Blood glucose levels during the glucose clamps were comparable on the different study days as were their swings. Specifically, blood glucose levels were: 12 IU ultra-fast insulin 5.0 ± 0.2 mmol/l (coefficient of variation 4.7%); 12 U insulin lispro 5.0 ± 0.2 mmol/l (4.5%); 12 IU human soluble insulin 4.9 ± 0.4 mmol/l (7.7%); 6 IU ultra-fast insulin 4.9 ± 0.3 mmol/l (5.6%); and 3 IU ultra-fast insulin 4.9 ± 0.2 mmol/l (4.6%).
Pharmacokinetic variables obtained with 12 IU of ultra-fast insulin, insulin lispro and human soluble insulin
Figure 1a shows that subcutaneous injection of ultra-fast insulin resulted in a more rapid increase in serum insulin than did injection of insulin lispro, which, in turn was more rapid than human soluble insulin. While the difference between ultra-fast insulin and human soluble insulin was significant, the difference between ultra-fast insulin and insulin lispro failed to reach statistical significance (tC
max) (Table 1, Fig. 1a). The decline of serum insulin levels was also more rapid with the ultra-fast insulin and insulin lispro. Figure 1 also shows a normalised graph comparing the different pharmacokinetic timing profiles. Serum C-peptide levels showed a moderate decline from baseline levels after s.c. injection of the different insulin formulations in all cases, including the different doses of ultra-fast insulin (data not shown).
Pharmacodynamic variables obtained with 12 IU of ultra-fast insulin, insulin lispro and human soluble insulin
The pharmacodynamic properties of the three different insulin formulations mirror the pharmacokinetic variables. Subcutaneous injection of 12 IU ultra-fast insulin resulted in a time–action profile characterised by a more rapid rise in glucose consumption (tGIRmax+50%) in comparison to 12 U insulin lispro and 12 IU human soluble insulin (Table 1, Fig. 1b). Maximal metabolic activity (tGIRmax) was observed earlier and the metabolic activity in the first 2 h after s.c. injection (AUCGIR 0–120) was higher with ultra-fast insulin than with human soluble insulin, but failed to reach statistical significance when compared with insulin lispro. Maximal and total metabolic activity (GIRmax; AUCGIR) were comparable with all three insulin formulations.
The three dose levels of ultra-fast insulin (3, 6 and 12 IU) showed the expected linear and proportional increases in insulin absorption (Table 1, Fig. 1c). In addition, the decline of late half-maximal levels tended to be more rapid with 6 and 3 IU than with 12 IU. With an increase in dose from 3 to 6 IU the AUCINS 0–120 min increased by a factor of 1.92 and from 6 to 12 IU by a factor of 1.56. The respective factors in the AUCGIR 0–120 min were 1.37 and 1.27.
The time to early half-maximal action, time to maximal action and time to late half-maximal action after maximal action were comparable with all three ultra-fast insulin doses (Table 1, Fig. 1d). The maximal metabolic action and the AUCs were different with the three different doses.
No serious adverse event occurred during this trial. Adverse events were headache and injection site pain, each reported by four participants (27%).