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REVIEW ARTICLE doi: 10.1111/j.1463-1326.2008.01015.

Insulin analogues: an example of applied medical science

B. Sheldon, D. Russell-Jones and J. Wright

Centre for Diabetes, Endocrinology & Research (CEDAR), Royal Surrey County Hospital, University of Surrey, Guildford, UK

Insulin analogues were developed to try and achieve more physiological insulin replacement from injection in the
subcutaneous site. Their pharmacokinetics and pharmacodynamics differ from human insulin when injected sub-
cutaneously because of alterations in the amino acid sequence of the insulin molecule. The rapid-acting insulin
analogues, lispro, aspart and glulisine, have a rapid onset of action and shorter duration of action because of changes to
the B26–30 portion of insulin inhibiting formation of dimers and hexamers. They appear to improve postprandial
glucose, incidence of hypoglycaemia and patient satisfaction and, when used in combination with basal insulin
analogues, improve glycosylated haemoglobin in comparison to conventional insulin therapy. Additionally, they have
been successfully used in children, pregnant women, in pump therapy and as part of premixed biphasic regimens. The
two basal insulin analogues, glargine and detemir, developed by adjusting the isoelectric point and adding a fatty acid
residue, respectively, have a protracted duration of action and a relatively smooth profile. Their pharmacokinetic and
pharmacodynamic profiles have been assessed using euglycaemic clamp protocols. Both analogues have a longer
duration of action, less of a peak of activity and a reduced variability with repeated injection. There is some evidence to
suggest that detemir may have a slight hepatoselective effect. Clinical studies have shown a lower relative risk of
hypoglycaemia and detemir appears to have a weight-sparing action. Insulin analogues represent a successful example
of applied medical science.
Keywords: insulin analogue, lispro, aspart, glulisine, glargine, detemir
Received 3 November 2008; accepted 3 November 2008

logues in that their amino acid structures were not


Introduction
identical to that of human insulin. These ‘analogues’
The discovery of insulin by Banting and Best is one of the differed from the new generation of insulin analogues in
greatest ever medical breakthroughs [1]. From that that the amino acid differences were because of species
moment, the lives of people with diabetes were trans- diversity rather than alterations tailored to achieve ther-
formed by treatment with insulin. For many years, treat- apeutic benefit.
ment was with different types of animal insulin, which, The first insulins available for clinical use contained
in themselves, might be considered to be insulin ana- numerous impurities and potency varied substantially

Correspondence:
Benjamin Sheldon, Centre for Diabetes, Endocrinology & Research (CEDAR), Royal Surrey County Hospital, University of Surrey,
Egerton Road, Guildford GU2 7XX, UK.
E-mail:
benjamin.sheldon@nhs.net
Conflict of interest:
Professor Russell-Jones has received honoraria for lectures and research grant funding from GSK, Eli Lilly, Pharmacia, Pfizer, Novo
Nordisk, MSD, Takeda Aventis and Novartis. Dr Sheldon has received research grant funding from the LIBRA Foundation affiliated
to Novo Nordisk. Dr Wright has received honoraria for lectures and research grant funding from GSK, Eli Lilly, Pharmacia, Pfizer,
Novo Nordisk, MSD, Takeda Aventis and Novartis.

# 2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11, 2009, 5–19 j 5
RA j Insulin analogues B. Sheldon et al.

from one batch to the next. Much effort was made to pro- the relationships between the physiological profiles of
duce more pure and more reliable batches of both bovine insulin action and its structure [9]. The discovery of the
and porcine insulins, ultimately resulting in the so-called insulin receptor and detailed maps of insulin receptor
‘mono-component’ insulins. interaction has enabled the scientific community to
Initially, treatment was with regular, crystalline insulin modify the insulin molecule to achieve therapeutic ben-
given by subcutaneous injection shortly before meals. In efit [10]. Unlike most other areas of drug discovery
order to reduce the frequency of injections, a number of where serendipity and luck play a major role, the insu-
attempts were made to modify insulin in order to prolong lin analogues have been specifically designed using
its duration of action by slowing its rate of absorption a systematic approach based on a detailed knowledge of
from injection sites. Substances used to achieve this biochemistry and physiological actions of insulin.
included gum arabic, lecithin and oil suspension, but It became clear that human insulin had evolved to be
none of these proved useful clinically [2]. released directly from the pancreas into the hepatic portal
The first successful insulin preparation with a pro- circulation and that the structure and physical properties
longed duration of action was protamine insulin [3], of unmodified insulin were not best suited to achieving
which is a complex of a fish protein (protamine) and physiological replacement by subcutaneous injection. It
insulin. When injected subcutaneously, protamine is also became clear in the 1990s that the goal of treatment
degraded by proteolytic enzymes, and the insulin is should not be the avoidance of multiple injections, but
released and absorbed. The duration of action of the imitation of physiological secretion of basal and post-
preparation was roughly twice as long as that of regular prandial insulin (figure 1) and that this could be most
unmodified insulin. The relative instability of initial effectively achieved using insulin regimens that, wher-
products was improved by the addition of a small ever possible, mimicked the pattern of endogenous
amount of zinc to form protamine zinc insulin (PZI), secretion [2]. The quest for more physiological insulin
and, with further modifications, to produce neutral pro- replacement was therefore directed at the development
tamine Hagedorn (NPH). Another method of extending of short-acting analogues to mimic postprandial insulin
the action of insulin was by the addition of an excess secretion and long-acting analogues to mimic basal or
of zinc ions in variable amounts to form amorphous background insulin secretion. This was given a further
crystalline suspensions, the so-called lente insulins [4]. boost with the advent of recombinant DNA technology,
Along with regular (soluble) insulin, PZI, NPH and which has made it possible to produce human insulin
lente insulin were the mainstay of insulin treatment regi- biosynthetically and, more recently, to modify the insu-
mens for many years, and the technology used to prolong lin molecule for potential therapeutic and physiological
the action of insulin remained relatively unchanged until advantage.
the 1990s. At this time the link between metabolic control Since their introduction, insulin analogues have taken
and the development of microvascular complications an increasing share of the insulin market in countries
became firmly established [5,6]. As a result, there was where physicians are allowed to prescribe them. The rea-
renewed interest in improving glycaemic control by son for the massive increase in their use is because of both
replacing insulin in a more physiological manner, even clinician and patient choice with regimens designed to
if this meant multiple injections [2]. achieve the best possible glycaemic control with the few-
In parallel with advances in extraction and modifica- est side effects, and in the most convenient way.
tion of animal insulins to achieve extended duration of
action and a reduction in allergy caused by impurities,
50
there was a massive effort from basic scientists to under-
stand more about insulin and its physiological actions. 40
We are fortunate that insulin and diabetes have been
a focus for academic discovery in medicine and in the Serum 30
vanguard of most advances. insulin
(mU/l) 20
The Nobel Prize–winning discovery of the amino acid
sequence of insulin by Frederick Sanger was followed
10
shortly afterwards by elucidation of the three-dimensional
structure of the insulin molecule by Hodgkin [7,8]. These 0
advances, combined with the development of the radio- 0800 1200 1600 2000 2400 0400 0800 Time (h)

immunoassay by Yalow and Berson (also a Nobel prize Fig. 1 Normal physiological profile of insulin concentra-
laureate) allowed for the first time an understanding of tion [97].

6 j Diabetes, Obesity and Metabolism, 11, 2009, 5–19 # 2009 Blackwell Publishing Ltd
B. Sheldon et al. Insulin analogues j RA

In the quest to develop insulin analogues, a whole range Europe and the USA in 1996. The amino acid sequence
of different compounds has been studied, which, in addi- of the molecule is modified with reversal of lysine at posi-
tion to being of clinical value, has advanced our under- tion 28 of the B chain and proline at position 29 (figure 2).
standing of the physiology of insulin and insulin action. This reversal causes a decreased tendency for self-
Insulin replacement therapy will always struggle to association, leading to faster absorption of monomeric
mimic insulin secretion from the pancreas, which deliv- insulin. Studies have shown that following sub-
ers insulin at high concentration via the portal vascular cutaneous injection absorption is more rapid, resulting
link to the liver, and, subsequently, at far lower concen- in an earlier and higher peak serum level and a shorter
tration to the other insulin-sensitive peripheral tissues, duration of action in comparison to unmodified human
particularly skeletal muscle. Of the insulin analogues, insulin (figure 3) [15,16]. Pharmacokinetic studies have
the T4 analogue is among the most novel, and its devel- shown that insulin lispro has peak activity at approxi-
opment has shed further light on the importance of this mately 1 h and duration of action between 3 and 4 h
portal vascular link to insulin action [11]. At a cellular [15,16] (table 2).
level, receptor affinity, the importance of the ‘off’ rate The second rapid-acting analogue to achieve regulatory
and of insulin-like growth factor-I (IGF-I) receptor bind- approval (in 2000) was insulin aspart. In this insulin, the
ing in terms of mitogenicity have all been studied proline at position B28 is substituted with the charged
[12,13]. aspartic acid (figure 2) [17]. This reduces self-association
In this review, we discuss the insulin analogues in three of the molecule, allowing only weak dimeric and hex-
classes; rapid acting, premixed and long acting in differ- americ formation and thereby rapid dissociation after
ent sections. subcutaneous injection.
Receptor interaction kinetic studies have shown that
insulin aspart behaves essentially like human insulin
Rapid-acting Analogues
with regard to both the insulin and IGF-1 receptor with
On theoretical grounds, early researchers thought that a similar potency to that of human insulin (table 3). Insu-
human soluble insulin should have a rapid action, but lin aspart is absorbed twice as fast as regular insulin and
in reality it was not as rapid as was predicted. It became reaches a maximum concentration in plasma of approxi-
apparent that this was because of the slow dissociation of mately twice that of human insulin. Its activity profile is
hexamers into monomers in the subcutaneous tissue, very similar to that of human lispro [17] (see table 2).
which delays the appearance of insulin into the The third rapid-acting analogue to receive regulatory
bloodstream. approval is glulisine in which lysine and glutamic acid
Insulin mapping has shown that the positions B26–30 are substituted for asparagine and glycine at positions B3
in the region of the insulin molecule are not critical for and B29 respectively (figure 2). It is thought that this
binding to the insulin receptor. However, this portion of latter substitution is predominantly responsible for its
the molecule is important in mediating the formation of pharmacokinetic properties. Studies indicate that gluli-
insulin dimers and hence hexamers, and this sequence sine has a very comparable pharmacokinetic and phar-
has been a focus for amino acid substitutions in order to macodynamic profile to insulin lispro [18,19] (figure 3
encourage the formation of insulin monomers. Several and table 2). A glucose clamp study showed that during
approaches have been tried [14] (table 1). a 2-h continuous insulin infusion, mean glucose infu-
The first rapid-acting analogue to become available was sion rates (area under the curve) for glulisine and
insulin lispro, which was approved for clinical use in human regular insulin were superimposible [19]. Over-
all, the bioequivalence of glulisine is similar to that of
human insulin [19].
Table 1 Rapid-acting analogues: adapted from strategies for Although insulins lispro, aspart and glulisine differ in
reducing insulin self-association [98,99] terms of molecular structure, they exhibit similar phar-
macokinetic and pharmacodynamic characteristics, and
Strategy Examples
there is no obvious theoretical advantage of one over
Charge repulsion AspB28, GluB29, AspB9,
another. All three are used in the treatment of both type
GluB27, AspB21, AspB25
Decrease interface hydrophobicity GluB16, GluB27, GluB26 1 and type 2 diabetes. The pharmacokinetic and pharma-
Remove metal-ion binding site AspB10 codynamic profiles of all three, and the activity profiles
Interfere with hydrophobic contacts LysB28, ProB29 following preprandial subcutaneous injection more
and b-sheet formation closely mimic the normal physiological insulin response
Steric hindrance ValB12Ò IIe
than soluble human insulin.

# 2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11, 2009, 5–19 j 7
RA j Insulin analogues B. Sheldon et al.

Insulin Aspart:
Single
Substitution

Insulin glulisine:
Double Insulin Lispro:
Substitution Inversion

Fig. 2 Rapid-acting analogues: amino acid modifications.

Clinical Evidence – Rapid-acting Analogues there was a 50% reduction in major hypoglycaemic epi-
sodes compared with human insulin [25]. It was believed
A number of studies have shown that treatment with lis-
that the more physiological profile of these short-acting
pro (administered immediately before meals) results in
analogues would translate into improved overall glycae-
a significant improvement in postprandial glucose levels
with a lower rate of hypoglycaemic events compared with mic control, but, disappointingly, a range of studies fol-
regular human insulin (injected 30–40 min before meals) lowing have failed to show this. A Cochrane review has
[20–22]. However, in these studies, these benefits were reviewed all of these and confirmed those findings
not associated with improvements in glycosylated hae- [26,27]. However, there is evidence that the risk of noc-
moglobin (HbA1c) values [20,21]. A similar improve- turnal and severe hypoglycaemia in type 1 diabetes is
ment in postprandial glucose control has been shown significantly reduced with both lispro and aspart when
for insulin aspart, and in one study this was achieved compared with human insulin, with reductions ranging
even when the insulin was administered 15 min after from 25% with insulin lispro to 72% with insulin aspart
the beginning of a meal [23,24]. in different studies [22,28]. A similar reduction in hypo-
Lower rates of hypoglycaemia are also seen with insu- glycaemic episodes is seen with the new insulin ana-
lin aspart; in one multicentre large trial, for example, logue glulisine, with no difference being observed

80 aspart/lispro 3-5 hours


Plasma Insulin levels mU/L

60
regular 5 -8 hours

40
NPH ~14 hours

20 detemir/glargine ~24 hours

0 12 24
Hours

Fig. 3 Time–action profiles of basal and bolus insulins. NPH, neutral protamine Hagedorn.

8 j Diabetes, Obesity and Metabolism, 11, 2009, 5–19 # 2009 Blackwell Publishing Ltd
B. Sheldon et al. Insulin analogues j RA

Table 2 Action profiles of regular human insulin and short- with type 1 diabetes. They appear to be safe and effective
acting insulin analogues [19,100,101] when used in this system and compare favourably with
regular human insulin [38–41]. Proponents of pump
Onset (h) Peak (h) Duration (h)
therapy cite the introduction of the rapid-acting ana-
Regular human insulin 0.5–1 2–3 6–8 logues as a major milestone in the development of this
Insulin lispro 0.2–0.5 0.5–2 3–4
treatment modality. Rates of hypoglycaemia and pump
Insulin aspart 0.2–0.5 0.5–2 3–5
Insulin glulisine 0.332 Tmax 92 min — tolerability are generally comparable between the rapid-
acting analogues, although one study suggests that insu-
between it and lispro [27,29,30]. In addition, there lin aspart produces less hypoglycaemia than lispro [40].
appears to be an increase in patient satisfaction with
short-acting analogues, which may reflect greater ease of Children
use, particularly because owing to their more rapid
onset of action, they can be injected immediately before There have been only a small number of randomized clin-
meals [31,32]. ical trials looking at short-acting analogues in children
and adolescents. However, the available evidence
[42,43] suggest that they offer similar benefits to those
Type 2 Diabetes
seen in adults, with better postprandial glucose excur-
In type 2 diabetes, the short-acting analogues are almost sions, reduced incidence of hypoglycaemia and im-
always used as an adjunct to basal insulin to try to proved quality of life when compared with human
improve glycaemic control. There are, however, some regular insulin. Additionally the greater flexibility of
studies, notably the 4T study [33], where prandial insu- short-acting analogues has been reported to suit the
lin substitution has been used successfully. The addi- more unpredictable lifestyle seen in the paediatric and
tion of prandial insulin analogues in patients failing to adolescent population [44].
achieve good control on basal insulin alone has been
shown to be effective in reducing HbA1c although some
Pregnancy
studies have failed to show a difference in HbA1c
between regimens using short-acting analogues and reg- Short-acting analogues have been used successfully to
ular human insulin in type 2 diabetes [32,34–36]. It is treat patients during pregnancy, either with continuous
thought that this may have reflected inadequate basal subcutaneous insulin infusion or in conventional insulin
insulin substitution in these studies. A recent meta- regimens. The few trials that have been performed show
analysis [37], however, concluded that all three short- no evidence of adverse effects but only potential benefit
acting insulin analogues provide better levels of HbA1c [45,46].
and postprandial glucose than regular human insulin Most clinicians and patients believe that short-acting
without an increase in the risk of hypoglycaemia. analogues have been a major therapeutic advance. The
reason that improvements in HbA1c have not always been
demonstrated is thought largely to be because of inappro-
Special Populations
priate basal insulin substitution. That has changed more
recently with the introduction of the basal analogues. In
Pump Therapy
a recent study comparing an all-analogue regimen with
All three short-acting insulin analogues have been used in a human insulin-only regimen, there were reductions
continuous subcutaneous insulin infusions or insulin were seen in HbA1c with a reduced frequency of hypo-
pump therapy, which is most commonly used in patients glycaemic episodes [47].

Table 3 Rapid-acting analogues: receptor affinity and mitogenicity [13,102]

Insulin-like growth
Insulin receptor Insulin receptor Metabolic potency factor-I receptor Mitogenic potency
affinity (%) off-rate (%) (lipogenesis) (%) affinity (%) (Saos/B10 cells) (%)

Human insulin 100 100 100 100 100


Insulin lispro 84  6 100  11 82  3 156  16 66  10
Insulin aspart 92  6 81  8 101  2 81  9 58  22 (MCF10 cells)
Insulin glulisine ;70 Similar to HI Not reported ;20–25 Less potent than HI

# 2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11, 2009, 5–19 j 9
RA j Insulin analogues B. Sheldon et al.

Pre-Mixed Insulins The Initiate Study published in 2005 showed that twice
daily biphasic insulin aspart was more effective in
Biphasic insulin analogues such as biphasic insulin
achieving HbA1c targets than once-daily insulin glargine
aspart (30% insulin aspart and 70% insulin aspart prot-
[52]. This was a 28-week treat to target trial in patients
amine) and biphasic insulin lispro (25% lispro and 75%
with type 2 diabetes who were not controlled on oral
lispro protamine) have more desirable pharmacological
medication. Over 230 patients were randomized to treat-
properties than conventional biphasic insulin mixtures
ment with either biphasic insulin aspart given twice
[48]. They exhibit a more rapid onset and a shorter dura-
daily or insulin glargine given once daily. Insulin doses
tion of action. Biphasic insulin analogues reduce post-
were titrated weekly for the first 12 weeks and then
prandial glucose more effectively than their human
every 2 weeks to achieve target fasting plasma glucose
insulin counterparts [48]. Biphasic analogues are also
levels. At the end of the 28-week period, the mean
more convenient for patients, as they can be injected
HbA1c was 6.9% in biphasic insulin aspart group and
either immediately before or after the start of a meal.
7.4% in the insulin glargine group (p < 0.001). In addi-
They have been widely used to treat patients with both
tion, 66% of people in the biphasic insulin aspart group
type 1 and type 2 diabetes and have been extensively
achieved an HbA1c of less than 7% compared with only
studied [49]. Although there are those who believe that
40% in the insulin glargine group (p < 0.001). However,
these insulin formulations have limited value [50], they
the frequency of minor hypoglycaemic episodes was
are popular in clinical practice, particularly in patients greater in the biphasic insulin aspart group compared
with type 2 diabetes and in non-compliant patients with with the insulin glargine group (3.4  6.6 vs. 0.7  2.0,
type 1 diabetes who prefer to take just two injections episodes p < 0.05).
a day. The most studied biphasic insulin analogue is The 1-2-3 Study [53] shows the feasibility of starting
biphasic insulin aspart 30/70 [51–53]. This produces insulin therapy with once-daily premixed analogue
a single peak of activity that is higher and with a more with a simple titration escalation protocol. In this study,
rapid onset than its human counterpart [48]. 100 patients with type 2 diabetes and a mean HbA1c at
In a randomized crossover study looking at 23 patients, baseline of 8.6% were started on treatment with
biphasic insulin aspart, given three times a day, was com- biphasic insulin aspart once daily given before their
pared to human soluble insulin, also given three times evening meal. After 16 weeks, 41% of patients had ach-
a day along with NPH at bedtime. HbA1c was signifi- ieved an HbA1c of less than 7%. Those not achieving
cantly improved with both treatments, but the improve- this were required to add a second daily dose of pre-
ment was significantly greater with biphasic insulin mixed analogue at breakfast and then, after a further
aspart than with the soluble and NPH insulin regimen. 16 weeks, a third injection, if not achieving an HbA1c of
Analysis of self-monitored blood glucose results revealed less than 7%. At the end of the study, the cumulative
significantly lower postprandial blood glucose levels in proportion of patients reaching a goal of less than 7%
the insulin aspart group despite which there was no dif- was 77%. A further large, multinational, randomized
ference in the frequency of hypoglycaemic episodes [54]. study of 394 patients with type 2 diabetes showed that
A large, randomized, multicentre, 24-week study of 428 biphasic insulin aspart taken three times a day with
patients with type 2 diabetes, confirmed the finding that meals was as effective as a basal–bolus insulin regimen
biphasic insulin aspart lowered plasma glucose levels consisting of three injections a day of soluble insulin
more effectively than biphasic human insulin [55]. aspart with meals plus a fourth daily injection of NPH at
Although there was no significant difference in HbA1c bedtime. The reductions in HbA1c were comparable in
between the two groups at the end of the 24 weeks in both groups as were the incidence of adverse events and
this study, the frequency of minor hypoglycaemic epi- hypoglycaemic episodes [54].
sodes was 30% lower with biphasic insulin aspart com- Although basal–bolus insulin regimens are more phys-
pared with the biphasic human insulin group although iological, they do require at least four insulin injections
this did not quite reach statistical significance. Only one per day and are clearly more labour intensive than regi-
study has compared biphasic insulin aspart with mens using biphasic insulin, which needs to be given
biphasic insulin lispro. This was a three-arm (biphasic once, twice or, occasionally, three times a day to achieve
insulin aspart vs. biphasic insulin lispro vs. biphasic glycaemic control. Thus for the less adherent patient,
human insulin) crossover study in 61 patients with type regimens using biphasic insulin analogues remain a ther-
2 diabetes [56]. Fasting blood glucose levels were simi- apeutic option. Despite the limitations in the pharmaco-
lar in all three groups and no regimen showed a clear kinetics and dynamics of biphasic insulin analogue
advantage over the other two. mixtures, the above studies show that many patients with

10 j Diabetes, Obesity and Metabolism, 11, 2009, 5–19 # 2009 Blackwell Publishing Ltd
B. Sheldon et al. Insulin analogues j RA

type 2 diabetes and some patients with type 1 diabetes can that its duration of action is longer (table 5). Glargine
achieve good glycaemic control using them. was the first long-acting analogue to receive regulatory
approval.
Insulin detemir is acylated with a fatty acid that pro-
Basal Insulin Analogues
motes increased self-association and enables reversible
In order to create long-acting insulin analogues, the fol- binding to albumin. Detemir differs from human insulin
lowing sites can be targeted: (i) the subcutaneous depot, in that the amino acid threonine in position B30 has been
(ii) in the circulation or (iii) the interstitial compartment removed, and lysine at B29 has been acylated with a myr-
(table 4). The detailed modifications that have been istic fatty acid residue (figure 4). At the injection site,
tried and successfully adopted include the modification insulin detemir remains in solution and the molecules
of the isoelectric point of insulin (insulin glargine) and combine with each other via the fatty acid side chains to
acylation with hydrophobic residues, which results in form hexamers and dihexamers, which then bind to
the binding to albumin (insulin detemir). Both these albumin. Self-association and reversible albumin bind-
long-acting analogues are firmly established in clinical ing are thought to explain the long depot residence
practice and have led to therapeutic benefit. time. Once detemir is absorbed into the bloodstream, it
The first approach was to bioengineer the insulin mol- dissociates into monomeric complexes and binds to
ecule in order to shift the isoelectric point towards neu- albumin, which also slows its distribution in the blood-
trality, thereby reducing its solubility at physiological pH stream to peripheral tissue targets, thereby increasing its
values. Application of this principle is exemplified by duration of action [60]. Although detemir is 98% bound
insulin glargine in which asparagine is replaced by gly- to albumin in the circulation, there is no evidence of
cine at position A21 of the insulin molecule and two argi- any interaction with other albumin-bound compounds
nine molecules added at position B30 (figure 4). This or difference in kinetics in low albumin states [61]. It
results in a shift of the isoelectric point from a pH of 5.4 has been proposed that the binding of detemir to albu-
to a pH of 6.7 [57]. Insulin glargine is injected as an min might act as a buffering mechanism against any
acidic solution (pH 4.0) and forms a precipitate in the rapid or irregular changes in absorption [62]. Clamp
neutral environment of the subcutaneous space, which studies have shown that detemir has a linear dose–
is then absorbed slowly. response relationship; the pharmacokinetic profile is
Results from insulin clamp studies show that glargine consistent across different ethnic and age groups and is
has a more protracted duration of action than NPH insu- unaffected by renal or moderate hepatic impairment
lin, and that its profile is relatively smooth and without [63]. The duration of action of detemir is 17–20 h at
a significant peak. Its duration of action is approximately physiological replacement doses (table 5) and like all
20 h [58,59] at physiological replacement doses (with insulin preparations, the larger the dose, the greater is
increasing doses, glargine, like all insulins has a longer the duration of action.
duration of action). In one study, Lepore et al. [59] Using a euglycaemic clamp protocol, Hordern et al.
found insulin glargine to have no peak and duration of [64] showed that detemir had a slight hepatoselective
action of 22  4 h. In a glucose clamp study, inter- action and that this might be advantageous by partially
subject variability of the rate of glucose infusion was restoring the portal/systemic gradient of insulin action,
shown to be lower with glargine than with NPH [58,59]. which is lost when insulin is given subcutaneously
Studies from different groups have found some discrep- (figure 5).
ancy between the duration of action (pharmacokinetic) Given that different techniques have been used to
and pharmacodynamic profile; this is probably because extend the duration of action of insulin analogues, com-
of differences in study protocols (figure 3). There is now parisons between serum insulin concentrations are of
a consensus that the activity profile of glargine is limited value. The pharmacodynamic profile as mea-
smoother and with less of a peak than that of NPH and sured by glucose infusion rates can be compared (fig-
ure 6), but only if similar methodology and protocols
Table 4 Strategies for protraction are used. The best comparison to date is that reported by
Heise and Pieber [65].
Modification of isoelectric point: precipitation at pH 7.4
Insulin glargine In addition to comparative studies on pharmacody-
Acylation with hydrophobic residues (and albumin binding) namics, Heise et al. [66] have compared the intrapatient
Insulin detemir variability, which was assessed as the coefficient of var-
Other iation in glucose infusion rates in a clamp study in sub-
Strengthening of hexamer association, e.g. Co(III)-hexamer
jects with type 1 diabetes following injection of the

# 2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11, 2009, 5–19 j 11
RA j Insulin analogues B. Sheldon et al.

Fig. 4 Basal insulin analogues: amino acid modifications.

same dose of different analogues. This study showed Glargine


that the insulin analogues in general had lower variabil-
ity compared with NPH. Additionally, detemir had Type 1 Diabetes
a lower variability compared with glargine. Coefficient
Glargine has been compared with NPH in a number of
of variation (%) of glucose infusion rate (area under
studies. These have shown a reduction in fasting blood
curve 0–24 h) was 68% (NPH), 48% (glargine) and 27%
glucose but not a reduction in HbA1c relative to NPH. In
(detemir). This protocol has been repeated in patients
one study, once-a-day glargine was compared to injec-
with type 2 diabetes with similar results [67].
tions of NPH both given in combination with rapid-acting
As with the rapid-acting analogues, there is no evi-
preprandial insulin. Final HbA1c concentrations of
dence from clinical studies of problems with mitogenic
approximately 6.5% were achieved in both groups; how-
safety, despite a slightly higher IGF-I receptor affinity of
ever, there were fewer episodes of hypoglycaemia in those
insulin glargine in some cell systems (table 3).
receiving glargine [68]. Similar findings have been seen
in a number of studies of different designs [69,70]. The
Efficacy frequency and rate of nocturnal hypoglycaemia was par-
ticularly reduced in those receiving glargine. All the clin-
In clinical practice, basal insulin analogues are widely
ical studies were powered for non-inferiority rather than
used in two different regimens: as a basal-only therapy
superiority with regard to HbA1c. Glargine has been
when initiating insulin, usually in combination with oral
shown to be very popular with patients and has been
antidiabetic agents for patients with type 2 diabetes; and
embraced by many patients with type 2 diabetes who
as a basal component of basal–bolus therapy in patients
were delighted to try an alternative to the conventional
with either type 1 or type 2 diabetes. A large number of
basal preparations that had not changed for 40 years.
studies have been performed comparing the long-acting
insulin analogues with NPH. These studies have largely
served as regulatory registration studies and are therefore Type 2 Diabetes
powered for non-inferiority. Because both analogues
Studies have been performed examining the effect of glar-
(detemir and glargine) are clear solutions whereas NPH
gine in comparison to NPH as an addition to oral hypo-
is a cloudy solution, studies have been predominantly
glycaemic agents in patients with type 2 diabetes. These
unblinded, and results need to be considered in this
studies have shown that glargine is as effective as NPH at
context.
lowering HbA1c and, if a rigid and strict titration algo-
Table 5 Action profiles of insulin and basal analogues [103] rithm is employed, both insulin preparations are effective
at lowering HbA1c. Where they differ strikingly is in the
Onset (h) Peak (h) Duration (h) frequency of hypoglycaemia and particularly nocturnal
Neutral protamine 1–2 5–7 13–18 hypoglycaemia with fewer episodes being reported with
Hagedorn insulin glargine [71,72].
Insulin glargine 1–2 4–5 20 An open-label, very large surveillance study has
Insulin detemir 1–2 6–8 17–20
shown encouraging results and has demonstrated that

12 j Diabetes, Obesity and Metabolism, 11, 2009, 5–19 # 2009 Blackwell Publishing Ltd
B. Sheldon et al. Insulin analogues j RA

3.5 Detemir
(9 nmol/kg) Effect on periphery (Rd G)

2.5 Effect on liver (Ra G)

mg/kg/min
Between treatment difference:
1.5 p<0.01

0.5
0
-0.5

3.5 NPH
(0.3IU/kg)

2.5
mg/kg/min

1.5

0.5
0
-0.5

0
0
9
0
0
9
0
0
0
0
0

0
30
90

75
15
20
27
33
38
45
51
57
63
69

84
Time (min)

Fig. 5 Relative peripheral and hepatic effects of insulin detemir and neutral protamine Hagedorn (NPH) [64].

self-directed insulin titration algorithms are effective favour of insulin detemir in only two of these studies
[73]. In a recent Cochrane review [74] comparing glar- [47,80]. Overall, however, detemir was shown to
gine with NPH, using strict and objective criteria for improve fasting blood glucose levels, but with no clini-
randomized clinical trials, four studies were entered cally significant difference in HbA1c compared with
into a meta-analysis [75–78]. The weighted mean was NPH. However, use of detemir is associated with a con-
estimated to be 0.1% (95% confidence interval (CI) 0.1 sistently lower risk of hypoglycaemia, particularly noc-
to 0.2; p ¼ 0.49) in favour of NPH (non-significant). turnal hypoglycaemia in these studies. A recent pooled
Using slightly less strict criteria, and with the addition analysis from four multi-centre randomized clinical tri-
of two other studies [72,79], the weighted mean differ- als involving over 1100 patients receiving detemir and
ence of change in HbA1c from baseline to study end- 810 receiving NPH, found that the relative risk of hypo-
point was estimated to be 0% (95% CI 0.1to 0.1; glycaemia was 22% lower in patients randomized to
p ¼ 0.93). Thus, no superiority in terms of lowering detemir (p < 0.001) [88,89]. A number of studies have
HbA1c was shown for insulin glargine. However, in the also shown a reduced variation in individual fasting
above Cochrane review, a significant reduction in the plasma glucose, and one study using involving CGMS
relative risk for symptomatic and overall hypoglycaemia showed a lower fluctuation of blood glucoses compared
with glargine was observed [risk ratio (RR) 0.84, 95% CI with NPH [82]. It is of considerable note that one study
0.75 to 0.95; p < 0.005]. If symptomatic nocturnal hypo- comparing an all-analogue basal–bolus regimen with
glycaemia was also examined there was a relative risk of a human soluble and NPH basal–bolus regimen showed
0.66 (95% CI 0.55 to 0.80; p < 0.001) in favour of treat- clear advantages in favour of the analogue regimen with
ment with glargine. These results are consistent with regard to HbA1c and hypoglycaemia [47].
most published studies on glargine in type 2 diabetes. To date, only one study has directly compared the
effects of detemir and glargine in patients with type 1
diabetes [81]. The results from this 26-week study
Insulin Detemir
showed that detemir was similar to glargine at improv-
ing HbA1c and nine-point plasma glucose profiles
Type 1 Diabetes
were similar on both insulins. There was, however,
Most studies have compared insulin detemir with NPH, a slightly reduced risk of both major and nocturnal
although there is one direct comparison with insulin glar- hypoglycaemia in those treated with detemir. Fur-
gine. Of nine studies [47,80–88] comparing detemir to ther comparative studies are required to confirm these
NPH, there was a significantly lower HbA1c level in findings.

# 2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11, 2009, 5–19 j 13
RA j Insulin analogues B. Sheldon et al.

Fig. 6 Basal insulin analogues: summary of pharmacodynamic data [65]. (a) glargine and (b) Levemir.

A consistent finding in studies of detemir in type 1dia- glycaemic control as measured by HbA1c levels whether
betes is the observation of less weight gain in comparison given pre-breakfast or in the evening [91]. A meta-analysis
to NPH (see below). was performed in the recent Cochrane [74] review
[90,92]. HbA1c levels were slightly lower with insulin
detemir than NPH but although statistically significant,
Type 2 Diabetes
the difference was well inside the inferiority margin of
A number of clinical trials have compared detemir with 0.4% and was not thought to be clinically significant.
NPH. The results have shown that in titration-directed The meta-analysis found that the overall relative risk of
algorithms, similar reductions in HbA1c are seen in pa- hypoglycaemic episodes was lower with detemir (RR
tients treated with NPH and detemir, but the number of 0.82; 95% CI 0.74 to 0.9; p < 0.0001), while the risk of
hypoglycaemic episodes is fewer with detemir [90–92]. nocturnal hypoglycaemia was even lower with detemir
The risk of nocturnal hypoglycaemia was 61% lower than (RR 0.63; 95% CI 0.52 to 0.76; p < 0.0001).
with detemir than NPH, together with lower within- A consistent finding from clinical trials with detemir is
subject variability of plasma glucose levels. Compared that it is associated with less weight gain in patients with
with NPH, detemir produced similar improvements in both type 1 and type 2 diabetes compared with both NPH

14 j Diabetes, Obesity and Metabolism, 11, 2009, 5–19 # 2009 Blackwell Publishing Ltd
B. Sheldon et al. Insulin analogues j RA

and insulin glargine [90,91,93]. The mechanism under-


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