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Management of diabetes mellitus:
is the pump mightier than the pen?
John C. Pickup
Abstract | Continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) reduces HbA 1c levels
and hypoglycaemia in patients with type 1 diabetes mellitus (T1DM) compared with multiple daily insulin
injections (MDI). The greatest reduction in HbA1c levels with CSII occurs in patients with the worst glycaemic
control; therefore, the most appropriate and cost-effective use of CSII in adults with T1DM is in those who
have continued, elevated HbA1c levels or disabling hypoglycaemic episodes with MDI (including the use of longacting insulin analogues and structured patient education). The disadvantages of CSII include higher costs
than MDI and the risk of ketosis in the event of pump failure. In children with T1DM, CSII may be used when
MDI is considered impractical or inappropriate. Pumps are not generally recommended for patients with type 2
diabetes mellitus but may improve control in some subgroups. A new generation of smaller insulin infusion
pumps with an integrated cannula, called patch pumps, could improve uptake of CSII in general. The important
clinical question is not whether CSII is more efficacious than MDI in general adult T1DM, but whether CSII
further improves glycaemic control when this control continues to be poor with MDI, and evidence exists that in
most cases it does.
Pickup, J. C. Nat. Rev. Endocrinol. 8, 425–433 (2012); published online 28 February 2012; doi:10.1038/nrendo.2012.28
Introduction
Over the past 30 years, two main intensified insulin regimens have been used to achieve strict glycaemic control
in patients with type 1 diabetes mellitus (T1DM). Both
were introduced in the late 1970s1,2 and aim to achieve
the best control by mimicking nondiabetic insulin secretion patterns: a slow, basal delivery throughout the 24 h
and boosts (boluses) at meal times.
Continuous subcutaneous insulin infusion (CSII), also
known as insulin pump therapy, uses a small, portable
electromechanical pump to infuse short-acting insulin
via a subcutaneously implanted cannula to provide
basal delivery, with patient-activated prandial boluses.3
Multiple daily insulin injections (MDI), also known as
basal–bolus therapy, is a regimen that employs longacting insulin formulations (originally isophane or
lente types but nowadays usually the insulin analogues
glargine or detemir) to supply the basal component, with
short-acting insulin injected at or before meals.4 Insulin
‘pens’ were introduced in 1981 as convenient injection
devices in which the insulin is contained in a cartridge
inside a pen-like implement, which incorporates a fine
replaceable needle.5 The convenience, ease of use and
less painful injection associated with insulin pens has
increased patient acceptance of multiple injections, and
pens are now commonly used as a part of MDI regimens
in many countries.
Competing interests
The author declares associations with the following companies:
Animas, Cellnovo, Medtronic, Roche. See the article online for
full details of the relationships.
Neither insulin pumps nor MDI (whether insulin is
delivered via a pen or a syringe and needle) should be
considered in isolation. Both are part of a package of measures for intensive insulin therapy that also includes frequent self-monitoring of blood glucose (SMBG), regular
exercise, structured diabetes education with advice on
insulin dosage adjustment for the size and composition
of the meal (‘carbohydrate counting’), dietary advice and
frequent contact with health-care professionals.
Understandably, the question of whether insulin pump
therapy is ‘better’ than MDI requires debate, because CSII
is more expensive and complex than MDI. Organizational
problems could arise in setting up an insulin pump service
with the necessary specialist team of at least one physician
with an interest in pumps and a diabetes specialist nurse
and dietitian trained in CSII procedures.6 Moreover, considerable advances in MDI have occurred over the past
few decades, with the introduction of long-acting insulin
analogues with more predictable subcutaneous absorption and flatter blood insulin profiles than traditional
long-acting insulin formulations7 and a renewed interest in structured diabetes education. 8 Together, these
advances have resulted in excellent levels of glycaemic
control in many individuals with T1DM.
In the UK, the National Institute for Health and Clini­
cal Excellence (NICE) has recommended CSII as a costeffective treatment option in adults with T1DM when
attempts to achieve target HbA1c levels with MDI have
resulted in disabling hypoglycaemia or when HbA 1c
levels have remained high (≥8.5%) despite best efforts
(Box 1).6 In children with T1DM, MDI is often considered
NATURE REVIEWS | ENDOCRINOLOGY Diabetes Research
Group, King’s College
London School of
Medicine, Guy’s
Hospital, London
SE1 1UL, UK.
[email protected]
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REVIEWS
Key points
■■ Continuous subcutaneous insulin infusion (CSII) can reduce HbA1c levels
and hypoglycaemia in many patients with type 1 diabetes mellitus (T1DM),
compared with multiple daily insulin injections (MDI)
■■ However, an MDI regimen that includes frequent self-monitoring of blood
glucose levels and structured diabetes education can achieve good glycaemic
control in many individuals with T1DM
■■ A trial of CSII is indicated in patients who do not achieve acceptable glycaemic
control with MDI because of continued, elevated HbA1c levels or disabling
hypoglycaemic episodes
■■ The greatest reduction in HbA1c levels with CSII occurs in patients with T1DM
who have the worst glycaemic control with MDI
■■ Blood glucose variability, quality of life and treatment satisfaction are also
usually improved with CSII versus MDI
■■ Sensor-augmented insulin pump therapy further improves glycaemic control,
with the best effect in patients with the highest HbA1c levels and in those who
use the sensor most often
Box 1 | Summary of NICE guidance on the indications for CSII
Adults and children ≥12 years with T1DM
CSII is recommended as a treatment option when attempts to achieve target
HbA1c levels with MDI have resulted in disabling hypoglycaemia or when HbA1c
levels have remained high (≥8.5%) despite a high level of care
Children <12 years with T1DM
CSII is recommended as a treatment option when MDI is considered impractical
or inappropriate, and with the expectation that children would normally undergo a
trial of MDI between the ages of 12 and 18 years
Other important points
■■ CSII should be discontinued (in adults and children ≥12 years who have been
started on CSII because of elevated HbA1c or disabling hypoglycaemia) if no
sustained improvement in HbA1c or rate of hypoglycaemic episodes occurs
■■ CSII should be initiated by a specialist team consisting of at least a diabetes
physician with a special interest in pump therapy, and a diabetes specialist
nurse and dietitian trained in CSII
■■ CSII should be considered in pregnancy or preconceptually in women with T1DM
when the target HbA1c (normally ≤6.1%) in the first trimester or preconceptually
cannot be achieved without disabling hypoglycaemia
■■ CSII is not generally recommended in type 2 diabetes mellitus, although some
subgroups may benefit
Abbreviations: CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin
injections; NICE, National Institute for Health and Clinical Excellence; T1DM, type 1
diabetes mellitus.
impractical or inappropriate to deliver at school because
children might be unwilling or unable to inject or need
a parent to come to school to give a lunchtime injection,
or they might be restricted from school trips and various
activities because of the need to inject.6,9 Under these
circumstances, CSII has been recommended by NICE
for children, without them first having to have failed to
achieve adequate glycaemic control with MDI. Other
countries have adopted similar guidelines for CSII use.8,10
A treatment pathway for the management of T1DM
by intensive insulin therapy can, therefore, be proposed
(Figure 1). In adults, MDI is usually the first-line intensive insulin regimen, and many (probably most) patients
can achieve target HbA1c levels with this strategy. For the
~20% of patients who have continued disabling hypo­
glycaemia and/or elevated HbA1c levels with MDI, a trial
of CSII is indicated. In most cases, CSII achieves a clinically significant improvement in glycaemic control in this
426 | JULY 2012 | VOLUME 8
group; however, in the minority who still have poor glycaemic control, other measures, such as combining pump
therapy with continuous glucose monitoring (CGM),
might be indicated (see below).
The important clinical issue is, therefore, not whether
insulin pumps are more efficacious than MDI in the
general adult population with T1DM, but whether pumps
improve glycaemic control when it continues to be poor
with MDI. Unfortunately, many of the trials that have compared CSII and MDI have been carried out in unselected
patients with T1DM, making judgments about the merit
and appropriate use of either therapy sometimes difficult.
Known benefits of CSII versus MDI
Hypoglycaemia reduction
A meta-analysis has shown that in patients with a clinically significant problem with severe hypoglycaemia
(namely, episodes requiring third-party assistance), the
frequency of such hypoglycaemia is reduced by a mean
of ~75% during treatment with CSII compared with MDI
(rate ratio 4.19, 95% CI 2.86–6.13).11 In this meta-analysis,
care was taken only to select trials of adequate duration
that involved the use of modern pumps and monomeric
insulins in the pump. In this analysis, there were relatively
few randomized controlled trials (RCTs) that compared
the rate of severe hypoglycaemia with MDI and CSII,12–14
compared with the larger number of observational studies.
Patients who experience the highest frequency of severe
hypoglycaemic episodes with MDI at baseline show the
greatest reduction with CSII, and the rate ratio (hypoglycaemia on MDI:CSII) can reach 10–20 in those with
very frequent severe hypoglycaemia on MDI (Figure 2).11
The meta-analysis also shows that both adults and children have reduced hypoglycaemia with CSII; however,
the reduction is somewhat smaller in children than adults
(for example, a mean rate ratio of about 3 in a 10-year
old child) because children generally have a shorter
duration of T1DM than adults and, therefore, less frequent hypoglycaemia—the frequency of hypoglycaemia
increases as duration of T1DM increases.15 Some reported
meta-analyses have indicated no significant reduction in
severe hypoglycaemia with CSII versus MDI,16,17 but these
studies have included short-term trials in which rates of
severe hypoglycaemic episodes cannot be accurately
assessed (<6 months) and trials with very low rates of
hypoglycaemia at baseline and the studies are, therefore,
misleading. Mild-to-moderate hypo­glycaemia, recorded
as SMBG-measured tests <3.5 mmol/l, is also reduced by
about 75% with CSII versus MDI.18
Reduced HbA1c levels
In several meta-analyses comparing glycaemic control
during CSII and MDI, the mean HbA1c difference between
the two therapies has been reported to be about 0.5–0.6%,
favouring CSII.11,19,20 A Cochrane review 21 has reported a
somewhat lower mean difference of 0.3%; however, this
review included studies of very short duration and early
trials from the 1980s when pumps were less reliable and
less technically sophisticated (for example, in the flexibility
of the infusion rate adjustments that were possible).
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Blood glucose variability
Glycaemic variability, particularly when unpredictable, is
a major frustration for patients with T1DM that prevents
logical alteration of insulin regimens in order to improve
glycaemic control. High glycaemic variability correlates
with an increased frequency of hypoglycaemia, 26 and
individuals with the most variability maintain the highest
HbA1c level on MDI,22 probably to avoid increasing the
frequency of hypoglycaemia as attempts are made to
tighten control. CSII reduces both the within-day and
day-to-day variability, as determined by a reduction in
the mean amplitude of glycaemic excursions27 and the
standard deviation or interquartile range of either daily
or successive fasting blood glucose levels.22 This improvement is probably because the large variation in subcutaneous absorption associated with large injected volumes
of long-acting insulin (±50% for isophane) is reduced
to about ±3% with CSII (probably because there is a
subcuta­neous insulin depot of only about 1 unit at any
time during basal rate infusion).28
CSII versus MDI with long-acting analogues
Most of the RCTs comparing glycaemic control with CSII
or MDI involve traditional isophane-based long-acting
insulin as the basal component of the MDI regimen,
rather than one of the more recently introduced longacting insulin analogues, glargine or detemir. These two
insulin analogues are now commonly used in MDI regimens. Many physicians consider it best practice either
to use glargine or detemir insulins as a first-line choice
for the basal insulin of MDI, or to switch patients to
glargine or detemir if they are not achieving target levels
of gly­caemic control with isophane-based MDI. Although
many patients achieve excellent control with these insulin
analogues, others do not, and as recommended by NICE
in the UK, these patients should be offered a trial of
CSII.6 A group of 16 patients with T1DM who had poor
glyca­emic control with isophane-based MDI and who
MDI:
■ Basal/bolus insulin injections
■ Structured education: including insulin dosage adjustment at meals, dietary advice
■ Frequent SMBG
■ Frequent contact with health-care professionals
Satisfactory glycaemic control ~80%
Continued disabling hypoglycaemia
and/or elevated HbA1c level ~20%
Much improved glycaemic control ~70–80%
Trial of CSII considered
Continued poor control ~20–30%
CGM and other measures
Figure 1 | A proposed treatment pathway for adults with type 1 diabetes mellitus.
MDI is the mainstay regimen for achieving strict glycaemic control; patients who
have a continuously elevated HbA1c level or frequent and disabling hypoglycaemia
with MDI (approximately 20%), should then be offered a trial of CSII. Most patients
have improved glycaemic control on insulin pump therapy but those who do not (for
example, because they have continued disabling hypoglycaemia) might benefit
from further measures such as sensor-augmented pump therapy (CSII with CGM).
Abbreviations: CGM, continuous glucose monitoring; CSII, continuous
subcutaneous insulin infusion; MDI, multiple daily insulin injections; SMBG,
self-monitoring of blood glucose.
Mean hypoglycaemia rate ratio
Both meta-regression of mean HbA1c levels from con­
ducted trials11 and data from individual patients22–24 show
that the greatest reduction in HbA1c levels with CSII
occurs in those with the highest HbA1c level on MDI at
baseline (Figure 3). Thus, although the mean HbA1c difference between the two therapies is a rather modest 0.5–
0.6% for the whole population with T1DM and unlikely
to be cost-effective, in the substantial number of patients
with an elevated HbA1c level on MDI, a marked reduction
can occur—for example, ~1.5–2.0% when the baseline
HbA1c value is 10%. Because of the curvilinear relationship between HbA1c level and microvascular risk,25 reductions in HbA1c level from this high starting point produce
a more marked reduction in the risk of diabetic complications and better cost-effectiveness than that achievable for
unselected patients with a lower mean HbA1c level. NICE
in the UK judged that, when quality of life improvements
are taken into account along with reductions in HbA1c
level, CSII is cost-effective when HbA1c levels on MDI
are ≥8.5% and, therefore, used this cut-off value in their
guidance (Box 1).
10
1
10
100
1,000
Mean hypoglycaemia rate on MDI
(episodes per 100 patient-years)
Figure 2 | Meta-regression of severe hypoglycaemia rate
ratio (MDI:CSII) with hypoglycaemia rate with MDI as a
covariate. Data were obtained from trials reported in a metaanalysis.11 The greatest effect of CSII at reducing severe
hypoglycaemia is in patients with type 1 diabetes mellitus
with the highest frequency of hypoglycaemia at baseline.
Abbreviations: CSII, continuous subcutaneous insulin
infusion; MDI, multiple daily insulin injections. Permission to
adapt obtained from John Wiley and Sons © Pickup, J. C. &
Sutton, A. J. Diabet. Med. 25, 765–774 (2008).11
remained poorly controlled on glargine MDI benefited
from a fall in HbA1c level from 8.7 ± 1.2% (mean ± SD) on
MDI to 7.2 ± 1.0% when they were transferred to CSII.29
Comparatively few RCTs have compared MDI using
long-acting analogues versus CSII. Doyle et al.30 randomly allocated adolescent patients with T1DM to
receive either CSII with aspart insulin or to MDI with
glargine and aspart, with a follow-up of 16 weeks. Whilst
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Mean HbA1c difference (%)
2.0
1.5
1.0
0.5
0.0
7
–0.5
8
9
10
11
Mean MDI HbA1c (%)
Figure 3 | Meta-regression of the mean difference in HbA1c
level (CSII versus MDI) with HbA1c on MDI as a covariate.
Data were obtained from trials reported in a metaanalysis.11 The greatest reduction in HbA1c level achieved
by CSII is in patients with type 1 diabetes mellitus with the
highest HbA1c level at baseline. Abbreviations: CSII,
continuous subcutaneous insulin infusion; MDI, multiple
daily insulin injections. Permission to adapt obtained from
John Wiley and Sons © Pickup, J. C. & Sutton, A. J. Diabet.
Med. 25, 765–774 (2008).11
the HbA1c level in adolescents treated by MDI did not
change over the study period (8.2% at baseline, 8.1% at
completion), the level in those on CSII fell from 8.1%
to 7.2% at completion (P <0.05 versus MDI). In a shortterm study, Hirsch et al.31 randomly allocated 100 patients
with T1DM to either CSII or MDI based on glargine for
5 weeks. The researchers reported significantly lower
serum levels of fructosamine (indicating lower average
blood glucose levels) and area under the curve of gly­
caemia measured by CGM for CSII than MDI. By contrast, Bolli et al.32 reported a similar decline in HbA1c
level when isophane-treated individuals with T1DM were
randomly allocated to either CSII or MDI with glargine
(–0.7% for CSII and –0.6% for MDI). However, the baseline HbA1c level of the participants of this study was not
excessively elevated (7.7% for CSII and 7.8% for MDI);
therefore, no significant treatment difference in terms of
reduction in HbA1c level would be expected (Figure 3).
The advantage of insulin pump therapy over MDI
has probably diminished somewhat since the advent of
long-acting insulin analogues,33 in the sense that fewer
patients ‘fail on MDI’ because of mild to moderate nocturnal hypoglycaemia or glycaemic variability, which are
often improved with glargine or detemir. However, little
or no evidence exists that HbA1c levels or the frequency
of severe hypoglycaemia are lower if MDI is based on
long-acting analogues rather than isophane.34,35
Thus, the number of patients who have continued episodes of severe hypoglycaemia and/or elevated HbA1c
with MDI and are, therefore, suitable for a trial of CSII
is probably largely unchanged after the introduction of
glargine-based or detemir-based regimens.
Quality of life and psychosocial factors
The discontinuation rate for CSII (those who revert
to MDI by choice or because their health-care profes­
sionals judge them to be receiving little or no value from
pump therapy) is low at most centres, at about ≤5%. This
428 | JULY 2012 | VOLUME 8
rate of satisfaction is surprisingly high considering the
com­plexity and demands of pump treatment. Formal
compari­sons of quality of life using validated measures
have given mixed results in some studies; for example,
Tsui et al.36 showed no benefit of CSII versus MDI—
although in this study, the baseline HbA1c level was again
relatively low at 7.7% for CSII and 8.2% for MDI, and no
difference in glycaemic control between treatments was
found. By contrast, many studies, both RCTs and observational studies, have reported a significant improvement
of quality of life with CSII compared with MDI.37–41
Patients on pump therapy in ordinary clinical practice
often report improvements in thinking, mood and wellbeing when they are transferred from MDI, and these and
other psychosocial factors are being increasingly reported
more formally in research studies of CSII. Knight et al.42
showed that the improvement in HbA 1c level upon
switching to CSII in children with T1DM was accompanied by improvements in a number of measures of cognition, such as perceptive reasoning, selective attention and
working memory. Parents reported fewer mood-related
symptoms and fewer behavioural problems in the children. Interestingly, quality of life improvements extend
to the parents as well as the children who are treated by
CSII, with lower parental stress, hypoglycaemia worry
and overall diabetes burden.41
Good and not-so-good control on CSII
Large international surveys of CSII indicate that most
patients have good glycaemic control with CSII; for
example, in nearly 15,000 pump patients in North
America and Europe the mean HbA1c level was 7.0%.43
How­ever, notable proportions of patients on CSII continue to have suboptimal glycaemic control, although
con­trol is usually much better than with MDI. In an audit
of 104 people with T1DM on CSII, 27% had an HbA1c
level of ≥8.5%.44 The reasons why glycaemic control
cannot be further improved in some individuals needs
further study, and a number of possible reasons are being
explored. Fear of hypoglycaemia is common in T1DM,
including patients on CSII,44 and, logically, some patients
might resist tightening glycaemic control because they
are concerned about hypoglycaemia; however, one study
has shown no correlation between the HbA1c achieved on
CSII and fear of hypoglycaemia.44
Other psychological factors probably play a more
impor­tant role in patients with suboptimal glycaemic
con­trol with CSII than fear of hypoglycaemia. Aberle
et al.45 found that a high HbA1c level on CSII correlated
with a high external locus of control, in which indivi­
duals believe that disease and life events are dependent
on external factors and beyond their control and that
no action needs to be taken. Generally, the best predictor of how well patients will do on CSII is their HbA1c
level with MDI: those who are poorly controlled on MDI
tend to be amongst the most poorly controlled on CSII,44
although they have the highest change in HbA1c from
baseline, as mentioned above. Thus, a patient with an
HbA1c level of 10.5% with MDI might expect to benefit
from about a 1.7% reduction in HbA1c after switching to
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CSII (Figure 3), but the outcome HbA1c level of 8.8% will
still be suboptimal.
Studies of patients with T1DM who have been treated
by CSII for several years show that the mean HbA1c level
for the group is best after about 6–12 months and then
deteriorates slightly, although good glycaemic control
is maintained.46,47 However, within the group, clinical
experi­ence shows that some individuals initially do well
with CSII, whereas their glycaemic control deteriorates
quite markedly after a year or so. Nevertheless, the proportion of ‘deteriorators’ and extent or worsening have
not been well-documented. One could speculate that
factors such as reduced enthusiasm or contact between
patient and/or health-care professionals or the develop­
ment of intercurrent illness or other issues could be
important in worsening of glycaemic control over time,
but no formal studies have been reported.
Pump features not enjoyed by MDI
Bolus profiles
The meal-time insulin bolus with CSII is probably
best delivered for most meals as quickly as possible.48
However, most pumps have the facility for selecting
alternative bolus profiles—either an extended or square
wave delivered typically over some hours, or a dual-wave
or combination-wave in which a proportion of insulin
is given immediately and the rest as an extended wave.
Experimental studies show that the square wave option
better controls blood glucose levels after a fatty meal,
when gastric empty­ing is slowed and insulin resistance
can occur for some hours.49 Extended-wave boluses might
also be useful in some cases of gastroparesis, in which
gastric emptying is also delayed.
Heinemann50 has, however, pointed out that rigorous
examination of many of the studies comparing postprandial glycaemic control after standard versus extended or
dual-wave boluses have problems of experimental design,
such as different premeal glucose or insulin levels on the
test days, and are, therefore, difficult to interpret. Overall,
the evidence base for the value of extended meal insulin
profiles is suggestive but relatively weak at the moment.
Bolus calculators
On-board bolus calculators or ‘wizards’ were introduced into insulin pumps in 2002 and serve to recom­
mend to the patient an appropriate meal insulin bolus
based on premeal blood glucose concentration, intended
carbo­hydrate to be eaten, target blood glucose levels,
insulin:carbohydrate ratio, insulin sensitivity and insulin
onboard (that remaining after the previous meal). Trial
evi­d ence, although limited, suggests that the mean
postprandial blood glucose concentration is reduced in
patients using bolus calculators versus manual estimation
of meal insulin. For example, Sashaj et al.51 found that
the mean peak postprandial glucose level in indivi­duals
randomly allocated to an insulin pump with use of bolus
calculator was 9.2 mmol/l compared with 10.5 mmol/l
during CSII without the calculator. Similar bolus calculators are now being introduced for MDI users; however,
they are yet not in common use.
Computer downloads
The data from most modern pumps can be downloaded
to a computer or to the web, and a wealth of information
is available to the patient and health-care professional,
such as number and magnitude of basal rate changes and
temporary rates; timing, size and type of meal boluses;
correction doses; pump alarms; carbohydrate given;
entered meter blood glucose values or CGM data, if in
use. This data is useful for uncovering pump problems
such as nonadherence or misunderstanding of pump procedures and often helps to optimise control. Interpreta­
tion of data can be time consuming. On a cross-sectional
basis, patients who use the download capability of pumps
have lower HbA1c values than those who do not,52 but that
might be because they are generally more motivated and
en­thusiastic in their diabetes care.
CGM connectivity
CGM can be used with CSII; this combination is sometimes known as sensor-augmented pump therapy. CGM
can also be used with MDI;53 however, for some insulin
pump models, CGM data can be wirelessly transferred
from the implanted glucose sensor to the pump itself,
giving a display of glucose values and trends that enable
the patient to optimise control. Meta-analysis of RCTs of
real-time CGM or SMBG used with either CSII or MDI
shows that CGM is associated with a significant lowering
of mean HbA1c level of ~0.3%.54 However, best-fit models
created using individual patient data from RCTs of realtime CGM versus SMBG indicate that the best effect
on HbA1c levels in patients using CGM occurs in those
who use the sensor most frequently and/or who have the
highest baseline HbA1c level.54 For example, a patient who
uses CGM 7 days per week and has a baseline HbA1c level
of 10% might expect a reduction in HbA1c of about 0.9%
when using CGM compared with SMBG.54
The most appropriate and cost-effective use of CGM
in pump users is, therefore, likely to be in those who have
not achieved target HbA1c levels after an extended trial
of CSII, and in those who use CGM almost daily. Why
some patients use the sensor less than others is not completely clear. Low use might be associated with patients
who are less engaged with their diabetes care in general,
perceive little benefit from CGM, have body image issues
connected with wearing the device or, most probably,
react negatively to the complexity, demands and burden
of current CGM use, such as sensor insertion, calibration
and responding to alarms.
Hypoglycaemia changes during CGM versus SMBG
when used with either CSII or MDI have been less wellstudied than HbA1c changes. Evidence exists for a signifi­
cant reduction in sensor-measured mild-to-moderate
hypoglycaemia with CGM versus SMBG.54,55 How­ever,
even though CGM was originally developed for the
clinical problem of frequent severe hypoglycaemia, the
approach has not been evaluated in an RCT specifically in
patients with this clinical problem. Uncertainty, therefore,
exists about the impact of this technology when used in
patients who have continued disabling hypo­glycaemia
on CSII.
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Hypoglycaemia, however, could be reduced by another
CGM-linked technology: low-glucose insulin-suspend
(LGS) pumps. One commercially available pump now
has an LGS facility whereby CGM values that fall below
a preset hypoglycaemic threshold automatically activate a
suspend of the basal insulin infusion rate for up to 2 h,
which enables glucose levels to re-enter the target range.
In a short-term trial, the duration of nocturnal hypoglycaemia during CSII when the LGS was activated
was reduced by 96% in those with the highest quartile
of hypoglycaemia at baseline.56 This technology is an
example of the ‘control-to-range’ strategy,57 whereby
glucose levels are allowed to fluctuate between quite wide
upper and lower limits. Control to range can be considered as a first step towards fully closed-loop insulin delivery and the ‘artificial pancreas’. Future insulin pumps of
this type are expected to have a trigger for the suspension
of insulin that is activated by the rate of fall and thus the
predicted rather than absolute glucose level. Subsequent
versions may also have activation of an insulin boost
when the CGM trace exceeds a preset high blood glucose
level threshold.
CSII versus MDI in diabetic pregnancy
CSII has potential advantages that would be especially
useful in pregnant women with T1DM, including
improved HbA1c level, and reduced frequency of hypoglycaemia and glycaemic fluctuations. But potential
dis­advantages include the risk of ketoacidosis if pump
delivery is interrupted and the sometimes long learning
curve for patients to become ‘pump-educated’.58 CSII is
safe and effective in pregnancy, but no convincing evidence exists from either observational studies or the
relatively few RCTs conducted that glycaemic control
or pregnancy outcomes differ between CSII or MDI.59–62
Maternal hypoglycaemia, ketoacidosis, retinopathy
progression, pre-eclampsia, spontaneous miscarriage,
congenital abnormalities, birth weight, neonatal hypoglycaemia and stillbirths have all been found to be similar
during CSII or MDI in pregnant women with T1DM.
In clinical practice, many health-care professionals
reserve CSII in pregnant women with T1DM for the
subset who have not achieved strict glycaemic control
with MDI. This subset often show an improvement when
they are switched to CSII.59 However, an RCT is needed
to compare glycaemic control with CSII versus MDI in
this group.
Patch pumps and technology developments
The term patch pump refers to a new generation of
insulin infusion pumps that are smaller than existing
pumps; they are usually attached to the body by an adhesive patch and have an integrated cannula and are, therefore, sometimes called ‘tubeless’ pumps.63 Many patch
pumps are simpler to operate than conventional pumps,
and some are controlled by a hand-held remote, perhaps
with a touch screen. This new technology has at least
two major implications. Firstly, the small size and relative
simplicity makes the pumps more suitable than conventional pumps for use in type 2 diabetes mellitus (T2DM).
430 | JULY 2012 | VOLUME 8
Patients with T2DM, who are often elderly, frequently
cannot tolerate the relatively large size of conventional
pumps. In addition, this type of pump can be managed
by relatively simple infusion regimens, such as one basal
rate throughout the day. Some manufacturers are, therefore, targeting their patch pumps specifically at patients
with T2DM. Secondly, the improved ease-of-use and
less obtrusive size promises that patient acceptance will
be good, which might increase uptake of insulin pump
therapy in general.
Potential disadvantages of CSII
Cost
Insulin pump therapy is more expensive than MDI, with
a typical pump costing about £2,500 or more in the UK,
with a 4–6 year warranty, and additional consumable
costs related to infusion sets, reservoirs and batteries.
The annualised cost of CSII was estimated to be about
£1,600 greater than that of MDI in 2009,3 but without
including the costs of extra staff training and medical,
nursing and dietitian time needed to run the service.
Several cost-effectiveness studies comparing CSII and
MDI have been published, 6,64–67 including one in the
UK NICE guidelines on CSII.6 The cost-effectiveness
models used incorporate the expected reduction in
HbA1c levels with CSII, and, therefore, the reduced risk
of microvascular disease and associated health-care
costs. Hypoglycaemia reduction has less effect on costs
but improves quality of life and can be factored into the
cost-effectiveness analysis.6
CSII is generally considered to be cost-effective in
these models, with an incremental cost-effectiveness
ratio varying from about £17,000 to £35,000 per qualityadjusted life year compared with MDI, depending on the
baseline HbA1c level with MDI. NICE has an informal
willingness-to-pay threshold of about £20,000–30,000
per quality-adjusted life year gained, and considers that
CSII is a cost-effective use of National Health Service
resources in the UK for the two clinical indications of
continued disabling hypoglycaemia and HbA 1c level
≥8.5% during MDI.
Pump complications
The frequency of diabetic ketoacidosis is not significantly
different during modern CSII versus MDI;6,16,68 however,
the potential risk of ketoacidosis is greater with CSII in
the event of pump malfunction with interrupted insulin
delivery, or with the increased insulin requirements
of illness, because of the smaller subcutaneous insulin
depot with CSII. For this reason, regular SMBG and a
prompt response to hyperglycaemia is a crucial part of
pump management.3 Skin infections at the site of infusion are rare and minimized by the standard practice of
changing the cannula and site every 2–3 days and a notouch technique for insertion.68 Modern insulin pumps
are very reliable and robust compared with the original
models of the 1970s and 1980s, but a variety of technical
pump and cannula problems still occur, and the system
is undoubtedly more complex and liable to malfunction
than the pens, syringes and needles of MDI.
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© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
CSII in type 2 diabetes mellitus
Insulin pump therapy is not generally recommended for
use in T2DM,6 a view that is based on the lack of RCT
evidence for any difference in glycaemic control between
CSII and MDI in T2DM.69–72 Nevertheless, in several
observational studies in which patients with T2DM have
been switched from MDI to CSII, the HbA1c fall is significant and clinically meaningful, with a weighted mean
change of about 0.95%.73–79 As with T1DM, individuals
who had the highest HbA1c level at baseline on MDI in
these studies had the greatest improvement when transferred to CSII. Often these patients were obese or insulin
resistant, had an elevated HbA1c level and coexistent diseases which made glycaemic control difficult with MDI.
The fall in HbA1c level is often associated with improved
quality of life and treatment satisfaction.80 Retrospective
surveys of patients with T2DM transferred from MDI to
CSII show that the fall in HbA1c level is maintained over
a follow-up period of up to 6 years.81
The use of U500 insulin (insulin at a strength of
500 units/ml) in patients with T2DM treated by CSII is
also being increasingly explored in subsets of patients
with poor glycaemic control. Lane et al.,82 for exam­ple,
studied 20 insulin-resistant patients with T2DM (mean
insulin dose 1.7 U/kg) who were uncontrolled on U100
(100 units/ml) insulin via CSII or MDI. When switched
to CSII with U500 insulin, the HbA1c level fell from a
mean of 8.60% to 7.37% over 12 months. Possibly,
the effectiveness of U500 CSII was connected with the
smaller volumes infused and the improved sub­cutaneous
ab­sorption, or with improved adherence.
The cost-effectiveness of CSII in T2DM has yet to be
fully explored, but it might be cost-effective in certain
groups. Wolff-McDonagh et al.83 reported a retrospective analysis of 15 patients with T2DM with an elevated
HbA1c level on MDI who were switched to CSII with a
follow-up of 1 year. The mean HbA1c level fell from 9.3%
to 8.3%, with an accompanying reduction in basal insulin
dose. The cost-effectiveness was estimated on the basis
of pump or injection supplies and insulin over a 4‑year
period (the lifetime of a pump), but the cost-effectiveness
resulting from HbA1c level changes was not considered.
CSII was found to be more expensive than MDI when the
insulin dose was <150 units per day but less expensive
by about US$12,000 when the dose was >150 units per
day. The best use of pumps in T2DM will probably correspond to them being targeted at subgroups of patients
with continued poor control on MDI, as with T1DM.
RCTs are now needed to test this hypothesis.
studies sometimes have better outcomes than those who
chose MDI,85 but that might be because they are the
more motivated, adherent and enthusiastic members of
the clinic.
The difficulty of demonstrating differences between
CSII and MDI when the baseline HbA 1c level in the
study is relatively good is mentioned above. Further­
more, whilst many studies take care to incorporate
structured patient education with carbohydrate counting and enthusiastic health-care attention and support
into both treatment regimens, some apparently do not.
Undoubtedly, in everyday clinical practice, if not in
trials, the glycaemic control in some patients on MDI
could be brought close to that achievable on CSII by
closer attention to education and other support from
health-care professionals. Equally, outcomes with insulin
pump therapy could sometimes be improved further by
appropriate education of staff and patients and by the
use of the measures outlined above, such as bolus calculators, optimal bolus timing and types, and computer
d­ownloads of pump data.
The answer to the question of whether the pump is
mightier than the pen is that for many with T1DM it
is not, and such patients can achieve good glycaemic
control using MDI. However, for the considerable
number of patients who cannot achieve target HbA1c
levels without disabling hypoglycaemia, good evidence
exists that insulin pump therapy can improve glycaemic
control in a large proportion, and they should be given
the op­portunity to undergo a trial of CSII.
Finally, the equitable use of insulin pump therapy in
T1DM deserves comment. The uptake of CSII in different countries is variable,3 ranging from <5% of patients
with T1DM in some countries such as the UK to >35% in
the USA. Furthermore, within some countries, patients
in certain areas have little or no access to pumps. On the
basis of the frequency of elevated HbA1c levels and severe
and disabling hypoglycaemia in patients with T1DM
using MDI, and allowing for individuals who might be
judged unsuitable or choose not to use CSII, the percentage of adults with T1DM who would benefit from insulin
pump therapy on clinical grounds alone can be estimated
at about 15–20%.86 A strong argument, therefore, exists
that insulin pumps should be used more often and more
consistently in adult T1DM than presently occurs in
many countries. CSII is safe and effective in children,
even when used as a first-line therapy from diagnosis.87,88
Given the difficulties of instituting MDI in children,9 CSII
also needs to be used more often in this patient group.
Conclusions
Comparisons of glycaemic control and other outcomes during CSII versus MDI need to be interpreted
with caution. For example, cross-sectional studies that
compare clinic patients who have chosen or been allocated to CSII or MDI by their health-care professional
sometimes demonstrate equivalent control,84 but the
pump patients might have been previously poorly controlled with MDI and then switched to CSII with good
effect. By contrast, patients who chose CSII in reported
Review criteria
This narrative review is based on data from individual
studies and meta-analyses known to the author.
Additional relevant studies were identified by searching
Ovid Medline, EMBASE and Google Scholar for articles
up to July 2011 with the search terms “insulin pump
therapy”, “continuous subcutaneous insulin infusion”,
“CSII”, “continuous glucose monitoring” and “diabetes
mellitus”, as well as cited literature in retrieved articles.
NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | JULY 2012 | 431
© 2012 Macmillan Publishers Limited. All rights reserved
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