Insulin Aspart

Insulin aspart, a rapid-acting human insulin analogue, provides more rapid absorption than regular human insulin after subcutaneous administration.

In most randomised, nonblind clinical trials in patients with type 1 diabetes mellitus, insulin aspart administered immediately before meals resulted in significantly lower mean glycosylated haemoglobin A_1c (HbA_1c) levels than regular human insulin (usually administered 30 minutes before a meal). Insulin aspart also significantly improved postprandial glycaemic control compared with regular human insulin. The efficacy of insulin aspart was similar to that of insulin lispro when administered to patients with type 1 diabetes mellitus via continuous subcutaneous infusion in a randomised, nonblind trial.

Preliminary data from randomised, nonblind trials suggest insulin aspart had a trend towards lower HbA_1c levels compared with regular human insulin in patients with type 2 diabetes mellitus.

Biphasic insulin aspart [30% soluble (rapid-acting) and 70% protamine-bound insulin aspart (BIAsp30)] generally provided significantly better postprandial glucose control than a similar mixture of biphasic regular human insulin (BHI30) in a randomised, nonblind trial in patients with type 1 or 2 diabetes mellitus. However, the long-term efficacy of BIAsp30 was similar to that of BHI30 after 2 years in a randomised, nonblind trial in patients with type 2 diabetes mellitus.

Patients with type 1 or 2 diabetes mellitus reported greater treatment satisfaction with insulin aspart or BIAsp30 than with regular human insulin or BHI30.

The overall incidence of hypoglycaemia with insulin aspart was lower than, or similar to, that of regular human insulin. Moreover, insulin aspart tended to be associated with a lower occurrence of nocturnal hypoglycaemia and severe hypoglycaemic events than regular human insulin.

Insulin aspart is a rapid-acting recombinant insulin analogue. It is identical to regular human insulin except for the substitution of aspartic acid for proline at position 28 of the B chain of the insulin molecule. As a result of this substitution, insulin aspart has a reduced tendency to self-associate compared with regular human insulin which means insulin aspart is absorbed more rapidly after subcutaneous injection than regular human insulin.

Symptoms of hypoglycaemia were induced at a comparable glycaemic threshold after insulin aspart or regular human insulin administration to patients with type 1 diabetes mellitus. Insulin aspart generated the same counter-regulatory, physiological and symptomatic responses to hypoglycaemia as regular human insulin, and had a similar effect on cardiac repolarisation.

Euglycaemic studies in healthy volunteers have shown the onset of the glucose-lowering activity of insulin aspart is faster and its duration of action shorter than regular human insulin. In the majority of these studies glucose infusion rates were higher and reached maximum levels significantly earlier with insulin aspart than with regular human insulin (p < 0.05 for both). The duration of the metabolic effect of insulin aspart was shorter than that of regular human insulin. Similar results were obtained in fasting healthy volunteers as plasma glucose levels fell to a significantly lower level (p < 0.001) in significantly less time (p < 0.005) with insulin aspart administration than with regular human insulin.

Insulin aspart administered immediately before meals provided better or similar postprandial glycaemic control compared with regular human insulin administered as recommended 30 minutes before meals in patients with type 1 or 2 diabetes mellitus. Insulin aspart significantly improved postprandial glucose control in patients with type 1 or 2 diabetes mellitus compared with regular human insulin injected immediately before a meal (p < 0.01). The duration of the metabolic effect of insulin aspart was shorter than that of regular human insulin in patients with type 1 diabetes mellitus.

A single-dose study in children and adolescents aged 6 to 17 years with type 1 diabetes mellitus found that insulin aspart lowered glucose levels significantly compared with regular human insulin (p < 0.05).

Biphasic insulins contain a mixture of rapid-acting and protamine-bound (slow-release) insulin in one dose. Biphasic insulin aspart (30% soluble and 70% protamine-bound insulin aspart; BIAsp30) had a greater metabolic effect and a faster onset of action than a similar mixture of biphasic regular human insulin (BHI30) in healthy volunteers.

In a study in patients with type 1 diabetes mellitus, BIAsp30 was more effective in controlling postprandial glucose than BHI30 administered 30 minutes before or immediately before a meal. BIAsp30 had a faster onset of action than BHI30 administered immediately before or 30 minutes before a meal in patients with type 1 diabetes mellitus. In patients with type 2 diabetes mellitus, twice daily BIAsp30 administered immediately before meals reduced the overall postprandial glucose excursion significantly compared with BHI30 also administered immediately before meals (p < 0.05). BIAsp30 also significantly reduced the maximum serum glucose level (C_max(SG)) and the time to C_max(SG) after breakfast (p < 0.05 for both). In another study, BIAsp30 was more effective in controlling postprandial glucose than a similar biphasic insulin lispro (soluble fraction 25%; protamine-bound fraction 75%; Mix25) administered immediately before a meal to patients with type 2 diabetes.

A direct comparison of the pharmacodynamics of insulin aspart and insulin lispro has shown that the two insulin analogues are comparable for postprandial glucose control in patients with type 1 diabetes mellitus.

The postprandial administration of insulin aspart (15 minutes after the start of a meal) was as effective in lowering postprandial glucose as insulin aspart administered immediately before a meal and regular human insulin administered 15 minutes before a meal.

Limited data from a single study in patients with type 2 diabetes mellitus have shown that insulin aspart has a similar effect on postprandial lipid profiles compared with regular human insulin.

The overall variability of pharmacodynamic parameters in healthy volunteers receiving insulin aspart was similar to that with regular human insulin.

The absorption of insulin aspart was more rapid than that of regular human insulin. The rate of disappearance of a single-dose of ≈0.1 U/kg ¹²⁵I-labelled insulin aspart after subcutaneous injection from the subcutis was significantly faster than the same dose of regular human insulin (p < 0.005). Maximum serum insulin concentrations (C_max(ins)) of insulin aspart (0.025 to 0.20 U/kg) were higher (138 to 518 vs 59 to 288 pmol/L; p < 0.05) and occurred earlier (31 to 71 vs 61 to 145 minutes; p < 0.05) than those after the same dose of regular human insulin after subcutaneous administration in healthy volunteers and in adults with type 1 or 2 diabetes mellitus. The serum insulin concentration returned to baseline faster after insulin aspart administration than after that of regular human insulin (the harmonic apparent half-life was reported as 76 vs 122 minutes; p < 0.05) in a study in healthy volunteers. The mean residence time was shorter (122 to 172 vs 153 to 222 minutes; p < 0.0001) after insulin aspart administration than after regular human insulin in studies in healthy volunteers or patients with type 1 diabetes mellitus. In a representative study in healthy volunteers, the area under the serum insulin concentration-time curve (AUC_ins) over 2 hours was significantly higher for insulin aspart (0.2 U/kg) than that of regular human insulin (1848 vs 966 nmol · h/L; p < 0.001), but was not significantly different over 10 hours (3138 vs 3174 nmol · h/L). However, the bioavailability was similar for the two insulins in healthy volunteers and patients with type 1 diabetes mellitus (101 to 112% relative to regular human insulin).

The C_max(ins) of insulin aspart was approximately twice that of regular human insulin (881 vs 422 pmol/L; p < 0.001) and was reached in half the time (40 vs 75 minutes; p < 0.001) when both insulins were administered to children and adolescents (aged 6 to 17 years). The AUC_ins over 5 hours of insulin aspart was significantly higher than that of regular human insulin (p < 0.001).

The pharmacokinetic parameters of insulin aspart and insulin lispro were generally similar in patients with type 1 diabetes. The C_max(ins) of insulin aspart was not significantly different to that of insulin lispro (295 and 374 vs 316 and 386 pmol/L). One study reported that insulin lispro exhibited a significantly shorter t_max(ins) (40 vs 49 minutes; p < 0.01) and a more rapid decline than insulin aspart as the time taken for insulin concentrations to decrease to 50% of the maximum insulin concentration was shorter than that of insulin aspart (t_50%late 113 vs 154 minutes; p < 0.02). However, another study found no significant difference for these parameters (t_max(ins) 44 vs 47 minutes; t_50%late 113 vs 116 minutes).

BIAsp30 was rapidly absorbed in healthy volunteers and patients with type 1 or 2 diabetes mellitus. The C_max(ins) of BIAsp30 was significantly higher (140 to 415 vs 93 to 334 pmol/L; p < 0.001) and occurred significantly earlier (60 to 115 vs 110 to 177 minutes; p < 0.05) than after BHI30 administration in healthy volunteers and patients with type 1 or 2 diabetes mellitus. The BIAsp30 AUCins over 1.5 hours was also significantly higher than that of BHI30 (p < 0.0001) in healthy volunteers; however, the AUCins over 24 hours was similar for the two biphasic insulins. The AUCins over 5 hours was significantly higher for BIAsp30 than for BHI30 in patients with type 2 diabetes mellitus (p < 0.001). The absorption of BIAsp30 was similar to that of Mix25 in patients with type 2 diabetes mellitus. The bioavailability of BIAsp30 was similar to that of BHI30 in healthy volunteers (104% relative to BHI30).

The distribution and metabolism of insulin aspart have not been studied in humans. The elimination of insulin aspart appears to be similar to regular human insulin.

Obesity, hepatic impairment or impaired renal function do not significantly affect the pharmacokinetics of insulin aspart. The effects of old age and pregnancy on the pharmacokinetics of insulin aspart have not yet been studied.

Several randomised, mainly nonblind, multicentre trials, including more than 3500 patients with type 1 or 2 diabetes mellitus, have assessed the efficacy of insulin aspart compared with regular human insulin as part of an intensive basalbolus regimen. The intermediate-acting insulin, Neutral Protamine Hagedorn (NPH) insulin, was administered once to three times daily as the basal insulin. Insulin aspart was administered at total daily dosages similar to those of the comparator insulin. Results from the majority of these clinical trials found that insulin aspart administered immediately before meals led to significantly lower mean glycosylated haemoglobin A_1c (HbA_1c) levels compared with regular human insulin (usually administered 30 minutes prior to a meal) in patients with type 1 diabetes mellitus (p < 0.05). Additionally, in general, insulin aspart resulted in significantly lower mean postprandial glucose levels and mean prandial blood glucose increments (90-minute postprandial blood glucose value minus preprandial blood glucose value) than those achieved with regular human insulin (p < 0.05). Fasting blood glucose levels with insulin aspart were similar to those seen with regular human insulin. Insulin aspart was more effective than regular human insulin after long-term therapy for 3 years in patients with type 1 diabetes mellitus, as HbAic levels were significantly lower with insulin aspart than with regular human insulin (p < 0.05).

In a 16-week clinical trial in 146 patients with type 1 diabetes mellitus, insulin aspart and insulin lispro had similar clinical efficacy when administered via continuous subcutaneous insulin infusion (CSII). Mean HbA_1c levels remained unchanged in the insulin aspart treatment group while HbA_1c levels increased slightly in the insulin lispro and regular human insulin treatment groups. Postprandial blood glucose levels decreased from baseline after insulin aspart and insulin lispro administration and tended to be lower than those after regular human insulin administration. The post-dinner blood glucose level was significantly lower in those receiving insulin aspart than in those receiving insulin lispro or human regular insulin (7.5 vs 9.1 and 9.5 mmol/L, respectively; p < 0.02 for both comparisons).

Preliminary data have shown that insulin aspart produced similar glycaemic control to regular human insulin administered 30 minutes before meals in children and adolescents (aged 7 to 17 years) with type 1 diabetes mellitus. Limited data from another trial have shown that the postprandial administration (within 30 minutes of the start of meals) achieved postprandial glucose control similar to that of insulin aspart administration before meals when administered to children.

Insulin aspart had a trend towards lower HbA_1c levels compared with regular human insulin in patients with type 2 diabetes mellitus, in two randomised, non-blind trials, both reported as abstracts. However, treatment with insulin aspart resulted in similar blood glucose profiles and prandial blood glucose increments to those of regular human insulin.

Preliminary data from a single trial has shown that BIAsp30 achieved comparable HbA_1c levels, but significantly better postprandial glucose control than BHI30 (p < 0.05) in a 12-week trial in patients with type 1 or 2 diabetes mellitus. Another trial showed that the efficacy of BIAsp30 and BHI30 at 2 years was similar in patients with type 2 diabetes mellitus.

The postprandial administration of BIAsp30 resulted in comparable postprandial glucose control to that of BIAsp30 administered immediately before meals in a 12-week trial in patients with type 2 diabetes mellitus. However, HbA_1c levels were not changed significantly over the 12 weeks of treatment.

BIAsp30 in combination with metformin improved glucose control in patients with type 2 diabetes mellitus.

Patients with type 1 or 2 diabetes mellitus generally reported greater treatment satisfaction with insulin aspart or BIAsp30 than with regular human insulin or BHI30.

Hypoglycaemia was the most common adverse event in patients with type 1 or 2 diabetes mellitus receiving insulin aspart in clinical trials. The administration of insulin aspart resulted in an overall incidence of hypoglycaemic events that was lower than, or similar to, that with regular human insulin. Insulin aspart was associated with significantly fewer major nocturnal hypoglycaemic episodes than regular human insulin in two trials (p < 0.02). Pooled data from trials in patients with type 1 diabetes mellitus (total n > 1900) showed that insulin aspart was associated with a 38% lower risk of major nocturnal hypoglycaemia than regular human insulin (p < 0.005), while the risk of major daytime hypoglycaemia was unchanged.

Patients with type 1 or 2 diabetes mellitus treated with BIAsp30 experienced half the number of major hypoglycaemic events compared with those receiving BHI30. The incidence of minor hypoglycaemic events with BIAsp30 was lower than, or similar to, that of BHI30. BIAsp30 also had a tendency for a lower risk of minor nocturnal hypoglycaemic events than BHI30.

Insulin aspart and regular human insulin are associated with a similar number and type of other adverse events such as headache, upper respiratory tract symptoms, pharyngitis and allergic reactions.

The immunological profiles of insulin aspart and regular human insulin are similar. Specific antibodies against insulin aspart were present in the serum at low levels (≈ 1% binding) in patients receiving insulin aspart. Similarly, those receiving regular human insulin also had low levels of specific antibodies. Cross-reacting antibody levels in patients receiving insulin aspart or regular human insulin generally increased from baseline after 3 months but had returned to baseline levels after 12 months of treatment.

Insulin aspart as the mealtime insulin in a basal-bolus regimen or via CSII is indicated in Europe and the US for use in adult patients with type 1 or 2 diabetes mellitus requiring insulin therapy to control hyperglycaemia. In Europe, insulin aspart is also approved for use in children with diabetes mellitus.

The dosage of insulin aspart should be individualised using the patient’s previous insulin history and/or current glucose levels. It is recommended that insulin aspart be administered immediately (5 to 10 minutes) before meals or postprandially when necessary. As for other short-acting insulins, when insulin aspart forms part of a basal-bolus regimen, the basal dose should be optimised and provided by an intermediate- or long-acting insulin. If administered via CSII, insulin aspart should not be diluted or mixed with any other insulin. Blood glucose levels should be monitored regularly and HbA_1c levels assessed periodically.

Insulin aspart may be mixed with NPH insulin; however, it is recommended that the mixture be administered immediately after mixing. The effect of mixing insulin aspart with other insulins has not been assessed and such use is not recommended.

Insulin aspart is contraindicated in patients who are hypersensitive to the preparation and must not be administered during periods of hypoglycaemia. There have been no clinical studies on insulin aspart in pregnancy or levels excreted in human breast milk, so caution is generally recommended for pregnant women or nursing mothers. There is also no information on the pharmacokinetics of insulin aspart in children under 6 years of age or in elderly patients. Hepatic or renal impairment or obesity do not appear to affect the pharmacokinetics of insulin aspart; however, close glucose monitoring for these patients and dose adjustments, if necessary, are recommended. A number of drugs can increase or decrease blood glucose levels and an adjustment to the required insulin aspart dose may be necessary.

BIAsp30 is indicated in Europe and the US for the treatment of diabetes mellitus. Dosages of BIAsp30 should be individualised. BIAsp30 should be administered via subcutaneous injection twice daily, immediately before breakfast and dinner. BIAsp30 should not be administered intravenously or via CSII. BIAsp30 should not be mixed with other insulins but can be combined with therapy with oral hypoglycaemic drugs, however a decrease in the dose may be necessary.

When a patient is changed from another insulin regimen to twice daily BIAsp30 caution is recommended. BIAsp30 is initially administered at similar doses to the previous insulin regimen and doses are modified according to the patients’ needs. BIAsp30 is contraindicated in episodes of hypoglycaemia or in patients hypersensitive to the preparation. The effects of BIAsp30 on special patient populations such as, children and adolescents, the elderly, patients with impaired hepatic or renal function, obese patients, pregnant or lactating women have not yet been studied, so caution is advised when BIAsp30 is administered to these patients. Like insulin aspart, the dosage of BIAsp30 may need to be modified when drugs that have a positive or negative effect on glucose metabolism are also administered to a patient receiving BIAsp30.