Dose–response relationship of insulin glulisine in subjects with type 1 diabetes

Abstract

Aim: Little is known about the dose–response relationships of rapid‐acting insulin analogues in subjects with diabetes. This study compared the dose–exposure and dose–response relationships of insulin glulisine and regular human insulin (RHI) in subjects with type 1 diabetes.Methods: Eighteen male subjects with type 1 diabetes (mean glycosylated haemoglobin, HbA1c, 7.7%; body mass index 24.5 kg/m2) received subcutaneous injections of insulin glulisine followed by RHI (both at doses of 0.075, 0.15 and 0.3 U/kg) in the same three‐way crossover, randomized order in a euglycaemic glucose‐clamp study.Results: Insulin glulisine and RHI showed dose‐proportional increases in exposure (INS‐AUCtotal) and maximum serum concentration (INS‐Cmax) in the dose ranges 0.075, 0.15 and 0.3 U/kg. At all doses, within 2 h after injection, about twice as much insulin glulisine was absorbed as RHI (INS‐AUC0–2h: 3855, 6832 and 13237 vs. 2356, 3630 and 6231 μU.min/mL; p < 0.05) and INS‐Cmax was reached in about half the time (INS‐Tmax: 47, 57 and 72 vs. 82, 104 and 119 min; p < 0.05). Corresponding glucose disposition was twice as large with insulin glulisine as with RHI (GIR‐AUC0–2h: 314, 491 and 536 vs. 127, 219 and 294 mg/kg; p < 0.05), but was similar in extent upon completion (GIR‐AUCtotal: 499, 1090 and 1476 vs. 416, 1076 and 1555 mg/kg; not significant). With escalating doses, a steady increase in insulin exposure was noticed for both insulins across the entire dose range, whereas glucose disposition increased in a dose‐proportional manner only for the dose range 0.075–0.15 U/kg with insulin glulisine only. For both insulins, the end of euglycaemia occurred at insulin concentrations <10 μU/mL, with a subsequent rise in plasma glucose taking 80–90 min to reach ≥8.3 mmol/L (≥150 mg/dL) and a difference in time of ∼120 min between the insulins at any dose.Conclusions: Insulin glulisine presents rapid, dose‐proportional absorption, resulting in saturable glucodynamic activity in subjects with type 1 diabetes.