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50 ❚ Prescriber September 2016 prescriber.co.uk
■ DRUG REVIEW
Diabetes mellitus is a common chronic condition character-
ised by absolute or relative insulin deciency, and its prev-
alence is increasing across the Western world and developing
countries. This is particularly true of type 2 diabetes mellitus
(T2DM) and UK data from the Quality and Outcomes Framework
(QOF), published in 2015, showed there to be almost 3.5 mil-
lion people in the UK with a diagnosis of diabetes.1 Diabetes
costs the NHS close to £10 billion annually, with the majority of
this cost going towards the treatment of diabetes-related com-
plications.2 Furthermore, it is suspected that there are at least
590,000 people in the UK with undiagnosed T2DM.2
This review discusses the role of insulin therapy in type 1
diabetes mellitus (T1DM) and T2DM in the UK, including current
guidelines and management options. Table 1 shows the current
recommendations from the WHO for the diagnosis of diabetes
mellitus.
Type 1 diabetes mellitus
T1DM makes up approximately 10 per cent of all cases of
diabetes mellitus and reduces life expectancy by up to 13
years.3 T1DM can occur at any age, but is usually diagnosed
in children and adolescents1 and its incidence has been ris-
ing steadily in developed countries since the 1950s.4 It is
Management of type 1 and
type 2 diabetes requiring insulin
DOROTHY ABIOLA, THOZHUKAT SATHYAPALAN, DAVID HEPBURN
Insulin is a required therapy for people
with type 1 diabetes, and its use in the
treatment of type 2 diabetes has been
increasing in recent years. This article
discusses the main types of insulin
currently available, their properties and
their role in the management of both
type 1 and type 2 diabetes.
Symptomatic (ie polyruria, polydipsia, unexplained weight
loss)
• Single fasting plasma glucose ≥7mmol/L
• Single random plasma glucose ≥11.1mmol/L
Asymptomatic
• A fasting plasma glucose ≥7mmol/L on two separate
occasions OR
• A random plasma glucose ≥11.1mmol/L on two separate
occasions OR
• An HbA1c ≥48mmol/mol (6.5%) on two separate
occasions OR
• An HbA1c ≥48mmol/mol AND a single elevated plasma
glucose (fasting ≥7mmol/L or random ≥11.1mmol/L)
Note:
HbA1c cannot be used for type 1 diabetes diagnosis
An HbA1c <48mmol/mol does not exclude type 2 diabetes
Table 1. Diagnostic criteria for diabetes mellitus, based on the
WHO’s 2006 Denition and Diagnosis of Diabetes Mellitus
and Intermediate Hyperglycaemia and 2011 Use of Glycated
Haemoglobin in the Diagnosis of Diabetes Mellitus
Prescriber September 2016 ❚ 51prescriber.co.uk
Insulin l DRUG REVIEW ■
caused by the absolute lack of insulin production due to auto-
immune destruction of the insulin-producing beta cells of the
pancreas. At clinical presentation, around 80–90 per cent of
the beta cells will have been destroyed,4 consequently leading
to hyperglycaemia. Patients typically present with one or more
of the classical symptoms caused by hyperglycaemia: polyuria,
polydipsia, lethargy and unexplained weight loss.5 People with
T1DM are absolutely dependent on exogenous insulin ther-
apy to prevent the development of ketosis and hyperglycae-
mia, ultimately leading to diabetic ketoacidosis if untreated.5
The NICE guideline on management of T1DM in adults was
updated in August 2015, providing specic recommendations
for diagnosis (see Table 2).6
Type 2 diabetes mellitus
In the UK, about 90 per cent of people with diabetes mellitus
have T2DM, which results from inadequate insulin secretion
(beta cell dysfunction) and/or reduced action of insulin on insu-
lin-responsive cells (insulin resistance) leading to deranged
glucose handling.7 A myriad of risk factors for T2DM have been
identied (see Table 3).8 Factors such as ethnicity play a sig-
nicant role in determining those at high risk of T2DM with
its prevalence increasing four-fold in people of Bangladeshi
and Indian origin, and ve-fold in women of Pakistani origin.9
There is good evidence linking obesity to T2DM associated with
the development of insulin resistance.9 Therefore, in terms of
management, encouraging improvement in lifestyle remains
paramount in controlling T2DM.
General aims of management
The principal aim of diabetes management is to restore blood
glucose to normal and thus reduce the incidence and progres-
sion of diabetes complications.10 Inadequately controlled blood
glucose levels can cause both macrovascular and microvascu-
lar damage, and subsequently lead to nephropathy, retinopathy,
neuropathy and cardiovascular diseases, all of which impact
profoundly on patients’ mortality, morbidity and quality of life.11
Therefore, healthcare professionals aim to help people with
diabetes to reach and maintain blood glucose control without
increasing the incidence of hypoglycaemia, which is the great-
est risk of insulin therapy.
Insulin therapy in T1DM
Treatment with insulin remains essential for the management of
T1DM4 (see Figure 1) via either subcutaneous injections or con-
tinuous subcutaneous insulin infusion (CSII) using a pump worn
24 hours per day. The aim of exogenous insulin is to mimic as
closely as possible the insulin prole of a person without dia-
betes;12 however, the main barrier to achieving optimal blood
glucose control remains the risk of hypoglycaemia. The principal
methods for assessing blood glucose control are measurement
of glycated haemoglobin (HbA1c) and self-monitoring of cap-
illary blood glucose (SMBG).6 In the NICE guideline, updated
in August 2015, the target HbA1c for people with T1DM is
≤48mmol/mol6 (normal range <42mmol/mol), alongside indi-
vidualisation of the target based on patients’ daily activities,
lifestyle, co-morbidities and likelihood of developing complica-
tions, but without causing problematic hypoglycaemia.6
There are three broad types of pharmaceutically produced
insulin preparations available:
• Animal insulins: extracted and puried from cows (bovine) or
pigs (porcine) and now used by very few patients with diabetes
• Human insulin: genetically engineered with an identical amino
acid sequence to endogenous human insulin
• Insulin analogues: genetically engineered insulins with a sim-
ilar but modied amino acid sequence to endogenous human
insulin and may be synthetically modied.
Insulins can also be grouped by their onset and duration of
action, as categorised in the BNF:
• Short-acting
• Intermediate and long-acting.
Short-acting insulins
Short-acting insulins are used principally to control the rise
in blood glucose that occurs following ingestion of carbohy-
drate, usually in a meal, and can be subdivided into soluble
short-acting (human insulins) and rapid-acting (analogues of
human insulin).12
Human and animal insulins given by subcutaneous injection
have an onset of action of about 30 minutes with a peak of
action of between two and four hours and a duration of around
• On clinical grounds:
- ketosis
- rapid weight loss
- BMI <25kg/m2
- age of onset <50 years
- personal or family history of autoimmune disease (new recommendation)
• Nevertheless, type 1 diabetes should not be ruled out in people >50
years and with a BMI >25kg/m2 (new recommendation)
• Anyone of any age or any BMI who presents with polyuria and
polydipsia, especially those with weight loss and nausea, should have
their random glucose and blood/urinary ketones checked. Ketonuria
or ketonaemia should raise suspicion of type 1 diabetes
• Diabetic ketoacidosis (ketonaemia ≥3mmol/L or 2+ ketonuria on
test strip; venous bicarbonate <15mmol/L or venous pH <7.3; or a
combination of them both) is a medical emergency
• Lesser degrees of ketosis with hyperglycaemia (>11mmol/L) will
probably also require urgent administration of insulin
• Consider further investigation, eg measurement of C-peptide or
diabetes-specic autoantibodies or both, if patient has atypical
features ie age >50 years, BMI>25kg/m2, slow evolution of
hyperglycaemia and if there is a degree of uncertainty about what
type of diabetes the patient has (new recommendation)
Table 2. Diagnosis of type 1 diabetes (in accordance with updated NICE
guideline on type 1 diabetes in adults, published August 20156)
■ DRUG REVIEW l Insulin
52 ❚ Prescriber September 2016 prescriber.co.uk
eight hours.10 Due to their relatively slow onset of action com-
bined with the slow decline in insulin at the injection site, there
can be poor matching with the postprandial rise in blood glu-
cose leading to a risk of hyperglycaemia and/or hypoglycaemia.13
Animal insulins are also much slower in action than comparable
human insulins due to the increased development of antibodies
targeted against the animal insulin and are now rarely used.
Rapid-acting insulin analogues were designed to resolve the
slow onset of subcutaneously administered human insulin and
provide a duration of action better matched to the postprandial
peak in blood glucose following a meal. They therefore attempt
to achieve a more physiological insulin prole in the blood and
as similar as possible to the prole seen in healthy individuals
where secretion of insulin into the portal circulation is main-
tained. These insulin analogues work faster due to more rapid
absorption from the subcutaneous injection site, so producing
a shorter postprandial lag phase. When used alongside longer
acting insulin analogues, the risk of hypoglycaemia14 and par-
ticularly nocturnal hypoglycaemia,13,14 can be reduced.
Hypoglycaemia and nocturnal hypoglycaemia are feared by
many people with T1DM. NICE guidance now advises doctors
to use rapid-acting insulin analogues rst-line for people with
T1DM using multiple daily injection (basal-bolus) regimens.6
Soluble short-acting human insulins are now used mainly intra-
venously for the treatment of diabetic ketoacidosis, hyperosmo-
lar hyperglycaemic state and during perioperative management
of people with diabetes in hospital.6
The updated NICE guideline recommends that people with
T1DM be advised to inject their bolus dose of rapid-acting insu-
lin analogue 10–15 minutes before their meal6 to ensure the
best match between the action prole of the insulin and the
postprandial rise in blood glucose. The dose of rapid-acting
insulin is usually determined by the carbohydrate content of the
meal using a method called carbohydrate counting, with a com-
mon dose being 1 unit of insulin for each 10 grams of ingested
carbohydrate. Thus most people with T1DM using a basal-bolus
regimen will take the rapid-acting insulin analogue three times
daily with main meals and possibly at other times when there
is any substantial ingestion of carbohydrate; the so-called bolus
part of the basal-bolus regimen.6,11
Rapid-acting insulin analogues available in the UK are:
• insulin aspart (NovoRapid)
• insulin glulisine (Apidra)
• insulin lispro (Humalog).
Intermediate and long-acting insulin
People with T1DM usually take either an intermediate or
long-acting insulin in addition to their mealtime doses of rap-
id-acting insulin analogues;6,12 the so-called basal part of the
basal-bolus regimen. These insulins are administered in an
attempt to mimic the background secretion of insulin from the
pancreas in the interprandial or fasting period. In the 2015
NICE guideline on T1DM in adults, it is recommended that insu-
lin detemir (Levemir) is used twice daily as the basal insulin of
rst choice alongside a rapid-acting insulin analogue.6 Insulin
detemir is an analogue insulin in which a fatty acid moiety12 has
been bound to the lysine molecule at the B29 amino acid posi-
tion resulting in it binding to albumin after injection. This results
in a prolonged duration of action and a relatively at action pro-
le without much of a peak.12 Insulin glargine (Lantus), another
long-acting insulin analogue, can be used as an alternative but
is usually administered once daily6 due to its longer duration of
action compared with insulin detemir.15
Long-acting insulin analogues are now preferred over the
intermediate-acting isophane insulins because their mode of
action is more predictable. Compared with isophane insulins,
long-acting insulin analogues provide marginally better blood
glucose control with less potential weight gain.10 However, the
most important factor is the achievement of optimal blood glu-
cose control without problematic hypoglycaemia and thus NICE
permits the use of other basal insulins if the person with T1DM
can achieve these blood glucose goals, including the use of
insulin detemir once daily.6
In the updated NICE guideline for adults with T1DM, it
is emphatically recommended that those newly diagnosed
with T1DM should not be offered non-basal–bolus insulin
regimens, eg twice daily mixed, basal only or bolus only.16
However not all people with T1DM can cope with a multiple
daily injection regimen and thus may take a mixed human
insulin.6 An example is Humulin M3, which is a mixture of sol-
uble short-acting human insulin and an intermediate-acting
human isophane insulin.6 Mixed human insulins are usually
given twice daily, before breakfast and the evening meal. If
hypoglycaemia becomes a problem then an alternative mixed
insulin preparation incorporating a rapid-acting insulin ana-
logue, such as NovoMix 30, can be used.6 These mixed insu-
lins can be useful in allowing insulin to be given by district
nurses to frail or elderly patients or to people with cognitive
decline who also have T1DM.
People with T1DM should regularly self-monitor their capil-
lary blood glucose6,12 and it is recommended that they do this
at least four times a day, in order to permit adjustment of their
insulin doses and to avoid hypoglycaemia. In some scenarios,
more regular monitoring is needed and they can self-monitor up
to 10 times a day if necessary.6 For example when:
• at increased risk of hypoglycaemia
• about to drive, as advised by DVLA tness to drive regulations
• they have not reached their target HbA1c
• experiencing periods of illness
• planning to become pregnant or are already pregnant
• before and after exercise.
• People of south east Asian (particularly Pakistani and
Bangladeshi) descent
• Overweight/obesity
• Older age
• Family history of diabetes
• Gestational diabetes
• Polycystic ovary syndrome
• Dyslipidaemia
• Sedentary lifestyle
Table 3. Risk factors for type 2 diabetes
Prescriber September 2016 ❚ 53prescriber.co.uk
Insulin l DRUG REVIEW ■
It is important that patients who need to monitor more fre-
quently are identied by their GP and diabetes specialist so
that they can be prescribed an adequate number of testing
strips for their blood glucose meter. Many patients report
anecdotally that they are not prescribed enough blood glucose
testing strips to match their monitoring needs. A number of
self-monitoring blood glucose meters can also be used to
measure capillary blood ketones and these strips should also
be prescribed.
NICE has also placed emphasis on structured education
programmes for people with T1DM. Dose Adjustment for
Normal Eating (DAFNE) is a programme that should be offered
to every patient with T1DM, 6 to 12 months after initial diagno-
sis.6 This programme is led by specialist diabetes nurses and
dieticians, and occurs over ve days, during which patients are
extensively educated in:6
• carbohydrate counting
• accurate calculation of bolus insulin doses
• how to set up background (basal) insulin
• how to correct deranged glucose levels (including sick day
rules).
An economic report by the York Health Economics Consortium
has suggested that DAFNE could potentially save about £2237
per patient over a 10-year period, as a result of a reduction in
diabetes complications, after deducting the cost to run the
programme.17
People with T1DM who do not achieve optimal glycaemic
control as determined by an HbA1c level >69mmol/mol on
a multiple daily injection (basal-bolus) regimen can also be
Continuous subcutaneous insulin
infusion
Recommended in individuals ≥12
years when:
• Attempts to achieve target
HbA1c with multiple daily
injections (MDI) result in the
person experiencing disabling
hypoglycaemia
• HbA1c has remained high on
MDI therapy >69mmol/mol
Mixed insulin
• Human mixed insulin twice daily
should only be given if basal-
bolus regimen is not possible
• Try a mixed analogue if human
insulin leads to hypoglycaemia
that affects the patient’s quality
of life
Basal-bolus regimen (rst-line)
Long-acting insulin (twice daily)
plus
rapid-acting insulin (before each
meal)
Must be initiated by a trained
specialist team and should only
be continued if it results in a
sustained improvement
Long-acting insulin
First-line: insulin detemir twice daily
Consider an alternative when:
• A person is achieving their
agreed targets using an existing
insulin regimen
• Twice-daily detemir is not
tolerated; instead offer once-
daily insulin glargine or detemir
• Detemir is not tolerated; offer
once-daily insulin glargine
Rapid-acting insulin
Offer rapid-acting insulin
analogues before meals, ie
• Insulin aspart (NovoRapid)
• Insulin lispro (Humalog)
• Insulin glulisine (Apidra)
If an adult with type 1 diabetes
has a strong preference for
alternative mealtime insulin,
respect their wishes and offer the
preferred insulin
Insulin regimen options for adults with type 1 diabetes
Figure 1. Insulin regimens for adults with type 1 diabetes
■ DRUG REVIEW l Insulin
54 ❚ Prescriber September 2016 prescriber.co.uk
referred to a specialist diabetes team for consideration of con-
tinuous subcutaneous insulin infusion therapy (CSII) provided
by an insulin pump.6 This type of treatment can also be con-
sidered if target HbA1c levels cannot be achieved without the
person suffering disabling hypoglycaemia. Generally, a rapid-act-
ing insulin analogue is used in the CSII pump. It is usual for
patients to have been DAFNE trained before commencing a CSII
regimen6 and for them to be seen in a specialist ‘pump clinic’
with access to continuous subcutaneous glucose monitoring
facilities. NICE states that CSII therapy should only be offered
to adults and children 12 years and older, although there is
increasing use of CSII in younger children attending paediat-
ric diabetes clinics and it is widely used in younger children
throughout Europe. NICE also advices that CSII should only be
continued if the therapy leads to a sustained improvement in
glycaemic control, shown by a fall in HbA1c or a sustained drop
in the number of hypoglycaemic episodes.18
Insulin therapy in adolescence
It is well documented that many adolescents with T1DM often
struggle to comply with their insulin regimens, increasing the
risk of diabetic ketoacidosis.19 It is important that clinicians
explore the reasons why patients in this age group are not com-
plying, eg fear of isolation from friends, weight loss, inconven-
ience when socialising, and ultimately remind the patient why
it is important to comply. In a case where the patient is not
complying, it may be necessary to readdress their insulin regi-
men and adjust to a more feasible option for the patient. These
problems can be compounded by physiological insulin resist-
ance, which is a feature of the adolescent period, meaning
that adolescents often need higher doses of insulin during this
time to maintain adequate glycaemic control.19 In an attempt
to support people with T1DM during this difcult period in their
lives, many diabetes services have set up transition clinics to
facilitate the move from paediatric to adult diabetes services.
Additionally, most transition or young adult diabetes clinics are
supported by clinical psychology services in a similar fashion
to paediatric clinics.
Insulin therapy in pregnancy
Pregnancy is also a challenging time for women with T1DM
and there are often changes in insulin sensitivity during the
different trimesters of pregnancy. Hypoglycaemia is most
common in the early phase of pregnancy, often compounded
For basal dose, offer isophane insulin
for injection at bedtime or twice daily
Consider premixed preparations
that include rapid-acting insulin
analogues, rather than premixed
preparations that include short-
acting human insulin, if:
• A person prefers injecting insulin
immediately before a meal
• Hypoglycaemia is a problem
• Blood glucose levels rise
markedly after meals
Consider twice-daily premixed
(biphasic) human insulin,
particularly if:
• HbA1c is 75mmol/mol (9.0%) or
higher
A once-daily regimen may also be
an option
Consider long-acting analogue
(insulin detemir) if:
• The person needs assistance from
a carer or healthcare professional
to inject insulin, and use of a
long-acting insulin analogue would
reduce the frequency of injections
from twice to once daily
• The person’s lifestyle is restricted
by recurrent symptomatic
hypoglycaemic episodes
• The person would otherwise
need twice-daily isophane insulin
injections in combination with oral
glucose-lowering drugs
• The person cannot use the device
to inject isophane insulin
Consider starting insulin therapy in type 2 diabetes patients who:
• Have not achieved a controlled HbA1c using three oral hypoglycaemic drugs
When starting insulin, continue with standard-release metformin if there
are no contraindications or intolerance
Figure 2. Management of type 2 diabetes with insulin
Prescriber September 2016 ❚ 55prescriber.co.uk
Insulin l DRUG REVIEW ■
by the maintenance of excellent blood glucose control, which
had been started before conception in most patients. In
planned pregnancies, there is an emphasis on prepregnancy
counselling and optimisation of blood glucose control in an
attempt to reduce the risk of congenital malformations. This
emphasis on excellent control should persist during the preg-
nancy to prevent macrosomia and early placental failure as
much as possible, which can occur in some diabetes preg-
nancies.
Insulin therapy in T2DM
Insulin therapy is not the rst-line treatment for T2DM and usu-
ally follows on from failure of standard oral agents or other
injectable therapies (see Figure 2). Due to the progressive
nature of T2DM, characterised by beta cell dysfunction and
impairment, over time most patients with T2DM fail to reach
their individualised HbA1c targets. Thus many people with
T2DM need to include insulin in their treatment to maintain
glucose control and slow down the progression of diabetes
complications.10
A number of studies have supported the initiation of insulin
in patients with T2DM early in the course of the disease.20 The
UK Prospective Diabetes Study (UKPDS) in 2008 suggested
that early insulin treatment in T2DM reduces the risk of macro-
vascular and microvascular complications.21 However, insulin
therapy in people with T2DM also carries some risks, not least
hypoglycaemia, as well as weight gain, which is often seen as a
major disadvantage by patients.20 A recent retrospective cohort
study22 controversially reported that the use of insulin therapy
in T2DM was associated with an increased mortality rate in
comparison with patients who were just on oral hypoglycaemic
agents. However, this was not a randomised controlled trial and
was likely to have been inuenced by the fact that patients with
poorer blood glucose control are treated with insulin. Therefore,
the association in this study between insulin therapy and mor-
tality is unlikely to be causal.
There has been an increase in the addition of insulin to
T2DM management over the last 20 years.22 However, the cor-
rect point at which to commence insulin therapy in T2DM and
where it stands in relation to newer hypoglycaemic therapies
such as glucagon-like peptide-1 (GLP-1) agonists and sodium-
glucose co-transporter 2 (SGLT2) inhibitors, such as canagli-
ozin, has been controversial.22 The most recent NICE guideline
for management of T2DM in adults, published in December
2015, recommends initiating insulin either at the point of fail-
ure of two oral agents (HbA1c >58mmol/mol) or alternatively
adding a third oral agent instead of insulin.23 Insulin therapy
combined with a GLP-1 agonist is recommended to be used only
on the advice of diabetes specialists.
When initiating insulin therapy in T2DM, the patient should
remain on metformin23 unless there is a contraindication or
intolerance to the metformin. A recently published retrospective
cohort study in people with T2DM has suggested an associa-
tion between using insulin plus metformin and reduced risk of
death and major cardiovascular outcomes compared with those
treated with insulin alone.24
Patients with T2DM should be commenced initially on an
isophane insulin23 once daily, injected before bedtime, or twice
daily, before breakfast and then either at evening mealtime or
at bedtime. If given at bedtime, this helps to avoid a peak of
action at around 2am to 3am, so reducing the risk of noctur-
nal hypoglycaemia and instead providing a peak at dawn when
insulin resistance is at its greatest.25 The main advantage of
using isophane insulins over long-acting insulin analogues is
the fact that they are less expensive. NICE only suggests the
use of long-acting insulin analogues such as insulin detemir
and insulin glargine should hypoglycaemia prove a problem with
isophane insulins. Another scenario is when once-daily admin-
istration is needed, for example facilitating a district nurse to
administer insulin glargine in the morning to a housebound
patient who is unable to inject their own insulin.
The recently updated NICE guideline on T2DM in adults also
recommends considering the use of premixed biphasic human
insulin twice daily if HbA1c is ≥75mmol/mol,23 eg Humulin M3,
although in our experience it is much easier to provide instruc-
tions for patients to self-adjust once- or twice-daily interme-
diate or long-acting insulin than a premixed biphasic insulin.
If the patient will be injecting immediately before a meal and
hypo glycaemia is a problem, or if the patient is markedly hyper-
glycaemic in the preprandial period, then the premixed prepa-
rations for these patients should include short-acting insulin
analogues rather than short-acting human preparations,23 eg
Novo Mix 30.
Insulin and driving
Hypoglycaemia may be less frequent in people with insulin-
treated T2DM than in those with T1DM, but it remains the most
common adverse effect of insulin therapy, and is par ticularly
worrying in people who have impaired hypoglycaemia aware-
ness. To be able to drive a car or motorcycle (Group 1), people
treated with insulin must notify the DVLA and meet the following
criteria:
• Have adequate awareness of hypoglycaemia
• Have had no more than one episode of severe hypoglycaemia
in the preceding 12 months
• Undertake appropriate blood glucose monitoring (test blood
glucose no more than two hours before the start of a journey
and every two hours while driving)
• Not be regarded as a likely risk to the public while driving
• Meet the visual standards for acuity and visual elds.
For insulin-treated people to be able to drive a bus or lorry
(Group 2), the DVLA stipulates that they must:
• Have full awareness of hypoglycaemia
• Have not had any severe hypoglycaemia in the preceding 12
months
• Undertake appropriate blood glucose monitoring (test blood
glucose at least twice daily including on days when not driving,
test blood glucose no more than two hours before the start of
a journey and every two hours while driving)
• Use a glucose meter with sufcient memory to store three
months of readings
■ DRUG REVIEW l Insulin
56 ❚ Prescriber September 2016 prescriber.co.uk
• Be able to demonstrate an understanding of the risks of hypo-
glycaemia
• Have no disqualifying complications of diabetes.
The DVLA advises people who are insulin treated to take
fast-acting carbohydrate before driving if their blood glucose is
less than 5mmol/L and not to drive if their blood glucose is less
than 4mmol/L; in this case they should take fast-acting carbo-
hydrate, wait and then retest before driving. If hypoglycaemia
occurs, they should not drive until 45 minutes after their blood
glucose has returned to normal as subtle cognitive impairment
can persist for a short period after blood glucose returns to
within the normal range and the person feels better. Further
details can be found on www.gov.uk in the document Assessing
Fitness to Drive – A Guide for Medical Professionals.
New developments
New longer acting insulin analogue formulations are being
developed in the hope of further reducing the chances of noc-
turnal hypoglycaemia. Insulin degludec (Tresiba), which has
recently been licensed by the European Medicines Agency,
has a metabolic effect that is still present 42 hours postinjec-
tion.10 Insulin degludec is also available at a higher strength
(200units/ml) than the European-wide standard of 100units/
ml,10 which could be an advantage in the more insulin-resistant
T2DM patient. When prescribing insulin degludec, it is impor-
tant to be aware of the strength prescribed as the 100units/
ml prelled pen allows one-unit dose adjustments, whereas the
200units/ml prelled pen allows two-unit dose adjustments.
The use of prelled pens has reduced the risk of dosing errors
but it is important that the patient using the pen is aware of
the strength and the value of the dose adjustment. The number
of units being injected, irrespective of the strength used, is
provided in a dose counter window on the pen every time the
patient dials up a dose.26
Some diabetologists have been using insulin degludec
200units/ml in very insulin-resistant diabetes patients in
place of unlicensed Humulin R 500units/ml, which needs to be
obtained on a named-patient basis.
Insulin glargine is also now available in a higher strength
of 300units/ml in the form of Toujeo and is also available in
a prelled pen.27 Insulin degludec and Toujeo are not speci-
cally mentioned in the 2015 NICE guideline on T2DM in adults,
although there is a comment about the use of any current or
future biosimilar product(s) of insulin glargine within the same
marketing authorisation and indication, and this could be inter-
preted to permit the use of Toujeo. It will also sanction the use
of the rst truly biosimilar insulin to be launched in the UK,
Abasaglar, a biosimilar version of insulin glargine. Biosimilars
are the equivalent of generic drugs, but for biological mole-
cules, and could potentially reduce the cost of medication.
Toujeo has been assessed by the Scottish Medicines
Consortium, which has recommended that its use should be
targeted to patients with T1DM who are at risk of, or experi-
ence, frequent or severe night-time hypoglycaemia.27 It can also
be considered an option as a once-daily therapy for patients
who require carer administration of their insulin, and in T2DM
patients who suffer from recurrent episodes of hypoglycaemia
or need assistance with their insulin injections.
Another development that was not included in the NICE
guideline on T2DM for adults is Xultophy, which is a combination
of liraglutide (a GLP-1 agonist) with insulin degludec in a xed-
dose combination, delivered by prelled pen device.28 Many
diabetologists have been using combined therapy with GLP-1
agonists and usually long-acting insulins with success in obtain-
ing improved blood glucose control without the weight gain seen
with insulin therapy alone. However, as GLP-1 agonists are also
administered by subcutaneous injection, this requires at least
two injections a day and the advent of Xultophy, which is admin-
istered as a single injection once daily, should make dosing
easier for patients and aid adherence.
Moreover, this may not be the only benet and recent clin-
ical trials have supported the use of a xed-dose combination
of a GLP-1 agonist and a long-acting insulin in achieving better
glycaemic control than either component given alone. More
importantly, top-line results presented at the American Diabetes
Association meeting in June 2016 showed that liraglutide signif-
icantly reduced the risk of major adverse cardiovascular events
compared with placebo but in addition to standard treatment
for diabetes. Other GLP-1 agonist-insulin combinations are also
in development and their exact position in the management of
T2DM is yet to be fully determined,28 but they could be used
either at the point of oral agent failure or as the next step
in intensication in people already using either a GLP-1 or a
long-acting insulin alone.
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Declaration of interests
Professor Thozhukat Sathyapalan has received research sup-
port from the Food Standards Agency, European Food Safety
Authority, Sandoz, Novo Nordisk, Sano-Aventis and Boehringer
Ingelheim. He has also received consultancy fees from Novo
Nordisk.
Dorothy Abiola is a nal year medical student at Hull York
Medical School, Thozhukat Sathyapalan is professor of
endocrinology and honorary consultant physician, and David
Hepburn is a consultant physician and honorary reader,
Department of Diabetes and Endocrinology at Hull and East
Yorkshire Hospitals NHS Trust and Hull York Medical School, Hull
Clinical question:
Is opioid analgesic treatment effective
in patients with low back pain?
Reference:
Shaheed CA, et al. JAMA Intern Med
2016;176(7):958–68.
Bottom line:
Effective pain control in patients with
low back pain (LBP) is still elusive.
Approximately half of all patients with
LBP who take an opioid analgesic will
stop treatment because of ineffective-
ness or adverse effects. Patients staying
the course will experience, on average,
a small decrease in pain relative to
patients who take placebo and will not
have improved function. (LOE = 1a)
Study design: Meta-analysis (RCT).
Funding source: Government.
Setting: Various (meta-analysis).
Synopsis:
To identify randomised controlled trials
that enrolled patients with nonspecic
LBP and evaluated an opioid analgesic,
the researchers searched ve databases
including Cochrane CENTRAL, as well as
reference lists of identied studies. They
retrieved 20 studies with an enrolment of
7295 patients; all but one study enrolled
patients with chronic LBP. The length of
studies was 12 weeks or less. Based
on 13 studies with moderate-quality evi-
dence, opioids reduced pain in the short
term, though the mean difference in pain
scores was minimal (mean difference:
10.1 on a scale of 0–100). This effect
size is similar to that for NSAIDs ver-
sus placebo for LBP in a prior Cochrane
review. Overall, opioid treatment did not
produce clinically important pain relief
compared with placebo, ie a mean differ-
ence in pain scores of at least 20, even
with doses as high as 240mg morphine
daily. Half of the studies had more than
50 per cent of the enrolled patients drop
out, either because of adverse effects or
lack of effectiveness.
POEMs
Opioid analgesia hard to tolerate and not effective for chronic low back pain
