Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes

Abstract

Aims: Two single-dose studies were conducted in Japan and Europe to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of new insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) in people with type 1 diabetes mellitus.

Methods: In two double-blind, randomized, crossover studies, 18 Japanese participants (aged 20-65 years) and 24 European participants (aged 18-65 years) with glycated haemoglobin levels ≤9.0% (≤75 mmol/mol) received single subcutaneous doses of Gla-300, 0.4, 0.6 and 0.9 U/kg (0.9 U/kg in the European study only), and Gla-100, 0.4 U/kg. A 36-h euglycaemic clamp procedure was performed after each dosing.

Results: The serum insulin glargine concentration (INS) and glucose infusion rate (GIR) developed more gradually into more constant and prolonged profiles with Gla-300 than with Gla-100. In support of this, the times to 50% of glargine exposure and insulin activity were longer for all Gla-300 doses than for Gla-100 during the 36-h clamp period, indicating a more evenly distributed exposure and metabolic effect beyond 24 h. Exposure to insulin glargine and glucose utilization were lower with the 0.4 and 0.6 U/ml Gla-300 doses in both studies compared with the 0.4 U/ml Gla-100 dose. Glucose-lowering activity was detected for up to 36 h with all doses of Gla-300.

Conclusions: Single-dose injections of Gla-300 present more constant and prolonged PK and PD profiles compared with Gla-100, maintaining blood glucose control for up to 36 h in euglycaemic clamp settings in Japanese and European participants with type 1 diabetes.

Keywords: insulin analogues; pharmacodynamics; pharmacokinetics; type 1 diabetes.

Figure 1

Designs of the (A) Japanese and (B) European studies. (A) Day (D); D-1, evening before D1 visit and insulin glargine 300 U/ml (Gla-300) or insulin glargine 100 U/ml (Gla-100) administration; D1, Gla-100 0.4 U/kg, Gla-300 0.4 U/kg or Gla-300 0.6 U/kg administered at approximately 10:00 h (14:00 h at latest) after adjustment for blood glucose during preclamp; D2, end of clamp. The study comprised three treatments (Gla-100 0.4 U/kg, Gla-300 0.4 U/kg and Gla-300 0.6 U/kg), three treatment periods (periods 1–3) and three sequences. (B) D1, Gla-100 0.4 U/kg, Gla-300 0.4 U/kg, Gla-300 0.6 U/kg or Gla-300 0.9 U/kg administered at approximately 09:00 h (14:00 h at latest) after adjustment for blood glucose during preclamp. The clamp was maintained for 36 h after dosing. The study comprised four treatments (Gla-100 0.4 U/kg, Gla-300 0.4 U/kg, Gla-300 0.6 U/kg and Gla-300 0.9 U/kg), four treatment periods (periods 1–4) and four sequences.

Figure 2

Serum insulin glargine concentration (INS), glucose infusion rate (GIR) and blood glucose profiles after a single dose in the Japanese study. (A) Median INS profiles (linear scale) with lower limit of quantification (LLOQ) of 5.02 µU/ml; (B) mean smoothed [locally weighted regression in smoothing scatterplots (LOESS) factor 0.15] 36-h body-weight-standardized GIR profiles; (C) mean smoothed (LOESS factor 0.15) 36-h blood glucose profiles.

Figure 3

Serum insulin glargine concentration (INS), glucose infusion rate (GIR) and blood glucose profiles after a single dose in the European study. (A) Median INS profiles (linear scale) with lower limit of quantification (LLOQ) of 5.02 µU/ml; (B) mean smoothed [locally weighted regression in smoothing scatterplots (LOESS) factor 0.15] 36-h body-weight-standardized GIR profiles; (C) mean smoothed (LOESS factor 0.15) 36-h blood glucose profiles.