutide AUC [0.97; CI (0.87, 1.08)] and C(max) [1.03, CI (0.93, 1.13)] were all within the no-effect boundary (0.80, 1.25) (bioequivalence criterion). A stable mean insulin detemir concentration with and without liraglutide was maintained at the end of the 24-h PK sampling period. PD: The sum of AUC(GIR) for liraglutide (1982 mg/kg) and insulin detemir (1058 mg/kg) when given alone was similar to that obtained when the two were co-administered (2947 mg/kg). No serious adverse events were reported and no adverse events led to study withdrawal.

Conclusion: Co-administration of liraglutide 1.8 mg at steady state and insulin detemir produces an additive glucose-lowering effect without affecting the PK profile of either therapeutic agent suggesting that the addition of insulin detemir to patients treated with liraglutide will not require titration algorithms different from when insulin is added to OADs. The co-administration of insulin detemir and liraglutide was well tolerated.