Pathophysiology/Complications ORIGINAL ARTICLE A Direct Comparison of Insulin Aspart and Insulin Lispro in Patients With Type 1 Diabetes 1 1 JOHANNES PLANK, MD BARBARA SEMLITSCH, RN human soluble insulin is performed as 1 1 ANDREA WUTTE, MSC ROMANA SOMMER, MD standard treatment regimen by a majority 1 2 GERNOT BRUNNER, MD SABINE HIRSCHBERGER, MD 1 1 of patients (2,3). However, postprandial ANDREA SIEBENHOFER, MD THOMAS R. PIEBER, MD blood glucose peaks and excursions are not comparable with nondiabetic sub- jects. Absorption of unmodified insulin from the injection site is a complex pro- cess affected by only partially changeable OBJECTIVE — Both rapid-acting insulin analogs, insulin aspart and lispro, attenuate pran- factors, such as anatomic area, blood dial glucose excursion compared with human soluble insulin. This trial was performed to study flow, injection volume, concentration of the pharmacokinetic and pharmacodynamic profiles of insulin aspart and insulin lispro in type 1 diabetic patients in a direct comparison and to investigate whether the administration of one insulin, and possible local degradation analog results in favorable effects on prandial blood glucose control. process (4–6). Therefore, considerable attention has been devoted to the devel- RESEARCH DESIGN AND METHODS — A total of 24 type 1 diabetic patients (age opment of insulin molecules with accel- 36 Ϯ 8 years, 16 men and 8 women, BMI 24.3 Ϯ 2.6 kg/m2, diabetes duration 17 Ϯ 11 years, erated absorption kinetics (7–9). This Ϯ HbA1c 7.9 0.8%) on intensified insulin therapy were recruited into a single-center, random- more physiological profile of these short- ized, double-blind, two-period, cross-over, glucose clamp trial. The subjects were given an acting insulin analogs leads to reduced individual need–derived dose of prandial insulin lispro or aspart immediately before a standard prandial glucose excursions (10–13). In mixed meal. well-controlled type 1 diabetic patients, postprandial administration of insulin as- RESULTS — With respect to blood glucose excursions from time 0 to 6 h (Exc ) and glu(0–6 h) part and insulin lispro has shown to be at from time 0 to 4 h (Excglu(0–4 h)), the pharmacodynamic effect of insulin aspart and insulin lispro can be declared equivalent. This was supported by comparison with maximum postprandial least as effective as mealtime application of soluble human insulin (14,15). These blood glucose excursions (Cmax(glu)) (estimated ratio aspart/lispro ANOVA [90% CI]: 0.95 [0.80–1.13], 0.97 [0.82–1.17], and 1.01 [0.95–1.07] for Excglu(0–6 h), Excglu(0–4 h), and pharmacokinetic properties should allow Cmax(glu), respectively). For pharmacokinetic end points (maximum postprandial insulin excur- greater flexibility, enable patients to ad- sions and area under the curve for insulin from time 0 to 6 h and from time 0 to 4 h), equivalence just their insulin dosage more precisely was indicated. No difference concerning absorption or elimination for time to maximal insulin according to the amount of ingested car- concentration, time to half-maximum insulin concentration, and time to decrease to 50% of bohydrates, and might improve quality of maximum insulin concentration was observed. life for type 1 diabetic patients (16,17). Though it is well documented that CONCLUSIONS — These data suggest that in type 1 diabetic patients, both insulin analogs are equally effective for control of postprandial blood glucose excursions. each analog has advantageous postpran- dial glucose control compared with hu- Diabetes Care 25:2053–2057, 2002 man soluble insulin, until now a complete direct comparison of pharmacokinetic and pharmacodynamic properties of both n accordance with the results of the Di- gression of long-term complications in analogs in a setting close to the daily life of abetes Control and Complication Trial, type 1 diabetes (1). To mimic the physio- diabetic patients has not been performed. near-normoglycemic blood glucose logical insulin secretion profile, intensi- The aim of this study was to investigate I prandial glycemia after the subcutaneous levels prevent the onset or delay the pro- fied insulin therapy with unmodified injection of insulin aspart or insulin lispro ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● after a standard meal and to determine From 1Diabetes und Metabolism, Department of Internal Medicine, Karl-Franzens University of Graz, Graz, whether one of the two analogs might 2 Austria; and Novo Nordisk Pharma, Mainz, Germany. have favorable effects on postprandial Address correspondence and reprint requests to Johannes Plank, Department of Internal Medicine, Karl-Franzens University, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail: johannes.plank@klinikum- blood glucose control. graz.at. Received for publication 17 May 2002 and accepted in revised form 21 July 2002. T.R.P. is a paid consultant of Novo Nordisk Pharma and Lilly. RESEARCH DESIGN AND Abbreviations: AUCins, area under the curve for insulin; Cmax, maximum baseline-corrected concentra- METHODS — The study was ap- tion; Excglu, blood glucose excursion; t50%decrease(ins), time to decrease to 50% of maximum insulin concen- proved by the local ethical committee of tration; t50% of peak(ins), time to half-maximum insulin concentration; tpeak(ins), time to maximal insulin concentration. the Karl-Franzens University Graz and A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion performed in accordance with the princi- factors for many substances. ples expressed in the Declaration of Hel- DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2053 Aspart versus lispro in type 1 diabetes sinki (18). All subjects gave written cose level of 6.7 mmol/l (range 5.6–7.8) Andersen et al. (23) for insulin aspart. The informed consent before entry into the (21). Adjustment of the insulin infusion difference between the lispro and aspart trial. rate was allowed until 11:00 A.M.(Ϫ60 correction was due to different constant min) and was kept constant thereafter values in the nonlinearity correction for- Subjects throughout the experiment. Experiments mula for the two analogs: true concentra- The patients recruited were adult men were only performed if plasma glucose tion ϭ S ϫ X/(T Ϫ X), where X is the and women according to World Health values remained stable between 5.6 and measured analog concentation (in pico- Organization criteria (19). Their duration 7.8 mmol/l during the 60-min period be- moles per liter) and S and T are constants of diabetes was Ն24 months, and all pa- fore test meal (idealized basal insulin re- (S ϭ 2,533 and T ϭ 1945 for lispro; S ϭ tients were treated with intensified insulin quirements). At 12:00 A.M. (time 0), the 1,503 and T ϭ 1,398 for aspart). therapy, including meal-related human patients received a single dose of insulin soluble insulin and NPH insulin twice aspart (100 units/ml Novorapid; Novo Statistical methods daily (n ϭ 19) or continuous subcutane- Nordisk, Bagsvaerd, Denmark) or insulin Statistical analysis was based on the inten- ous insulin therapy (n ϭ 5), for at least 3 lispro (100 units/ml Humalog; Eli Lilly, tion-to-treat population. The trial was di- months. None of the patients had active Indianapolis, IN) in random order. The mensioned as an equivalence trial based proliferative retinopathy, clinical signifi- corresponding substance was adminis- on the primary efficacy end point, blood cant nephropathy or neuropathy, recur- tered at the next visit. A standardized glucose excursion from time 0 to 6 h rent severe hypoglycemia, or required meal was served (595 kcal; 50% carbohy- (Exc ) relative to the standardized Ն ⅐ Ϫ1 ⅐ Ϫ1 glu(0–6h) 1.4 units kg day insulin. We ran- drates, 15% proteins, and 35% fat) and meal. A sample size of 24 subjects was domized 8 women and 16 men with a ingested without any time delay. This Ϯ Ϯ calculated on the basis of a paired t test mean ( SD) age of 36 8 years (range meal was identical for all patients on all using the Scuirmann’s Two One-sided Ϯ 2 20–47), BMI 24.3 2.6 kg/m (18.3– study days. The dose of insulin to cover Test Procedure, assuming that the true 29.4), diabetes duration 17 Ϯ 11 years the standardized meal was kept identical Ϯ Ϯ difference between the treatments is zero, (3–44), and HbA1c 7.9 0.8% (6.6– for both visits (mean 7.1 1.3 IU, range and was estimated to give a power of 80%. 9.8). Their mean daily total insulin dose 5–9) and was derived from the individual Based on recently published guidelines was 49.1 Ϯ 13.9 IU (27–83) and was de- need in accordance to the patient’s log Ϯ (24), equivalence was established if the rived from a bolus need of 24.7 11.3 IU book. For evaluation of blood glucose and 90% CI of the ratio of the mean differ- (9–47) and basal insulin requirements of serum insulin, blood samples were drawn ences was within 80–125%, correspond- 24.4 Ϯ 7.6 IU (12–36). at 15-min intervals, from Ϫ45 min to ing to Ϯ0.22 on the log scale. Exc time of insulin injection (0 min), every 10 glu(0–6h) and Exc were calculated as the Study design min until 120 min, and thereafter every glu(0–4h) total area between the glucose concentra- The study was conducted as a single- 20 min until the end of the experiment. tion profile and the horizontal line de- center, randomized, double-blind, two- To avoid hypoglycemia in the postpran- fined by the average of the baseline values period, cross-over, clamp trial. The dial phase (if glucose level fell below 3.3 Ϫ Ϫ Ϫ subjects fulfilling all inclusion criteria af- mmol/l), glucose was infused intrave- at 45, 30, and 15 min and logarith- ter the screening visit were assigned a pa- nously.