Drugs 2007; 67 (3): 407-434

ADIS DRUG EVALUATION 0012-6667/07/0003-0407/$49.95/0

© 2007 Adis Data Information BV. All rights reserved.

Insulin Lispro
A Review of its Use in the Management of
Diabetes Mellitus
Dene Simpson, Paul L. McCormack, Gillian M. Keating and Katherine A. Lyseng-
Williamson
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA

Various sections of the manuscript reviewed by:

K. Cypryk, Clinic of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland; G.
Forlani, Metabolic Diseases Unit, Department of Internal Medicine and Gastroenterology, University of
Bologna, Bologna, Italy; D.R. Hadden, Department of Endocrinology, Royal Victoria Hospital, Belfast,
Northern Ireland; H. Lawall, Klinikum Karlsbad-Langensteinbach, Karlsbad, Germany; G.D. Lopaschuk,
Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada; G. Tamas, Diabetes
Unit, Department of Medicine, Semmelweis University, Budapest, Hungary.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘insulin lispro’, identified using MEDLINE and EMBASE,
supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the
reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the
company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘insulin lispro’. Searches were last updated 7 February 2007.
Selection: Studies in patients with who received insulin lispro. Inclusion of studies was based mainly on the methods section of the trials.
When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and
pharmacokinetic data are also included.
Index terms: Insulin lispro, human insulin analogue, diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
4.1 Insulin Lispro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
4.1.1 In Type 1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
4.1.2 In Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
4.2 Insulin Lispro Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
4.2.1 In Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
4.2.2 In Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
4.3 Continuous Subcutaneous Infusion of Insulin Lispro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
4.4 Insulin Lispro In Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
4.4.1 Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
4.4.2 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
4.4.3 Fasting Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
408 Simpson et al.

4.5 Health-Related Quality of Life and Patient Satisfaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
5.1 Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
5.2 Other Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
5.3 In Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
7. Place of Insulin Lispro in the Management of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Summary
Abstract Insulin lispro, alone (Humalog®) or as premixture (Humalog Mix25® or Humalog
Mix50®) is indicated for the treatment of hyperglycaemia in diabetes mellitus in
many countries worldwide. It is a recombinant human insulin analogue and,
except for the transposition of two amino acids, is identical to endogenous human
insulin. Insulin lispro has a faster onset of action and shorter duration of activity
than regular human insulin, and the time-action profile of insulin lispro mimics
that of the physiological response of endogenous human insulin to food intake. In
diabetic patients, from young children to the elderly, it has demonstrated post-
prandial blood glucose control similar to or better than that achieved with regular
human insulin, without an increased risk of hypoglycaemia. In some trials, the risk
of hypoglycaemia, including nocturnal episodes, was less in insulin lispro recipi-
ents than in regular human insulin recipients. Insulin lispro alone, or as a
premixture with the longer-acting insulin neutral protamine lispro, can be admin-
istered immediately before or after meals. This convenient and flexible injection
schedule may enable patients, including those with a non-routine lifestyle or
unpredictable eating or exercising habits, to achieve the tight glycaemic control
required to minimise long-term complications of diabetes and contributes to
patient satisfaction with treatment.

Pharmacological Insulin lispro is a recombinant human insulin analogue that is equipotent on a

Properties molar basis to regular human insulin with respect to hypoglycaemic activity, but
with a faster onset of action, an earlier peak and a shorter duration of action. The
blood glucose profile achieved with insulin lispro indicates that the optimal time
of administration of insulin lispro is within 15 minutes before ingestion of a meal,
but it can also be administered immediately or shortly after a meal. As a result of
its shorter duration of action, insulin lispro is associated with lower postprandial,
but higher postabsorptive and preprandial blood glucose levels, than regular
human insulin, resulting in similar overall glycaemic control for the two insulins.
Commercially available premixtures of 25% insulin lispro and 75% insulin
neutral protamine lispro (insulin lispro Mix25) and 50% of each (insulin lispro
Mix50) have been shown to provide better 24-hour or mealtime glycaemic control
than mixtures of human regular insulin with neutral protamine Hagedorn (NPH)
insulin.
The incidence of specific or cross-reacting insulin antibodies in patients with
type 1 or type 2 diabetes treated with insulin lispro was similar to that in patients
treated with recombinant regular human insulin.

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
Insulin Lispro: A Review
Therapeutic Efficacy
© 2007 Adis Data Information BV. All rights reserved.
409
In patients with type 1 diabetes receiving insulin, intensive premeal administration
of insulin lispro reduced mean 2-hour postprandial glucose levels relative to a
similar regular human insulin-based regimen, but fasting or preprandial blood
glucose levels were generally similar for the two insulins. Overall, long-term
glycaemic control (as assessed by glycosylated haemoglobin [HbA1c] values) was
essentially similar for the two insulins. The risk of hypoglycaemia was not greater
with insulin lispro than with regular human insulin and was significantly lower in
some trials.
Insulin lispro was also effective in the treatment of type 2 diabetes. In patients
with early type 2 disease who had not previously used insulin, insulin lispro
prompted a significantly greater reduction from baseline in mean overall 2-hour
postprandial blood glucose excursions than glibenclamide (glyburide). The addi-
tion of insulin lispro to an oral antihyperglycaemic or NPH insulin regimen was
effective at improving or regaining blood glucose control (reducing postprandial
blood glucose and HbA1c values) in patients with secondary oral antihypergly-
caemic treatment failure. Patients with type 2 diabetes who were already receiving
insulin therapy had 2-hour postprandial blood glucose levels or blood glucose
excursions with insulin lispro that were generally significantly lower than with
regular human insulin. Glycaemic control (HbA1c values) and the incidence of
hypoglycaemic episodes did not generally differ significantly between the insulin
lispro and the other treatment groups in these trials.
Premixed insulin lispro achieved glycaemic control in patients with either type
of diabetes that was similar to that with self-mixed insulin lispro and NPH insulin,
or premixed or self-mixed regular human insulin and NPH insulin, with a
generally similar risk of hypoglycaemia. In patients with type 2 diabetes, insulin
lispro Mix25 twice daily and insulin lispro Mix50 three times daily demonstrated
greater efficacy (significantly lower HbA1c values and postprandial blood glucose
levels) than insulin glargine (a long-acting insulin) at bedtime. Twice-daily insulin
lispro Mix25 demonstrated similar efficacy to twice-daily biphasic insulin aspart.
In patients (including the elderly) with type 2 diabetes who had been previously
inadequately controlled on a sulfonylurea, glycaemic control was significantly
better with insulin lispro Mix25 than with oral glibenclamide, although the rate of
hypoglycaemic episodes tended to be higher in the group receiving insulin than in
the glibenclamide group.
The administration of insulin lispro delivered as a continuous subcutaneous
insulin infusion (CSII) using an external pump, relative to the administration of
insulin lispro as multiple daily injections, improved glycaemic control (and at a
lower insulin dose and with fewer hypoglycaemic episodes) in patients with type 1
diabetes, and achieved similar glycaemic control in elderly patients with type 2
diabetes. Comparing insulins delivered as a CSII, insulin lispro achieved similar
or better glycaemic control than that achieved with regular human insulin and
achieved similar glycaemic control to that achieved with insulin aspart. Insulin
lispro as a CSII has also been successfully used in children.
Children receiving insulin lispro achieved postprandial blood glucose levels
that were similar to or lower than those achieved with regular human insulin, with
similar overall glycaemic control and risk of hypoglycaemia. Adolescents receiv-
ing insulin lispro experienced significantly lower postprandial blood glucose
Drugs 2007; 67 (3)
410 Simpson et al.

levels and a lower rate of hypoglycaemia than recipients of regular human insulin,
but overall glycaemic control was similar for both groups.
Prospective and retrospective studies in pregnant women with diabetes indi-
cate that glycaemic control and maternal and fetal outcomes with insulin lispro
therapy were generally similar to those with regular human insulin and in line with
data available for other insulins.
In large crossover trials, patients with type 1 diabetes using insulin lispro
preferred the flexibility and convenience and were more satisfied with their
treatment than patients using regular human insulin. Trials in patients with type 2
diabetes indicated that there was no difference in treatment satisfaction between
insulin lispro and regular human insulin, but the use of insulin lispro mixtures was
preferred over that of glibenclamide.
Tolerability The tolerability of rapid-acting insulins is essentially concerned with hypogly-
caemia. The largest trials in adult patients with type 1 or 2 diabetes receiving
insulin lispro demonstrated significantly lower rates of hypoglycaemia, including
nocturnal episodes, in insulin lispro recipients than in regular human insulin
recipients. In almost all the other trials, the incidence of hypoglycaemia in insulin
recipients of all ages was similar to or less than that in regular human insulin or
other comparator insulin recipients.

1. Introduction with the longer-acting insulin neutral protamine lis-

The original introduction of human insulins con-
stituted a great advance in the manufacture of insu-
lins and in the treatment of patients with diabetes
mellitus. Recombinant human insulin analogues,
which overcome some of the disadvantages of stan-
dard human insulins, now represent another impor-
tant milestone in the development of an optimal
treatment for diabetes.[1,2]
Insulin lispro (Humalog®)1 is a recombinant
human insulin analogue that differs from endoge-
nous human insulin in the transpositioning of two
amino acids. It is one of three rapid-acting insulin
analogues available. Insulin lispro is equipotent to
regular human insulin (fast-acting soluble insulin
derived from humans), but with a more rapid onset
and shorter duration of hypoglycaemic action. It,
therefore, more closely mimics the physiological
human insulin response to food ingestion.[1,2]
This article provides a summary of the pharma-
cological properties of insulin lispro and focuses on
its therapeutic use as a single agent or as premixtures
pro as a basal insulin (Humalog Mix25® [25% insu-
lin lispro and 75% insulin neutral protamine lispro;
hereafter referred to as insulin lispro Mix25] and
Humalog Mix50® [50% of each insulin; hereafter
referred to as insulin lispro Mix50]).
2. Pharmacodynamic Properties
Insulin lispro is a recombinant human insulin
analogue with a primary structure identical to that of
regular human insulin, except for transposition of
the two amino acids at positions 28 and 29 on the B
chain from proline-lysine to lysine-proline.[3] This
minor change in the amino acid sequence results in
an insulin analogue with a reduced tendency for self
association relative to regular human insulin,[3]
which in turn leads to more rapid absorption and a
shorter duration of action than regular human insu-
lin[4] (see section 3). Insulin lispro forms stable
hexamers in the presence of zinc and phenol in the
pharmaceutical preparation, but these rapidly disso-
ciate into monomers upon injection into subcutane-

1 The use of trade names is for identification purposes only and does not imply endorsement.

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
Insulin Lispro: A Review
ous tissue; in contrast, hexameric complexes of reg-
ular human insulin dissociate more slowly.[5]
At a cellular level, the actions of insulin lispro on
glucose and amino acid uptake, as well as on bio-
chemical signalling, are essentially the same as
those of human regular insulin.[6]
Insulin lispro is equipotent or slightly less potent
than regular human insulin in binding to the human
insulin receptor and slightly more potent than regu-
lar human insulin in binding to the insulin-like
growth factor type 1 (IGF-I) receptor, but the differ-
ences are considered unlikely to affect receptor-
mediated activity in vivo.[4,7] Similarly, the dissocia-
tion rate of insulin lispro from the insulin receptor is
equivalent to that of regular human insulin.[4] The
mitogenic potency of insulin lispro is lower than that
for regular human insulin, indicating a low propen-
sity to promote tumours.[7]
Insulin lispro is equipotent on a molar basis to
regular human insulin with respect to glucose-low-
ering activity.[5,8] However, the hypoglycaemic ac-
tivity of insulin lispro has a faster onset (beginning
within 15 minutes), peaks earlier and has a shorter
duration of action than regular human insulin,[5,8]
which reflects the faster absorption and elimination
of insulin lispro (see section 3).
In patients with type 1 diabetes, subcutaneous
injection of insulin lispro 0.15 U/kg decreased plas-
ma glucose to a 3 mmol/L plateau earlier than the
same dose of regular human insulin (60 vs 120
minutes; p < 0.05), reflecting faster attainment of
peak plasma insulin concentration (60 vs 90 min-
utes; p < 0.05).[9] Insulin lispro has a duration of
clinical activity of 2–5 hours.[10]
The required quantity of glucose infused between
60 and 375 minutes in order to prevent plasma
glucose levels decreasing below 3 mmol/L was
≈3-fold higher after insulin lispro administration
than after regular human insulin administration, and
the required duration of infusion was shorter with
insulin lispro (240 vs 375 minutes).[9] Relative to
regular human insulin, insulin lispro produced
greater suppression of hepatic glucose production;
insulin lispro also slightly stimulated glucose
utilisation.[9]
© 2007 Adis Data Information BV. All rights reserved.
411
In patients with type 2 diabetes of relatively
recent onset, insulin lispro produced a significantly
lower area under the plasma concentration-time
curve (AUC) value for glucose and greater suppres-
sion of glucagon than regular human insulin.[11]
Relative to a single prebreakfast injection of pre-
mixed regular human insulin plus neutral protamine
Hagedorn (NPH) insulin, separate injections of insu-
lin lispro plus NPH insulin before breakfast and
lunch (equating to the same total number of insulin
units) in patients with type 1 diabetes produced an
≈60% lower AUC for glucose and improved the
regulation of leptin and ghrelin, suggesting the po-
tential for better long-term control of body
weight.[12]
The optimal time of administration of insulin
lispro is generally considered to be between 15
minutes to immediately before ingestion of a
meal,[13,14] but earlier administration (15–30 minutes
before a meal) is probably preferable in patients
with type 1 diabetes who have preprandial hypergly-
caemia.[15] Administration of insulin lispro 15–20
minutes after starting a meal still provided good
glycaemic control in patients with type 1 diabe-
tes,[14] and was particularly relevant to high-fat
meals, in which situation it reduced the incidence of
postprandial hypoglycaemia, although blood glu-
cose excursions were significantly (p < 0.01) greater
than with preprandial administration.[13]
As a result of its short duration of action, meal-
time insulin lispro requires supplementation with a
longer-acting insulin to achieve optimal glycaemic
control. Mealtime administration of insulin lispro
resulted in significantly (p < 0.05) lower postprandi-
al blood glucose and higher postabsorptive (beyond
3–3.5 hours) blood glucose than mealtime adminis-
tration of regular human insulin in patients with type
1 diabetes, all of whom were receiving once-daily
NPH insulin at bedtime.[16] The mean 24-hour blood
glucose AUC and glycosylated haemoglobin
(HbA1c) values over 3 months, therefore, did not
differ between these treatments.
Premixed formulations combining rapid- and
longer-acting insulins are commonly used because
of their convenience. Adding variable amounts of
Drugs 2007; 67 (3)
412
NPH insulin to insulin lispro at mealtimes signifi-
cantly (p < 0.05) lowered mean 24-hour blood glu-
cose AUC (1470 vs 1580 mg • h/L) and HbA1c
(6.41% vs 6.96%) relative to mealtime insulin lispro
alone.[16] Although mixtures of insulin lispro and
NPH insulin are stable when mixed in the syr-
inge,[17] they are unstable during long-term stor-
age.[18] However, the pharmacodynamic properties
of insulin lispro are completely preserved when
mixed with insulin neutral protamine lispro, a
longer-acting form of the insulin.[18] A number of
small studies in patients with type 1 or type 2
diabetes have demonstrated that insulin lispro
Mix25 provides better 24-hour or mealtime gly-
caemic control than mixtures of 30% regular human
insulin and 70% NPH insulin (hereafter referred to
as human insulin 30/70).[19-22] The results of larger
studies examining premixed insulin lispro are dis-
cussed in section 4.2.
Insulin lispro does not lose effectiveness after
long-term use.[23] In patients with type 1 diabetes
who had been treated for 1–5.4 years (mean 1.8
years), postprandial glucose excursions were signifi-
cantly (p < 0.001) lower after treatment with insulin
lispro than after treatment with regular human insu-
lin prior to a meal following an overnight fast.[23]
No significant differences were observed be-
tween insulin lispro and regular human insulin in the
physiological, symptomatic and counter-regulatory
hormone responses to acute hypoglycaemia (the au-
tonomic reaction) in patients with type 1 diabe-
tes.[9,24]
The incidence of specific or cross-reacting insu-
lin antibodies in patients with type 1 or 2 diabetes
treated with insulin lispro was similar to that in
patients treated with recombinant regular human
insulin, and insulin antibody levels generally did not
change throughout treatment with insulin lispro in
clinical trials,[25-29] even after treatment for up to 5.4
years.[23] In the long-term study in patients with type
1 diabetes, median levels of antibody to regular
human insulin and insulin lispro were 0.65% and
0.35%, while that for cross-reactive antibody was
6.15%.[23]
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
Although insulin lispro showed a 1.5-fold in-
crease in IGF-1 receptor binding relative to human
insulin, it has not demonstrated increased
mitogenicity when studied in vitro in a human oste-
osarcoma cell line.[1]
3. Pharmacokinetic Properties
The pharmacokinetic properties of subcutaneous
insulin lispro appear to be similar in healthy volun-
teers and patients with type 1 or type 2 diabetes.
There are no data on the effect of age, gender,
obesity, smoking or pregnancy on the pharmacoki-
netics of the drug.[5,8] The absorption kinetics of
insulin lispro have been well documented, but there
is very little published data on its distribution, me-
tabolism or elimination.
Although the absolute bioavailability of insulin
lispro (55–77% with doses of 0.1–0.2 U/kg) in
healthy volunteers and patients with type 1 or type 2
diabetes is similar to that of regular human insulin,[8]
insulin lispro is more rapidly absorbed from subcu-
taneous sites than regular human insulin and has a
shorter duration of action (section 2).[5]
The maximum serum insulin concentration
(Cmax) following subcutaneous administration of in-
sulin lispro is significantly higher than that of regu-
lar human insulin and the time to Cmax (tmax) is
significantly shorter.[5,8] In 12 healthy male volun-
teers administered single-dose insulin lispro or regu-
lar human insulin 0.2 U/kg subcutaneously, respec-
tive mean Cmax values were 229 versus 182 pmol/L
and mean tmax values were 78 versus 156 minutes
(both p < 0.05).[30] The tmax in healthy volunteers
receiving subcutaneous insulin lispro 0.1–0.4 U/kg
was 30–90 minutes compared with 50–120 minutes
in those receiving equivalent doses of regular human
insulin, with similar results seen in patients with
type 1 diabetes.[8]
Serum insulin concentrations return to baseline
levels faster with insulin lispro than with regular
human insulin.[5,8] Hence, the AUCs from time zero
to 420 minutes for the two agents are similar (45.9
vs 54.3 nmol/L), despite the AUCs from zero to 120
minutes being significantly higher for insulin lispro
Drugs 2007; 67 (3)
Insulin Lispro: A Review
than for regular human insulin (20.6 vs 13.2 nmol/L;
p < 0.05).[30]
The rate of absorption of insulin lispro is faster
than that of regular human insulin, regardless of
whether the site of subcutaneous injection is deltoid,
femoral or abdominal.[8] However, abdominal ad-
ministration of insulin lispro results in higher serum
concentrations and a shorter duration of action than
thigh or deltoid administration of insulin lispro.[8,30]
The addition of zinc to increase the stability of
insulin lispro (as in insulin neutral protamine lispro)
resulted in a 22% decrease in Cmax and a 26%
increase in tmax, but these differences did not sub-
stantially affect the overall kinetics of the hypogly-
caemic effect.[5,31]
The pharmacokinetic characteristics of insulin
lispro are preserved when it is mixed with a longer-
acting insulin (e.g. NPH insulin) just prior to injec-
tion or when combined with insulin neutral prota-
mine lispro in stable premixed preparations.[17,18]
The more rapid absorption and elimination of
insulin lispro relative to regular human insulin is
generally maintained in patients with varying de-
grees of either renal[8] or hepatic[8,32] impairment,
although some studies have shown increased insulin
concentrations in patients with renal or hepatic fail-
ure, with an increased response to insulin as renal
function declined;[8,32] careful glucose monitoring
with insulin dose adjustment may be needed in
patients with renal or hepatic dysfunction.[8]
In vitro perfusion studies have demonstrated that
insulin lispro at concentrations of 100 or 200 μU/mL
(mimicking peak plasma concentrations following
doses of about 13U and 26U) does not cross the
human placenta, but small concentration-dependent
transfers occurred at concentrations ≥580 μU/
mL.[33,34]
The volume of distribution for insulin lispro is
identical to that for human regular insulin (0.26–
0.36 L/kg).[8]
The metabolism of insulin lispro has not been
studied in humans, but animal studies indicate that
the metabolism of insulin lispro is identical to that of
regular human insulin.[8] The systemic clearance of
subcutaneous insulin lispro is similar to that of
© 2007 Adis Data Information BV. All rights reserved.
413
human regular insulin (0.72 vs 0.75 L/h/kg follow-
ing a 10U dose in healthy volunteers), while the
mean residence time (101 vs 235 minutes) and elim-
ination half-life after subcutaneous administration
(60 vs 90 minutes) are significantly shorter.[5,8,31]
4. Therapeutic Efficacy
The efficacy of insulin lispro has been investigat-
ed in numerous trials in patients diagnosed with type
1 or 2 diabetes according to the WHO[35] or Ameri-
can Diabetes Association criteria.[36] Because of the
volume of clinical data on insulin lispro, only fully
published trials, with the exception of three recent
studies available only as abstracts,[37-39] with a speci-
fied minimum total number of patients (see subsec-
tions for details) have been included in this review.
In the clinical trials reviewed, intensive premeal
administration of insulin lispro (two or three times
daily before meals) was accompanied by basal insu-
lin administration. No basal insulin was adminis-
tered when insulin lispro was administered as a
continuous subcutaneous insulin infusion (CSII).
Target blood glucose levels for the determination of
insulin dosage adjustment, where stated, were
slightly different between trials, but similar for the
treatment groups in each trial, and were typically
fasting or preprandial levels <7–8 mmol/L and post-
prandial levels <10 mmol/L. Hypoglycaemia was
defined as signs or symptoms of hypoglycaemia
with or without a blood glucose level of typically <3
or <3.5 mmol/L (more or less stringent limits [<2 or
<3.9 mmol/L] in a few trials), with severe episodes
generally being defined as those for which the pa-
tients needed assistance.
Because of the obvious problem that blinding
presents when specified premeal insulin administra-
tion times are different, all but one trial[40] (section
4.1.1) were non-blind. Analyses were based on the
intent-to-treat patient population, unless otherwise
specified.
Primary study endpoints were not always report-
ed, but included standard measures of glycaemic
control: HbA1c levels, postprandial blood glucose
levels and the frequency of hypoglycaemic epi-
sodes. HbA1c values were generally recorded at
Drugs 2007; 67 (3)
414
baseline and study end. The blood glucose profile
was derived from the mean values of the multipoint
blood glucose levels taken on specified days before
study visits during the trial, but, where specified, the
mean levels following a test meal were reported.
Because hypoglycaemia is a reflection of glycaemic
control and is also classified as an adverse event,
this parameter is discussed both in this section and in
section 5.1.
Duration of diabetes was generally 11–17 years
in patients with type 1 diabetes and 7–16 years for
patients with type 2 diabetes (except in one trial in
patients with early type 2 diabetes, in which it was 4
years[41]). Participants were generally insulin exper-
ienced, but some participants in trials in type 2
diabetes were insulin naive. Unless stated otherwise,
all insulins were administered subcutaneously and
all reported values are means.
4.1 Insulin Lispro
4.1.1 In Type 1 Diabetes Mellitus
Clinical data for the efficacy of subcutaneous
insulin lispro compared with regular human insulin
as premeal intensive therapy for patients with
type 1 diabetes is based on several randomised,
multicentre trials ranging in duration from 3–12
months.[25,40,42-48] Only studies including ≥85 pa-
tients are discussed here.
Trials generally only enrolled insulin-exper-
ienced patients ≥18 years of age, but two trials[42,43]
also included adolescents (aged ≥12 years). Mean
baseline HbA1c values overall or per treatment
group were typically 6.4– 8.7% (or unspecified[40]);
in two trials,[40,46] patients with a baseline HbA1c
level ≥1.5 times the upper limit of normal (ULN;
which was defined as 6.1%[46] or 6.3%[40]) were
excluded. All trials had a run-in period of 2–6
weeks.
As only two in three patients have been observed
to adhere to the longer interval required between
injections of regular human insulin and meals, the
double-blind trial[40] enrolled patients that injected
their regular human insulin within 15 minutes of a
meal on >50% of occasions. Once randomised, pa-
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
tients were instructed to inject insulin lispro or regu-
lar human insulin ‘shortly before meals’.[40]
In all trials, premeal bolus insulin lispro or regu-
lar human insulin was complemented with a basal
insulin regimen (NPH or ultralente insulin). See
table I for further trial design details.
Insulin lispro was generally associated with sig-
nificantly lower 2-hour postprandial blood glucose
levels than regular human insulin in terms of both
overall values[25,42] and values obtained after each of
two or more meals[40,44-48] (table I).
Mean overall 2-hour postprandial blood glucose
levels were significantly decreased with insulin lis-
pro in the largest[42] and one other trial,[25] and were
also significantly lower with insulin lispro after two
or more meals (breakfast and lunch,[40,45] breakfast
and evening meal (supper)[44,48] or after all three
meals[46,47]) in other trials (table I). Patients using
insulin lispro had overall mean 2-hour postprandial
blood glucose excursions (difference in blood glu-
cose levels before and after meals)[25,42,43] or mean
values for two or more meals[40,46,48] that were sig-
nificantly less than patients using regular human
insulin (table I). In most trials, there were negative
excursions (overall mean or 2-hour postprandial ex-
cursions for one or more meals) with insulin lispro
(table I).
Where reported,[40,45,48] bedtime blood glucose
levels were generally not significantly different be-
tween treatment groups. Values with insulin lispro
were similar to those with regular human insulin in
two studies,[40,48] but were with significantly higher
with insulin lispro in another (8.1 vs 7.5 mmol/L;
p = 0.03).[45]
The majority of fasting blood glucose level val-
ues were similar between treatment groups (table I).
However, in one trial, the overall mean (not shown
in table), as well as mean individual preprandial
values, were significantly higher with insulin lispro
than with regular human insulin[40] (table I) and, in
another, the presupper values were higher with insu-
lin lispro (8.7 vs 7.5 mmol/L; p < 0.01).[46]
The long-term glycaemic control (HbA1c values)
achieved with insulin lispro was similar to that
achieved with human regular insulin, although small
Drugs 2007; 67 (3)
Insulin Lispro: A Review 415

Table I. Efficacy of subcutaneous insulin lispro (LP) compared with regular human insulin (HI) in adult[25,40,44-48] or adult and adolescent[42,43]
patients (pts) with type 1 diabetes mellitus. Results of fully published, randomised, non-blinded[25,42-48] or double-blinded,[40] cross-
over[25,40,42,44-46,48] or parallel-group,[43,47] multicentre trials that enrolled ≥85 pts (mean age 31–39y). Mean values reported, unless otherwise
specified
Reference (study No. of Regimena HbA1c Premeal BG 2h pp BG 2h pp BG excursion Rate of
duration [mo]) ITT pts (%) (before TM, (after TM or B/L/S) (after TM or B/L/S) hypo-
or B/L/S) [mmol/L] [mmol/L] glycaemiab
[mmol/L]
Anderson et al.[42] [3+3] 1008 LP 8.2 11.6 11.2*** –0.4*** 6.4***
1008 HI 8.2 11.3 12.9 1.6 7.2
Anderson et al.[43] [12] 162 LP 8.1* 11.1c 12.2 1.1** 4.4
174 HI 8.3 10.3c 13.0 2.7 4.5
Annuzzi et al.[44] [3+3] 85 LP 8.1* 10.1/8.2/9.7c 8.3*/8.3/8.1** 256
85 HI 8.3 10.2/7.7/9.2c 9.3/9.1/9.3 204
Gale[40] [3+3] 93 LP 7.5 9.1/7.6/9.1 8.3**/7.4***/9.1 –0.9***/–0.1***/0.2** 2.6
93 HI 7.4 8.4*/7.2*/7.9** 9.3/8.8/9.4 0.9/1.6/1.4 3.1
Heller et al.[45] d [4+4] 135 LP 6.0 (6.4) 8.5/6.1/6.8c 7.4*/6.6*/7.2c 775* (883)
135 HI 6.2 (6.4) 7.5/6.5/6.8c 8.5/7.2/7.3c 1156 (702)
Holleman et al.[46] [3+3] 199 LP 7.6 9.3/7.2/8.7 7.7***/7.5***/7.7*** –1.5***/0.3***/–1.0*** 2249
199 HI 7.5 8.9/7.3/7.5** 9.7/8.6/8.9 0.8/1.3/1.3 2344
Pfützner et al.[25] [3+3] 107 LP 7.3 9.8 9.0*** –0.9c 8.6**
107 HI 7.3 10.2 11.0 0.8***c 9.6
Valle et al.[47] [3] 586 LP 8.1 8.2***/8.4**/9.4*** 1.8
598 HI 8.2 9.4/9.0/10.7 1.8
Vignati et al.[48] [2+2] 379 LP 7.9 8.3/6.7/9.0 8.6***/10.1/8.6** –0.1***/3.7/–0.7** 4.6
379 HI 7.8 8.0/6.4/8.8 9.8/9.9/9.6 1.5/3.2/0.6 4.5
a Insulin was administered three times daily before meals, except twice daily (before breakfast and supper) in one trial[48] and not
specified in another.[25] Apart from the double-blind trial, in which LP or HI was administered ‘shortly before’ meals,[40] LP was
administered immediately before meals and HI was administered at intervals before meals of 30 min,[45-47] 30–45 min[42-44] or ‘as
usual for each patient’.[48] Treatment regimens also included once- or twice-daily basal insulin therapy.
b Expressed as the no. of episodes per pt per month[40,43,47,48] or per study period,[42] no. of episodes per month[25] or total no. of
episodes during the study period(s).[44-46]
c Values estimated from a graph.
d Given the presence of a period effect, period 1 results are reported, with period 2 results in parenthesis.
B = breakfast; BG = blood glucose; HbA1c= glycosylated haemoglobin; ITT = intent-to-treat; L = lunch; pp = postprandial; S = supper; TM =
test meal (B); * p < 0.05, ** p < 0.01, *** p ≤ 0.001 vs comparator(s).

but statistically significant reductions in HbA1c val-
ues for insulin lispro recipients relative to human
regular insulin recipients were shown in two tri-
als[43,44] (table I).
The risk of hypoglycaemia was similar
to[40,43,44,46-48] or significantly less than[25,42,45] that
seen with regular human insulin (table I). There was
also a significantly (p < 0.01) lower rate of nocturnal
(midnight to 6am) hypoglycaemic episodes with
insulin lispro than with regular human insulin in
several trials (0.7 vs 1.8 episodes per month,[40] 52
vs 181 episodes in the first treatment period,[45] 176
vs 312 episodes during the study period[46] and 1.25
vs 2.25 episodes per patient over the study period
[values estimated from a graph]).[42] In two trials,
these improvements were accompanied by a signifi-
cantly greater fasting blood glucose level (table I)[40]
or a significantly increased number of hypogly-
caemic episodes between 6am and 12 noon (783 vs
612 episodes during the study period; p = 0.015).[46]
The incidence of severe episodes of hypoglycaemia
was significantly less in patients using insulin lispro
than in those using regular human insulin in two
studies (36 vs 58 episodes during the study period
[p = 0.04][46] and 13.8% vs 18.7% [as a percentage
of the total number of episodes; p < 0.001][47]) but

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
416
was similar between treatment groups in the other
trials (or too infrequent for a significant difference
to show[45]).
4.1.2 In Type 2 Diabetes
In Patients With Early Disease
A randomised, non-blinded, parallel-group,
study compared insulin lispro with glibenclamide
(glyburide) in patients with early type 2 diabetes (a
C-peptide response of ≥0.4 nmol/L after 1mg intra-
venous glucagon).[41] Participants who had an
HbA1c value <1.7 times the ULN (baseline value
7.5–7.7%) and who were not using insulin were
randomised to lispro three times daily (n = 75) or
oral glibenclamide 5–10 mg/day (n = 68) for 6
months.
As expected, insulin lispro prompted a signifi-
cantly greater reduction from baseline in mean over-
all 2-hour postprandial blood glucose excursions
than oral glibenclamide (–0.3 vs –1.0 mmol/L;
p = 0.013).[41] However, long-term HbA1c values
(7.4% vs 7.6%) and the proportion of patients re-
porting hypoglycaemic episodes (6.5% vs 13.8%)
did not differ significantly between treatment
groups.[41]
In Patients With Secondary Oral
Antihyperglycaemic Agent Failure
The efficacy of insulin lispro with[49-52] or with-
out[53] oral antihyperglycaemic agents has been in-
vestigated in patients with type 2 diabetes and sec-
ondary oral antihyperglycaemic agent failure.
Randomised trials of 2–6 months’ duration[49-53] in
≥60 patients are discussed (see table II for trial
design details). Baseline HbA1c values were 9–11%.
In patients with type 2 diabetes and secondary
oral treatment failure who were switched to insulin
lispro or regular human insulin,[53] postprandial glu-
cose profiles significantly improved from baseline
with both insulins, but 2-hour postprandial blood
glucose levels with insulin lispro were significantly
reduced relative to regular human insulin (table II).
HbA1c values and the rate of hypoglycaemia were
similar with the two insulins (table II), as were
premeal blood glucose values.[53]
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
The addition of insulin lispro to an oral antihy-
perglycaemic or NPH insulin regimen was effective
at improving or regaining blood glucose control
(reducing postprandial blood glucose and HbA1c
values; table II). At study end, HbA1c levels were
significantly lower with insulin lispro plus gliben-
clamide than with NPH insulin plus gliben-
clamide[50,51] or metformin plus glibenclamide[51]
(table II). In addition, insulin lispro plus NPH insu-
lin was associated with significantly lower HbA1c
levels than insulin lispro plus metformin or regular
human insulin plus NPH insulin,[49] and insulin lis-
pro plus metformin was associated with significant-
ly lower HbA1c levels than glimepiride plus
metformin or human insulin 30/70 plus NPH insulin
at bedtime[52] (table II). The reduction from baseline
in HbA1c values was significantly greater with insu-
lin lispro plus glibenclamide than with NPH insulin
plus glibenclamide in one trial (–1.6% vs –1.2%;
p = 0.003),[50] but not in another trial.[51]
Insulin lispro combined with metformin, gliben-
clamide or NPH insulin also reduced postprandial
blood glucose levels relative to regimens that in-
cluded regular human insulin, or metformin plus
glibenclamide or an oral antihyperglycaemic agent
with NPH insulin[49-51] (table II). Bedtime blood
glucose levels were significantly (p < 0.001) lower
with insulin lispro plus metformin or NPH insulin
than with regular human plus NPH insulin (8.03 and
9.21 vs 10.23 mmol/L), and significantly (p = 0.007)
lower with insulin lispro plus metformin than with
insulin lispro plus NPH insulin (8.03 vs 10.23
mmol/L).[49] There were no consistent trends among
treatment groups with regard to fasting blood glu-
cose levels (table II).
The incidence of hypoglycaemic episodes was
similar among treatment groups,[50,51] except in the
smallest study in which the overall incidence was
very low in the regular human insulin plus NPH
insulin group[49] (table II).
In trials that reported on changes in body-
weight,[50,51] there was a predictably lower weight
gain in patients receiving metformin plus gliben-
clamide than in comparator groups in one trial.[51] In
the other trial,[50] there was a significantly greater
Drugs 2007; 67 (3)
Insulin Lispro: A Review 417

Table II. Efficacy of subcutaneous insulin lispro (LP) in adult patients (pts) with type 2 diabetes mellitus and secondary oral antihypergly-
caemic agent failure. Results of fully published, randomised, non-blinded, parallel-group, multicentre trials that enrolled ≥60 adult pts (mean
age 54–64y). Mean values reported, unless otherwise specified
Study; No. of Regimen (mg)a HbA1c Fasting or premeal BG 2h pp BG (overall or after Rate of Weight gain
duration [mo] ITT pts (%) (overall or before B/L/S) B/S or B/L/S) [mmol/L] hypo- (kg[50] or
[mmol/L] glycaemiab kg/m2[51])
Altuntas et 20 LP + MET 850 bid 7.4 9.2/7.5†††‡‡/9.0c 8.0†††/8.2††/8.4†† 0.4
al.[49] [6] 20 LP + NPH 6.7*†† 8.5*††/8.6†/9.0c 7.9†††/8.9††/9.0†† 0.6
20 HI + NPH 7.5 9.2/9.4/11.1 10.6/10.7/11.1 0.009*‡
Bastyr et al.[50] 139 LP + GLI bidd 8.4# 9.5 9.2### 1.0 1.2
[2] 149 LP + NPH 8.5 9.2 9.2### 1.2 1.5
135 NPH + GLI bidd 8.7 8.0**‡‡‡ 11.8 0.7 0.6*‡‡
Bastyr et al.[51] 41 LP + GLI 10 bid 7.7##§ 10.6 10.9§§e 1.1 3.4
[3] 40 MET 500 bid + 8.3 9.7 12.7e 0.7 0.4**###
GLI 10 bid
50 NPH + GLI 10 bid 8.5 8.5**§ 12.2e 0.6 2.3
Kokić et al.[52] 29 LP + METf 8.0§g –2.2h –4.3h
[3] 29 GLP + METf 8.5g –1.3h –1.7h
29 HI 30/70 + NPH 8.0g –0.6h –1.5h
Ross et al.[53] 70 LP bid + NPH 8.0 9.5‡/8.4‡ 1.8
[5.5] 79 HI bid + NPH bid 8.0 10.9/9.7 1.7
a LP was administered immediately before meals; HI 30–40 min before meals; NPH insulin at bedtime[49-52] or twice daily;[53] and HI
30/70 twice daily.[52] GLI, GLP and MET were administered orally.
b Expressed as the percentage of hypoglycaemic episodes,[49] mean no. of episodes per 30d[50] or mean no. of episodes per pt per
30d.[51,53]
c Presupper BG was significantly lower than with HI + NPH (p-value not reported).
d Because of different formulations of GLI in the EU and US, dosages were 10mg before breakfast and 5mg before supper (EU) or
10mg before both breakfast and supper (US).
e Blood glucose values after test meal.
f Dosage of MET and/or GLP not stated.
g HbA1c values significantly different for treatment groups at baseline; 10.0% LP + MET vs 9.21% for GLP + MET or HI 30/70 + NPH
(p < 0.05 for both comparisons).
h Mean decrease from baseline.
B = breakfast; BG = blood glucose; bid = twice daily; GLI = glibenclamide; GLP = glimepiride; HbA1c = glycosylated haemoglobin; HI =
regular human insulin; HI 30/70 = 30% HI and 70% NPH; ITT = intent-to-treat; L = lunch; MET = metformin; NPH = neutral protamine
Hagedorn insulin; pp = postprandial; S = supper; * p < 0.05, ** p < 0.001 vs LP + MET or LP + GLI; † p < 0.05, †† p ≤ 0.001, ††† p < 0.0001
vs HI + NPH; ‡ p < 0.05, ‡‡ p < 0.01, ‡‡‡ p < 0.001 vs LP + NPH; # p < 0.05, ## p < 0.01, ### p < 0.001 vs NPH + GLI; § p < 0.05, §§ p <
0.01 vs MET + GLI or MET + GLP.

gain in the insulin lispro groups than in the NPH
insulin plus glimepiride group (table II), with a
significant weight gain from baseline in all three
treatment groups (p < 0.01).[50]
In Patients Already On Insulin
The efficacy of insulin lispro relative to regular
human insulin in adults (mean age 57–59 years)
with type 2 diabetes who had been using insulin for
at least 2 months has been investigated in several
randomised trials of 4–12 months’ duration (see
table III for trial design details). Results of trials in
>100 patients are discussed. After a run-in period of
2–6 weeks, patients received insulin lispro or regu-
lar human insulin administered with a longer-acting
insulin.[43,48,54] Baseline HbA1c values were
7.9–8.9%.
Postprandial glucose profiles significantly im-
proved from baseline with intensive premeal admin-
istration of either insulin lispro or regular human
insulin in patients with type 2 diabetes,[43,53] but
2-hour postprandial blood glucose levels[54] and/or
2-hour postprandial blood glucose excursions[43,54]
with insulin lispro were significantly reduced rela-

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
418 Simpson et al.

Table III. Efficacy of subcutaneous insulin lispro (LP) compared with regular human insulin (HI) in patients (pts) with type 2 diabetes
mellitus.[43,48,54] Results of fully published, randomised, non-blinded, crossover[48,54] or parallel-group,[43] multicentre trials that enrolled >100
pts (mean age 57–59y). Mean values reported, unless otherwise specified
Study; No. of Regimena HbA1c (%) Fasting or 2h pp BG 2h pp BG excursion Rate of
duration [mo] ITT pts premeal BG (after TM or B/L/S) (after TM or B/L/S) hypoglycaemiab
(before TM [mmol/L] [mmol/L]
or B/L/S)
[mmol/L]
Anderson et al.[54] 722 LP tid 8.2 10.7 12.1 1.4*** 3.2*
[3+3] 722 HI tid 8.2 10.2* 13.1 3.0 3.4
Anderson et al.[43] [12] 145 LP tid 8.2 10.4 11.9 1.4**c 1.5
150 HI tid 8.4 10.2 12.9 2.6c 1.6
Vignati et al.[48] [2+2] 328 LP bid 8.1. 8.8/7.5/9.5 9.5***/10.3/9.7 0.7***/2.9/0.2 1.9
328 HI bid 8.1 8.5/7.6/9.3 10.4/10.0/10.1 1.9/2.5**/0.9 1.9
a Premeal administration intervals for insulins were: LP immediately before meals and HI 30–45 min[43,54] or ‘as usual’[48] before
meals. Basal insulin was administered once or twice daily according to the metabolic needs of the pt.[43,48,54]
b Expressed as the no. of episodes per pt per month.
c Values estimated from a graph.
B = breakfast; BG = blood glucose; bid = twice daily; HbA1c = glycosylated haemoglobin; ITT = intent-to-treat; L = lunch; pp = postprandial;
S = supper; tid = three times daily; TM = test meal (B); * p < 0.05, ** p < 0.01, *** p < 0.001 vs comparator.

tive to regular human insulin (table III). HbA1c
values were similar with the two insulins, as were
premeal blood glucose values, except in the largest
trial in which the fasting blood glucose was signifi-
cantly higher with insulin lispro than with regular
human insulin[54] (table III).
The largest trial[54] showed a significantly lower
rate of hypoglycaemia in the insulin lispro group
than in the regular human insulin group. Moreover,
the incidence of hypoglycaemic episodes between
midnight and 6am in this trial[54] was 36% lower in
insulin lispro recipients than in regular human insu-
lin recipients (0.47 vs 0.73 episodes per patient per
month; p < 0.001). In the other trials, there tended to
be a numerically lower incidence of hypoglycaemic
episodes at study endpoint than at baseline in both
insulin lispro and regular human insulin treatment
groups;[43,48,54] however, the mean incidence of hy-
poglycaemic episodes at study endpoint was similar
for both therapies (table III). In one trial,[43] the
incidence of hypoglycaemic episodes over 12
months decreased 33% from baseline in both treat-
ment groups.
4.2 Insulin Lispro Mixtures
4.2.1 In Type 1 Diabetes
Randomised, crossover trials[55-57] have investi-
gated the efficacy of insulin lispro premixtures in
patients with type 1 diabetes (see table IV for trial
design details). Only studies in >70 patients are
reviewed. In one study,[56] some patients received
insulin lispro Mix75 (75% insulin lispro and 25%
insulin neutral protamine lispro), which is not com-
mercially available. Patients received insulin lispro
or regular human insulin, plus NPH insulin, or
human insulin 30/70 or 50/50 (50% regular human
insulin and 50% NPH insulin) during the 4–12 week
run-in periods. Patients had HbA1c values <9.2% at
enrolment[57] or mean values of 7.9–8.1%.[55,56]
Intensive premeal treatment with premixed insu-
lin lispro achieved overall glycaemic control
(HbA1c values) that were similar to those with pre-
mixed human insulin[57] insulin lispro self-mixed
with NPH insulin[56] and with a premeal regimen of
regular human insulin alone[55] (table IV).
Postprandial blood glucose levels with premixed
insulin lispro were similar to those with insulin
lispro self-mixed with NPH insulin,[56] human insu-
lin (except insulin lispro Mix25 plus Mix50 gave a
lower postbreakfast blood glucose level)[57] or regu-

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
Insulin Lispro: A Review 419

Table IV. Efficacy of subcutaneous premixed insulin lispro (LP) and insulin neutral protamine lispro (NPL) in patients (pts) with type 1
diabetes mellitus. Results of fully published, randomised, non-blinded, crossover, multicentre trials that enrolled >70 adult pts (mean age
31–42y). Mean values reported, unless otherwise specified
Study; No. of ITT pts Regimena HbA1c (%) 2h pp BG (after B/ Rate of
duration [mo] L/S) [mmol/L] hypoglycaemiab
Herz et al.[55] [3+3] 109 LP Mix50 8.1 10.2/9.3/8.4*c 6.0/2.9
109 HI 8.2 10.1/8.8/9.6c 6.1/2.8
Roach et al.[56]d [2+2] 89 LP Mix75 or LP Mix50e 7.8 8.8/8.6/9.1 2.9
89 LP + NPH (self-mixed) 7.9 9.1/8.6/8.8 2.1*
Roach et al.[57] [3+3] 37 LP Mix50 + LP Mix25f 7.7 6.9**/9.9/9.7 1.5
37 HI 50/50 + HI 30/70f 7.4 9.1/9.5/9.5 2.9
a Regimens were administered two[57] or three[55,56] times daily. Administration was during the following premeal intervals: LP mixtures
0–5 min[55,57] or not specified;[56] HI 30 min[55] and HI mixtures 30–45 min.[57] All pts, except those in one study,[57] received a
bedtime dose of NPH.
b Expressed as the no. of episodes per pt per month,[56] no. of nocturnal episodes per pt per study period[57] or no. of episodes per pt
(daytime/night-time).[55]
c Some values estimated from a graph.
d Trial was primarily designed to investigate the noninferiority of premixed LP relative to self-mixed LP and NPH insulin for blood
glucose levels in the late postprandial period. Noninferiority was shown, as the one-sided 95% confidence interval for the between-
group difference in the average of prelunch, predinner and bedtime BG levels was 0.53 mmol/L, which was less than the predefined
limit of 0.75 mmol/L.
e LP Mix75 before each meal (n = 19), or LP Mix50 before breakfast (n = 22) or lunch (n = 47) with LP Mix75 before the other two
meals. LP Mix75 is not commercially available.
f 50/50 mixtures before breakfast and 25/75 or 30/70 mixtures before supper.
B = breakfast; BG = blood glucose; HbA1c = glycosylated haemoglobin; HI = regular human insulin; HI 30/70 = 30% HI and 70% NPH;
HI 50/50 = 50% HI and 50% NPH; ITT = intent-to-treat; L = lunch; LP Mix25 = 25% LP and 75% NPL; LP Mix50 = 50% LP and 50% NPL;
LP Mix75 = 75% LP and 25% NPL; NPH = neutral protamine Hagedorn insulin; pp = postprandial; S = supper; * p < 0.05, ** p ≤ 0.001 vs
comparator.

lar human insulin regimens (except insulin lispro
Mix50 gave a lower postsupper blood glucose lev-
el)[55] [table IV]. Premeal and bedtime blood glucose
levels were similar among treatment groups.[55,56]
Moreover, premixed insulin lispro was considered
noninferior to insulin lispro self-mixed with NPH
insulin, as assessed by mean late postprandial blood
glucose levels.[56]
The frequency of hypoglycaemic episodes was
variable among groups (table IV), with the rate
being similar for premixed insulin lispro and pre-
mixed human insulin,[57] but significantly higher in
patients using insulin lispro Mix75 or Mix50 than in
those using self-mixed insulin lispro and NPH.[56]
Rates were similar for premixed insulin lispro and
regular human insulin.[55]
4.2.2 In Type 2 Diabetes
Several randomised studies have investigated the
effect of insulin lispro Mix25 or Mix50 on gly-
caemic control relative to that of oral gliben-
clamide[58-60] or other insulin regimens[38,61-64] in pa-
tients with type 2 diabetes. See table V for design
details of these trials. In additional crossover trials,
the effect of insulin lispro Mix25 on glycaemic
excursion was compared with that of NPH insu-
lin,[37] and the efficacy of insulin lispro Mix25 twice
daily was compared with that of insulin lispro
Mix50 before breakfast plus insulin lispro Mix25
before supper.[65] Previous to randomisation, pa-
tients were inadequately controlled on oral an-
tihyperglycaemic agents,[58-60] or had been treated
with oral antihyperglycaemic medications with or
without insulin,[38] insulin[37,61-63,65] or diet and/or
oral antihyperglycaemic agents.[64] Only studies
that randomised >70 patients are discussed. Where
stated, the run-in periods were 10 days to 6
weeks[38,58-62,64,65] and baseline HbA1c values were
7.8–8.9%[37,38,61,63,64] or ≈10%.[58-60]
As is typical with other insulin regimens in pa-
tients with type 2 diabetes that had previously been
inadequately controlled with a sulfonylurea, gly-

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
420 Simpson et al.

Table V. Efficacy of subcutaneous premixed insulin lispro (LP) and insulin neutral protamine lispro (NPL) in patients (pts) with type 2
diabetes mellitus. Results of non-blinded,[38,58-64], crossover[61-63] or parallel-group,[38,58-60,64] multicentre studies that randomised >70 pts
(mean age 52–60y,[60-64] 68y[58,59] or not stated[38]). Mean values reported, unless otherwise specified
Study; No. of Regimen HbA1c (%) 90 min[61] or Change from baseline Rate of
duration [mo] ITT pts 2h[38,58-60,62,63] pp BG in overall 2h pp BG hypoglycaemiaa
(after B/S or B/L/S) excursion [mmol/L]
[mmol/L]
Compared with oral glibenclamide (GLI) in pts inadequately controlled on sulfonylurea agentsb
Galic et al.[58] [4] 37 LP Mix25 –1.4**c 10.3***/10.6* 0.06
35 GLI –0.6c 13.3/12.3 0.01
Herz et al.[59] [4] 71 LP Mix25 8.6*** 9.7***/10.1*** 0.31
72 GLI 9.4 13.1/12.6 0.01*
Roach et al.[60] [4] 85 LP Mix25 8.5***d 10.4***d/10.7***d 0.3d
87 GLI 9.4d 13.0d/13.0d 0.05***d

Compared with other insulin regimense

Kazda et al.[64] [24] 54 LP Mix50 tid –1.1†c –1.8†d 44
52 LP tid –1.2†c –2.1†d 54
53 GLA bedtime –0.3c –0.1d 32
Malone et al.[63] 97 LP Mix25 bid + 7.5***d 9.4***/9.1***/9.6***d 0.61d,g
METf
[16+16] 97 GLA bedtime + 8.1d 10.8/10.6/11.1d 0.44d
METf
Niskanen et al.[61] 132 LP Mix25 bid 8.0h 9.7/9.8/10.0 0.62
[12+12] 132 ASP Mix30 bid 8.1d 9.5/9.7/9.6 0.69
Roach et al.[62] 89 LP Mix25 bid 7.8 8.9*/9.3* 0
[12+12] 89 HI 30/70 bid 8.1 10.0/10.3 0
Robbins et al.[38] i 157 LP Mix50 tid + 7.1*** 8.7*/8.4***/8.7*** –1.0*** 0.7*
METf
[24] 158 GLA bedtime + 7.5 9.2/9.8/10.7 0.6 0.3
METf
a Expressed as the proportion of pts experiencing ≥1 episode during the 24wk treatment period,[64] mean[38,59,60,63] or median[62] no. of
episodes per pt per 30d, change from baseline in the no. of episodes per pt per 30d,[58] or no. of episodes per mo during the last
8wk of a 12wk treatment period.[61]
b LP Mix25 was administered twice daily and GLI (nonmicronised formulation) was administered before breakfast (10mg) and before
dinner (5mg).
c Change from baseline.
d Primary or co-primary endpoint.
e Where stated, LP, LP mixtures and ASP Mix30 were administered immediately before meals;[61,62,64] and HI mixtures were
administered premeal at a median of 28 min.[62]
f MET dose 1500–2550[63] or 1000–2000[38] mg/d.
g LP + MET group reported a lower rate of nocturnal hypoglycaemic episodes than GLA + MET (0.14 vs 0.34 episodes per pt per
30d; p = 0.002), but a higher rate of daytime episodes (0.46 vs 0.10 episodes per pt per 30d; p = 0.003).
h Primary endpoint was HbA1c value at 12wk. ASP Mix30 was considered noninferior to LP Mix25, as the upper limit of the 90%
confidence interval for a between-group difference in HbA1c values was 0.275, which was less than the predefined limit (0.4) for a
between-group difference.
i Available as an abstract.
ASP Mix30 = 30% insulin aspart and 70% insulin protamine aspart; B = breakfast; BG = blood glucose; bid = twice daily; GLA = insulin
glargine; HbA1c = glycosylated haemoglobin; HI = regular human insulin; HI 30/70 = 30% HI and 70% NPH; ITT = intent-to-treat; L = lunch;
LP Mix25 = 25% LP and 75% NPL; LP Mix50 = 50% LP and 50% NPL; MET = metformin; NPH = neutral protamine Hagedorn insulin; pp =
postprandial; S = supper; tid = three times daily; * p < 0.05, ** p < 0.01, *** p ≤ 0.001 vs comparator; † p ≤ 0.001 vs GLA.

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
Insulin Lispro: A Review
caemic control with the insulin lispro Mix25 was
significantly better than with oral gliben-
clamide,[58-60] including in trials in elderly patients
(aged 60–80 years).[58,59] HbA1c values and post-
prandial blood glucose levels were significantly
lower with insulin lispro Mix25 than with gliben-
clamide (table V) and prebreakfast blood glucose
levels were also significantly lower (8.2–9.5 vs
9.8–10.5 mmol/L; p < 0.05).[58-60] The rate of hypog-
lycaemic episodes was significantly higher with the
insulin lispro mixture than with glibenclamide in
two trials (table V).[59,60]
In the trials in elderly patients,[58,59] the timing of
the insulin administration (pre- or postmeal) made
no significant difference to glycaemic control
(HbA1c value and postprandial blood glucose val-
ues).[58,59]
Insulin lispro Mix25 is a favourable alternative to
human insulin 30/70 in patients with type 2 diabetes;
postprandial blood glucose levels were lower in
patients receiving premixed insulin lispro than in
patients receiving the human insulin mixture, al-
though the HbA1c values achieved were similar for
both mixtures (table V).[62]
Glycaemic control (postprandial blood glucose
and HbA1c levels) and the rate of hypoglycaemia
with insulin lispro Mix25 was similar to that of
insulin aspart Mix30 (insulin aspart 30% and insulin
protamine aspart 70%) [table V];[61] insulin aspart
Mix30 was considered to be noninferior to insulin
lispro Mix25 as the upper limit of the 90% confi-
dence interval (CI) for the between-group difference
in HbA1c values was 0.275, thus meeting the criteria
for noninferiority (i.e. upper 90% CI limit <0.4).
Premeal blood glucose levels were similar with both
treatments.[61]
Premeal insulin lispro,[64] insulin lispro Mix50[64]
or insulin lispro Mix25[63] or Mix50[38] plus
metformin was associated with significantly lower
postprandial blood glucose levels[38,63] and/or glu-
cose excursions,[38,64] and significantly better HbA1c
values[38,63,64]) than insulin glargine (a long-acting
insulin) at bedtime (with[38,63] or without[64]
metformin) [table V]. Premixed insulin lispro[38,63,64]
and insulin lispro alone[64] were associated with
© 2007 Adis Data Information BV. All rights reserved.
421
significantly higher fasting blood glucose
levels[38,63] or significantly smaller reductions in
fasting blood glucose levels[64] than insulin glargine.
The blood glucose profile improvements with
insulin lispro Mix25 or Mix50 were not associated
with an increase in the rate of hypoglycaemic epi-
sodes (table V).
In preliminary results from a 26-week crossover
study in 191 patients,[37] mean total glucose excur-
sions were understandably lower with premeal insu-
lin lispro Mix25 than with twice-daily NPH insulin
(0.25 vs 1.0 mmol/L; p = 0.004).
In the 16-week crossover trial comparing insulin
lispro Mix50 before breakfast plus insulin lispro
Mix25 before supper with insulin lispro Mix25
twice daily (n = 116),[65] insulin lispro Mix50 before
a carbohydrate-rich breakfast was associated with
significantly (p ≤ 0.001) better postprandial gly-
caemic control than insulin lispro Mix25 (postpran-
dial blood glucose 10.9 vs 12.4 mmol/L; 2-hour
postprandial blood excursion 1.4 vs 3.5 mmol/L).
There were no significant between-group differ-
ences in HbA1c values (both 8.1%) or the incidence
of hypoglycaemic episodes in the first 8-week treat-
ment phase (32% vs 26%).[65]
4.3 Continuous Subcutaneous Infusion of
Insulin Lispro
The efficacy of insulin lispro as a CSII via an
external pump has been compared with that of a
regimen of multiple daily injections (insulin lispro
before meals and NPH insulin as basal insulin[67])
and of CSIIs of regular human insulin[66,68] or insulin
aspart[66] in randomised trials in patients with type 1
diabetes. In a trial in elderly patients with type 2
diabetes,[69] the efficacy of insulin lispro CSII was
also compared with a multiple daily injection regi-
men (premeal insulin lispro with glargine as basal
insulin). Patients had received prior treatment with
insulin for ≥1,[69] ≥3[66] or ≥6 months.[67,68] Trials
were preceded by run-in periods of 1–8 weeks.[66-69]
See table VI for further trial design details. Patients
had baseline HbA1c levels of or 7.2–7.5%[66,68] or
8.1–8.4%.[67,69] The use of CSII of insulin lispro for
Drugs 2007; 67 (3)
422 Simpson et al.

Table VI. Efficacy of a continuous subcutaneous insulin infusion (CSII) of insulin lispro (LP) in patients (pts) with type 1 diabetes
mellitus[66-68] or elderly pts (age ≥60y) with type 2 diabetes.[69] Results of fully-published, randomised, non-blinded, parallel-group[66,69] or
crossover,[67,68] multicentre trials that enrolled >100 pts. Mean pt age was 35–43y [66-68] or 66–67y. Mean values reported, unless otherwise
specified
Study; No. of ITT pts Regimena HbA1c (%) 1h,[67] 90 min[66] or 2h[68] pp BG Rate of
duration [mo] (after B/L/S) [mmol/L] hypoglycaemiab
In type 1 diabetes
Bode et al.[66] [4] 28 LP CSII 7.12 9.0/9.5/9.2c 4.4
59 ASP CSII 7.3 9.0/9.5/7.6*c 3.7
58 HI CSII 7.35 10.5/10.7/9.4c 4.8
Hoogma et al.[67] [6+6] 256 LP CSII 7.45** 8.8/8.7/8.0c,d 49.3**
256 LP + NPH (MDI) 7.67 9.7/8.7/8.5c 55.4
Renner et al.[68] [4+4] 113 LP CSII 6.77* 7.0**/7.6**/7.2** 12.4
113 HI CSII 6.90 8.6/8.7/8.3 11.0

In elderly pts with type 2 diabetes

Herman et al.[69] [12] 53 LP CSII 6.6 81
54 LP + GLA (MDI) 6.4 90
a LP (as part of multiple daily injection regimen and as bolus doses via CSII pump) and ASP were administered immediately before
meals; HI was administered 30 min before meals; NPH insulin was administered at least once daily; and GLA was administered at
bedtime.
b Expressed as the average no. of episodes per pt for the two 4mo study periods,[68] mean no. of hypoglycaemic events per pt
year[67] or percentage of pts experiencing ≥1 episode[69] or mean no. of episodes per pt per 30d.[66]
c Values estimated from a graph.
d Mean daily BG 8.6 vs 9.4 mmol/L with LP + NPH MDI (p < 0.001).
ASP = insulin aspart; ;BG = blood glucose; GLA = insulin glargine; HbA1c = glycosylated haemoglobin; HI = regular human insulin; ITT =
intent-to-treat; MDI = multiple daily injections; NPH = neutral protamine Hagedorn insulin; pp = postprandial; * p < 0.05, ** p ≤ 0.001 vs
comparator(s).

the treatment of children and adolescents with type 1
diabetes is discussed in section 4.4.1
CSII of insulin lispro achieved similar[69] or bet-
[67]
ter glycaemic control than a regimen of multiple
daily injections of insulin lispro and a basal insulin
(table VI).
In patients with type 1 diabetes, CSII of insulin
lispro achieved a lower HbA1c value than multiple
daily injections of insulin lispro and NPH insulin at
a significantly reduced (p < 0.001) total insulin
dose.[67] Although postprandial blood glucose levels
were similar with the two regimens, the mean daily
blood glucose was significantly lower with insulin
lispro as a CSII than as multiple daily injections
(table VI). There was also a significantly lower rate
of hypoglycaemia (table VI) [including severe epi-
sodes, 0.2 vs 0.5 events per patient year; p < 0.001]
with CSII of insulin lispro.[67]
When delivered as a CSII in patients with type 1
diabetes who were experienced in using the pump
system, HbA1c values achieved were similar with
insulin lispro and insulin aspart, with similar post-
prandial blood glucose levels except for the postsup-
per level, which was significantly lower with insulin
aspart than with insulin lispro or regular human
insulin (table VI).[66] CSII of insulin lispro achieved
similar glycaemic control (HbA1c value and post-
prandial blood glucose levels) as that achieved with
CSII of regular human insulin in one study (with
unequal randomisation),[66] and significantly lower
HbA1c values than CSII of regular human insulin in
another study (table VI).[68] Rates of hypoglycaemia
were similar overall with CSII delivery of insulin
lispro, insulin aspart and regular human insulin (ta-
ble VI).
In the trial of insulin lispro as a CSII in elderly
patients with type 2 diabetes, glycaemic control,
total insulin dose and rate of hypoglycaemia with
CSII of insulin lispro were similar to those with
multiple daily injections of insulin lispro and insulin
glargine (table VI).

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
Insulin Lispro: A Review 423

Table VII. Efficacy of subcutaneous insulin lispro (LP) compared with regular human insulin (HI) in prepubertal children (aged 3–11y[70] or
5–10y[71]) and adolescents (aged 9–18y)[72] with type 1 diabetes mellitus. Results of fully published, randomised, non-blinded, crossover,
multicentre studies. Mean values reported, unless otherwise specified
Study; No. of ITT pts Regimena HbA1c (%) 2h pp BG (after B/S or B/ Rate of
duration [mo] L/S) [mmol/L] hypoglycaemiab
In children (mean age 8y)
Deeb et al.[70] [3+3+3] 60 LP (before meals) 8.4 11.7†***/8.8** 14.7
60 LP (after meals) 8.5 13.5/9.9 13.6
60 HI 8.4 15.0/10.8 13.8
Fairchild et al.[71] [3+3] 35 LP 8.3 12.1/11.7/9.7 13.5
35 HI 8.1 11.7/11.6/10.1 10.8

In adolescents (mean age 15y)

Holcombe et al.[72] [4+4] 481 LP 8.7 9.7***/8.1/8.6** 4.0*
481 HI 8.7 10.6/8.5/9.3 4.4
a LP or HI administered twice[70,71] or three times[70,72] daily before meals unless otherwise stated. LP was administered immediately
before,[71,72] 0–15 min before,[70] or immediately after[70] meals. HI was administered 30 min[71] or 30–45 min[70,72] before meals. Basal
insulin was also administered in all trials.
b Expressed as the no. of episodes per 30d,[70] no. of episodes per pt per 30d[72] or mean no. of episodes per pt per 3mo.[71]
B = breakfast; BG = blood glucose; HbA1c = glycosylated haemoglobin; ITT = intent-to-treat; L = lunch; pt(s) = patient(s); pp = postprandial;
S = supper; * p < 0.05, ** p ≤ 0.01, *** p < 0.001 vs HI; † p < 0.05 vs LP (after meals).

4.4 Insulin Lispro In Special
Patient Populations
4.4.1 Children and Adolescents
The efficacy of insulin lispro in prepubertal chil-
dren[70,71] and adolescents[72] with type 1 diabetes
who had previously been receiving insulin has been
investigated in randomised studies. The trials were
preceded by run-in periods of 1–2 months. See table
VII for further trial design details. Where stated,
baseline HbA1c values were 8.2–8.4%.[70,71] The use
of insulin lispro as a treatment for diabetic
ketoacidosis[73] or as a CSII[74-76] in young patients is
also discussed in this section.
In children and adolescents, glycaemic control
assessed by HbA1c values did not differ between
insulin lispro and regular human insulin therapy (in
conjunction with a basal insulin regimen) [table
VII]. Children receiving insulin lispro achieved
postprandial blood glucose levels similar to[71] or
significantly lower[70] than those achieved by recipi-
ents of regular human insulin, and postbreakfast
blood glucose levels were significantly lower with
insulin lispro administered before meals than after
meals.[70] Fasting or premeal blood glucose levels
were generally similar for the two treatments.[70,71]
Adolescents experienced lower postbreakfast (9.7 vs
10.6 mmol/L; p < 0.001) and postsupper (8.6 vs 9.3
mmol/L; p = 0.003) blood glucose levels with insu-
lin lispro than with regular human insulin, but both
groups had similar HbA1c values.[72]
The overall rate of hypoglycaemia in children
was similar with insulin lispro and regular human
insulin (table VII)[70,71] and, although not different
between time periods in one trial,[70] significantly
higher with insulin lispro in the time period between
6am and 12 noon in another trial (5.69 vs 3.31
episodes per patient per 3 months; p = 0.02).[71] In
adolescents,[72] the rate of hypoglycaemia was sig-
nificantly lower in patients using insulin lispro than
those using regular human insulin (table VII) [in-
cluding episodes between midnight and 6am].
Subcutaneous insulin lispro is a treatment option
for children and adolescents with diabetic
ketoacidosis. In a study of 60 episodes in children
with a mean age of 11–12 years, the condition
resolved (according to standard recovery criteria)
with either of the randomised treatments: 2-hourly
subcutaneous insulin lispro or CSII of regular
human insulin.[73] However, CSII of regular human
insulin prompted earlier recovery (within 0–6 hours)
than 2-hourly insulin lispro (within 6–12 hours).[73]

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (3)
424
CSII of insulin lispro appears to be an acceptable
treatment regimen for young diabetic patients. Fifty-
six patients (mean age 17 years; range 7–23 years),
who had used an insulin pump for CSII for at least 6
months prior to the study, achieved HbA1c values of
8.3% from a mean baseline value of 8.5% (p < 0.05)
after 6–35 months of insulin lispro as a CSII in a
noncomparative study.[74] The average number of
hypoglycaemic episodes per week decreased in 41%
of patients, increased in 18% and was stable in 30%
of patients. The number of severe episodes (patients
required assistance) per 100 patient-years decreased
from 12.3 to 9.5 (reduction not significant).[74]
CSII of insulin lispro achieved the same level of
glycaemic control as a regimen of multiple daily
injections of regular human insulin and NPH insulin
in children (aged 9–14 years) who had previously
been treated with insulin in a small randomised,
non-blinded, crossover study (n = 23; duration 3.5
months per regimen).[75] HbA1c values achieved
(8.0% vs 8.1%) and the number of hypoglycaemic
episodes experienced (20 vs 22) were similar in both
treatment groups.[75] At baseline, total insulin daily
dose was similar in both treatment groups, but de-
creased with the use of CSII and increased with the
use of multiple daily insulin injections (daily dose at
endpoint 0.84 vs 1.09 U/kg; p = 0.003).[75] Weight
gain, according to the body mass index standard
deviation score, was 0.35 versus 0.37 for CSII of
insulin lispro compared with multiple daily injec-
tions of regular human insulin and NPH insulin
(p = 0.01). Although there was no significant differ-
ence in the subscale scores on the Diabetes Quality
of Life Questionnaire for Youth (DQOLY) between
treatment groups, the DTSQ total score was signifi-
cantly better with CSII of insulin lispro than with the
multiple daily injections regimen (30.6 vs 21.9;
p < 0.001).[75]
In children aged <10 years (n = 27; mean age 4.6
years) who had previously used a CSII regimen,
CSII of insulin lispro achieved similar HbA1c values
and pre- and postprandial blood glucose levels as
CSII of regular human insulin in a randomised, non-
blinded, crossover study (two periods of 16
weeks).[76] However, midnight and 3am blood glu-
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
cose levels were significantly (p < 0.05) higher with
insulin lispro than with regular human insulin and it
was suggested that nocturnal basal insulin adminis-
tration rates be adjusted accordingly. Insulin lispro
as a CSII was the treatment of choice for 74% of
parents caring for these young patients.[76]
4.4.2 Pregnancy
Data for the use of insulin lispro in pregnant
women with diabetes (type 1 or 2 or gestational
diabetes) are available from small prospec-
tive[39,77-79] or retrospective studies.[80,81]
The hypoglycaemic efficacy of insulin lispro dur-
ing pregnancy appears to be at least similar to that of
regular human insulin. Two nonrandomised studies
(n = 69[77] and 71[78]) examined the maternal and
fetal outcomes in pregnant women with type 1 dia-
betes receiving intensive insulin therapy with insu-
lin lispro or regular human insulin. In one of the
studies,[78] there were no significant differences be-
tween treatment groups in HbA1c values or inci-
dences of hypoglycaemia. In the other study,[77]
HbA1c values were lower in the group receiving
insulin lispro (6.5% vs 7.2% [values estimated from
a graph]; p = 0.022), but the frequency of hypogly-
caemic episodes was similar between groups.[77]
Two studies retrospectively examining outcomes in
62[80] and 76[81] pregnancies in women with type 1
diabetes receiving insulin lispro, also reported im-
proved[81] or normalised[80] glycaemic control.
Insulin lispro was also at least as effective as
regular human insulin in randomised trials in pa-
tients with gestational diabetes.[39] In preliminary
data from a trial in 96 women, overall glycaemic
control with insulin lispro or insulin aspart was
similar to that with regular human insulin.[39] How-
ever, the rapid-acting insulin analogues were associ-
ated with better prandial glucose tolerance and more
proportioned fetal growth than regular human insu-
lin.[39] Similarly, in another trial in 49 women,[79]
both insulin lispro and regular human insulin thera-
pies resulted in optimal preprandial blood glucose
levels that were significantly (p < 0.01) lower than
those in the control group of 50 non-diabetic preg-
nant women, but insulin lispro therapy resulted in
significantly (p < 0.05) lower postprandial blood
Drugs 2007; 67 (3)
Insulin Lispro: A Review
glucose levels (1 hour after each meal and 2 hours
after lunch) than regular human insulin.[79]
4.4.3 Fasting Patients
In a randomised, non-blinded, crossover, mul-
ticentre study in 151 patients with type 2 diabetes
who had previously used insulin and were observing
the Ramadan fast, the efficacy of the insulin lispro
Mix25 was compared with that of human insulin 30/
70.[82] In each 14-day treatment period, insulin was
administered immediately before the morning meal
(consumed before sunrise) and evening meal (con-
sumed after sunset). The trial had a 4-week run-in
period, during which patients received human insu-
lin 30/70 before the morning and evening meal.
The evening premeal blood glucose level was
significantly lower with insulin lispro Mix25 than
with human insulin 30/70 insulin (7.1 vs 7.5 mmol/
L; p = 0.03), but the morning premeal level was
similar for both groups.[82] Postprandial blood glu-
cose levels after supper were significantly lower
with insulin lispro Mix25 than with human insulin
30/70 (10.5 vs 11,6 mmol/L; p ≤ 0.001) and, after
breakfast, were similar for both treatment groups
(11.6 vs 12.0 mmol/L). The blood glucose profile
improvements with insulin lispro Mix25 were not
associated with an increase in the rate of hypogly-
caemic episodes (0.4 episodes per patient per 14
days for both groups).[82]
4.5 Health-Related Quality of Life and
Patient Satisfaction
Health-related quality of life (HR-QOL) was a
secondary endpoint in two large crossover tri-
als,[42,54] in patients with type 1[42] or type 2[54]
diabetes (reported by Kotsanos et al.[83]), as well as
in several smaller studies.[40,46,51,59,60]
In the study that randomised 1008 patients with
type 1 diabetes to insulin lispro or regular human
insulin (table I),[42] 468 patients completed the Dia-
betes Quality of Life Clinical Trial Questionnaire
(DQLCTQ), which is composed of 142 questions
(higher score indicates better HR-QOL) covering
four primary domains (energy/fatigue, health dis-
tress, treatment flexibility and treatment satisfac-
tion) and 30 secondary domains.[83] There were no
© 2007 Adis Data Information BV. All rights reserved.
425
differences between treatment groups for the ener-
gy/fatigue or health distress domains (presumably
because there was good glycaemic control in both
groups), but treatment flexibility and treatment sat-
isfaction scores improved to a significantly
(p ≤ 0.001) greater extent with insulin lispro than
with regular human insulin (flexibility 3.1 vs 0.8 and
satisfaction 4.7 vs 0.4).[83]
In one of two[40,46] smaller crossover trials in
patients with type 1 diabetes, 144 of 199 randomised
patients chose to continue therapy with insulin lispro
rather than regular human insulin,[46] and in the
other, 42% of the participants preferred insulin lis-
pro compared with 29% who preferred regular
human insulin (the remainder stated no prefer-
ence).[40] In one study,[46] a greater proportion of
patients using insulin lispro than those using regular
human insulin indicated that the flexibility in their
lifestyle was easier in general, as was the flexibility
regarding timing of meals and the planning of physi-
cal and social activities. In the other study,[40] there
was no difference in scores for satisfaction on the
Diabetes Treatment Satisfaction Questionnaire
(DTSQ) between treatment groups comparing insu-
lin lispro with regular human insulin.
In the large crossover trial that randomised pa-
tients with type 2 diabetes to insulin lispro or regular
human insulin (table III),[54] 474 of 722 patients
were evaluated for HR-QOL.[83] There were no sta-
tistically significant differences in score changes
from baseline between treatment groups in any of
the four primary domains of the DQLCTQ.
In smaller studies in patients with type 2 diabe-
tes,[51,59,60] there was no difference in treatment satis-
faction (as assessed by the DTSQ) between those
receiving insulin lispro, NPH insulin or metformin
(each in combination with glibenclamide)[51] and
recipients of insulin lispro Mix25 were more satis-
fied with their treatment than those receiving gliben-
clamide.[59,60] In one study in elderly patients,[59]
treatment acceptance questionnaire scores (scale of
1 [very low] to 5 [very high] for overall treatment
satisfaction) were higher with insulin lispro Mix25
than with glibenclamide (4.35 vs 3.98; p = 0.01). In
the other study, responses to seven questions (three
Drugs 2007; 67 (3)
426
assessing treatment satisfaction and four assessing
symptoms, with higher scores indicating greater
treatment satisfaction or greater incidence of symp-
toms) were graded on a 5-point scale. Patients using
insulin lispro scored significantly better in six of
seven questions (p < 0.001) and in the overall
weighted score (2.0 vs 0.7; p < 0.001).[60] In both
trials, significantly (p < 0.05) more insulin lispro
recipients than glibenclamide recipients indicated
willingness to continue with their therapy (92% vs
79%[59] and 89% vs 63%[60]).
5. Tolerability
5.1 Hypoglycaemia
The tolerability of rapid-acting insulins is essen-
tially concerned with hypoglycaemia. The occur-
rence of hypoglycaemia is also a major efficacy
outcome and is defined and reviewed in section 4.
This section briefly summarises the occurrence of
hypoglycaemia with insulin lispro or premixtures of
insulin lispro. Data are derived from clinical trials
reviewed in section 4, a meta-analysis[84] and the
manufacturer’s prescribing information.[8,10]
The largest trials[42,54] in patients with type 1 or 2
diabetes using insulin lispro demonstrated a signifi-
cantly lower rate of hypoglycaemia, including noc-
turnal episodes, in insulin lispro recipients than in
regular human insulin recipients (section 4.1 and
tables I and II).
In almost all other trials in adult patients with
type 1 diabetes, the rate of hypoglycaemia with
insulin lispro was similar to[43,44,46-48] or slightly (but
significantly) lower[25,45] than that with regular
human insulin (section 4.1.1 and table I) and there
was also a lower rate of nocturnal (between mid-
night and 6am) hypoglycaemia with insulin lispro in
trials that reported on this endpoint (section
4.1.1).[40,45,46]
In the other trials of adult patients with type 2
diabetes receiving insulin monotherapy, there was a
similar rate of hypoglycaemic episodes in insulin
lispro and regular human insulin recipients[43,48,53]
(section 4.1.2 and table III).
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
A meta-analysis,[84] which included one unpub-
lished trial and several of the trials reviewed in
section 4,[40,42,46,48,54,72] revealed a significantly low-
er incidence of severe hypoglycaemia with insulin
lispro than with regular human insulin (3.1% vs
4.4%; p = 0.02) in patients with type 1 diabetes
(n = 4666), despite there being no significant be-
tween-group difference in any of the individual tri-
als, none of which were powered for this endpoint. It
should be noted that patients with a history of severe
hypoglycaemic episodes were excluded from some
trials, making the occurrence of this event fairly rare
and leaving the power of the studies for this event
questionable.
In the trial in adolescent patients with type 1
diabetes,[72] rates of hypoglycaemia were signifi-
cantly lower with insulin lispro than with regular
human insulin and, in trials in children,[70,71] the
rates were similar for the two insulins (section 4.4.1
and table VII).
In trials of premixed insulin lispro in patients
with type 1 diabetes (section 4.2.1 and table IV),
insulin lispro Mix25 plus Mix50[57] and insulin lis-
pro Mix50[55] were associated with a similar risk of
hypoglycaemia as human insulin 50/50 plus 30/
70[57] or regular human insulin.[55]
In patients with type 2 diabetes, the rates of
hypoglycaemia were similar for premixed insulin
lispro and other insulin regimens[61-64,82] (table V),
but the risk of hypoglycaemia was greater with
insulin lispro Mix25 than with glibenclamide in two
trials[59,60] (section 4.2.2 and table V).
5.2 Other Adverse Events
The frequency of adverse events in clinical stud-
ies was similar for insulin lispro and regular human
insulin.[8] Lipodystrophy (1/1000 to <1/100 with
insulin lispro[10]), hypokalaemia, hypersensitivity
(local injection-site reactions [1/100 to <1/10][10] or
systemic allergy [1/10 000 to <1/1000][10]), pruritus
and rash are potential adverse effects associated
with the use of any insulin.[8,10]
Pooled data relating to treatment-emergent ad-
verse events[85] in studies in adults with type 1 or 2
diabetes (n = 3634),[40,42,43,48,86] showed no differ-
Drugs 2007; 67 (3)
Insulin Lispro: A Review
ences between treatment groups (insulin lispro and
regular human insulin) for individual events. The
tolerability profile of both insulins was similar and
essentially reflected general health complaints in a
patient population monitored for up to 12 months,
with the most common adverse events being head-
ache, flu symptoms, pharyngitis, rhinitis and infec-
tion (each with an incidence 9.4–12.5%).[85]
5.3 In Pregnancy
Data on a large number of exposed pregnancies
do not indicate an adverse effect of insulin lispro on
pregnancy or the health of the fetus/newborn.[8,10]
In one (n = 71)[78] of two fully published prospec-
tive, nonrandomised studies comparing insulin lis-
pro and regular human insulin during pregnan-
cy,[77,78] the insulins were associated with a similar
frequency of preterm labour or Caesarean sec-
tion.[78] In the other study (n = 69),[77] the frequency
of hypoglycaemic episodes was similar between
treatment groups, despite a lower HbA1c value for
the insulin lispro group, and the course of pregnancy
(duration, frequency of preterm labour or Caesarean
section) and perinatal outcome (birthweight or fre-
quency of macrosomia) were also similar for the two
treatment groups. Although insulin lispro has been
reported to be 50–70% more bound to IGF-1 recep-
tors than human insulin (suggesting a potential for
retinal neovascularisation), there was no evidence of
worsening of diabetic retinopathy during insulin
lispro treatment in this trial.[77]
In two studies retrospectively examining out-
comes in 62[80] and 76[81] pregnancies in women
with type 1 diabetes receiving insulin lispro, there
were no adverse effects on the development or pro-
gression of retinopathy.[80,81] Maternal or fetal out-
comes were no different to the outcomes seen with
the use of other insulin regimens.[80,81]
Currently published rates of major anomalies in
infants born to mothers with diabetes treated with
insulin are 2.1–16.8%.[87,88] In a retrospective study
examining 496 women with 533 pregnancies who
used insulin lispro (97% of patients had type 1
diabetes),[87] the rate of major congenital abnormali-
ties was 5.4%. In a retrospective study examining
© 2007 Adis Data Information BV. All rights reserved.
427
635 evaluable pregnancies, there was no significant
difference between insulin lispro and regular human
insulin in the reported rates of abnormalities in
babies born to mother with gestational diabetes
(6.6% vs 7.9%) or pre-gestational type 1 or 2 diabe-
tes (3.8% versus 15.8%).[88]
6. Dosage and Administration
Insulin lispro (alone or as Mix25 or Mix50) is
indicated for the treatment of hyperglycaemia in
patients with diabetes.[8,10]
Insulin lispro is administered subcutaneously
shortly (EU)[10] or within 15 minutes (US)[8] before
meals and may, if necessary, be given immediately
after meals.[8,10] If required, intravenous administra-
tion of insulin lispro may be used for the treatment
of diabetic ketoacidosis or during acute illnesses or
surgery.[10]
Dosages of insulin lispro, as with dosages of
other insulins, are determined according to target
blood glucose levels appropriate for the patient.[8,10]
Intensive monitoring of blood glucose levels is es-
sential to ensure adherence to target levels.[8,10] A
basal insulin is generally included with insulin lispro
in the insulin regimen, except perhaps in patients
with type 2 diabetes who are receiving oral an-
tihyperglycaemic agents, or in patients who are re-
ceiving insulin lispro as a CSII using an insulin
pump.[8,10]
Although no adverse effects of insulin lispro on
the fetus or newborn infant have been identified,[10]
the US prescribing information state that there are
limited data for the use of insulin lispro during
pregnancy and suggests that it should only be ad-
ministered if the benefits outweigh the potential risk
to the fetus.[8]
Further details regarding the administration of
insulin lispro are provided in the manufacturer’s
prescribing information.[8,10]
7. Place of Insulin Lispro in the
Management of Diabetes
Practice guidelines and goals for diabetes therapy
for suitable patients[89-91] reflect the well established
findings that intensive glycaemic control reduces
Drugs 2007; 67 (3)
428
the risk of microvascular complications (reti-
nopathy, nephropathy and neuropathy) of diabe-
tes.[92,93]
Intensive therapy focuses on maintaining blood
glucose levels as close to normal as possible, ac-
cording to predefined targets and reflected in near-
normal HbA1c values, with frequent dosage adjust-
ments according to self-monitored blood glucose
readings.[89,90] In patients with type 1 diabetes, this
entails the administration of a rapid- or short-acting
insulin before meals to cope with the postprandial
rise in blood glucose levels (and between meals as
correction doses or for snacks) and a longer-acting
insulin as basal background insulin to mimic the
physiological second-phase secretion of insulin,
which regulates hepatic glucose metabolism and,
therefore, determines between-meal and nocturnal
blood glucose levels.[89,92] In patients with type 2
diabetes, first-line treatment involves diet and exer-
cise, followed by oral antihyperglycaemic agents
and/or insulin if HbA1c values are >7.5%.[90] Con-
cerns associated with the possible cardiovascular
effects of sulfonylureas, as well as the demonstra-
tion of efficacy for postprandial blood glucose con-
trol using regular human insulin and the possibility
of the subsequent recovery of β-cell function, have
highlighted the use of rapid-acting insulins to boost
the prandial insulin response in patients with type 2
diabetes.[41]
Tight glucose control is a challenge for the dia-
betic patient; commitment and motivation in pa-
tients are essential factors for achieving this control.
Improving the acceptance of, or satisfaction with,
insulin therapy may contribute to treatment compli-
ance and improved treatment outcomes.
Regular human insulin was the original short-
acting insulin for mealtime use.[94] Because of its
slow onset of activity (30–60 minutes), it needs to be
administered at least 30 minutes before a meal to
ensure the postprandial presence of sufficient insu-
lin to reduce the subsequent rise in blood glucose
level. Its duration of activity (6–8 hours) means it is
active for longer than may be necessary to control
postprandial blood glucose levels, potentially pre-
cipitating hypoglycaemia.[94] Moreover, patients oft-
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
en do not adhere to the prescribed interval between
injections and eating[40] and, if the insulin is admin-
istered too close to eating, the onset of activity will
not be in time to counteract the postprandial increase
in blood glucose level. The importance of postpran-
dial blood glucose is receiving increased attention as
a marker for overall blood glucose control and com-
plications in patients with type 1 or 2 diabetes, as
postprandial blood glucose excursions are associat-
ed with the risk of cardiovascular disease, regardless
of fasting blood glucose levels.[41,95]
Insulin lispro, insulin aspart and insulin glulisine
are rapid-acting insulin analogues.[2,96,97] There are
limited comparative clinical data for these insulins.
Insulin lispro has a faster onset of action (10–15 vs
30–45 minutes) and a shorter duration of action
(2–5[10] vs 6–8 hours) than regular human insulin,
with maximum effect exerted between 1–3 hours[10]
(section 2). Because insulin lispro is rapidly ab-
sorbed and short-acting, it can be administered im-
mediately before meals, or even after meals if neces-
sary (section 6). This flexibility in injecting insulin
lispro may be more convenient in some patient
groups, including older patients who have a risk of
hypoglycaemia and who may have memory loss and
trouble with consuming a predefined amount of
food, and patients with variable eating habits and
exercise routines, including those who may eat late
at night.[94] The flexibility that insulin lispro treat-
ment provides may contribute to treatment compli-
ance and patient satisfaction (section 4.5).
Barriers to intensive treatment and tight blood
glucose control include the motivation or capability
of the patient, and the perception of potential in-
crease in the risk of hypoglycaemia. Intensive treat-
ment in the Diabetes Control and Complications
Trial (DCCT) was associated with a 3-fold increase
in the incidence of severe hypoglycaemia relative to
conventional treatment,[92] probably due to the un-
physiological insulin-activity profile of convention-
al insulin treatment.[98] Following the DCCT, the
focus on maintaining near-normal blood glucose
levels prompted a decline in HbA1c values, but a
corresponding increase in the incidence of severe
hypoglycaemic episodes.[99] A further decline in
Drugs 2007; 67 (3)
Insulin Lispro: A Review
HbA1c values following the introduction of insulin
lispro, however, was not associated with an increase
in the incidence of hypoglycaemia.[99] Since then,
numerous clinical trials of insulin lispro have con-
firmed that the risk of hypoglycaemia is not in-
creased with the use of this insulin, but is generally
similar to, and sometimes lower than, the risk with
other insulins (section 5.1); in the largest trials, the
rate of nocturnal episodes was significantly less with
insulin lispro than with regular human insulin (sec-
tion 4.1). This may be because there is minimal
overlap of duration of insulin activity between insu-
lin lispro and the longer-acting insulin neutral prota-
mine lispro or NPH insulin. It should be noted that
most trials reviewed were primarily focused on effi-
cacy, other factors affecting hypoglycaemia were
not always recorded and there were differences
among trials in the reporting of this parameter.
Overall, in well designed prospective clinical
trials in adults, adolescents or children with type 1 or
2 diabetes, intensive premeal therapy with insulin
lispro, with a longer-acting insulin as basal therapy,
achieved postprandial blood glucose levels or post-
prandial blood glucose excursions that were gener-
ally lower than those achieved with a similar regular
human insulin-based regimen (section 4). Gly-
caemic control (HbA1c values) was, however, gen-
erally similar for both therapies (section 4). This is
understandable, considering patients sometimes ex-
perienced a higher fasting or preprandial blood glu-
cose with the use of insulin lispro, due to its shorter
duration of activity (section 4.1.1). Adjustment of
basal insulin therapy is, therefore, important when
switching from regular human insulin to insulin
lispro therapy, so that target pre- and postprandial
blood glucose levels are achieved and optimal con-
trol is exercised.[100-102]
Insulin is recommended in patients with type 2
diabetes, when the HbA1c value has deteriorated to
>7.5% despite oral agent therapy and attention to
diet.[89] In patients with type 2 diabetes switching
from oral antihyperglycaemic agents to insulin, regi-
mens include NPH insulin at night or twice daily,
premixed insulins twice daily, or more intensive
regimens depending on the patients requirements.[89]
© 2007 Adis Data Information BV. All rights reserved.
429
As with switching from oral antihyperglycaemic
agents to any other insulin, there is evidence of
patients benefiting from switching to insulin lispro.
They experienced lower postprandial blood glucose
excursions with a similar risk of hypoglycaemia
compared with those receiving oral glibenclamide,
although both therapies provided similar overall
glycaemic control (section 4.1.2). Patients with sec-
ondary failure of oral antihyperglycaemic agents
who added insulin lispro to an oral antihypergly-
caemic agent regimen or NPH insulin fared better
(had lower postprandial blood glucose levels and
lower HbA1c values) than those who added
metformin, a sulfonylurea or regular human insulin
to an NPH insulin regimen; the insulin lispro combi-
nation was associated with better glycaemic control
than other typical treatment regimens for type 2
diabetes (one or more antihyperglycaemic agents
with or without NPH insulin), with generally no
increased risk of hypoglycaemia (section 4.1.2).
Predictably, weight gain was significantly less with
oral antihyperglycaemic agents than insulin regi-
mens.
The administration of a combination of a short-
acting insulin with once- or twice-daily longer-act-
ing insulin to smooth out the blood glucose profile
prompted the development of premixtures of fixed
combinations of these insulins. Premixed insulins
offer the efficacy and time-action profiles of the
individual insulins with the convenience of fewer
daily injections and the advantage of not having to
physically mix the insulins, which can be challeng-
ing for some patients and possibly lead to dose
inaccuracies.[94] The use of insulin premixtures may,
therefore, be advantageous in elderly patients who
may have impaired dexterity or cognitive function.
Premixed insulin formulations are generally ad-
ministered twice daily, although a further injection
at lunchtime can be added in some patients.[103]
While insulin premixtures can be used in patients
with either type of diabetes, their use is considered
more appropriate in patients with some endogenous
insulin activity or in patients who do not require
intensive treatment.[98,103] The convenience of
minimising the number of injections can be lost if
Drugs 2007; 67 (3)
430
between-meal correction doses of rapid-acting insu-
lin are required.[2] Some patients, particularly those
with irregular eating and exercising habits, may
need to switch to basal-bolus insulin therapy if pre-
mixed insulin formulations do not provide adequate
glycaemic control.
In clinical trials, patients with either type of dia-
betes who administered insulin lispro premixtures
achieved glycaemic control similar to those using
self-mixed insulin lispro and NPH insulin, or pre-
mixed or self-mixed regular human and NPH insu-
lin. There was generally a similar risk of hypogly-
caemia with insulin lispro Mix25 and Mix50 and
other insulin regimens (section 4.2). As, expected,
glycaemic control was significantly better with insu-
lin lispro Mix25 than with oral glibenclamide in
patients (including the elderly) with type 2 diabetes
that had been previously inadequately controlled on
a sulfonylurea, although the rate of hypoglycaemic
episodes tended to be higher in the group receiving
insulin (section 4.2.2). The glycaemic control in
elderly patients was irrespective of whether the insu-
lin was administered before or after meals, which
could be an important advantage for this patient
population.
Patients with particular dietary patterns, such as
an Italian diet (low in fat and high in complex
carbohydrates)[104] or fasting patients (during Rama-
dan) [section 4.4.3][82] may also benefit from an
appropriate choice of premixed insulin lispro.
Insulin lispro was found to be stable and suitable
for use in a pump.[98] When delivered as a CSII,
insulin lispro was associated with improved gly-
caemic control (at a lower insulin dose and with
fewer hypoglycaemic episodes) than a multiple dai-
ly injection regimen in patients with type 1 diabetes
and achieved similar glycaemic control to a multiple
daily injection regimen in elderly patients with type
2 diabetes (section 4.3). Comparing insulins deliv-
ered as a CSII, insulin lispro achieved glycaemic
control similar to or better than that achieved with
regular human insulin and achieved glycaemic con-
trol similar to that achieved with insulin aspart (sec-
tion 4.3).
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
According to the DCCT, younger patients with
diabetes should, within reason, also maintain near-
normal blood glucose levels to minimise the long-
term complications of the disease.[105] Strict gly-
caemic control is more difficult in children who, by
nature, have erratic eating and exercise patterns, as
well as in adolescents who may resist parental su-
pervision. An insulin treatment regimen with a flexi-
ble schedule that can be tailored to food consump-
tion and exercise may be important in maintaining
target blood glucose levels. Twice- or three-times-
daily insulin lispro (along with basal insulin admin-
istration) has proved a clinically acceptable treat-
ment for diabetes in young patients (section 4.4.1).
Overall glycaemic control was generally similar for
insulin lispro and regular human insulin in children
and adolescents, although, in adolescents,[72] post-
prandial blood glucose levels and the risk of hypog-
lycaemia were lower with insulin lispro than with
regular human insulin (section 4.4.1). Insulin lispro
administered as a CSII via an external pump has also
been successfully administered in young children,
with blood glucose control similar to that with regu-
lar human insulin (section 4.4.1).
Diabetes itself can adversely affect the outcome
of pregnancies, both for the mother (retinopathy
progression, pre-eclampsia, spontaneous abortion
and preterm labour) and the infant (fetal abnormali-
ties and macrosomia).[106] Because adverse out-
comes appear to be related more to hyperglycaemia
than to the type of insulin used, tight postprandial
blood glucose control, as well as good overall gly-
caemic control, at conception and during the course
of pregnancy is considered fundamental for optimis-
ing pregnancy outcomes in diabetic patients.[106,107]
To this end, intensive premeal insulin regimens,
together with dietary advice and frequent blood glu-
cose monitoring are recommended.[107] Data on a
large number of exposed pregnancies do not indicate
an adverse effect of insulin lispro on pregnancy or
the health of the fetus/newborn (section 5.3).[8,10]
Early case reports of retinopathy progression and
fetal abnormalities sparked a concern that has not
been verified during the subsequent extensive use of
insulin lispro during pregnancy.[98,108,109] Retrospec-
Drugs 2007; 67 (3)
Insulin Lispro: A Review
tive and small prospective studies in pregnant wo-
men with diabetes indicate that glycaemic control
(section 4.4.2) and maternal and fetal outcomes
(section 5.3) with insulin lispro therapy were gener-
ally similar to those with regular human insulin.
Since the introduction of human insulins, cases of
insulin allergy are rarely reported. In multiple case
reports (reviewed by Castéra et al.[110]), rapid-acting
insulin analogues (insulin lispro and insulin aspart)
were effectively used to continue insulin treatment
or induce tolerance in patients with type 1 or 2
diabetes who were allergic to a newly introduced
insulin or had developed an allergy to a regularly
used insulin.
A detailed pharmacoeconomic review of insulin
lispro suggests that current cost-benefit data favour
the inclusion of insulin lispro in formularies and
their reimbursement by third-party payers.[111]
In conclusion, insulin lispro is indicated for the
treatment of hyperglycaemia in diabetes in many
countries worldwide. It is a recombinant human
insulin analogue that is identical to endogenous
human insulin, except for the transposition of two
amino acids. Insulin lispro has a faster onset of
action and shorter duration of activity than regular
human insulin, and the time-action profile of insulin
lispro mimics that of the physiological response of
endogenous human insulin to food intake. In diabet-
ic patients, from young children to the elderly, it has
demonstrated similar or better postprandial blood
glucose control similar to or better than that
achieved with regular human insulin, without an
increased risk of hypoglycaemia. In some trials, the
risk of hypoglycaemia, including nocturnal epi-
sodes, was less in insulin lispro recipients than in
regular human insulin recipients. Insulin lispro
(alone or as Mix25 or Mix50) can be administered
immediately before or after meals. This convenient
and flexible injection schedule may enable patients,
including those with a non-routine lifestyle or un-
predictable eating or exercising habits, to achieve
the tight glycaemic control required to minimise
long-term complications of diabetes and contributes
to patient satisfaction with treatment.
© 2007 Adis Data Information BV. All rights reserved.
431
Disclosure
During the peer review process, the manufacturer of the
agent under review was offered an opportunity to comment
on this article; changes based on any comments received were
made on the basis of scientific and editorial merit.
References
1. Vajo Z, Fawcett J, Duckworth WC. Recombinant DNA technol-
ogy in the treatment of diabetes: insulin analogs. Endocr Rev
2001; 22 (5): 706-17
2. Hirsch I. Insulin analogues. N Engl J Med 2005; 352 (2): 174-83
3. Ciszak E, Beals JM, Frank BH, et al. Role of C-terminal B-chain
residues in insulin assembly: the structure of hexameric
LysB28ProB29-human insulin. Structure 1995 Jun 15; 3 (6):
615-22
4. Llewelyn J, Slieker LJ, Zimmermann JL. Preclinical studies on
insulin lispro. Drugs Today 1998; 34 Suppl. C: 11-21
5. Wilde MI, McTavish D. Insulin lispro: a review of its pharma-
cological properties and therapeutic use in the management of
diabetes mellitus. Drugs 1997 Oct; 54: 597-614
6. Somwar R, Sweeney G, Ramlal T, et al. Stimulation of glucose
and amino acid transport and activation of the insulin signaling
pathways by insulin lispro in L6 skeletal muscle cells. Clin
Ther 1998; 20: 125-40
7. Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of
receptor binding and metabolic and mitogenic potencies of
insulin analogs designed for clinical use. Diabetes 2000 Jun;
49: 999-1005
8. Eli Lilly and Company. Humalog® (insulin lispro injection): US
prescribing information [online]. Available from URL: http://
humalog.com [Accessed 2006 Nov 2]
9. Torlone E, Fanelli C, Rambotti AM, et al. Pharmacokinetics,
pharmacodynamics and glucose counterregulation following
subcutaneous injection of the monomeric insulin analogue
[Lys(B28), Pro(B29)] in IDDM. Diabetologia 1994 Jul; 37 (7):
713-20
10. Eli Lilly and Company Limited. Humalog® (insulin lispro injec-
tion): summary of product characteristics [online]. Available
from URL: http://emc.medicines.org.uk [Accessed 2006 Aug
29]
11. Murase Y, Yagi K, Sugihara M, et al. Lispro is superior to
regular insulin in transient intensive insulin therapy in type 2
diabetes. Intern Med 2004 Sep; 43 (9): 779-86
12. Griffen SC, Oostema K, Stanhope KL, et al. Administration of
lispro insulin with meals improves glycemic control, increases
circulating leptin, and suppresses ghrelin, compared with regu-
lar/NPH insulin in female patients with type 1 diabetes. J Clin
Endocrinol Metab 2006 Feb; 91 (2): 485-91
13. Strachan MW, Frier BM. Optimal time of administration of
insulin lispro: importance of meal composition. Diabetes Care
1998 Jan; 21 (1): 26-31
14. Schernthaner G, Wein W, Sandholzer K, et al. Postprandial
insulin lispro: a new therapeutic option for type 1 diabetic
patients. Diabetes Care 1998 Apr; 21: 570-3
15. Rassam AG, Zeise TM, Burge MR, et al. Optimal administra-
tion of lispro insulin in hyperglycemic type 1 diabetes. Diabe-
tes Care 1999 Jan; 22: 133-6
16. Ciofetta M, Lalli C, Del Sindaco P, et al. Contribution of
postprandial versus interprandial blood glucose to HbA1c in
type 1 diabetes on physiologic intensive therapy with lispro
insulin at mealtime. Diabetes Care 1999 May; 22: 795-800
Drugs 2007; 67 (3)
432
17. Joseph SE, Korzon-Burakowska A, Woodworth JR, et al. The
action profile of lispro is not blunted by mixing in the syringe
with NPH insulin. Diabetes Care 1998 Dec; 21: 2098-102
18. Heise T, Weyer C, Serwas A, et al. Time-action profile of novel
premixed preparations of insulin lispro and NPL insulin. Dia-
betes Care 1998 May; 21: 800-3
19. Herz M, Arora V, Campaigne BN, et al. Humalog Mix25
improves 24-hour plasma glucose profiles compared with the
human insulin mixture 30/70 in patients with type 2 diabetes
mellitus. S Afr Med J 2003 Mar; 93: 219-23
20. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 insulin as
premeal therapy in type 2 diabetic patients. Diabetes Care 1999
Mar; 22: 459-62
21. Malone JK, Yang H, Woodworth JR, et al. Humalog Mix25
offers better mealtime glycemic control in patients with type 1
or type 2 diabetes. Diabetes Metab 2000 Dec; 26 (6): 481-7
22. Malone JK, Woodworth JR, Arora V, et al. Improved postpran-
dial glycemic control with Humalog Mix75/25 after a standard
test meal in patients with type 2 diabetes mellitus. Clin Ther
2000 Feb; 22: 222-30
23. Garg SK, Anderson JH, Perry SV, et al. Long-term efficacy of
Humalog in subjects with type 1 diabetes mellitus. Diabet Med
1999 May; 16: 384-7
24. McCrimmon RJ, Frier BM. Symptomatic and physiological
responses to hypoglycaemia induced by human soluble insulin
and the analogue lispro human insulin. Diabet Med 1997 Nov;
14: 929-36
25. Pfützner A, Küstner E, Forst T, et al. Intensive insulin therapy
with insulin lispro in patients with type 1 diabetes reduces the
frequency of hypoglycemic episodes. Exp Clin Endocrinol
Diabetes 1996; 104 (1): 25-30
26. Roach P, Strack T, Arora V, et al. Improved glycaemic control
with the use of self-prepared mixtures of insulin lispro and
insulin lispro protamine suspension in patients with types 1
and 2 diabetes. Int J Clin Pract 2001 Apr; 55: 177-82
27. Fineberg SE, Huang J, Brunelle R, et al. Effect of long-term
exposure to insulin lispro on the induction of antibody re-
sponse in patients with type 1 or type 2 diabetes. Diabetes Care
2003 Jan; 26: 89-96
28. Fineberg NS, Fineberg SE, Anderson JH Jr, et al. Immunologic
effects of insulin lispro [Lys (B28), Pro (B29) human insulin]
in IDDM and NIDDM patients previously treated with insulin.
Diabetes 1996 Dec; 45 (12): 1750-4
29. Recasens M, Aguilera E, Morinígo R, et al. Insulin lispro is as
effective as regular insulin in optimising metabolic control and
preserving β-cell function at onset of type 1 diabetes mellitus.
Diabetes Res Clin Pract 2003 Jun; 60 (3): 153-9
30. Rave K, Heise T, Weyer C, et al. Intramuscular versus subcuta-
neous injection of soluble and lispro insulin: comparison of
metabolic effects in healthy subjects. Diabet Med 1998 Sep;
15: 747-51
31. Hoffman A, Ziv E. Pharmacokinetic considerations of new
insulin formulations and routes of administration. Clin
Pharmacokinet 1997 Oct; 33: 285-301
32. Czock D, Aisenpreis U, Rasche FM, et al. Pharmacokinetics and
pharmacodynamics of lispro-insulin in hemodialysis patients
with diabetes mellitus. Int J Clin Pharmacol Ther 2003 Oct; 41
(10): 492-7
33. Boskovic R, Feig DS, Derewlany L, et al. Transfer of insulin
lispro across the human placenta: in vitro perfusion studies.
Diabetes Care 2003 May; 26 (5): 1390-4
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
34. Holcberg G, Tsadkin-Tamir M, Sapir O, et al. Transfer of
insulin lispro across the human placenta [letter]. Eur J Obstet
Gynecol Reprod Biol 2004 Jul 15; 115 (1): 117-8
35. World Health Organisation. Department of Noncommunicable
Disease Surveillance. Definition, diagnosis and classification
of diabetes mellitus [online]. Available from URL: http://
www.who.int [Accessed 2006 Oct 25]
36. Expert Committee on the Diagnosis and Classification of Diabe-
tes Mellitus. Report of the Expert Committee on the Diagnosis
and Classification of Diabetes Mellitus. Diabetes Care 1997;
20: 1183-97
37. Rivas M, Acosta A, Roman K. Glycemic excursion with insulin
lispro Mix75/25 vs NPH and pen device satisfaction in type 2
diabetes in Puerto Rico [abstract no. 1855-P]. Diabetes 2006
Jun; 55 Suppl. 1: 428
38. Robbins DC, Beisswenger PJ, Moses RG, et al. Comparison of
insulin lispro mid mixture (MM) plus metformin (Met) with
glargine (G) plus met on HbA1c (A1c) and blood glucose (BG)
profiles in patients with type 2 diabetes (T2D) [abstract no.
0988]. Diabetologia 2006 Sep; 49 Suppl. 1: 603-4
39. Ghio A, Volpe L, Lencioni C, et al. Safety and efficacy of short-
acting insulin aspart and lispro analogues in patients with
gestational diabetes mellitus (GDM) [abstract no. 0947].
Diabetologia 2006 Sep; 49 Suppl. 1: 576
40. Gale EAM. A randomized, controlled trial comparing insulin
lispro with human soluble insulin in patients with type 1
diabetes on intensified insulin therapy. UK Trial Group. Diabet
Med 2000 Mar; 17: 209-14
41. Forst T, Eriksson JW, Strotmann HJ, et al. Metabolic effects of
mealtime insulin lispro in comparison to glibenclamide in
early type 2 diabetes. Exp Clin Endocrinol Diabetes 2003 Apr;
111: 97-103
42. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Reduction of
postprandial hyperglycemia and frequency of hypoglycemia in
IDDM patients on insulin-analog treatment. Multicenter Insu-
lin Lispro Study Group. Diabetes 1997 Feb; 46 (2): 265-70
43. Anderson JH Jr, Brunelle RL, Koivisto VA, et al. Improved
mealtime treatment of diabetes mellitus using an insulin ana-
logue. Multicenter Insulin Lispro Study Group. Clin Ther
1997; 19 (1): 62-72
44. Annuzzi G, Del Prato S, Arcari R, et al. Preprandial combina-
tion of lispro and NPH insulin improves overall blood glucose
control in type I diabetic patients: a multicenter randomized
crossover trial. Nutr Metab Cardiovasc Dis 2001 Jun; 11: 168-
75
45. Heller SR, Amiel SA, Mansell P, et al. Effect of the fast-acting
insulin analog lispro on the risk of nocturnal hypoglycemia
during intensified insulin therapy. Diabetes Care 1999 Oct; 22:
1607-11
46. Holleman F, Schmitt H, Rottiers R, et al. Reduced frequency of
severe hypoglycemia and coma in well-controlled IDDM pa-
tients treated with insulin lispro. Diabetes Care 1997 Dec; 20:
1827-32
47. Valle D, Santoro D, Bates P, et al. Italian multicentre study of
intensive therapy with insulin lispro in 1184 patients with Type
1 diabetes. Diabetes Nutr Metab 2001 Jun; 14: 126-32
48. Vignati L, Anderson JH Jr, Iversen PW, et al. Efficacy of insulin
lispro in combination with NPH human insulin twice per day
in patients with insulin-dependent or non-insulin-dependent
diabetes mellitus. Clin Ther 1997; 19: 1408-21
49. Altuntas Y, Ozen B, Ozturk B, et al. Comparison of additional
metformin or NPH insulin to mealtime insulin lispro therapy
with mealtime human insulin therapy in secondary OAD fail-
ure. Diabetes Obes Metab 2003 Nov; 5 (6): 371-8
Drugs 2007; 67 (3)
Insulin Lispro: A Review
50. Bastyr EJ III, Johnson ME, Trautmann ME, et al. Insulin lispro
in the treatment of patients with type 2 diabetes mellitus after
oral agent failure. Clin Ther 1999 Oct; 21: 1703-14
51. Bastyr EJ III, Stuart CA, Brodows RG, et al. Therapy focused on
lowering postprandial glucose, not fasting glucose, may be
superior for lowering HbA1c. Diabetes Care 2000 Sep; 23:
1236-41
52. Kokić S, Buković D, Radman M, et al. Lispro insulin and
metformin versus other combination in the diabetes mellitus
type 2 management after secondary oral antidiabetic drug
failure. Coll Antropol 2003 Jun; 27 (1): 181-7
53. Ross SA, Zinman B, Campos RV, et al. A comparative study of
insulin lispro and human regular insulin in patients with type 2
diabetes mellitus and secondary failure of oral hypoglycemic
agents. Clin Invest Med 2001 Dec; 24: 292-8
54. Anderson JH Jr, Brunelle RL, Keohane P, et al. Mealtime
treatment with insulin analog improves postprandial hypergly-
cemia and hypoglycemia in patients with non-insulin-depen-
dent diabetes mellitus. Multicenter Insulin Lispro Study
Group. Arch Intern Med 1997 Jun 9; 157 (11): 1249-55
55. Herz M, Arora V, Sun B, et al. Basal-bolus insulin therapy in
Type 1 diabetes: comparative study of pre-meal administration
of a fixed mixture of insulin lispro (50%) and neutral prota-
mine lispro (50%) with human soluble insulin. Diabet Med
2002 Nov; 19: 917-23
56. Roach P, Bai S, Charbonnel B, et al. Effects of multiple daily
injection therapy with Humalog mixtures versus separately
injected insulin lispro and NPH insulin in adults with type I
diabetes mellitus. Clin Ther 2004 Apr; 26 (4): 502-10
57. Roach P, Trautmann M, Arora V, et al. Improved postprandial
blood glucose control and reduced nocturnal hypoglycemia
during treatment with two novel insulin lispro-protamine for-
mulations, insulin lispro Mix25 and insulin lispro Mix50. Clin
Ther 1999 Mar; 21: 523-34
58. Galic E, Vrtovec M, Bozikov V, et al. The impact of the timing
of Humalog Mix25 injections on blood glucose fluctuations in
the postprandial period in elderly patients with type 2 diabetes.
Med Sci Monit 2005 Dec; 11 (12): PI87-92
59. Herz M, Sun B, Milicevic Z, et al. Comparative efficacy of
preprandial or postprandial Humalog Mix75/25 versus glybu-
ride in patients 60 to 80 years of age with type 2 diabetes
mellitus. Clin Ther 2002 Jan; 24: 73-86
60. Roach P, Koledova E, Metcalfe S, et al. Glycemic control with
Humalog Mix25 in type 2 diabetes inadequately controlled
with glyburide. Clin Ther 2001 Oct; 23: 1732-44
61. Niskanen L, Jensen LE, Rastam J, et al. Randomized, multina-
tional, open-label, 2-period, crossover comparison of biphasic
insulin aspart 30 and biphasic insulin lispro 25 and pen devices
in adult patients with type 2 diabetes mellitus. Clin Ther 2004
Apr; 26 (4): 531-40
62. Roach P, Yue L, Arora V, et al. Improved postprandial glycemic
control during treatment with Humalog Mix25, or a novel
protamine-based insulin lispro formulation. Diabetes Care
1999 Aug; 22: 1258-61
63. Malone JK, Bai S, Campaigne BN, et al. Twice-daily pre-mixed
insulin rather than basal insulin therapy alone results in better
overall glycaemic control in patients with Type 2 diabetes.
Diabet Med 2005 Apr; 22 (4): 374-81
64. Kazda C, Hulstrunk H, Helsberg K, et al. Prandial insulin
substitution with insulin lispro or insulin lispro mid mixture vs.
basal therapy with insulin glargine: a randomized controlled
trial in patients with type 2 diabetes beginning insulin therapy.
J Diabetes Complications 2006; 20 (3): 145-52
© 2007 Adis Data Information BV. All rights reserved.
433
65. Roach P, Arora V, Campaigne BN, et al. Humalog Mix50
before carbohydrate-rich meals in type 2 diabetes mellitus.
Diabetes Obes Metab 2003 Sep; 5 (5): 311-6
66. Bode B, Weinstein R, Bell D, et al. Comparison of insulin aspart
with buffered regular insulin and insulin lispro in continuous
subcutaneous insulin infusion: a randomised study in type 1
diabetes. Diabetes Care 2002 Mar; 25: 439-44
67. Hoogma RPLM, Hammond PJ, Gomis R, et al. Comparison of
the effects of continuous subcutaneous insulin infusion (CSII)
and NPH-based multiple daily insulin injections (MDI) on
glycaemic control and quality of life: results of the 5-nations
trial. Diabet Med 2006 Feb; 23 (2): 141-7
68. Renner R, Pfützner A, Trautmann M, et al. Use of insulin lispro
in continuous subcutaneous insulin infusion treatment: results
of a multicenter trial. Diabetes Care 1999 May; 22: 784-8
69. Herman WH, Ilag LL, Johnson SL, et al. A clinical trial of
continuous subcutaneous insulin infusion versus multiple daily
injections in older adults with type 2 diabetes. Diabetes Care
2005 Jul; 28 (7): 1568-73
70. Deeb LC, Holcombe JH, Brunelle R, et al. Insulin lispro lowers
postprandial glucose in prepubertal children with diabetes.
Pediatrics 2001 Nov; 108: 1175-9
71. Fairchild JM, Ambler GR, Genoud-Lawton CH, et al. Insulin
lispro versus regular insulin in children with type 1 diabetes on
twice daily insulin. Pediatr Diabetes 2000 Sep; 1 (3): 135-41
72. Holcombe JH, Zalani S, Arora VK, et al. Comparison of insulin
lispro with regular human insulin for the treatment of type 1
diabetes in adolescents. Clin Ther 2002 Apr; 24: 629-38
73. Della Manna T, Steinmetz L, Campos PR, et al. Subcutaneous
use of a fast-acting insulin analog: an alternative treatment for
pediatric patients with diabetic ketoacidosis. Diabetes Care
2005 Aug; 28 (8): 1856-61
74. Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous
subcutaneous insulin infusion therapy for children and adoles-
cents: an option for routine diabetes care. Pediatrics 2001 Feb;
107: 351-6
75. Weintrob N, Benzaquen H, Galatzer A, et al. Comparison of
continuous subcutaneous insulin infusion and multiple daily
injection regimens in children with type 1 diabetes: a random-
ized open crossover trial. Pediatrics 2003 Sep 1; 112 (3): 559-
64
76. Tubiana-Rufi N, Coutant R, Bloch J, et al. Special management
of insulin lispro in continuous subcutaneous insulin infusion in
young diabetic children: a randomized cross-over study. Horm
Res 2004; 62 (6): 265-71
77. Loukovaara S, Immonen I, Teramo KA, et al. Progression of
retinopathy during pregnancy in type 1 diabetic women treated
with insulin lispro. Diabetes Care 2003 Apr; 26: 1193-8
78. Cypryk K, Sobczak M, Pertyńska-Marczewska M, et al. Preg-
nancy complications and perinatal outcome in diabetic women
treated with Humalog (insulin lispro) or regular human insulin
during pregnancy. Med Sci Monit 2004 Feb; 10 (2): P129-32
79. Mecacci F, Carignani L, Cioni R, et al. Maternal metabolic
control and perinatal outcome in women with gestational dia-
betes treated with regular or lispro insulin: comparison with
non-diabetic pregnant women. Eur J Obstet Gynecol Reprod
Biol 2003 Nov 10; 111 (1): 19-24
80. Garg SK, Frias JP, Anil S, et al. Insulin lispro therapy in
pregnancies complicated by type 1 diabetes: glycemic control
and maternal and fetal outcomes. Endocr Pract 2003; 9 (3):
187-93
81. Masson EA, Patmore JE, Brash PD, et al. Pregnancy outcome in
type 1 diabetes mellitus treated with insulin lispro (Humalog).
Diabet Med 2003 Jan; 20: 46-50
Drugs 2007; 67 (3)
434
82. Mattoo V, Milicevic Z, Malone JK, et al. A comparison of
insulin lispro Mix25 and human insulin 30/70 in the treatment
of type 2 diabetes during Ramadan. Diabetes Res Clin Pract
2003 Feb; 59: 137-43
83. Kotsanos JG, Vignati L, Huster W, et al. Health-related quality-
of-life results from multinational clinical trials of insulin lis-
pro: assessing benefits of a new diabetes therapy. Diabetes
Care 1997 Jun; 20 (6): 948-58
84. Brunelle RL, Llewelyn J, Anderson JH Jr, et al. Meta-analysis
of the effect of insulin lispro on severe hypoglycemia in
patients with type 1 diabetes. Diabetes Care 1998 Oct; 21:
1726-31
85. Glazer NB, Zalani S, Anderson JH Jr, et al. Safety of insulin
lispro: pooled data from clinical trials. Am J Health Syst
Pharm 1999 Mar 15; 56: 542-7
86. Bastyr EJ III, Kotsanos J, Vignati L, et al. Insulin lispro (LP)
reduces hypoglycemia rate in persons with type II diabetes at
high risk for hypoglycemia [abstract no. 202]. Diabetes 1996
May; 45 Suppl. 2: 56
87. Wyatt JW, Frias JL, Hoyme HE, et al. Congenital anomaly rate
in offspring of mothers with diabetes treated with insulin lispro
during pregnancy. Diabet Med 2005 Jun; 22 (6): 803-7
88. Bhattacharyya A, Brown S, Hughes S, et al. Insulin lispro and
regular insulin in pregnancy. QJM 2001; 94: 255-60
89. European Diabetes Policy Group 1999. A desktop guide to type
2 diabetes mellitus. Diabet Med 1999; 16 (9): 716-30
90. European Diabetes Policy Group 1998. A desktop guide to type
1 (insulin-dependent) diabetes mellitus. Diabet Med 1999; 16
(3): 253-66
91. American Diabetes Association. Standards of medical care in
diabetes: 2006. Diabetes Care 2006 Jan; 29 Suppl. 1: S4-42
92. Diabetes Control and Complications Trial Research Group. The
effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-depen-
dent diabetes mellitus. N Engl J Med 1993 Sep; 329 (14): 977-
86
93. UK Prospective Diabetes Study (UKPDS) Group. Intensive
blood-glucose control with sulphonylureas or insulin com-
pared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 1998 Sep;
352: 837-53
94. Oiknine R, Bernbaum M, Mooradian AD. A critical appraisal of
the role of insulin analogues in the management of diabetes
mellitus. Drugs 2005; 65 (3): 325-40
95. DECODE Study Group. Glucose tolerance and mortality: com-
parison of WHO and American Diabetes Association diagnos-
tic criteria. European Diabetes Epidemiology Group. Lancet
1999 Aug 21; 354: 617-21
96. Chapman TM, Noble S, Goa KL. Insulin aspart: a review of its
use in the management of type 1 and 2 diabetes mellitus. Drugs
2002; 62 (13): 1945-81
97. Robinson DM, Wellington K. Insulin glulisine. Drugs 2006; 66
(6): 861-9
98. Heller S. Insulin lispro: a useful advance in insulin therapy.
Expert Opin Pharmacother 2003; 4 (8): 1407-16
© 2007 Adis Data Information BV. All rights reserved.
Simpson et al.
99. Chase HP, Lockspeiser T, Peery B, et al. The impact of the
Diabetes Control and Complications Trial and Humalog insu-
lin on glycohemoglobin levels and severe hypoglycemia in
type 1 diabetes. Diabetes Care 2001 Mar; 24: 430-4
100. Del Sindaco P, Ciofetta M, Lalli C, et al. Use of the short-acting
insulin analogue lispro in intensive treatment of type 1 diabetes
mellitus: importance of appropriate replacement of basal insu-
lin and time-interval injection-meal. Diabet Med 1998 Jul; 15
(7): 592-600
101. Rossetti P, Pampanelli S, Fanelli C, et al. Intensive replacement
of basal insulin in patients with type 1 diabetes given rapid
acting insulin analogue at mealtime. Diabetes Care 2003; 26
(1): 1490-6
102. Ristic S, Bates PC. Effects of rapid acting insulin analogues on
overall glycemic control in type 1 and type 2 diabetes mellitus.
Diabetes Technol Ther 2003; 5 (1): 57-66
103. Garber AJ. Premixed insulin analogues for the treatment of
diabetes mellitus. Drugs 2006; 66 (1): 31-49
104. Coscelli C, Iacobellis G, Calderini C. Importance of premeal
injection time in insulin therapy: Humalog Mix25 is conve-
nient for improved post-prandial glycemic control in type 2
diabetic patients with Italian dietary habits. Acta Diabetol
2003; 40 (4): 187-92
105. White NH, Cleary PA, Dahms W, et al. Beneficial effects of
intensive therapy of diabetes during adolescence: outcomes
after the conclusion of the Diabetes Control and Complications
Trial (DCCT). J Paediatr 2001; 139 (6): 804-12
106. Carr KJ, Idama TO, Masson EA, et al. A randomised controlled
trial of insulin lispro given before or after meals in pregnant
women with type 1 diabetes: the effect on glycaemic excur-
sion. J Obstet Gynaecol 2004 Jun; 24 (4): 382-6
107. Gottlieb PA, Frias JP, Peters KA, et al. Optimizing insulin
therapy in pregnant women with type 1 diabetes mellitus. Treat
Endocrinol 2002; 1 (4): 235-40
108. Carr KJ, Lindow SW, Masson EA. The potential for the use of
insulin lispro in pregnancy complicated by diabetes. J Matern
Fetal Neonatal Med 2006 Jun; 19 (6): 323-9
109. Buchbinder A, Miodovnik M, Khoury J, et al. Is the use of
insulin lispro safe in pregnancy? J Matern Fetal Neonatal Med
2002 Apr; 11 (4): 232-7
110. Castéra V, Dutour-Meyer A, Koeppel MC, et al. Systemic
allergy to human insulin and its rapid and long acting analogs:
successful treatment by continuous subcutaneous insulin lispro
infusion. Diabetes Metab 2005 Sep; 31 (4): 391-400
111. Dunn CJ, Plosker GL. Insulin lispro: a pharmacoeconomic
review of its use in diabetes mellitus. Pharmacoeconomics
2002; 20 (14): 989-1025
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