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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superseded in due course.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

2
 INSULIN ASPART
INTRODUCTION
In the UK about 3-4 people per 1000 population
have type 1 (insulin dependent) diabetes and
another 10 - 20 per 1000 have type 2 diabetes. The
current treatment of choice for type 1 diabetes is
the injection of soluble insulin about 30 minutes
before a meal, normally in combination with
intermediate-acting or long-acting insulin.
Insulin aspart is a rapid-acting insulin analogue.
Another human insulin analogue, insulin lispro,
has been available since June 1996. Such rapid-
acting insulin analogues were developed to allow a
more physiological meal-time insulin profile, than
occurs with soluble insulin. Insulin aspart has a
more rapid onset than soluble insulin. This allows
the patient to inject insulin immediately before a
meal.
PHARMACOLOGY
Insulin aspart is an analogue of human insulin in
which the amino acid proline at position 28 of the
B chain in the insulin molecule has been
substituted with aspartic acid. The biological
properties of insulin aspart are similar to human
insulin once absorbed and appear to produce a
similar glucose-lowering effect.
PHARMACOKINETICS
The pharmacokinetics of insulin aspart have been
studied in healthy volunteers [1], type 1 [2] and
type 2 [3] diabetic patients and in type 1 diabetic
children and adolescents [4].
In pharmaceutical preparations of soluble human
insulin, the insulin molecules self-associate into
hexamers which dissociate slowly into monomeric
insulin, before absorption from subcutaneous
tissue. This may account for the slow rise in the
absorption rate and prolonged action of soluble
compared to endogenous insulin.
The substitution of aspartate for proline in insulin
aspart, reduces the tendency to self-associate into
hexamers. This results in more rapid absorption,
which leads to an earlier peak and a shorter
3
duration of action than soluble insulin. Time to
peak plasma concentration is about half of that for
soluble insulin. The time to maximum
concentration is 40 - 60 minutes. Duration of
action is about 3 - 5 hours [5].
In children (6 - 12 years) and adolescents (13 - 17
years) with type 1 diabetes insulin aspart was
rapidly absorbed with similar time to maximum
concentration as in adults [4].
The pharmacokinetics have not been investigated
in elderly or patients with decreased renal or liver
function.
EFFICACY
The majority of clinical trials with insulin aspart
have only been published in abstract form and have
been open-label.
The short-term efficacy (24 hour glycaemic
control) of insulin aspart was evaluated in a
multicentre, randomised, double-blind crossover
study enrolling 104 male patients with type 1
diabetes [6]. Mean age was 34.3 years and mean
duration of diabetes 15 years. 90 subjects
completed the trial. Following a four week run-in
period, patients were administered either insulin
aspart or regular human insulin (Actrapid) before
meals and NPH insulin as basal insulin, at bedtime,
for 4 weeks. Patients were then treated for a
further four weeks with the comparator insulin.
Doses were adjusted on an individual basis to
maintain premeal and night-time (0200 hours)
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
hypoglycaemic episodes. Over a 24 hour period,
the glucose excursion outside the defined normal
range was significantly improved with insulin
aspart, with the excursion 22% less than with
human insulin (4713 vs. 5260mmol/L/min;
p<0.01). In particular, insulin aspart reduced
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
with insulin aspart than with human insulin
whereas night-time control was poorer.
Fructosamine levels, the primary variable, were
not significantly different between treatments
 INSULIN ASPART
indicating no difference in blood glucose
control. Hypoglycaemic episodes requiring
third party intervention occurred less frequently
during therapy with insulin aspart (20 vs. 44
events; p<0.002), although the overall incidence
of all hypoglycaemic episodes was similar
during the two treatments.
Clinical efficacy and safety was studied mainly
in three phase III trials which have only been
published in abstract form [7-9]. All three were
of similar design being six month, multicentre,
randomised, open-label, parallel group trials.
The trials evaluated the long-term efficacy of
insulin aspart compared with human insulin in
type 1 [7,8] and type 2 diabetics [9]. The
studies compared insulin aspart given
immediately before meals with human insulin
given 30 minutes prior to meals, plus once or
twice daily NPH insulin as the basal insulin
component. The primary outcome measure was
the glycated haemoglobin (HbA1C), an indicator
of long-term glycaemic control. Secondary
outcome measures are detailed in table1.
Type 1 Studies
After six months therapy, Home et al [7] found
mean HbA1C to be 0.12 (95% CI: 0.03-0.22)
percentage points lower (p<0.02) with insulin
aspart than with human insulin. Although
statistically significant the difference was small
and of doubtful clinical significance [5]. Mean
prandial glucose increment (mean difference
between premeal and postmeal glucose values)
was significantly lower in the insulin aspart
group compared with those receiving human
insulin, a difference of 1.15mmol/L (p<0.0001)
at six months. There was no significant
difference in the incidence of hypoglycaemic
episodes between treatment groups. Treatment
satisfaction, assessed by a WHO questionnaire,
was improved with insulin aspart over soluble
insulin (p<0.0001).
Hoogwerf et al [8] found that after six months
therapy mean HbA1C was lower for the insulin
aspart group (7.8% +/- 1.1) compared with the
human insulin group (8.0% +/- 1.2; p=0.005).
Again, although statistically significant, the
difference was of limited clinical significance.
Mean post-prandial blood glucose levels were
4
lower in the insulin aspart patients than in the
human insulin group (p<0.016). The mean
prandial glucose increment was lower in the
insulin aspart group than in the human insulin
group, a difference of 1.4mmol/L (p<0.0001).
The frequency of hypoglycaemic episodes was
comparable between treatments. Relative risk
of major nocturnal hypoglycaemia was 50%
(95% CI: 29-86%) with insulin aspart compared
to soluble human insulin. This study was
extended for a further six months but the results
are only available in poster form. Twelve-
month data on 467 insulin aspart patients and
208 human insulin patients showed that the
significant reduction in HbA1C seen at six
months was maintained at twelve months [10].
A six month study by Bott et al [11] included a
quality of life (QOL) assessment in 424 type 1
diabetic patients. This multicentre, randomised,
open-label study found that insulin aspart was
associated with improved QOL regarding
nutritional restrictions. Improved satisfaction
was mainly due to increased nutritional and
leisure time flexibility. There do not appear to
have been any differences in other aspects of the
questionnaire such as physical complaints,
social relations and fear of hypoglycaemia. The
authors calculated a “number needed to treat” of
10 for an important increase in QOL.
Type 2 Studies
Raskin et al [9] studied the efficacy of insulin
aspart in 182 patients with type 2 diabetes
requiring insulin. All patients received basal
injections of NPH insulin at bedtime. The
abstract makes no mention of concomitant oral
hypoglycaemic therapy. After six months
therapy there was no significant difference in
HbA1C levels between the two groups. Other
measures of glycaemic control were also
comparable. No statistically significant
difference in hypoglycaemic episodes was
observed. Safety and efficacy has not been
studied beyond six months in type 2 diabetes.
 INSULIN ASPART
Insulin aspart has not been directly compared
with insulin lispro.
PROMOTIONAL DATA
Insulin aspart is marketed as a “new rapid
acting insulin analogue that offers more
flexibility”. The promotional literature focuses
on:
1. Improved post-prandial glucose control with
insulin aspart.
2. Improved long-term metabolic control as
indicated by HbA1C over 12 months [10].
3. Reduced risk of major nocturnal glycaemia
by up to 50% [8].
4. Increased patient satisfaction as compared to
soluble insulin. [11].
ADVERSE EFFECTS
The safety profile of insulin aspart appears
comparable to soluble human insulin. The
incidence of hypoglycaemic events after insulin
aspart was similar or less frequent than after
human insulin [6-9].
CONTRAINDICATIONS (Refer to SPC)
Contraindications include hypo-glycaemia and
hypersensitivity to insulin aspart or any of the
excipients. Animal studies have not shown any
differences between insulin aspart and human
insulin regarding teratogenicity. There are no
restrictions on insulin aspart use during
lactation. Cautions include inadequate dosing
or discontinuation of treatment, which may lead
to hyperglycaemia and ketoacidosis. As with
human insulins, tight glycaemic control may
result in the loss of usual warning signs of
hypoglycaemia and patients should be advised
accordingly. Patients transferred from another
type of insulin should be carefully monitored to
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
like soluble insulin, interacts with a number of
drugs known to affect glucose metabolism [5].
References
1. Home PD et al. Comparative pharmacokinetics and
pharmacodynamics of the novel rapid-acting insulin
analogue, insulin aspart, in healthy volunteers.
Eur J Clin Pharmacol 1999;55:199-203.
2. Lindholm A et al. Improved post-prandial glycaemic
control with insulin aspart - a randomised double-
blind cross-over trial in type 1 diabetes mellitus.
Diabetes Care 1999;22:801-805.
3. Rosenfalck AM et al. Effects of the rapid-acting
analogue insulin aspart on post-prandial glycaemic
excursions compared to human soluble insulin
Actrapid given immediately or 30 minutes before a
meal in insulin treated type 2 diabetes patients (Abs).
Diabetes 1999;48(S1):A116.
4. Mortensen H et al. Pharmacokinetics of a rapid-
acting human insulin analogue, insulin aspart, in
children and adolescents with type 1 diabetes (Abs).
Diabetes 1999;48(S1):A358.
5. NovoRapid. Summary of Product Characteristics.
Novo Nordisk - Sep 1999.
6. Home PD et al. Improved glycemic control with
insulin aspart. A multicenter randomised double-blind
crossover trial in type 1 diabetic patients. Diabetes
Care 1998;21:1904-9.
7. Home PD et al. Improved long-term blood glucose
control with insulin aspart versus human insulin in
people with type 1 diabetes (Abs). Diabetes
1999;48(S1):A358.
8. Hoogwerf B et al. Insulin aspart - a mealtime
alternative to soluble human insulin in type 1 diabetes
(Abs). Diabetologia 1999;42(S1):A237.
9. Raskin P et al. Human insulin analog (insulin aspart,
Iasp) is comparable to human insulin (HI) in type 2
diabetes (Abs). Diabetes 1999;48(S1):A355.
10. Hoogwerf B et al. Insulin aspart - a mealtime
alternative to soluble human insulin in type 1
diabetes. Poster presented at: 35th Annual Meeting of
the European Association for the study of Diabetes
(EASD), Brussels 28 Sept - 2 Oct 1999.
11. Bott U et al. Effect of the insulin analogue insulin
aspart on quality-of-life and treatment satisfaction in
type 1 diabetic patients (Abs). Diabetologia
1999;42(S1):A237.
 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