Injections Of Insulin Aspart Research Articles

Comparison of effects of insulin aspart three times a day versus insulin detemir once a day on oxidative stress in patients with type 2 diabetes

The main purpose of this study was to investigate whether treatment with long-acting insulin once a day or short-acting insulin three times before each meal daily has a stronger antioxidative effect in patients with type 2 diabetes. These patients had not been treated previously with insulin and were hospitalized for initiation of glycemic control by insulin injection. The patients (n=43) were assigned consecutively and alternately to a group treated with insulin aspart injection three times daily just before each meal and a group treated with insulin detemir injection once daily before bedtime. The results showed that insulin aspart three times a day produced a greater improvement in plasma glucose, and particularly in mean postprandial plasma glucose, compared with insulin detemir once a day (p = 0.0006 for comparison of changes between the two insulin treatments). The amount of insulin needed to approach the target levels of plasma glucose was larger in the insulin aspart group (26.0 ± 10.7 U/day vs. 13.7 ± 4.9 U/day; p < 0.0001). However, only insulin detemir significantly decreased oxidative stress evaluated based on the level of urinary 8-iso-prostaglandin F2α (p = 0.0079), although the mechanisms are not fully evident.

Influence of BMI, Age and Duration of Diabetes Mellitus on Glycaemic Control with Twice-Daily Injections of Biphasic Insulin Aspart 30 versus Multiple Daily Injections of Insulin Aspart (JDDM 18)

Good glycaemic control in patients with diabetes mellitus often requires insulin supplementation therapy. Recent developments of analogue insulin and premixed formulations have increased the therapeutic options for patients who need such therapy. This study aimed to retrospectively clarify appropriate treatment regimens according to age, body mass index (BMI) and duration of diabetes in Japanese patients with type 2 diabetes previously entered in an open-label, randomized trial that compared convenience-oriented biphasic insulin aspart 30 versus multiple injections of insulin aspart with or without NPH insulin. Japanese insulin-naïve patients were randomized to receive either biphasic insulin aspart 30 twice daily or insulin aspart three times daily with or without multiple injections of NPH insulin for a treatment period lasting 6 months. Reduction of glycosylated haemoglobin (HbA(1c)) at the end of 6 months was not different in the two treatment groups irrespective of BMI, age and duration of diabetes. However, the achievement rate of HbA(1c) <7.0% was significantly higher in patients with a BMI <25 kg/m2 in the multiple-injection group and tended to be higher in patients with a diabetes duration <10 years in the twice-daily injection group. Twice-daily injections of biphasic insulin aspart 30 may be more suitable for obese patients whereas multiple injections of insulin aspart with or without NPH insulin may be preferable for those with a longer duration of diabetes.

Comparative Device Assessments

The purpose of this study was to compare pen device-naïve patients' preferences for Humalog KwikPen (insulin lispro injection) (Eli Lilly and Company, Indianapolis, IN) to use of a vial and syringe and FlexPen(R) (insulin aspart injection) (Novo Nordisk A/S, Bagsvaerd, Denmark). This open-label, randomized, crossover 1-day study tested the hypotheses that KwikPen was preferred to vial and syringe, and if this was found to be a significant preference, that KwikPen was preferred to FlexPen. Accuracy of doses prepared, ease of use via insulin device assessment battery, and preference via insulin device preference battery were administered following each pen evaluation, and a final preference question administered following the evaluation of both pens. Clinical measures were not included as subjects injected into an appliance to simulate the injection experience. Primary outcome variables were evaluated by Question 13 of the insulin device preference battery and the final preference question. Among 232 enrolled patients randomized to 1 of 4 sequences (n = 58), Humalog KwikPen was significantly preferred over vial and syringe and over FlexPen. After patients were asked to assess Humalog KwikPen or FlexPen versus V&S by choosing "strongly agreed" or "agreed" to the following attributes: easy to use, easy to hold in their hands when injecting, and easy to press the injection button, the results exhibited significant differences in patient responses. Humalog KwikPen was significantly more accurate and was preferred to vial and syringe in appearance, quality, discretion, convenience, public use, easy to learn, easy to use, reliability, dose confidence, following insulin regimen, overall satisfaction, and recommendation to others. Humalog KwikPen was significantly preferred over vial and syringe and FlexPen. When compared with vial and syringe, Humalog KwikPen and FlexPen were easier to use and operate, demonstrated superior accuracy of doses prepared, and preferred by pen-naïve users.

Optimal dose and timing of insulin Aspart to mimic first phase insulin response in patients with recently onset type 2 diabetes

Objective To assess the optimal dose and timing of subcutaneous injection of insulin Aspart (IAsp) in relation to meal to mimic first phase insulin response in patients with recently diagnosed type 2 diabetes. Design and methods Twenty patients were randomised in a double blind, double dummy design to four standard meal tests with pre-meal injection of insulin Aspart 0.08 IU/kg BW 30 min before the meal, insulin Aspart 0.04 IU/kg BW 30 or 15 min before the meal and placebo. Results All three insulin regimes significantly reduced postprandial glucose increment (area under the curve AUC −30 to 240 min ) and peak plasma glucose increment (Δ C max) compared with placebo. Postprandial glucose increment AUC −30 to 240 min but not Δ C max was significantly lower with IAsp 0.08 IU/kg BW as compared to IAsp 0.04 IU/kg BW, ( p < 0.03 and p = 0.18). One patient experienced hypoglycaemia after injection of IAsp 0.08 IU/kg BW. No difference in postprandial glucose profile was demonstrated whether IAsp 0.04 IU/kg BW was administrated 15 or 30 min before mealtime. Conclusions IAsp 0.04 IU/kg BW injected subcutaneously 15 or 30 min before meal reduced the postprandial blood glucose increment without risk of hypoglycaemia in patients with recently diagnosed type 2 diabetes. Doubling of the IAsp dose significantly reduced the postprandial glucose increment but increased the risk of hypoglycaemia.

Six-month multicentric, open-label, randomized trial of twice-daily injections of biphasic insulin aspart 30 versus multiple daily injections of insulin aspart in Japanese type 2 diabetic patients (JDDM 11)

To evaluate glycemic control using convenience-oriented biphasic insulin analog compared with intensified insulin therapy, we conducted a 6-month multicentric, open-label, randomized trial in Japanese insulin-naïve patients with type 2 diabetes mellitus. A total of 160 adult patients at 19 centers were randomized into two groups: those who received twice-daily injections of biphasic insulin aspart 30 and those on three-times-daily injections of insulin aspart with or without NPH insulin (multiple daily injections). At 6 months, mean HbA 1c decreased by approximately 2.5% in both groups. Reduction of HbA 1c on both regimens was better in patients whose prior therapy before starting the study was only diet and exercise (−5.0%) than in patients who were previously taking oral antidiabetic agents (−1.0%). No incidence of major hypoglycemia was observed in either regimen. These results suggest that convenience-oriented insulin therapy using biphasic insulin analog is as useful as intensified insulin therapy with insulin analog for the treatment of type 2 diabetes mellitus over 6 months. Furthermore, early induction of insulin therapy in individuals hitherto using only diet and exercise may provide good glycemic control. This study suggests that convenience-oriented biphasic insulin aspart 30 might be a useful option for the treatment of type 2 diabetes mellitus, especially for insulin-naïve patients over 6 months, although it should be changed to another regimen when expected efficacy is not obtained.

Precipitation of Insulin Aspart and Insulin Glulisine Products Used for Continuous Subcutaneous Insulin Infusion

The commercially available insulin products insulin aspart injection (IAsp) and insulin glulisine injection (IGlu), used for continuous subcutaneous insulin infusion (CSII), have been compared with respect to resistance towards isoelectric insulin precipitation. Additionally, a hybrid product consisting of the insulin aspart analogue in an IGlu product composition (the hybrid product was termed IAsp (Apidra)) has been examined. The degree of isoelectric insulin precipitation was examined by reverse-phase high performance liquid chromatography while reducing pH through addition of diluted HCl. The pH at which isoelectric precipitation occurred differed between IAsp and IGlu as reflected by the pH level at which 50% of the insulin precipitated (IAsp, pH 5.86; IGlu, pH 6.64). The amount of H(+)-equivalents per microliter of product required to induce isoelectric precipitation differed between IAsp and IGlu as reflected by the amount of acid required to cause 50% insulin precipitation (5.27 and 4.14 nmol of H(+)-equivalents, respectively). Data from IAsp(Apidra) suggest that the observed difference between IAsp and IGlu can be attributed to a combination of the different insulin analogue molecules and different product compositions of IAsp and IGlu. Resistance towards isoelectric precipitation is highest for IAsp and lowest for IGlu because of the lower pH and higher amount of acid required to induce isoelectric insulin precipitation of IAsp. Isoelectric precipitation will alter the pharmacokinetic properties of the insulin and could lead to occlusion of the infusion catheter during CSII. However, further studies are required to elucidate the potential clinical relevance of the observed differences in in vitro resistance towards isoelectric precipitation between IAsp and IGlu.

Precipitation of Insulin Products Used for Continuous Subcutaneous Insulin Infusion

Commercially available insulin products used for continuous subcutaneous insulin infusion have been compared with respect to resistance towards isoelectric insulin precipitation. The degree of isoelectric insulin precipitation of insulin aspart injection (IAsp), insulin lispro injection (ILis), and buffered human regular insulin injection (BHR) was examined while reducing pH through addition of diluted HCl or exposure to CO2. The pH at which defined fractions of the insulins precipitated differed among the three products; 10% and 90% precipitation, respectively, was observed at pH 6.41 and pH 6.30 for ILis, pH 6.18 and pH 5.95 for BHR, and pH 5.90 and pH 5.67 for IAsp, in accordance with the isoelectric points of these insulin species. The amount of H(+)-equivalents per microliter of product to reach 10% precipitation was found to be highest for IAsp (5.49 nmol of H(+)-equivalents), with ILis and BHR almost equivalent to each other (4.46 and 4.32 nmol of H(+)-equivalents, respectively). Exposure to a CO2-enriched environment resulted in the same order of insulin precipitation of the three products as tested with HCl. Resistance towards isoelectric precipitation is highest for IAsp, lowest for ILis, and intermediate for BHR. Isoelectric precipitation will alter the pharmacokinetic properties of the insulin and could lead to occlusion of the infusion catheter, causing elevated blood glucose and ultimately causing diabetic ketoacidosis if no intervention is made. Causal relationships between the observed differences in resistance towards isoelectric precipitation of the insulin products, the mechanism behind catheter occlusion, and the clinical relevance of the observations require further studies.

Efficacy Comparison between preprandial and postprandial insulin aspart administration with dose adjustment for unpredictable meal size

Background: Patients with type 1 diabetes mellitus (DM) may encounter situations in which meal size and content is unpredictable. In theory, postprandial injection of rapid-acting insulin analogues could prove more effective in achieving glucose control at such times because this treatment strategy could allow adjustment of insulin dose for the actual size of the meal consumed rather than being based on an estimate of what will be consumed. Objective: This study compared the postprandial glycemic control achieved with meal-related insulin aspart injected immediately before a meal with that injected immediately after a meal. Methods: This randomized, crossover study was conducted at Sansum Diabetes Research Institute, Santa Barbara, California. Adult patients with type 1 DM were enrolled. At study visit 1, patients were randomly assigned to inject insulin aspart 0 to 5 minutes before the start of the meal or immediately after the meal. The timing of injection relative to the meal was reversed at study visit 2. The meal-related dose was calculated based on the anticipated caloric and carbohydrate intake (preprandial injection) or actual calories and carbohydrates ingested (postprandial injection). Postprandial blood glucose concentrations were evaluated as markers of efficacy of postprandial aspart administration. Results: Twenty patients were enrolled in the study (mean [SE] duration of DM, 22.5 [3.2] years; mean [SE] body mass index, 26.2 [1.0] kg/M 2; age range, 22–82 years); 19 completed it. Total glucose AUC during the meal test was 22% less when insulin aspart was injected immediately before the study meal (mean [SE], 23,014 [1832] mg/dL.min) than when injected immediately after the meal (mean [SE], 29,535 [2243] mg/dL·min) ( P < 0.001), but baseline-adjusted AUC was similar. Maximum mean (SD) glucose concentrations in the postprandial period were <180 mg/dL, the current DM treatment goals specified by the American Diabetes Association (149.0 [9.9] mg/dL and 102.0 [9.2] mg/dL, following postprandial insulin aspart injection and preprandial injection, respectively; P < 0.001). There was variation in the number of calories consumed, but patients consumed a similar number of calories in the 2 treatment regimens. The frequency of postprandial hypoglycemia was comparable. Adjustment of postprandial insulin aspart dose for the actual meal size consumed maintained postprandial glucose concentrations within currently recommended treatment guidelines. Conclusions: Preprandial insulin aspart injection produced a better glucose profile and is preferred when conditions permit. However, both preprandial and postprandial insulin aspart administration achieved postprandial glucose concentrations within currently recommended treatment guidelines.

A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus

Background: The accuracy and convenience of pen devices for insulin injection have improved quality of life for patients with insulin-treated diabetes mellitus (DM). Prefilled, disposable pens have the advantage of simplicity, with minimal training and attention required and no installation of new cartridges necessary. Objective: The aim of this study was to assess patient preference, efficacy, and safety profiles of a prefilled, disposable pen (FlexPen®) and conventional vial/syringe injection method for insulin injection therapy among patients with DM. Methods: In a multicenter, randomized, open-label, crossover study, patients with type 1 or 2 DM were transferred from previous QD or BID conventional insulin therapy to a mixture of 70% insulin aspart protamine suspension and 30% insulin aspart injection (NovoLog® Mix 70 30 ) for 4 weeks of dose optimization using their usual type of syringe. Patients were then randomly assigned to use either vial/syringe or a prefilled, disposable pen to inject the biphasic insulin aspart 70 30 mixture for the next 4 weeks, followed by 4 weeks of use of the other injection device. Efficacy, safety profiles, and patient preference for the delivery systems were compared. Results: A total of 121 patients (mean [SD] age, 57.0 [12.4] years; age range, 28–81 years; mean [SD] body mass index, 31 [5.5] kg/m 2) were enrolled. One hundred three patients completed the study. Seventy-four percent of patients ( 78 105 ) indicated a preference for the pen over the vial/syringe method (95% CI, 71%–87%), compared with 20% ( 21 105 ) who preferred the vial/syringe. Eighty-five percent ( 88 104 ) considered the pen more discreet for use in public (compared with 9% [ 9 104 ] for the vial/syringe), 74% ( 77 104 ) considered it easier to use overall (compared with 21% [ 22 104 ] for the vial/syringe), and 85% ( 89 105 ) found the insulin dose scale on the pen easier to read (compared with 10% [ 10 105 ] for the vial/syringe). Patients had statistically significant improvement in glycosylated hemoglobin values during the study ( P < 0.05). No statistically significant differences in fasting plasma glucose, mean 4-point blood glucose profiles, or serum fructosamine values were found between groups. Overall, the safety profiles during treatment periods with the pen were comparable to those with the vial/syringe. Conclusions: In this trial, differences in efficacy and safety profiles between the vial/syringe and prefilled, disposable pen appeared negligible. However, more patients expressed a preference to continue use of the pen.

Clinical pharmacokinetics and pharmacodynamics of insulin aspart.

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (t(max)) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bioavailability of insulin aspart are similar to those of human insulin. The pharmacokinetics of insulin aspart have been studied in healthy Caucasian and Asian-Japanese volunteers, in patients with type 1 and 2 diabetes mellitus, and in children with diabetes, with both pre- and postprandial administration and during continuous subcutaneous insulin infusion (CSII). The pharmacokinetic profile was similar to that of another rapid-acting insulin analogue, insulin lispro, on the basis of published information for that agent. Pharmacodynamic studies show a smaller excursion of postprandial glucose with insulin aspart injected subcutaneously just before the meal compared with soluble human insulin injected 30 minutes before the meal in patients with type 1 diabetes mellitus, and an equivalent control in patients with type 2 diabetes displaying residual insulin production. In a treatment study, glucose excursions evaluated from 24-hour glucose profiles showed less variability with insulin aspart compared with human insulin. Adverse events, including hypoglycaemia-induced ventricular repolarisation and hypoglycaemic threshold and awareness, did not differ between insulin aspart and human insulin. The available data suggest that subcutaneous injections of insulin aspart just before meals better mimic the endogenous insulin profile in blood compared with human insulin, resulting in improved glucose control in a meal-related insulin regimen. This review summarises the clinical pharmacokinetics and pharmacodynamics of insulin aspart in relation to human insulin and insulin lispro.

Pharmacokinetics and pharmacodynamics of insulin aspart, a rapid-acting analog of human insulin, in healthy Japanese volunteers

Pharmacokinetic and pharmacodynamic properties of a rapid-acting analog of human insulin, insulin aspart, were compared with those of soluble human insulin in Japanese healthy subjects. Subcutaneous single injections (0.025 and 0.05 U/kg body weight (BW)) of insulin aspart produced a significantly earlier peak of exogenous insulin level in comparison with human insulin (30.8±13.8 versus 61.3±14.6 min, P<0.9001 for 0.025 U/kg; and 39.2±18.8 versus 99.2±53.8 min, P<0.005 for 0.05 U/kg). The peak serum level of insulin aspart was higher than that of human insulin (23.0±6.0 versus 9.9±3.1 μU/ml for 0.025 U/kg; and 30.9±9.2 versus 13.3±4.1 μU/ml for 0.05 U/kg, P<0.0001). The time to the minimal level of glucose after insulin aspart was significantly shorter compared with human insulin ( P<0.05 for 0.025 U/kg BW and P<0.01 for 0.05 U/kg BW). The Δ change in blood glucose induced by insulin aspart was larger than that observed for human insulin at any dose ( P<0.001). The repeated injection of insulin aspart before each meal also resulted in a rapid rise in exogenous insulin level with peak level obtained approximately 40 min after insulin aspart at any dose. When compared with results of other trials with insulin aspart, the present results showed that pharmacokinetic and pharmacodynamic profiles of the rapid-acting analog insulin aspart in Japanese subjects are no different from those in nonJapanese subjects.