Direct Comparison of Insulin Lispro and Aspart Shows Small Differences in Plasma Insulin Profiles After Subcutaneous Injection in Type 1 Diabetes

Two rapid-acting insulin analogs, lispro and aspart, are now available for clinical use (1).

The aim of our study was to compare the plasma-insulin profiles of these analogs after subcutaneous injection in patients with type 1 diabetes.

Fourteen patients with type 1 diabetes (six men and eight women, [mean ± SEM] 35.4 ± 3.3 years of age [range 22–59], HbA_1c 7.3 ± 0.3% [reference range 3.2–5.4], BMI 24.7 ± 1.1 kg/m², and diabetes duration 22.9 ± 2.6 years) were recruited for the study. Only two patients had measurable C-peptide levels (0.04 and 0.11 nmol/l). All patients were on multiple-injection therapy with a breakfast insulin dose of 11.1 ± 0.7 U (range 6–14) and no intermediate-acting insulin in the morning.

The study was designed as a single blind randomized crossover study. On the first day, seven patients were randomized to insulin lispro (Humalog, U-100; Eli Lilly, Indianapolis, IN), and the other seven were randomized to insulin aspart (NovoRapid, U-100; Novo-Nordisk, Bagsveard, Denmark). On the second study day (5–21 days later), the patients received the alternative insulin analog. The patients continued their usual insulin treatment between the study days.

All patients arrived to the clinic fasting. After an initial blood sampling, they were given 10 U s.c. of one of the insulins in the abdominal wall at 7:30 a.m. A standardized breakfast, which had an energy content of 418 kcal and a nutrient content of 21 g protein, 11 g fat, and 59 g carbohydrates, was served immediately thereafter. Plasma free insulin and blood glucose concentrations were measured, as indicated in Fig. 1. If blood glucose was 3.5 mmol/l or lower, 20 ml glucose 30% was injected. One patient was excluded from the analysis because, by mistake, he took a large extra dose of insulin the night before the study.

Free insulin was measured after polyethylene glycol precipitation by Mercodia Iso-Insulin (ELISA; Mercodia AB, Uppsala, Sweden), a two-site enzyme immunoassay containing two monoclonal antibodies against insulin. Identical results were obtained when equimolar concentrations of human insulin, insulin lispro, and insulin aspart were tested, indicating 100% cross-reactivity between lispro, aspart, and human insulin in this assay.

Blood glucose was analyzed with the Hemocue method (Hemocue, Mission Viejo, CA). Serum IGF binding protein–1 was determined by an immuno-enzymometric assay with a kit from Medix Biokemica (Kauniainen, Finland). Differences among groups were tested with Wilcoxon’s signed-rank test. Areas under the curve (AUC) were calculated with the trapezoidal method.

The fasting-free insulin concentration was 56 ± 16 pmol/l before administration of insulin aspart and 30 ± 15 pmol/l before administration of insulin lispro (NS) (Fig. 1). Both insulin analogs gave marked peaks of free insulin concentrations—lispro at 40 ± 3 min and aspart at 49 ± 3 min after injection, respectively (P = 0.01). The maximum insulin concentration was 316 ± 31 pmol/l on insulin lispro and 295 ± 27 pmol/l on insulin aspart (NS) (Fig. 1). The increase from 0 to 15 min after injection was 109 ± 17 pmol/l after injection of insulin lispro and 53 ± 11 pmol/l after injection of insulin aspart (P = 0.02). Fasting insulin lispro levels reached 50% of peak concentration at 20 ± 1 min and aspart at 30 ± 3 min (P = 0.02) (Fig. 2). The decrease of free insulin concentration from peak concentration to 50% of the maximum concentration was found at 113 ± 10 min during insulin lispro and 154 ± 14 min during insulin aspart (P = 0.02) (Fig. 2). The fasting blood glucose concentration was 11.2 ± 1.0 mmol/l before injection of insulin aspart and 13.7 ± 1.4 mmol/l before injection of insulin lispro (NS). The course of the blood glucose profiles was similar, with peak concentrations after 40 min, and there was no difference between total AUC.

The concentration of fasting IGFBP-1, a liver-derived protein (2), was 12.3 ± 3.4 μg/l on insulin aspart and 16.8 ± 3.9 μg/l on insulin lispro. The concentrations fell to 8.3 ± 1.4 and 13.5 ± 4.5 μg/l 2.5 h after injection and to 7.4 ± 1.6 and 11.5 ± 4.1 μg/l after 5.5 h, respectively (all differences between the insulin analogs were nonsignificant).

The time period from injection to half the maximum value and to peak insulin concentration was significantly shorter during insulin lispro, indicating a faster absorption of this insulin.

The impression from previous studies is that insulin aspart gives a somewhat broader peak than lispro (3,4). We found a significantly more rapid lowering of the free insulin concentration to 50% of the peak concentration with lispro. The plasma profile of free insulin obtained is dependent on the rate of absorption of insulin from subcutaneous tissue and the elimination of insulin from the circulation. Because the metabolic clearance of insulin analogs is predominately receptor mediated (5) and because lispro and aspart have about the same affinity for the insulin receptor (1), it seems probable that they will have about the same clearance rate and that the lowering of free insulin after the peak is mainly due to the rate of absorption.

From the clinical point of view, the most important observation is that insulin analogs are absorbed much faster than human insulin after subcutaneous injection, with higher insulin peaks and shorter duration of action (3,4). Because high postprandial glucose and lipid levels have been emphasized as risk factors, especially in type 2 diabetes (6), this may be of importance. In this respect, the relatively rapid rise of free insulin levels after injection of insulin lispro might be an advantage. The slightly slower decrease of free insulin concentrations after the insulin peak of insulin aspart might influence the need for daytime basal insulin and the need for a snack between the main meals of certain patients.

We previously found no difference in IGFBP-1 concentrations when using human regular insulin or insulin lispro (7), and in this study there was no difference between insulin aspart and lispro.

The main finding of our study is that the free insulin profiles of aspart and lispro resemble each other, but insulin lispro shows a more rapid uptake, reaches the maximum peak concentration earlier, and shows a more rapid decline than insulin aspart. We believe this finding may be of clinical importance.