Supplement issue

Pharmacokinetic and Pharmacodynamic Advantages of

Insulin Analogues and Premixed Insulin Analogues Over
Human Insulins: Impact on Efficacy and Safety
Arturo Rolla, MD
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

ABSTRACT

Human insulin preparations administered to patients with diabetes mellitus fail to reproduce the
normal physiologic pattern of insulin secretion. Modifications have been made in the amino acid
sequence of the insulin molecule with the aim of overcoming the pharmacokinetic shortcomings of
human insulins. Such modifications have produced long-acting analogues, with relatively flat time–
action profiles, for controlling glycemic levels between meals; and rapid-acting analogues with a fast
onset and short duration of action, for controlling postprandial hyperglycemia. Premixed formulations
of the rapid-acting analogues, containing both rapid-acting soluble and intermediate-acting protami-
nated forms, are also available. Trials of long-acting insulin analogues have consistently shown
efficacy in controlling fasting plasma glucose and glycosylated hemoglobin (HbA1c), as well as a
markedly reduced risk of hypoglycemia compared with neutral protamine Hagedorn insulin. The
rapid-acting and premixed analogues offer better control of postprandial glucose excursions than do
regular human insulin, resulting in similar or lower HbA1c levels. Furthermore, the analogues can
offer patients greater flexibility and more convenience in administration compared with human
insulins. This review provides an overview of the insulin analogues available today and describes their
structure, pharmacokinetics, pharmacodynamics, efficacy, and safety.
© 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, S9 –S19

KEYWORDS: Insulin analogues; Pharmacodynamics; Pharmacokinetics; Premixed insulin analogue

Normal physiologic insulin secretion consists of 2 com-
ponents: a steady low basal insulin release to maintain
basal glucose levels within a narrow range in between
meals, and prandial-related rapid insulin surges, secreted
in response to meals in order to control and limit post-
prandial glucose (PPG) excursions.1 Insulin therapy tries
to reproduce the physiologic secretion of the ␤-cells as
closely as possible, but available human insulin products
administered subcutaneously do not match this profile
very well. Soluble human insulins aggregate into hexam-
ers at the injection site and are absorbed too slowly to
Statement of author disclosure: Please see the Author Disclosures
section at the end of this article.
Requests for reprints should be addressed to Arturo Rolla, MD, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, Mas-
sachusetts 02215.
E-mail address: arolla@caregroup.harvard.edu.
address postprandial surges in glucose in time, whereas
intermediate-acting human insulins display unpredictable
peaks followed by a tailing-off in action. An ideal rapid-
acting insulin would have a fast onset and peak concen-
tration, with a short duration of action. An ideal long-
acting insulin, on the other hand, would simulate the
continuous low level of basal ␤-cell insulin secretion,
with a relatively flat time-action profile and an extended
duration of action, allowing once-daily dosing.
Insulin analogues are synthetic insulins with small changes
in the amino acid sequence made in order to attain better
pharmacokinetic characteristics. Both long-acting and rapid-
acting analogues with these characteristics have been devel-
oped. Premixed insulin analogues consist of a mixture of a
rapid-acting insulin analogue and a slower-acting protaminated
form of the analogue in various proportions, to provide both
basal and prandial insulin effects in a single injection. Al-
though available in vials, insulin analogue preparations are also

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2008.03.022
S10 The American Journal of Medicine, Vol 121, No 6A, June 2008

Figure 1 Diagrams indicating how the structure of insulin has been

modified to produce the long-acting insulin analogues. Ala ⫽ alanine;
Arg ⫽ arginine; Asn ⫽ asparagine; Cys ⫽ cysteine; Gln ⫽ glutamine;
Glu ⫽ glutamic acid; Gly ⫽ glycine; His ⫽ histidine; Ile ⫽ isoleucine;
Leu ⫽ leucine; Lys ⫽ lysine; Phe ⫽ phenylalanine; Pro ⫽ proline;
Ser ⫽ serine; Thr ⫽ threonine; Tyr ⫽ tyrosine; Val ⫽ valine.

available in pen devices to make their use simpler and more
discreet for patients, as well as decrease dosing errors.
This article reviews the pharmacokinetic and pharmaco-
dynamic properties of insulin analogues in relation to their
efficacy, safety, and convenience. Pharmacokinetic and
pharmacodynamic data obtained in healthy volunteers, or in
subjects with either type 1 or type 2 diabetes mellitus, are
cited as relevant. Efficacy and safety of the insulin ana-
logues in type 1 diabetes have been extensively reviewed
recently2,3; therefore the efficacy and safety sections of this
review are limited to type 2 diabetes.
LONG-ACTING INSULIN ANALOGUES
Structure
The long and relatively flat time–action profile of long-
acting insulin analogues has been achieved by slight mod-
ifications of the amino acid sequence of the insulin molecule
(Figure 1). Insulin glargine, commonly known as
“glargine,” (Lantus; Aventis Pharmaceuticals, Bridgewater,
NJ) was developed by replacing the asparagine at position
A21 with glycine, and 2 arginines were added to the C-
terminus of the B-chain. This alteration resulted in low
Rolla Advantages of Insulin Analogues Over Human Insulins
TABLE 1 Pharmacodynamic data for glargine and detemir in type 1 diabetes mellitus*
Glargine 0.3 U/kg
Onset of action (hr) 1.5 ⫾ 0.3
End of action (hr) 22 ⫾ 4
Duration (hr) 20.5 ⫾ 3.7
NPH ⫽ neutral protamine Hagedorn.
Adapted from Diabetes8 and Diabetes Care.12
*Onset of action is defined as the time after injection of insulin at which the rate of intravenous insulin consistently decreased by 50% compared with
the 20-minute preinjection time period. End of action is defined as the time at which plasma glucose consistently increased to ⬎150 mg/dL. Duration of
action is defined as the difference between onset and end of action.
aqueous solubility at neutral pH. Glargine is supplied in an
acidic solution, which becomes neutralized at the injection
site, leading to formation of microprecipitates from which it
is slowly released into the circulation.4
Insulin detemir, commonly called “detemir” (Levemir;
Novo Nordisk, Bagsvaerd, Denmark) differs from human
insulin in that the threonine in position B30 has been
omitted, and a C14 fatty acid chain (myristic acid) has
been attached to the lysine at position B29. Detemir is
formulated as a neutral solution that remains soluble
upon injection into the subcutaneous tissue. Increased
self-association and consequently slow systemic absorp-
tion of detemir molecules from the injection site prolong
its effect. The reversible binding of detemir to albumin
molecules at the injection site also contributes to its
prolonged action, while albumin binding in the circula-
tion may buffer the changes in absorption rate and po-
tentially limit pharmacodynamic variability.5,6
Pharmacokinetics/Pharmacodynamics
Neutral protamine Hagedorn (NPH) insulin is now the only
intermediate-acting human insulin available in the United
States. NPH insulin has a distinct and variable peak in
activity, which increases the risk for hypoglycemia, partic-
ularly at night. Also, patients must inject NPH insulin twice
daily to ensure sufficient insulin levels over a 24-hour pe-
riod. Long-acting insulin analogues, in contrast, offer serum
insulin levels that are smoother and provide coverage for up
to 24 hours with a single injection.
Pharmacokinetic data for insulin and its analogues can-
not easily be compared across different clinical studies
because their results depend on many variables (e.g., cohort
type, dose of insulin used, level of glycemia in clamp
studies, assay used for measuring insulin). Pharmacokinetic
data are most useful when comparisons are made between
different insulins in the same study using randomized cross-
over designs with appropriate washout periods. Further-
more, pharmacokinetic data may not be directly comparable
between glargine, detemir, and NPH insulin because of
different mechanisms of protraction that influence the
plasma concentration of “free” insulin.
Therefore, pharmacodynamic data are generally consid-
ered to be more relevant, as the glucose-lowering profiles of
different insulin products can be determined directly. These
S11
NPH 0.3 U/kg Detemir 0.4 U/kg NPH insulin 0.3 U/kg
0.8 ⫾ 0.2 1.6 ⫾ 1.1 1.8 ⫾ 1.2
14 ⫾ 3 21.5 ⫾ 3.3 15.3 ⫾ 9.0
13.2 ⫾ 2.8 19.9 ⫾ 3.2 12.7 ⫾ 9.9
data are usually shown as continuous profiles with calcula-
tion of discrete values for onset, peak, and duration of action
(as for example in the package inserts of the different
analogues).
Pharmacodynamic data on insulin preparations are usu-
ally determined using clamp studies, which measure the
glucose infusion rate needed to maintain a specified
“clamped” glycemic level after administration of the insulin
under study. Using clamp studies, prolonged duration of
action and relatively flat activity has been shown for
glargine compared with NPH insulin in healthy volunteers,7
and in patients with type 18 and type 29 diabetes. Similarly,
a long duration of action and relatively flat action have been
shown for detemir in healthy volunteers10,11 and in patients
with type 112 and type 213 diabetes. Representative data on
the duration of action from 2 of these studies are shown in
Table 1.8,12 A clamp study that compared glargine and
detemir showed that their pharmacodynamic profiles (over-
all blood glucose-lowering effect and duration) were similar
at the same doses (Figure 2).14
With regard to pharmacodynamic effect, detemir dem-
onstrated less intrasubject variability than either NPH insu-
lin or glargine in patients with type 1 diabetes,15 and less
intrasubject variability than glargine in patients with type 2
diabetes.13 NPH insulin was not included in the latter study.
Lower intrasubject variability can minimize glycemic vari-
ability and potentially reduce the risk for hypoglycemic
episodes, or glucose levels above the hyperglycemic thresh-
old. Intrasubject variability in the pharmacodynamic effect
of glargine has been reported in 1 study,16 and was compa-
rable to that of NPH insulin.
Frequency and Timing of Administration
Long-acting insulin analogues in patients with type 2
diabetes are frequently used in combination therapy with
oral antidiabetic agents, or in basal-bolus insulin therapy.
Glargine is indicated for once-daily administration, at a
consistent time every day.4,17 Detemir can be adminis-
tered once or twice daily: once daily with the evening
meal or at bedtime; twice daily, with the evening dose
either with dinner, at bedtime, or 12 hours after the
morning dose.18
S12 The American Journal of Medicine, Vol 121, No 6A, June 2008

Clinical Efficacy and Safety in Type 2

Diabetes
Clinical efficacy and safety of the long-acting insulin ana-
logues are covered elsewhere in this supplement,19 but for
the sake of completeness are summarized here.
In various clinical trials in patients with type 2 diabetes,
long-acting insulin analogues have demonstrated similar
efficacy to NPH in controlling blood glucose levels, but
with a substantially reduced risk for hypoglycemia. Risk
reductions of 21% to 48% were reported for glargine versus
NPH insulin,20 and 21% to 25% fewer patients in the
glargine groups reported symptomatic hypoglycemia.21,22
Nocturnal hypoglycemia was reported by 55% to 58%
fewer patients in the glargine groups.21,23 The risk for hy-
poglycemia with detemir is consistently reduced by about
50% compared with NPH insulin.24,25 Two studies have
also shown a lower risk for nocturnal hypoglycemia with
detemir (by about 50%).24,26 Both glargine20,21,27,28 and
detemir24-26,29 have demonstrated similar improvements in
fasting plasma glucose (FPG) and glycosylated hemoglobin
(HbA1c) compared with NPH insulin. Data from large “real-
life” observational studies show that HbA1c and FPG im-
proved significantly from baseline with detemir30-32 and
with glargine.33
Weight gain is often a concern with insulin therapy,
especially in patients with type 2 diabetes.34 Weight gain
with glargine is similar to that found with NPH insulin in Figure 2 Glucose infusion rate profiles for long-acting
patients with type 2 diabetes.20,27,28 Treatment with detemir insulin analogues in type 2 diabetes mellitus. (Reprinted with
has resulted in significantly less weight gain compared with permission from Diabetes.14 © American Diabetes
NPH insulin in patients with type 2 diabetes.24,26,29 Possible Association.)
theories to explain this weight advantage of detemir have
been reviewed elsewhere.35
trations (Figure 4),39,40 which provides better control of
RAPID-ACTING INSULIN ANALOGUES PPG excursions. Elevated PPG is an earlier and frequent
abnormality in type 2 diabetes and is a stronger predictor of
Structure cardiovascular disease than elevation of fasting blood glu-
The key advantages of rapid-acting analogues are their cose (FBG).41, 42 Control of PPG is essential because, as
quick onset of action, earlier peak, and short duration of HbA1c levels decrease, PPG contributes proportionately
action, which mimic the postprandial increase in ␤-cell more and more to the glycation of hemoglobin.43
insulin secretion in individuals without diabetes more Because rapid-acting insulin analogues have similar
closely than does short-acting regular human insulin (RHI). properties, including the mechanism of dissociation in the
Three rapid-acting insulin analogues are currently available: injection site, pharmacokinetic and pharmacodynamic data
insulin aspart (“aspart”) NovoLog; Novo Nordisk), insulin are more closely related within the group compared with
lispro (“lispro”) (Humalog; Eli Lilly and Company, India- long-acting insulin analogues. Pharmacokinetic data for the
napolis, IN) and insulin glulisine (“glulisine”) (Apidra; rapid-acting analogues are shown in Table 2.40,44,45 Rapid
sanofi-aventis). For each rapid-acting insulin analogue, ⱖ1 onset and shorter duration of action than RHI have been
amino acid has been replaced (Figure 3). These changes shown consistently in healthy volunteers for lispro,46 as-
reduce the normal tendency of insulin molecules to self- part,47 and glulisine48; in patients with type 1 diabetes for
assemble into hexamers once injected, thereby facilitating lispro,49 aspart,50 and glulisine51; and in patients with type
rapid absorption into the systemic circulation and resulting 2 diabetes for lispro,52 aspart,53 and glulisine.54
in a fast onset of glucose-lowering effect and relatively The rapid onset of action was shown to translate into
short duration of action.36-38 better control of PPG, compared with RHI, in patients with
type 2 diabetes. With aspart, PPG excursions were lower by
Pharmacokinetics/Pharmacodynamics 20% in comparison with RHI (P ⫽ 0.034).53 With lispro,
Rapid-acting insulin analogues are absorbed more rapidly 2-hour post-dinner PPG values were 151.2 mg/dL versus
than RHI, attaining earlier and higher peak serum concen- 176.6 mg/dL with RHI (P ⫽ 0.02).52
Rolla Advantages of Insulin Analogues Over Human Insulins S13

Figure 3 Diagrams indicating how the structure of insulin has

been modified to produce the rapid-acting insulin analogues. Ala ⫽
alanine; Arg ⫽ arginine; Asn ⫽ asparagine; Asp ⫽ aspartic acid;
Cys ⫽ cysteine; Gln ⫽ glutamine; Glu ⫽ glutamic acid; Gly ⫽
glycine; His ⫽ histidine; Ile ⫽ isoleucine; Leu ⫽ leucine; Lys ⫽
lysine; Phe ⫽ phenylalanine; Pro ⫽ proline; Ser ⫽ serine; Thr ⫽
threonine; Tyr ⫽ tyrosine; Val ⫽ valine.
S14 The American Journal of Medicine, Vol 121, No 6A, June 2008

In a comparative study of lispro and aspart in healthy

volunteers, the maximal concentration of both analogues
was achieved 40 minutes after injection.55 A clamp study of
lispro and glulisine in type 1 diabetes patients showed
similar rates of absorption, with the maximum concentra-
tion occurring at 50 to 60 minutes, compared with 82 min-
utes for RHI.56
It has been suggested that rapid-acting analogues display
slightly less intrapatient variability in their time–action pro-
files than RHI. In healthy volunteers, intrasubject variability
in the time to maximum serum concentrations was lower
with both aspart57 and with lispro,40 compared with RHI.
No reports on intrasubject variability of glulisine were
found.

Frequency and Timing of Administration

RHI has to be given ⱖ30 minutes before meals, which is
often inconvenient for patients and frequently is not done.
On the other hand, all the rapid-acting insulin analogues can
be administered just before a meal.40,44,45 This is a practical
benefit for patients and may be particularly advantageous
for children, whose eating patterns may be unpredictable, or
when eating at restaurants.

Clinical Efficacy and Safety in Type 2
Diabetes
In type 2 diabetes, rapid-acting insulin analogues can be
used as the bolus component of basal-bolus insulin therapy,
in continuous subcutaneous insulin infusion, or, rarely, in
premeal-only administration without basal insulin. Most of
the available pharmacokinetic/pharmacodynamic trial evi-
dence is for basal-bolus regimens.58
The rapid-acting analogues have been shown to provide
greater control of PPG (Table 3) and equivalent or better
control of HbA1c compared with RHI.49,59-62 The rapid-
acting analogues do not increase the overall risk of hypo-
glycemia relative to RHI, and their safety and tolerability is
similar to that of RHI.49,62,63
PREMIXED INSULIN ANALOGUES
Premixed insulin analogues provide both rapid-acting and
longer, intermediate-acting insulins in a single injection,
thereby limiting the number of daily injections required,
while still providing both postprandial and basal coverage.
These preparations are mainly used by patients with type 2
diabetes but they may also be used by certain patients with
type 1 diabetes. In addition, patients do not need to inject or
self-mix insulins from different vials, making the treatment
simpler and potentially decreasing the possibility of dosage
errors, particularly when used in pen devices. On the other
hand, premixed analogue formulations have a fixed propor-
tion of both types of insulin, making it impossible to adjust
only 1 of the components.
Figure 4 Insulin and glucose profiles of rapid-acting in-
sulin analogues. (A) Serum insulin profile of aspart is
shown as an example; profiles for lispro and glulisine are
similar. (B) Blood glucose levels after injection of lispro or
regular human insulin. Baseline insulin concentration was
maintained by infusion of human insulin 0.2 mU/min per
kg. (Reprinted with permission from Acta Diabetol39 and
Eli Lilly and Company.40)
Structure
Biphasic insulin aspart 70/30 (“BIAsp 30”) (NovoLog Mix
70/30; Novo Nordisk) is composed of 70% aspart protami-
nated suspension and 30% soluble rapid-acting aspart. The
soluble component (aspart) is absorbed more rapidly, and
targets PPG better than does RHI. The remaining 70%, in
crystalline form as protaminated aspart, has a prolonged
absorption profile and provides basal coverage.64
Lispro 75/25 (“Mix 25”) (Humalog Mix 75/25; Eli Lilly)
comprises 75% intermediate-acting protaminated lispro sus-
pension and 25% rapid-acting lispro.65 In lispro 50/50
(Humalog Mix 50/50, Eli Lilly), the 2 components are
present as 50% protaminated lispro suspension and 50%
lispro. Lispro 50/50 can be used for patients who have meals
with large amounts of carbohydrates, so that the greater
proportion of the rapid-acting analogue provides better post-
prandial coverage. However, lispro 50/50 is used much less
frequently than BIAsp 30 and Mix 25, and very few studies
on its use have been published.
Rolla Advantages of Insulin Analogues Over Human Insulins S15

TABLE 2 Pharmacokinetic values for rapid-acting analogues compared with regular human insulin (RHI)*

Subjects tmax insulin (min) Cmax insulin

Healthy volunteers and type 1 diabetes (0.15 U/kg) Aspart 40–50 82.1 mU/L†
RHI 80–120 35.9 mU/L†
Healthy volunteers and type 1 diabetes (0.1–0.4 U/kg) Lispro 30–90 Not reported
RHI 50–120
Type 1 diabetes (0.2 U/kg) Glulisine 55 (34–91) 82 (42–134) ␮U/mL
RHI 82 (52–308) 46 (32–70) ␮U/mL
Cmax ⫽ maximum concentration; tmax ⫽ time to maximum concentration.
Adapted from Eli Lilly and Company, Novo Nordisk, and Aventis Pharmaceuticals.40,44,45
*Data are reported for healthy volunteers or patients with type 1 diabetes mellitus, as available.
†Results reported for type 1 diabetes.

TABLE 3 Trials of rapid-acting insulin analogues versus human insulin (HI) for use in basal-bolus therapy in patients with type 2
diabetes mellitus: glycosylated hemoglobin (HbA1c) and postprandial glucose (PPG)

Study Treatment Groups/Comparison N Duration HbA1c Analogue-HI PPG*

IAsp
Bretzel et al (2004)61† IAsp or RHI ⫾ NPH ⫹ OADs IAsp 75, 3 mo ⫺0.18%Hb (estimated)‡ 7.9 mg/dL lower (P ⫽ NR)
HI 80
ILis
Ross et al (2001)52 ILis or HI ⫹ basal insulin ⫹ 148 5.5 mo NS 23.4–25.2 mg/dL lower post
OADs, not on insulin breakfast and postdinner
(estimated§) (P ⬍0.02)
IGlu
Dailey et al (2004)62 IGlu vs RHI ⫹ NPH in both 876 26 wk ⫺0.16%Hb (estimated§) 6.5–9.2 mg/dL lower
groups ⫹ OADs (P ⫽ 0.0029) (estimated§) (P ⬍0.05)
IAsp ⫽ insulin aspart; IGlu ⫽ insulin glulisine; ILis ⫽ insulin lispro; NPH ⫽ neutral protamine Hagedorn; NR ⫽ not reported; NS ⫽ not significant;
OADs ⫽ oral antidiabetic drugs; RHI ⫽ human insulin.
Adapted from Clin Invest Med52 and Diabetes Care.62,63
*At 90 minutes or 2 hours or from 8-point blood glucose profiles for analogue relative to HI.
†This trial also included a human premix group (results not shown).
‡Confidence interval (95%) for IAsp–HI difference: (⫺0.21% to 0.57%Hb); P ⫽ 0.025.
§“Estimated” indicates that differences were estimated from reported final values or from figures.

Pharmacokinetics/Pharmacodynamics ble 5 and Figure 5).67,68 BIAsp 30 provided better PPG

The main advantages of premixed insulin analogues over
human premixed insulin (BHI) (consisting of 70% NPH and
30% soluble human insulin) are a more rapid onset of
action, an earlier and greater peak concentration, a conse-
quential greater limitation of PPG excursions, and more
convenient meal-time dosing. For example, BIAsp 30
reached peak serum concentrations 30% to 50% faster than
BHI, and the peak concentrations were 30% to 50% higher,
in healthy volunteers (Table 4).64,66,67 Serum insulin area-
under-the-curve values (AUC0⫺90 min) were higher with
BIAsp 30 in the critical 90-minute period following injec-
tion (Table 1). Comparable pharmacokinetic data for Mix
25 could not be found in the published literature. However,
a graphic presentation of a pharmacodynamic study of Mix
25 showed that it limited PPG excursions better than did
BHI.66
When BIAsp 30 was compared with Mix 25 and BHI in
patients with type 2 diabetes, the premixed analogues both
reached peak serum concentrations much faster, and the
peak concentrations were higher, compared with BHI (Ta-
control, as assessed by the 5-hour glucose excursion, com-
pared with either BHI 30 or Mix 25 (298.8 ⫾ 81.0 mg/dL
per hr, 361.8 ⫾ 88.2 mg/dL per hr, and 340.2 ⫾ 109.8
mg/dL per hr, respectively).68 In healthy volunteers, the
intrasubject variability of BIAsp 30 was comparable with
that of the human premixed insulins.64 No reports on intra-
subject variability of Mix 25 could be found.
Frequency and Timing of Administration
Premixed insulin analogues may be used 1, 2, or 3 times a
day, according to the individual patient’s needs. In contrast,
premixed human insulins should not be dosed more than
twice daily because of their overlapping peaks in action.
In the early stages of insulin therapy in type 2 diabetes, 1
injection of a premixed insulin analogue, usually given before
dinner, achieves glycemic control goals in ⬎40% of patients,
making it a simple method of initiating insulin therapy.69
Premixed insulin analogues should be injected near meal
times; they should not be injected at bedtime because the
rapid-acting component may cause nocturnal hypoglycemia.
S16 The American Journal of Medicine, Vol 121, No 6A, June 2008

In practice, the premixed insulin analogues are most

7.8 ⫾ 2.8 nmol/kg/90

752 ⫾ 191 mU/L/min

often dosed twice daily before meals (before breakfast and

min (P ⬍0.0001)

114 ⫾ 66 mU/L/hr
dinner), in order to reduce PPG after these 2 meals with the

(P ⬍0.0001)
TABLE 4 Pharmacokinetic values for premixed insulin analogues compared with premixed human (Mix25)* insulin for biphasic insulin aspart 30 (BIAsp 30)† versus human

rapid-acting insulin component. Reduction of lunchtime

(P ⬍0.05)
PPG can be covered by the extended effect of the prebreak-
fast dose. Patients who have late and heavier lunches and/or
insulin

BHI

late dinners, as may be customary in certain parts of Europe,

may not achieve adequate glycemic coverage with 2 injec-
min

1,403 ⫾ 372 mU/L/min tions of premixed analogues; in these cases a third injection
12.5 ⫾ 5.3 nmol/kg/90
or AUC0–120

before lunch can further improve all PPG and HbA1c lev-
136 ⫾ 72 mU/L/hr
els.69 The possibility of using the same type of insulin in
type 2 diabetes from the initiation of therapy with 1 injec-
tion a day, progressing to 2 or 3 injections a day as the
min

disease advances, simplifies the administration of insulin

BIAsp 30
AUC0–90

and the education of patients.

min

Premixed insulins are a convenient choice for patients

with consistent mealtimes and lifestyles. Patients with suf-
ficient diabetes education may increase or decrease the dose
15.5 ⫾ 3.7 mU/L

79 ⫾ 43 mU/L
101 ⫾ 8 pmol/L

of premixed insulins before meals according to the blood

(P ⬍0.0001)

(P ⬍0.0001)

(P ⬍0.05)

glucose level at the time and the size of the meal. Patients
living more flexible lifestyles with inconsistent mealtimes
may need to use basal-bolus therapy. As with any insulin
BHI

therapy, starting low and adjusting in small increments with

‡Values are shown for BIAsp; similar pharmacokinetic values for Mix25 could not be found in the published literature.

appropriate self-measurement of blood glucose is the way to

monitor insulin therapy and determine the most suitable
183 ⫾ 12 pmol/L

23.4 ⫾ 5.3 mU/L

96 ⫾ 54 mU/L

insulin preparation and dose adjustment.19,70

Mixtures containing RHI should be given 30 to 60 min-
Cmax insulin

BIAsp 30

utes before a meal, which is impractical for many patients.

AUC ⫽ area under the curve; Cmax ⫽ maximum concentration; tmax ⫽ time to maximum concentration.

The absorption rate of BIAsp 30 and Mix 25 allows dosing

within 15 minutes of meal initiation.71-73 This may be more
convenient for many patients, particularly children and
those with busy schedules.
(P ⬍0.0001)

(P ⬍0.0001)

(P ⬍0.05)

Clinical Efficacy and Safety in Type 2

177 ⫾ 13

137 ⫾ 83

Diabetes
*Lispro 75/25 (Humalog Mix 75/25; Eli Lilly and Company, Indianapolis, IN).
BHI

110
tmax insulin (min)

Comparison with BHI. Premixed insulin analogues have

been shown to be clinically effective and appear to be as
Adapted from Diabetes Care,64 Eur J Clin Pharmacol,66 and Clin Ther.67

well tolerated as premixed human insulins. In trials, HbA1c

89 ⫾ 32
BIAsp 30
115 ⫾ 3

control was as good as with BHI for BIAsp 3074-76 and Mix
25.77 There was no increase in the risk for hypoglyce-
†NovoLog Mix 70/30; Novo Nordisk, Bagsvaerd, Denmark.
60

mia,75,77 and some studies showed a trend toward reduced

hypoglycemic events.75,76 PPG values 5.4 to 30.6 mg/dL
Healthy volunteers

Healthy volunteers

lower than with BHI have been reported in trials with BIAsp
Patients with type

3074 and Mix 25.77,78

2 diabetes
Population

mellitus

Comparison with basal insulin. The efficacy of premixed

insulin analogues in type 2 diabetes has been compared with
that of glargine used as combination therapy with oral
antidiabetic agents. Mean PPG for all meals combined was
16.2 mg/dL lower (P ⬍0.05) with Mix 25 compared with
premixed insulin (BHI)‡

Jacobsen et al (2000)66

McSorley et al (2002)67

glargine when used once daily in a test meal study.79 Mean

64
Weyer et al (1997)

HbA1c reductions were 2.79% with BIAsp 30 versus 2.36%

with glargine (P ⬍0.01),63 and 1.00% with Mix 25 versus
0.42% with glargine (P ⬍0.001).80,81 The risk for minor
hypoglycemias was greater with BIAsp than with
Study

glargine,63 but nocturnal hypoglycemia was lower with Mix

25 than with glargine.81
Rolla Advantages of Insulin Analogues Over Human Insulins S17

TABLE 5 Pharmacokinetic values for premixed insulin analogues compared with premixed human insulin (BHI) for biphasic insulin
aspart 30 (BIAsp 30)* versus (Mix 25)† and Lispro 75/25 BHI

tmax insulin (min) Cmax insulin (pmol/L) AUC0–5 h (pmol/L ⫻ hr)

BIAsp 30 Mix 25 BHI BIAsp 30 Mix 25 BHI BIAsp 30 Mix 25 BHI

115 ⫾ 59 100 ⫾ 41 169 ⫾ 71 415 ⫾ 244 360 ⫾ 211 237 ⫾ 156 1079 ⫾ 535 1031 ⫾ 621 741 ⫾ 426
AUC ⫽ area under the curve; Cmax ⫽ maximum concentration; tmax ⫽ time to maximum concentration.
Adapted from Diabetes Care.68
*NovoLog Mix 70/30; Novo Nordisk, Bagsvaerd, Denmark.
†Humalog Mix 75/25; Eli Lilly and Company, Indianapolis, IN.

Figure 5 Onset and duration of action of premixed insulin analogue

biphasic insulin aspart 70/30 (BIAsp 30) (NovoLog Mix 70/30; Novo
Nordisk, Bagsvaerd, Denmark) and Lispro 75/25 (Mix25) (Humalog
Mix 75/25; Eli Lilly and Company, Indianapolis, IN) compared with
human premixed insulin (BHI 30) in patients with type 2 diabetes
mellitus. Error bars represent 2SEM. (Reprinted with permission from
Diabetes Care.68 © American Diabetes Association.)

SUMMARY AUTHOR DISCLOSURES

Compared with NPH insulin, the long-acting insulin analogues
provide relatively more reproducible serum concentrations and
longer time–action profiles for up to 24 hours with a single
injection. The rapid-acting insulin analogues are absorbed
more rapidly than RHI, attaining a quick peak and short dura-
tion of action, more similar to the prandial ␤-cell insulin
secretion. Premixed insulin analogues have a faster and greater
glucose-lowering activity than premixed human insulins.
These pharmacokinetic and pharmacodynamic advan-
tages translate into clinical benefits for patients with either
type 1 or type 2 diabetes. With the long-acting analogues,
the relative risk for hypoglycemia is reduced considerably
compared with NPH insulin, whereas the rapid-acting and
premixed analogues can provide improved glycemic con-
trol, particularly after meals, compared with human insulin
along with more convenient dosing. Therapy with the ana-
logues thus provides an improved balance between glyce-
mic control and the risk for hypoglycemia, together with
greater flexibility in timing of dosing and thus increased
convenience for patients.
The author of this article has disclosed the following indus-
try relationships:
Arturo Rolla, MD, is a member of the Speakers’ Bureau
for Eli Lilly and Company, GlaxoSmithKline, Novo Nor-
disk A/S, Roche Laboratories, and Takeda Pharmaceuticals
North America, Inc.
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