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INSULIN ASPART

Summary

Insulin aspart is the second insulin analogue to be licensed for type 1 and type 2 diabetes mellitus.
It has a more rapid onset of action than soluble human insulin, thus enabling the patient to inject
insulin immediately before a meal. Insulin aspart and human insulin appear to be equally potent in
glucose-lowering effect.


Trials have been conducted in patients with type 1 and type 2 diabetes but are not yet fully published.
In two trials in type 1 diabetic patients, insulin aspart statistically significantly improved the primary
endpoint, HbA1C, at six months compared with soluble human insulin. However the difference was
small and of doubtful clinical significance. In type 2 patients there was no significant difference, at
six months, in HbA1C levels between treatments.


In trials in type 1 patients, the post-prandial blood glucose levels were lower with insulin aspart than
with human insulin. This probably reflects the more rapid onset of action of insulin aspart. In
type 2 patients blood glucose variability was comparable between insulin aspart and human insulin.


The incidence of hypoglycaemia following insulin aspart was similar or lower than that after human
insulin.


Insulin aspart has not been directly compared with insulin lispro.

Date Published: May 2000 Monograph Number: 4/99/06 Marketed: September 1999

Region of origin to whom queries should be directed: South and West (Bristol)

● The information contained herein will be ● Not to be used for commercial purposes.
superseded in due course. ● Copyright DIPG 1999.
INSULIN ASPART

APPROVED NAME: Insulin Aspart

BRAND NAME: NovoRapid® (Novo Nordisk)

PRESENTATION: 10ml vials, 3ml cartridges for use with a NovoPen© 3 and 3ml
preloaded pens containing 100 units/ml.

THERAPEUTIC CLASS: Insulin analogue [BNF 6.1.1.1]

LICENSED INDICATIONS: Treatment of patients with diabetes mellitus.

DOSAGE AND ADMINISTRATION: Dosage, by subcutaneous injection, according to patient’s response.


Generally given immediately before a meal. Normally used in
combination with intermediate-acting or long-acting insulin.

THERAPEUTIC COMMENT: A rapid onset insulin analogue for administration immediately before
meals. It provides an alternative to insulin lispro. No direct
comparisons with the latter have been undertaken.

SECTOR OF USE: Hospital [Y] Primary Care [Y]

NEW CLASS OF DRUG: [N]

COST/COURSE: 10ml vial £15.71 5 x 3ml cartridges £26.78


5 x 3ml preloaded pens £28.31

TREATMENT ALTERNATIVES: Insulin Lispro 10ml vial £15.71 5x 3ml cartridges £26.78

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INSULIN ASPART

INTRODUCTION duration of action than soluble insulin. Time to


peak plasma concentration is about half of that for
In the UK about 3-4 people per 1000 population soluble insulin. The time to maximum
have type 1 (insulin dependent) diabetes and concentration is 40 - 60 minutes. Duration of
another 10 - 20 per 1000 have type 2 diabetes. The action is about 3 - 5 hours [5].
current treatment of choice for type 1 diabetes is
the injection of soluble insulin about 30 minutes In children (6 - 12 years) and adolescents (13 - 17
before a meal, normally in combination with years) with type 1 diabetes insulin aspart was
intermediate-acting or long-acting insulin. rapidly absorbed with similar time to maximum
concentration as in adults [4].
Insulin aspart is a rapid-acting insulin analogue.
Another human insulin analogue, insulin lispro, The pharmacokinetics have not been investigated
has been available since June 1996. Such rapid- in elderly or patients with decreased renal or liver
acting insulin analogues were developed to allow a function.
more physiological meal-time insulin profile, than
occurs with soluble insulin. Insulin aspart has a EFFICACY
more rapid onset than soluble insulin. This allows
The majority of clinical trials with insulin aspart
the patient to inject insulin immediately before a
have only been published in abstract form and have
meal.
been open-label.
PHARMACOLOGY
The short-term efficacy (24 hour glycaemic
Insulin aspart is an analogue of human insulin in control) of insulin aspart was evaluated in a
which the amino acid proline at position 28 of the multicentre, randomised, double-blind crossover
B chain in the insulin molecule has been study enrolling 104 male patients with type 1
substituted with aspartic acid. The biological diabetes [6]. Mean age was 34.3 years and mean
properties of insulin aspart are similar to human duration of diabetes 15 years. 90 subjects
insulin once absorbed and appear to produce a completed the trial. Following a four week run-in
similar glucose-lowering effect. period, patients were administered either insulin
aspart or regular human insulin (Actrapid) before
PHARMACOKINETICS meals and NPH insulin as basal insulin, at bedtime,
for 4 weeks. Patients were then treated for a
The pharmacokinetics of insulin aspart have been further four weeks with the comparator insulin.
studied in healthy volunteers [1], type 1 [2] and Doses were adjusted on an individual basis to
type 2 [3] diabetic patients and in type 1 diabetic maintain premeal and night-time (0200 hours)
children and adolescents [4]. blood glucose levels within the normal range (4.0-
7.0 mmol/L) and postprandial blood glucose levels
lower than 10 mmol/L in the absence of
In pharmaceutical preparations of soluble human hypoglycaemic episodes. Over a 24 hour period,
insulin, the insulin molecules self-associate into the glucose excursion outside the defined normal
hexamers which dissociate slowly into monomeric range was significantly improved with insulin
insulin, before absorption from subcutaneous aspart, with the excursion 22% less than with
tissue. This may account for the slow rise in the human insulin (4713 vs. 5260mmol/L/min;
absorption rate and prolonged action of soluble p<0.01). In particular, insulin aspart reduced
compared to endogenous insulin. excursions of blood glucose in excess of 7 mmol/L
without an effect on excursions less than 4
mmol/L. Daytime glucose control, as assessed by
maximum and minimum glucose levels, was better
The substitution of aspartate for proline in insulin with insulin aspart than with human insulin
aspart, reduces the tendency to self-associate into whereas night-time control was poorer.
hexamers. This results in more rapid absorption, Fructosamine levels, the primary variable, were
which leads to an earlier peak and a shorter not significantly different between treatments
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INSULIN ASPART

indicating no difference in blood glucose lower in the insulin aspart patients than in the
control. Hypoglycaemic episodes requiring human insulin group (p<0.016). The mean
third party intervention occurred less frequently prandial glucose increment was lower in the
during therapy with insulin aspart (20 vs. 44 insulin aspart group than in the human insulin
events; p<0.002), although the overall incidence
group, a difference of 1.4mmol/L (p<0.0001).
of all hypoglycaemic episodes was similar
during the two treatments. The frequency of hypoglycaemic episodes was
comparable between treatments. Relative risk
Clinical efficacy and safety was studied mainly of major nocturnal hypoglycaemia was 50%
in three phase III trials which have only been (95% CI: 29-86%) with insulin aspart compared
published in abstract form [7-9]. All three were
to soluble human insulin. This study was
of similar design being six month, multicentre,
randomised, open-label, parallel group trials. extended for a further six months but the results
The trials evaluated the long-term efficacy of are only available in poster form. Twelve-
insulin aspart compared with human insulin in month data on 467 insulin aspart patients and
type 1 [7,8] and type 2 diabetics [9]. The 208 human insulin patients showed that the
studies compared insulin aspart given significant reduction in HbA1C seen at six
immediately before meals with human insulin months was maintained at twelve months [10].
given 30 minutes prior to meals, plus once or
twice daily NPH insulin as the basal insulin A six month study by Bott et al [11] included a
component. The primary outcome measure was quality of life (QOL) assessment in 424 type 1
the glycated haemoglobin (HbA1C), an indicator
diabetic patients. This multicentre, randomised,
of long-term glycaemic control. Secondary
outcome measures are detailed in table1. open-label study found that insulin aspart was
associated with improved QOL regarding
Type 1 Studies nutritional restrictions. Improved satisfaction
was mainly due to increased nutritional and
After six months therapy, Home et al [7] found
mean HbA1C to be 0.12 (95% CI: 0.03-0.22) leisure time flexibility. There do not appear to
percentage points lower (p<0.02) with insulin have been any differences in other aspects of the
aspart than with human insulin. Although questionnaire such as physical complaints,
statistically significant the difference was small social relations and fear of hypoglycaemia. The
and of doubtful clinical significance [5]. Mean authors calculated a “number needed to treat” of
prandial glucose increment (mean difference 10 for an important increase in QOL.
between premeal and postmeal glucose values)
was significantly lower in the insulin aspart Type 2 Studies
group compared with those receiving human
insulin, a difference of 1.15mmol/L (p<0.0001) Raskin et al [9] studied the efficacy of insulin
at six months. There was no significant aspart in 182 patients with type 2 diabetes
difference in the incidence of hypoglycaemic requiring insulin. All patients received basal
episodes between treatment groups. Treatment
injections of NPH insulin at bedtime. The
satisfaction, assessed by a WHO questionnaire,
was improved with insulin aspart over soluble abstract makes no mention of concomitant oral
insulin (p<0.0001). hypoglycaemic therapy. After six months
therapy there was no significant difference in
Hoogwerf et al [8] found that after six months HbA1C levels between the two groups. Other
therapy mean HbA1C was lower for the insulin
measures of glycaemic control were also
aspart group (7.8% +/- 1.1) compared with the
human insulin group (8.0% +/- 1.2; p=0.005). comparable. No statistically significant
Again, although statistically significant, the difference in hypoglycaemic episodes was
difference was of limited clinical significance. observed. Safety and efficacy has not been
Mean post-prandial blood glucose levels were studied beyond six months in type 2 diabetes.
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INSULIN ASPART

Insulin aspart has not been directly compared like soluble insulin, interacts with a number of
with insulin lispro. drugs known to affect glucose metabolism [5].

PROMOTIONAL DATA References

Insulin aspart is marketed as a “new rapid 1. Home PD et al. Comparative pharmacokinetics and
pharmacodynamics of the novel rapid-acting insulin
acting insulin analogue that offers more analogue, insulin aspart, in healthy volunteers.
flexibility”. The promotional literature focuses Eur J Clin Pharmacol 1999;55:199-203.
on:
2. Lindholm A et al. Improved post-prandial glycaemic
control with insulin aspart - a randomised double-
1. Improved post-prandial glucose control with blind cross-over trial in type 1 diabetes mellitus.
insulin aspart. Diabetes Care 1999;22:801-805.

3. Rosenfalck AM et al. Effects of the rapid-acting


2. Improved long-term metabolic control as analogue insulin aspart on post-prandial glycaemic
indicated by HbA1C over 12 months [10]. excursions compared to human soluble insulin
Actrapid given immediately or 30 minutes before a
3. Reduced risk of major nocturnal glycaemia meal in insulin treated type 2 diabetes patients (Abs).
Diabetes 1999;48(S1):A116.
by up to 50% [8].
4. Mortensen H et al. Pharmacokinetics of a rapid-
4. Increased patient satisfaction as compared to acting human insulin analogue, insulin aspart, in
children and adolescents with type 1 diabetes (Abs).
soluble insulin. [11]. Diabetes 1999;48(S1):A358.

ADVERSE EFFECTS 5. NovoRapid. Summary of Product Characteristics.


Novo Nordisk - Sep 1999.
The safety profile of insulin aspart appears
6. Home PD et al. Improved glycemic control with
comparable to soluble human insulin. The insulin aspart. A multicenter randomised double-blind
incidence of hypoglycaemic events after insulin crossover trial in type 1 diabetic patients. Diabetes
Care 1998;21:1904-9.
aspart was similar or less frequent than after
human insulin [6-9]. 7. Home PD et al. Improved long-term blood glucose
control with insulin aspart versus human insulin in
CONTRAINDICATIONS (Refer to SPC) people with type 1 diabetes (Abs). Diabetes
1999;48(S1):A358.
Contraindications include hypo-glycaemia and 8. Hoogwerf B et al. Insulin aspart - a mealtime
hypersensitivity to insulin aspart or any of the alternative to soluble human insulin in type 1 diabetes
excipients. Animal studies have not shown any (Abs). Diabetologia 1999;42(S1):A237.
differences between insulin aspart and human 9. Raskin P et al. Human insulin analog (insulin aspart,
insulin regarding teratogenicity. There are no Iasp) is comparable to human insulin (HI) in type 2
restrictions on insulin aspart use during diabetes (Abs). Diabetes 1999;48(S1):A355.
lactation. Cautions include inadequate dosing 10. Hoogwerf B et al. Insulin aspart - a mealtime
or discontinuation of treatment, which may lead alternative to soluble human insulin in type 1
to hyperglycaemia and ketoacidosis. As with diabetes. Poster presented at: 35th Annual Meeting of
the European Association for the study of Diabetes
human insulins, tight glycaemic control may (EASD), Brussels 28 Sept - 2 Oct 1999.
result in the loss of usual warning signs of
11. Bott U et al. Effect of the insulin analogue insulin
hypoglycaemia and patients should be advised aspart on quality-of-life and treatment satisfaction in
accordingly. Patients transferred from another type 1 diabetic patients (Abs). Diabetologia
type of insulin should be carefully monitored to 1999;42(S1):A237.
assess whether a dosage adjustment is
necessary. This may be needed after the first
dose or during the first several weeks or months
of therapy. The fast onset of action of insulin
aspart should be considered in patients with
diseases or medication where delayed food
absorption might be expected. Insulin aspart,
5
TABLE 1 Summary of insulin aspart key clinical trials

Ref Study design Population Drug treatment/duration Primary Outcome Secondary outcome measures
measure
6 Randomised, 90 male patients with 4 weeks I Asp + 4 weeks H I Fructosamine * Derived from 24 hr glucose profiles:
multicentre, double- type 1 diabetes of AUC Cmax & Cmin

INSULIN ASPART
blind, crossover mean duration 15 yrs * 8-point blood glucose profiles
* Incidence of hypoglycaemia
8 Randomised, 882 patients with 6 months HbA1C * 8-point blood glucose profiles: prandial
multicentre, open- type 1 diabetes of I Asp n=596 increments
label, parallel group mean duration 15 yrs H I n=286 * Incidence of hypoglycaemia
6

7 Randomised, 1065 patients with 6 months HbA1C * 8-point blood glucose profiles: prandial
multicentre, open- type 1 diabetes I Asp n=707 increments
label, parallel group H I n=358 * Incidence of hypoglycaemia

9 Randomised, 182 patients with 6 months HbA1C * 8-point blood glucose profiles: prandial
multicentre, open- type 2 diabetes I Asp n=91 increments
H I n=91 * Incidence of hypoglycaemia
label, parallel group

I Asp - insulin aspart, H I - human insulin