Chapter
| 36 |
Diabetes mellitus, insulin, oral antidiabetes
agents, obesity
Mark Evans, Rahat Tauni
SYNOPSIS
Diabetes mellitus affects at least 2% of many
national populations. Its successful management
requires close collaboration between the patient
and health-care professionals.
• History of pharmacological treatment of diabetes.
• Insulins in current use (including choice,
formulations, adverse effects, hypoglycaemia, insulin
resistance).
• Oral antidiabetes drugs.
• Treatment of diabetes mellitus.
• Diabetic ketoacidosis.
• Surgery in diabetic patients.
• Obesity and overweight.
Diabetes overview
Diabetes is best regarded as a group of related conditions
in which blood glucose levels tend to rise. Diabetes is
common and increasing. In large part, this global increase
in diabetes may be related to increased levels of obesity.
Diabetes can lead to serious medical complications – blindness from retinopathy, renal failure, gangrene and limb
amputation, cardiovascular disease and premature death.
Aggressive therapy with a combination of pharmacological
therapies aimed at lowering blood glucose and blood pressure
and optimising lipids can reduce the risk of these complications. In particular, follow-up data from two major diabetes
randomised control trials (UKPDS in type 2 diabetes and
608
DCCT-EDIC in type 1 diabetes) suggest that the beneficial
effects of early intensive glycaemic control on microvascular
complications tend to last years after the glycaemic control
is relaxed (termed a ‘legacy’ or ‘metabolic memory’ effect
emphasising the importance of early optimal glycaemic
control).
History of insulin therapy
in diabetes
Diabetes was known to ancient Greek medicine with the
description of ‘a melting of the flesh and limbs into urine
… the patients never stop making water but the flow is
incessant … their mouth becomes parched and their body
dry’.1
Insulin (as pancreatic islet cell extract) was first administered to a 14-year-old insulin-deficient patient on 11 January
1922 in Toronto, Canada. R.D. Lawrence, an adult sufferer
from diabetes who developed the disease in 1920 and who,
because of insulin, lived until 1968, has told how:
Many doctors, after they have developed a disease, take
up the speciality in it … But that was not so with me. I
was studying for surgery when diabetes took me up. The
great book of Joslin said that by starving you might live
four years with luck. [He went to Italy and, whilst his
health was declining there, he received a letter from a
1
The Extant Works of Aretaeus, trans. Francis Adams (London 1856) p.
338 (quoted by Ackerknecht E H 1982 A short history of medicine.
Johns Hopkins, Baltimore, pp. 71–72).
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
biochemist friend which said] there was something called
‘insulin’ appearing with a good name in Canada, what
about going there and getting it. I said ‘No thank you;
I’ve tried too many quackeries for diabetes; I’ll wait and
see’. Then I got peripheral neuritis … So when [the
friend] cabled me and said, ‘I’ve got insulin – it works
– come back quick’, I responded, arrived at King’s
College Hospital, London, and went to the laboratory as
soon as it opened … It was all experimental for [neither
of us] knew a thing about it … So we decided to have
20 units a nice round figure. I had a nice breakfast. I
had bacon and eggs and toast made on the Bunsen. I
hadn’t eaten bread for months and months … by 3
o’clock in the afternoon my urine was quite sugar free.
That hadn’t happened for many months. So we gave a
cheer for Banting and Best.2But at 4 pm I had a terrible
shaky feeling and a terrible sweat and hunger pain. That
was my first experience of hypoglycaemia. We
remembered that Banting and Best had described an
overdose of insulin in dogs. So I had some sugar and a
biscuit and soon got quite well, thank you.3
• Type 1 (formerly, insulin-dependent diabetes mellitus,
IDDM), which typically (but not always) occurs in
younger people who cannot then secrete sufficient
insulin.
• Type 2 (formerly, non–insulin-dependent diabetes
mellitus, NIDDM), which usually occurs in older people
who are typically (although not always) obese. Type 2
diabetes is best thought of as a group of conditions
characterised by a variable combination of reduced
insulin secretion and resistance to insulin’s blood
glucose lowering action.
• Other causes: including gestational diabetes, disease
processes affecting the liver or pancreas such as cystic
fibrosis causing a ‘secondary’ diabetes, monogenic
forms (maturity onset diabetes of the young, MODY).
These terms and abbreviations are used in this chapter.
Sources of insulin
Insulin is synthesised and stored (bound to zinc) in granules
in the β-islet cells of the pancreas. Daily secretion typically
amounts to 30–40 units, which is about 25% of total
2
F G Banting and C H Best of Toronto, Canada (see also Journal of
Laboratory and Clinical Medicine 1922; 7:251).
3
Abbreviated from Lawrence R D 1961 King’s College Hospital Gazette
40:220. Transcript from a recorded after dinner talk to students’
Historical Society.
| 36 |
pancreatic insulin content. The principal factor that evokes
insulin secretion is a high blood glucose concentration. In
addition, insulin release following oral intake of carbohydrate
is facilitated by the action of ‘incretin factors’ such as GLP-1
(see later) released from specialised neuroendocrine cells
in the small bowel.
Insulin is a polypeptide with two peptide chains (A chain,
21 amino acids; B chain, 30) linked by two disulphide
bridges. The basic structure having metabolic activity is
common to all mammalian species, but there are minor
species differences:
• Bovine insulin differs from human insulin by three
amino acids.
• Porcine insulin differs from human insulin by only
one amino acid.
• Human insulin is made either by enzyme
•
Diabetes mellitus is classified broadly as:
Chapter
modification of porcine insulin, or by using
recombinant DNA to synthesise the pro-insulin
precursor molecule for insulin. This is done
by artificially introducing the DNA into either
Escherichia coli or yeast.4
Insulin analogues are now widely used and have
modifications introduced to the A and/or B chains,
which result in more rapid onset and offset of action
(rapidly acting analogues), or slower offset
(long-acting analogues) than naturally occurring
insulin. As the commercial patents for some of the
older insulin analogues expire, a number of
‘biosimilar’ insulins are being developed, and it is
likely that a number of alternative therapeutic
options will appear over the next 5 years.
Insulin receptors
Insulin receptors (comprising 2 α and 2 β subunits) are
present on the surface of target cells such as liver, muscle
and fat. Insulin binding results in tyrosine autophosphorylation of the β subunit. This then phosphorylates other
substrates so that a signalling cascade is initiated and biological responses ensue. Downstream effects of stimulation of
the insulin receptor include both immediate/short-term
actions (e.g. translocation of the glucose transporter GLUT4
to the surface of target cell) and longer-term actions (e.g.
increased expression of glucokinase and reduced expression
of gluconeogenic and ketogenic enzymes in the liver).
4
The three forms of human insulin have the same amino acid
sequence, but are separately designated as insulin emp (Enzyme
Modified Porcine), prb (Pro-insulin Recombinant in Bacteria) and pyr
(Precursor insulin Yeast Recombinant). Although one of the incentives
for introducing human insulin was avoidance of insulin antibody
production, the allergies to older insulins were caused largely by
impurities in the preparations, and are avoided equally well by using
the highly purified, monocomponent porcine and bovine insulins.
609
Section
|8|
Endocrine system, metabolic conditions
Actions of insulin
• Reduction in blood glucose is due to increased glucose
•
uptake in peripheral tissues (which oxidise glucose or
convert into glycogen or fat) and a reduction in
hepatic output of glucose (diminished breakdown/
increased synthesis of glycogen and diminished
gluconeogenesis).
Other metabolic effects. Although, therapeutically,
insulin is thought of as a blood glucose–lowering
hormone, it has a number of other cellular actions.
Insulin is an anabolic hormone, enhancing protein
synthesis (which has resulted in cases of misuse by
bodybuilders). It also inhibits both breakdown of fats
(lipolysis) and ketogenesis. Insulin also has actions
on electrolytes, stimulating potassium uptake into
cells and renal sodium retention (anti-natriuretic
effect). Within brain, insulin may have actions to
stimulate memory and act as a nutritional signal to
help control appetite/food intake.
Uses
• Diabetes mellitus is the main indication.
• Insulin promotes the passage of potassium into
•
cells by stimulating cell surface Na/K ATPase action,
and this effect is utilised to correct hyperkalaemia
(see p. 485).
Insulin-induced hypoglycaemia can also be used as a
stress test of anterior pituitary function (growth
hormone and corticotropin and thus cortisol are
released).
Pharmacokinetics
In health, insulin is secreted by the pancreas, enters the
portal vein and passes straight to the liver, where half of it
is taken up. The rest enters and is distributed in the systemic
circulation so that its concentration (in fasting subjects) is
only about 20% of that entering the liver. Insulin is released
continuously and rhythmically from the healthy pancreas
with additional increases following carbohydrate ingestion.
As described below, modern insulin regimens in diabetes
aim to match this pattern as far as possible.
In contrast to the natural pancreatic release, when insulin
is injected subcutaneously during the treatment of diabetes,
it enters the systemic circulation so that both liver and other
peripheral organs receive the same concentration. It is
inactivated in the liver and kidney; about 10% appears in
the urine. The plasma t1/2 is only 5 min, although clearance
of ‘tissue’ insulin levels lags behind this; this is noteworthy
610
when stopping intravenous insulin infusions as it may take
60 min for effects to wear off.
Most commonly, insulin is self-delivered by patients
using either a syringe with a fixed needle (after drawing up
insulin from a vial) or an insulin pen device (supplied as
a preloaded disposable pen or with replaceable cartridges).
Within hospital, soluble insulin may be delivered by
intravenous infusion. Typically, 50 units of soluble insulin
is dissolved in 50 mL isotonic saline (i.e. insulin concentration 1 unit/mL).
An alternative and increasingly popular method for
delivering insulin, especially in type 1 diabetes, is for patients
to use continuous subcutaneous insulin infusion devices
(‘insulin pumps’). These small cell-phone–size personal
devices provide a continuous basal delivery of soluble insulin
(usually analogue, see below) with an additional insulin
bolus when needed to cover meals or to correct high blood
glucose values. Insulin pumps have become more sophisticated over the last decade, with patients able to set multiple
pre-programmed basal insulin rates and/or temporary
infusion rates for such things as exercise or illness. Most
pumps now have inbuilt software to calculate bolus doses
from blood glucose/carbohydrate data. Some of the currently
available insulin pumps link to subcutaneous continuous
glucose monitors and, excitingly, the expectation is that this
hardware will allow the development of an ‘artificial pancreas’
with insulin delivery controlled partially or totally by realtime glucose sensing.
Preparations of insulin (Table 36.1)
Dosage is measured in international units standardised by
chemical assay. There are three major factors:
• Strength (concentration).
• Source (human, porcine, bovine).
• Formulation (short acting vs delayed action).
Broadly speaking, four different types of insulin with
differing time-courses of action are available for treating
diabetes (illustrated in Fig. 36.1):
1. Short duration of action (and rapid onset). Soluble
insulin (also called ‘neutral’ or ‘regular’ insulin). The
most recent additions to this class of insulin, lispro,
aspart and glulisine, are modified human insulins
with changes in the B chain resulting in more rapid
absorption after subcutaneous injection and thus a
faster onset and shorter duration of action. A new
formulation of aspart (faster-acting insulin aspart,
Fiasp) includes arginine and niacinamide, which act
to increase further the speed of absorption from
subcutaneous depots.
2. Intermediate duration of action (and slower onset).
Preparations in which the insulin has been
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
Chapter
| 36 |
Table 36.1 Insulin preparations
Preparations
Onset of action
(approx.)
Peak activity
(approx.)
Duration of
action (approx.)A
Short-acting insulins
Human sequence
Actrapid
Humulin S
Insuman Rapid
30–45 min
2–3.5 h
5–7 h
Animal sequence
Hypurin Porcine Neutral
Hypurin Bovine Neutral
As above
As above
As above
Rapid-acting analogues
Apidra (insulin glulisine)
Humalog (Insulin lispro)
NovoRapid (Insulin aspart)
10–20 min
1.5–2.5 h
4.5–6 h
“Ultra–rapid-acting”
analogue
Fiasp (faster-acting insulin aspart)
5–20 min
1–2.5 h
4–6 h
Humalog Mix 25
Humalog Mix 50
Humulin M3
Hypurin Porcine 30/70
Insuman Comb 15
Insuman Comb 25
Insuman Comb 50
NovoMix 30
10–45 min
2–8 h
12–20 h
Biphasic insulins
Isophane insulins and similar
Human sequence
Humulin I
Insulatard
Insuman Basal
1–3 h
4–9 h
12–20 h
Animal sequence
Hypurin Bovine Isophane
Hypurin Porcine Isophane
Hypurin Bovine Lente
Hypurin Bovine Protamine Zinc
As above
As above
As above
Abasaglar (insulin glargine)
Levemir (insulin detemir)
Lantus (insulin glargine)
1–2 h
6–10 h
18–24 h
Toujeo (insulin glargine U300)
N/AB
N/AB
24–36 h
Tresiba (insulin degludec)
N/AB
N/AB
Up to 48 h
30–60 min
2–6 h
6–24 h
Long-acting analogues
U500 concentrated insulin
Humulin R C
A
Duration of action for many insulin preparations may be longer when larger doses are used.
N/A = onset and peak of action not applicable for long action profile of Toujeo and Tresiba.
U500 humulin R use restricted to severe insulin resistance cases with shared care. As with many other insulins, pharmacodynamics vary
depending on dose, and this patient group often requires very large doses, thus extending pharmacodynamic parameters.
B
C
611
|8|
Endocrine system, metabolic conditions
Aspart, lispro (4–6 hr)
Relative plasma insulin level
Section
Regular (6–10 hr)
NPH (12–20 hr)
0
2
4
6
8
10
Glargine and
Degludec (36–48 hr) levemir
(20–24 hr)'
12
14
16
18
20
22
24
Hours
Fig. 36.1 Approximate pharmacokinetic profiles of human insulin and insulin analogues. The relative duration of action of the
various forms of insulin is shown. The duration will vary widely both between and within persons. (From Hirsch I B 2005 Insulin
analogues. New England Journal of Medicine 352:174–183.)
Fig. 36.2 Amino acid alterations in insulin analogues. The diagram shows the structure of native insulin, and the modifications of
this structure in a number of commercially available alternatives.
modified physically by combination with protamine
or zinc to give an amorphous or crystalline
suspension; this is given subcutaneously and slowly
dissociates to release insulin in its soluble form.
Isophane (NPH) insulin, a suspension with
612
protamine, is still widely used. Insulin zinc
suspensions (amorphous or a mixture of amorphous
and crystalline) are now rarely used.
3. Longer duration of action. Newer analogues glargine,
detemir and degludec (Fig. 36.2) have become widely
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
used, especially in type 1 diabetes. Small changes in
the amino acid structure of glargine result in a
significant slowing of absorption from subcutaneous
depots. A more concentrated preparation of glargine
300 units/mL (Toujeo) has an even longer action
profile. In contrast, detemir owes its protracted action
to fatty acylation. After absorption, detemir is thus
bound to circulating albumin which delays its action.
Degludec has a single amino acid substitution and a
long fatty acyl chain attached resulting in a markedly
prolonged action profile.
4. A biphasic mixture of soluble or short-acting analogue
insulin with isophane insulin.
Notes for prescribing insulin
Allergy to purified or analogue insulins is very rare.
Antibodies to insulin do occur, but are largely thought to
be of no clinical significance.
Compatibility. Soluble insulin may be mixed in the syringe
with insulin zinc suspensions (amorphous, crystalline) and
with isophane and mixed (biphasic) insulin, and used at
once. Long-acting analogue insulins, and protamine insulin
suspensions, should not be mixed in a syringe with short-acting
insulins.
Intravenous insulin. Only soluble (neutral) insulin should
be used. Analogue and regular insulin have identical action
profiles when given i.v., although the latter tends to be more
widely used.
The standard strength of insulin preparations is 100 units/
mL (U100). Preparations of 200 units/mL (Humalog and
tresiba) and 300 units/mL (Toujeo) are used, but only in
prefilled insulin pen devices to avoid confusion. Rarely is
500 units/mL of insulin used in patients with marked insulin
resistance so that health-care providers should be aware of
this. Biological standardisation of insulin has been replaced
by physicochemical methods (high-performance liquid
chromatography, HPLC).
Choice of insulin regimen
There are three common regimens incorporating the insulin
types described above for patients requiring insulin:
1. ‘Basal bolus’ therapy: multiple injections of short-acting
insulin are given during the day to mimic prandial
secretion of insulin by the pancreas, combined with
once- or twice-daily intermediate or long-acting
insulin to provide the background insulin. This
approach aims to mimic the non-diabetic pattern of
insulin release. The total insulin dose is usually
apportioned to be 40–60% background and 40–60%
prandial.
Chapter
| 36 |
2. When choosing the short-acting insulin in a basal
bolus regimen, soluble insulin is given 30 min before
meals. Short acting analogues may be given
immediately before, during or even after the meal,
although recent data suggest that even these insulins
may be more effective if given 15 min prior to eating.
The more rapid waning of action profile also means
that the risk of hypoglycaemic reactions before the
next meal may be lower with the analogues. For
choice of background insulin, long-acting analogues
may give less risk of nocturnal hypoglycaemia than
NPH insulin (see Fig. 36.1), although NPH insulins
may offer greater flexibility if patients need to change
background insulin from day to day (as with some
sportsmen or pregnant women, for example).
3. Insulin pump therapy uses the same principles as
basal bolus insulin but uses only fast-acting (usually
analogue) insulin. In this case, the ‘background’
action comes from the fact that insulin is delivered
continuously, analogous to insulin release from the
non-diabetic pancreas.
4. Twice-daily therapy involves two injections of biphasic
insulin. Although less ‘physiological’ than basal
bolus, it is simpler, with fewer insulin injections. The
available mixtures are listed in Table 36.1. The most
commonly used is 30 : 70 (soluble: NPH). Typically
one-half to two-thirds of the daily dose may be given in
the morning before breakfast and one-half to one-third
before the evening meal. A combination of biphasic
insulin with breakfast and fast-acting insulin with the
evening meal and bedtime background insulin may
be useful in some children with type 1 diabetes to
avoid having to inject insulin at school.
5. Background or prandial insulin alone may be sufficient
in type 2 diabetes when patients progress from oral
therapy on to insulin. In this situation, oral therapy is
usually continued in combination with insulin.
Dose and injection technique
A typical insulin-deficient patient with type 1 diabetes needs
0.5–0.8 units/kg insulin per day with approximately 50%
as background. Increasingly, patients with type 1 diabetes
are not being prescribed fixed insulin doses. Instead, patients
are being trained in how to self-adjust insulin doses, to
allow for factors which will influence how much insulin is
needed: meals with differing carbohydrate contents, digesting
and skipping meals, exercise/activity, illness/stress, alcohol,
travel, menstrual cycle. These same principles apply to insulin
delivered by an insulin pump, although many patients require
lower total insulin doses by this route.
Initial treatment dose for a patient with type 1 diabetes,
without ketoacidosis, is usually 0.3 units/kg daily. This initial
613
Section
|8|
Endocrine system, metabolic conditions
management is aimed at introducing patients to regular
insulin injections and blood glucose testing and aiming to
tighten glycaemic control gradually over the first few weeks/
months. Some patients with type 1 diabetes may have a
significant residual insulin secretory capacity and may require
no insulin for some months after diagnosis, often termed
the ‘honeymoon’ period. Others may be started initially on
low doses of either background insulin alone or prandial
insulin, depending on their clinical status and whether they
have any residual endogenous insulin secretion at diagnosis/
presentation.
For type 2 diabetes, glycaemic targets have become lower
over the last decade so that increasing numbers are treated
with insulin. Although dosing calculators have been used,
particularly in some clinical trials, in practice patients are
often started on low doses of insulin using a simple regimen
and then the dose/regimen is built up as indicated by blood
glucose response. Most of these patients are insulin resistant,
and a useful therapeutic strategy is to combine adjuvant
oral therapy (metformin, pioglitazone or sodium glucose
cotransporter 2 inhibitors) with injected insulin. Severe
insulin resistance merits specialist investigation for a possible
underpinning cause.
Injection technique has pharmacokinetic consequences
according to whether the insulin is delivered into the
subcutaneous tissue or (inadvertently) into muscle, and
patients should standardise their technique. The introduction
of a range of needles of appropriate length and pen-shaped
injectors has enabled patients to inject perpendicularly to
the skin without risk of intramuscular injection. The absorption of insulin is as much as 50% more rapid from shallow
intramuscular injection. Clearly, factors such as heat or
exercise that alter skin or muscle blood flow can markedly
alter the rate of insulin absorption.
Sites of injection should be rotated to minimise local
complications (lipodystrophy). Absorption is faster from
arm and abdomen than it is from thigh and buttock.
Adverse effects of insulin
Hypoglycaemia
Hypoglycaemia is the main adverse effect of the therapeutic
use of insulin. It occurs with excess insulin dosing. Common
causes are misjudging or missing meals, activity/exercise
and alcohol. Hypoglycaemia is problematic because
the brain relies largely, if not exclusively, on circulating
glucose as its source of fuel. A significant fall in blood
glucose can result in impaired cognition, lethargy, coma,
convulsions and perhaps even death (hypoglycaemia was
implicated in one series in 4% of deaths in patients with
type 1 diabetes who were younger than 50 years of age).
Hypoglycaemia is a major factor for insulin-treated patients,
614
with fear of hypoglycaemia being rated as highly as fear
of other complications of diabetes such as blindness or
limb amputation. Hypoglycaemia is a particular problem
for some patients who lose symptomatic awareness of (and
associated counterregulatory neurohumoral defences against)
hypoglycaemia.
When human insulin first became available, a number
of patients reported that they had less symptomatic awareness
of hypoglycaemic episodes. Although the bulk of the subsequent scientific studies examining this failed to detect any
significant differences in responses to hypoglycaemia between
human and animal insulins, the possibility remains that
some patients do react differently and a small number of
patients still prefer to use porcine insulin. In practice, the
debate about human versus animal insulin has become less
topical as non-human analogue insulins are being increasingly used in routine clinical practice.
Prevention of hypoglycaemia depends largely upon patient
education, but regular mild episodes of hypoglycaemia are
an almost unavoidable aspect of intensive glycaemic control,
at least with currently available insulin replacement regimens.
Patients should be vigilant, particularly if they have reduced
symptomatic awareness of hypoglycaemia, carry rapid acting
carbohydrates with them and monitor blood glucose regularly, especially with exercise and before driving a motor
vehicle.
Treatment of hypoglycaemia is to give 15–20 g of rapidly
acting carbohydrates by mouth (e.g. dextrose tablets, fruit
juice or glucose drinks) if the patient is not cognitively
obtunded, repeated after 10 min if needed. Where the
conscious level is impaired, rescue needs to be non-oral
therapy with either i.v. glucose (dextrose) or glucagon. For
i.v. glucose, current advice is to avoid using 50% dextrose
which is irritant, especially if extravasation occurs. Administration of 50–100 mL of 20% glucose (i.e. 10–20 g), is less
thrombogenic. Glucagon (t1/2 4 min) is a polypeptide
hormone (29 amino acids) from the β-islet cells of the
pancreas. It is released in response to hypoglycaemia from
the non-diabetic pancreas (although not in type 1 diabetes
for reasons that are unclear) and is a physiological regulator
of insulin effect, acting by causing the release of liver glycogen
as glucose. Glucagon is used as a ‘stopgap’ treatment for
insulin-induced hypoglycaemia, although it is ineffective
in prolonged or repeated hypoglycaemia where hepatic
glycogen will be exhausted. The main advantage of glucagon
is that it is available in kits for home use so that 1 mg s.c.
or i.m. can be useful when rescue is needed by parents/
carers/partners without waiting for paramedic assistance.
The response to rescue is usually rapid. After initial therapy,
the patient should be given a snack containing slowly
absorbable ‘starchy’ carbohydrate to avoid relapse. The
patient’s treatment regimen should also be carefully reviewed
with appropriate educational input. In particular, it is useful
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
to ask whether this is part of a pattern of repeated episodes
or an ‘on-off’ event with a clear precipitant.
After large overdoses of insulin (particularly long acting)
or sulfonylurea, 20% glucose may be needed by continuous
i.v. infusion for hours or days. With very large overdoses, for
example, where several hundred units have been administered
to self-harm, it may be possible surgically to excise the
depot of insulin from the injection site if it can be clearly
identified. After prolonged hypoglycaemia, cerebral oedema
may occur. Full recovery of cognitive function generally
lags behind restoration of blood glucose, but if the patient
does not respond clinically to restoration of blood glucose
within 30 min, cerebral oedema and i.v. dexamethasone
therapy should be considered. Although the brain appears
to be more resilient to hypoglycaemia than to other insults
such as anoxia or trauma, very severe and prolonged
hypoglycaemia can undoubtedly result in permanent brain
damage.
Lipohypertrophy may occur if an injection site is repeatedly
used, because of the local anabolic effects of insulin. Aesthetics aside, lipohypertrophy is a practical issue as insulin
absorption from injection into areas of fatty hypertrophy
becomes more variable and unpredictable, resulting in both
hyperglycaemia and hypoglycaemia. Lipoatrophy at injection
sites is rarer (but still occurs) with modern, purified insulins
and is thought to be related to a local immune reaction to
insulin. More generalised allergic reactions to insulin are
fortunately rare. If either lipodystrophy or lipoatrophy are
present, the site should be avoided.
Non-insulin antidiabetes drugs
Chapter
| 36 |
successful therapy probably requires at least 30% of normal
β-cell function to be present. Secondary failure (after months
or years) occurs due to declining β-cell function.
Their main adverse effects are hypoglycaemia and weight
gain. Hypoglycaemia can be severe and prolonged (for days),
and may be fatal in 10% of cases, especially in the elderly
and patients with heart failure in whom long-acting agents
should be avoided. Erroneous alternative diagnoses such as
stroke may be made. Sulfonamides, as expected, potentiate
sulfonylureas both by direct action and by displacement
from plasma proteins.
Several sulfonylureas are available (Table 36.2). Choice
is determined by the duration of action as well as the patient’s
age and renal function, and unwanted effects. The long-acting
sulfonylureas, e.g. glibenclamide, are associated with a greater
risk of hypoglycaemia; for this reason they should be avoided
in the elderly, for whom shorter acting alternatives, such as
gliclazide, or non-sulfonylurea options (see below) are
preferred. In patients with impaired renal function, gliclazide,
glipizide and tolbutamide are preferred as they are not
excreted by the kidney. Gliclazide is a commonly used
second-generation agent. If the dose exceeds 80 mg, the
drug should be taken twice daily before meals, or once daily
if prescribed as a modified-release preparation. Glimepiride
is designed to be used once daily and provokes less hypoglycaemia than glibenclamide.
Meglitinides such as repaglinide (t1/2 1 h) are short-acting
oral hypoglycaemic agents that have not been widely used
in clinical practice. Like sulfonylureas, they act by blockade
of ATP-dependent potassium channels (see Table 36.2).
The shorter-action profile of meglitinides compared with
sulfonylureas should in theory reduce risk of hypoglycaemia.
Incretin analogues and mimetics. Exenatide, liraglutide,
Non-insulin antidiabetes drugs are either (i) secretagogue
therapy to increase endogenous insulin release, (ii) insulin
sensitisers to reduce insulin resistance, (iii) drugs increasing
excretion of glucose through kidneys, or (iv) drugs aimed
at modifying absorption of glucose.
(i) Insulin secretagogues
Sulfonamide derivatives (sulfonylureas) act to increase
endogenous insulin secretion by blocking ATP-sensitive
potassium channels on the β-islet cell plasma membrane. This
results in the release of stored insulin in response to glucose.
The discovery of sulfonylureas was serendipitous. In 1930
it was noted that sulfonamides could cause hypoglycaemia,
and in 1942 severe hypoglycaemia was found in patients
with typhoid fever during a therapeutic trial of sulfonamide.
Sulfonylureas were introduced into clinical practice in 1954
and continue to be widely used in type 2 diabetes. Sulfonylureas are ineffective in totally insulin-deficient patients;
lixisenatide, dulaglutide and albiglutide are functional analogues
of incretin, a glucagon-like peptide-1 (GLP-1) and a naturally
occurring peptide that enhances insulin secretion in response
to a rise in blood glucose. Aside from boosting insulin
secretion, they have other actions which offer potential
advantages over other insulin secretagogues in diabetes:
reducing glucagon secretion, slowing gastric emptying and
acting on brain GLP-1 receptors to reduce appetite. Animal
studies suggest that there may be a stimulatory effect of
GLP-1 analogues on beta cell mass, although this has not
yet been demonstrated reliably in humans. GLP-1 therapy
is currently aimed at overweight patients with type 2 diabetes
where sulfonylureas or insulin therapy may promote weight
gain. GLP-1 analogues are administered subcutaneously once
or twice daily, although longer-acting analogues are now
available. This allows a regimen with injections no more
than once weekly. Oral preparations are currently in clinical
trials. The main adverse effect is nausea, which may be
sufficient to prevent use.
615
Section
|8|
Endocrine system, metabolic conditions
Table 36.2 Principal non-insulin antidiabetes drugs
Drug
Total daily dose
(mg unless
otherwise stated)
Dosing schedule
(doses/day unless
otherwise stated)
Duration of
action (h unless
otherwise stated)
Biguanide
Metformin
500–3000
2–3
8–12
Metformin MR
500–2000
1–2
8–12
Alogliptin
25
1
>24
Linagliptin
5
1
>24
Saxagliptin
2.5–5
1
>24
Sitagliptin
25–100
1
>24
Vildagliptin
50
1
>24
100–300
1
>24
Dipeptyl peptidase IV inhibitors
Sodium glucose cotransporter 2 inhibitors
Canagliflozin
Dapagliflozin
5–10
1
>24
Empagliflozin
10–25
1
>24
Albiglutide
30–50
Once weekly
>7 days
Dulaglitide
0.75–1.5
Once weekly
>7 days
Exenatide (Byetta)
5–10 μg
2
12
Exenatide (Bydureon)
2
Once weekly
>7 days
Liraglutide
0.6–1.8
1
24
Lixisenatide
10–20 μg
1
Up to 24
GLP-1 analogue therapy
Table does not show combination therapies.
Dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4
inhibitors like Sitagliptin, vildagliptin, linagliptin, saxagliptin
and alogliptin are being increasingly used. They offer an
alternative strategy for targeting the GLP-1 pathway by
inhibiting breakdown of native GLP-1. The main benefits
of these agents are oral administration, weight neutrality and minimal risk of hypoglycaemia compared with
sulphonylureas; they are generally less efficacious than
direct GLP-1 agonists. Side-effects include nausea, skin
rash and nasopharyngitis, although they are generally very
well tolerated. Most DPP-4 inhibitors are excreted renally.
Dose adjustments are needed in renal impairment, although
616
linagliptin is mostly excreted through the gastrointestinal
tract, thus offering an alternative to metformin in renal
impairment.
(ii) Insulin sensitisers
Biguanides (see Table 36.2) have been available since 1957.
Metformin is now the only biguanide in use. The most
important physiological effect appears to be an increase in
hepatic insulin sensitivity/reduction of hepatic glucose
production. Recent studies have suggested that the intracellular
target of metformin in the liver is the enzyme adenosine
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
monophosphate–activated protein kinase (AMPK) system.
AMPK is a conserved regulator of the cellular response to
low energy, being activated when intra-cellular ATP levels
decrease and AMP concentrations increase.5
Metformin (t1/2 5 h) is best taken with or after meals.
Metformin can be used in combination with either insulin
or other oral antidiabetic agents, and is the first-line agent
in the management of type 2 diabetes in most global
guidelines. It is also being used in the management of type
1 diabetes in conjunction with insulin, especially in overweight individuals and as the first-line agent in gestational
diabetes. The drug is ineffective in the absence of insulin.
Minor adverse reactions are common, including nausea,
diarrhoea and a metallic taste in the mouth. These symptoms
are usually transient or subside after reduction of dose and
can be minimised by building doses up slowly and ensuring
that metformin is taken with or after food. A modified release
preparation, Metformin MR, is reported to be better tolerated
in some patients who suffer gastrointestinal side-effects with
regular metformin.
More serious, but rare, is lactic acidosis. When this condition
does occur, it is usually against the background of significant
medical illnesses which tend to increase circulating lactic
acid levels, particularly renal impairment, liver failure,
or cardiogenic or septic shock. Metformin is therefore
contraindicated in these conditions, including relatively mild
renal impairment, and use should be reviewed when plasma
creatinine is >130 mmol/L (or eGFR <45 mL/min/1.73 m2)
and stopped when plasma creatinine is >150 mmol/L (or
eGFR <30 mL/min/1.73 m2).
Most clinical guidelines recommend that metformin is best
withdrawn temporarily before general anaesthesia and/or
administration of iodine-containing contrast media because
of concerns about precipitating renal impairment (although
the evidence for this is unclear) or risks of lactic acidosis
if renal impairment develops. Lactic acidosis may require
treatment with i.v. isotonic sodium bicarbonate.
Apart from diabetes, the insulin-sensitising effects of
metformin may also be useful in polycystic ovary syndrome,
a condition in which insulin resistance occurs and may
contribute to the hyperandrogenism and consequent hirsutism and disordered menstrual cycles which characterise
this condition.
Thiazolidinediones. Pioglitazone reduces peripheral
insulin resistance, leading to a reduction of blood glucose
concentration. This class of drugs stimulates the nuclear
Chapter
| 36 |
hormone receptor, peroxisome proliferator–activated receptor
(PPARγ), which causes differentiation of adipocytes. The
major action is to stimulate peripheral insulin sensitivity
and thus glucose uptake in skeletal muscle, although the
mechanism by which this ‘cross-talk’ from adipocytes to
muscle occurs is unclear. They are slower to act than either
metformin or sulfonylureas.
The main adverse effects of thiazolidinediones are weight
gain (typically 3–4 kg of weight gain in the first year of use),
fluid retention (with peripheral oedema in 3–4% of patients)
and decreased bone density.
(iii) Agents that increase urinary
glucose excretion
SGLT-2 inhibitors. Sodium-glucose cotransporter-2 is the
main cotransporter in renal proximal convoluted tubules
involved in glucose reabsorption via the kidneys. Inhibition
of SGLT-2 by drugs like canagliflozin, dapagliflozin and
empagliflozin reduces the renal threshold of glucose (usually
around 10 mmol/L) and leads to glycosuria, thereby reducing
glucose load in blood. These agents are given orally, are
weight reducing, but tend to be less efficacious even in mild
renal impairment (eGFR below 45–60 mL/min). Recent data
(EMPA-REG OUTCOME) suggest that empagliflozin reduces
cardiovascular mortality and morbidity in patients with high
cardiovascular risk. The main side-effect is urogenital infections. Glycosuria also causes a degree of diuresis and may
cause orthostatic hypotension in some patients. There has
been concern about euglycaemic ketoacidosis; therefore,
ketone testing is advised in patients who are unwell even
if blood sugars are normal. Recent clinical trial data suggest
a risk of increased lower limb amputation in canagliflozin
studies. It is unclear what the mechanism is and whether
this applies to other SGLT2 inhibitors.
(iv) Agents which reduce glucose absorption
Acarbose is an α-glucosidase inhibitor that reduces the
digestion of complex carbohydrates and slows their absorption from the gut and thus reduces postprandial glycaemia.
The usual dose is 50–300 mg/day. Adverse effects are common,
mainly flatulence and diarrhoea, which lead to a high
discontinuation rate. In high doses it may cause frank
malabsorption. Acarbose may be combined with a sulfonylurea. Overall, it is rarely used nowadays.
Antidiabetics and cardiovascular outcome studies. Fol-
5
The discovery of the AMPK response, and of other players in the
pathway, has enabled experiments to be performed in which the
hepatic response to metformin is selectively knocked out. In the
mouse, at least, these experiments show that actions of metformin at
other sites are of little importance.
lowing initial reports of a possible link between adverse
cardiovascular outcomes and rosiglitazone (a thiazolidinedione) use in 2007, the US Food and Drug Administration
(FDA) industry guidance in 2008 required all new antidiabetic
agents to have sufficient cardiovascular outcome data showing
617
Section
|8|
Endocrine system, metabolic conditions
no increased risk before they could have regulatory approval
for use. Most cardiovascular outcome trials (CVOTs) have
used non-inferiority designs to rule out unacceptable adverse
cardiovascular events, although, to date, EMPA-REG and
LEADER trials examining empagliflozin and liraglutide,
respectively, have shown superiority of empagliflozin and
liraglutide, respectively, in reducing major cardiovascular
events in high-risk individuals.
Choice of oral antidiabetic drugs in
type 2 diabetes
In general terms, a hierarchy of therapies exists for type 2
diabetes, progressing from diet and lifestyle alone (described
later), through monotherapy with oral agents, combinations
of oral therapies and then onto insulin/injection therapy
either alone or in combination with oral treatment. The
nature of ‘typical’ type 2 diabetes is that glucose intolerance
tends to progress so that many patients will need to escalate
therapy with time to avoid worsening glycaemia (and warning
patients of this early after diagnosis helps avoid subsequent
disappointment and demotivation). It is also worth emphasising that this ‘typical’ time course is not universal. Analogous
to type 1 diabetes, some patients may present with marked
symptomatic hyperglycaemia requiring immediate insulin
therapy (and indeed some of these may have an unrecognised
late onset of type 1 diabetes).
The evidence base for the most effective strategies for
using antidiabetic therapy continues to evolve, and the
following is UK NICE (National Institute for Health and
Care Excellence) guidance set out as a guide for readers.
Current advice is that metformin (where not contraindicated
and if tolerated) is useful primary monotherapy for most
patients with type 2 diabetes. DDP-4 inhibitors and SGLT-2
inhibitors are increasingly used as second- or third-line agents,
and may even be used as the first-line agent if metformin
is not tolerated. Sulfonylurea therapy is now less often used
as first-line therapy but is an alternative to metformin or
can be added in to dual therapy as needed. Thiazolidinediones
can also be used in combination with the above. GLP-1
agonists may be considered when overweight is a consideration. The therapeutic target is to maintain the HbA1c
(glycosylated haemoglobin) below 6.5–7.5% (<48–58 mmol/
mol), and insulin may eventually be required, either alone
(see earlier section on insulin regimens) or in combination
with metformin (and/or other agents).
Diet and diabetes
Specialised diet and lifestyle advice is of paramount importance in managing diabetes. Patients should be allowed to
follow their own preferences as far as is practicable. They
should receive dietary advice on a high complex carbohydrate
618
diet (~65% of total calories) with low fat (<30% of calories)
and an emphasis on reduction in saturated fat in favour
of mono- and polyunsaturates. Caloric intake may need
to be restricted and patients encouraged to achieve an
ideal body-weight. Although certain foods are marketed as
‘diabetic’, there are concerns about whether these may be
low in glucose but high in calories. Diet should be high
in fibre with plenty of fresh fruits and vegetables. Advice
about alcohol intake and smoking should be given (and
where appropriate, information about what to do when/
after drinking alcohol because of the effects causing delayed
hypoglycaemia). This should be combined with advice about
activity/exercise levels.
As indicated earlier, increasing numbers of patients with
type 1 diabetes are now taught how to count dietary
carbohydrates, allowing them to adjust their insulin doses
around dietary intake/activity/alcohol.
The advice above may need further modifying in those
with ischaemic heart disease and/or established nephropathy.
Interactions with non-diabetes drugs
Some examples are listed below to show that the possibility
of interactions of practical clinical importance is a real one.
In general, whenever a patient with diabetes takes other
drugs it is prudent to be on the watch for disturbance of
glycaemic control.
β-adrenoceptor–blocking drugs may impair the sympathetically mediated (β2 receptor) release of glucose from the liver
in response to hypoglycaemia and also reduce the adrenergically mediated symptoms of hypoglycaemia (except sweating). Insulin hypoglycaemia may thus be more prolonged
and/or less noticeable. Ideally, a patient with diabetes needing
a β-adrenoceptor blocker should be given a β1-selective
member, e.g. bisoprolol.
Thiazide diuretics at a higher dose than those now generally
used in hypertension can precipitate/worsen diabetes, probably by reducing insulin secretion.
Hepatic enzyme inducers may enhance the metabolism of
sulfonylureas that are metabolised in the liver (tolbutamide).
Cimetidine, an inhibitor of drug-metabolising enzymes,
increases metformin plasma concentration and effect.
Monoamine oxidase inhibitors potentiate oral agents and
perhaps also insulin. They can also reduce appetite and so
upset control.
Interaction may occur with alcohol (hypoglycaemia with
any antidiabetes drug).
Salicylates and fibrates can increase insulin sensitivity,
resulting in lower blood glucose.
The action of sulfonylureas is intensified by heavy sulfonamide dosage, and some sulfonamides increase free tolbutamide concentrations, probably by competing for plasma
protein–binding sites.
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
The use of glucagon as rescue therapy for hypoglycaemia
is described above. Adrenaline/epinephrine raises the blood
sugar concentration by mobilising liver and muscle glycogen
(a β2-adrenoceptor effect), and suppressing secretion of
insulin (an α-adrenoceptor effect). Hyperglycaemia may
occur in patients with phaeochromocytoma, and is usually
reversed by α-adrenoceptor blockade (see p. 404).
Adrenal steroids, either endogenous or exogenous, antagonise the actions of insulin. Although this effect is only slight
with mineralocorticoids, glucocorticoid hormones increase
gluconeogenesis and reduce glucose uptake and utilisation by
the tissues. The therapeutic use of high-dose glucocorticoids
(e.g. in neurosurgical, rheumatological and respiratory conditions) may precipitate frank diabetes in some patients or
worsen blood glucose control in those with established diabetes. Steroid-induced diabetes often requires insulin rather
than oral hypoglycaemic therapy, particularly for flexibility if
steroid doses are being tapered down. Similarly, patients with
Cushing’s syndrome may also develop ‘secondary diabetes’
with a marked resistance to insulin. In contrast, patients with
hypoadrenalism from Addison’s disease, hypopituitarism, or
following steroid withdrawal after prolonged glucocorticoid
therapy may be abnormally sensitive to insulin action and
prone to recurrent hypoglycaemia.
Growth hormone antagonises the actions of insulin in
the tissues. Like Addison’s disease, growth hormone deficiency
may cause increased insulin sensitivity and/or a tendency
for hypoglycaemia. Acromegalic patients may develop
insulin-resistant diabetes.
Oral contraceptives can impair carbohydrate tolerance,
although the effects are usually relatively mild.
Thyroid hormone excess may increase the requirements
Chapter
| 36 |
on metformin who are planning or starting a pregnancy to
continue metformin and for those who are on any other
oral antidiabetics to change to metformin and/or insulin.
There is no definitive evidence though that oral drugs are
associated with fetal malformations. Other drugs (blood
pressure and lipid lowering) should be reviewed and stopped
or altered to agents judged safe in pregnancy as appropriate.
Oral folic acid should be started in advance of pregnancy.
Diabetes can present de novo during pregnancy. Although
this is usually gestational diabetes which resolves after
delivery, it is worth remembering that rarely type 2 or type
1 diabetes can present in pregnancy.
Risks associated with pregnancy in diabetes include an
increased rate of fetal loss and malformations. Maternal
hyperglycaemia can lead to fetal hyperglycaemia with
consequent fetal islet cell hyperplasia, high birth-weight
babies (leading to mechanical obstetric challenges) and
postnatal hypoglycaemia.
Note that glycosuria is not a reliable guide of blood glucose
values in pregnancy. The renal threshold for glucose (also
of lactose) falls, so that glycosuria and lactosuria may occur
in the presence of a normal blood glucose.
Insulin requirements increase steadily after the third
month. Some women develop a marked intolerance of oral
carbohydrates with a tendency for large postprandial rises
in blood glucose. During labour, i.v. insulin infusion may
be needed. Use of β2-adrenoceptor agonists and of dexamethasone (to prevent respiratory distress syndrome in the
prematurely newborn) causes hyperglycaemia and increased
insulin (and potassium) needs.
Of note, insulin requirements reduce immediately after
delivery and may remain low during the following weeks,
particularly with lactation/breast feeding.
for insulin.
Drug-induced diabetes
Diazoxide (see p. 423) is chemically similar to thiazide
diuretics, but stimulates the ATP-dependent K+ channel that
is blocked by the sulfonylureas. Although formerly used as
an antihypertensive agent, its current use in therapeutics is
confined to the rare indication of treating hypoglycaemia
due to islet cell tumour (insulinoma). Adrenocortical steroids
are also diabetogenic (see above).
Pregnancy and diabetes
During (and indeed before) pregnancy, close control of
diabetes is critical. Ideally, pregnancy should be planned
and women should be seen in a pre-conception clinic to
optimise care. Glycaemic targets are tight, aiming for HbA1c
values as close to the non-diabetic range (<6.5 % or
<48 mmol/mol) as possible. Current practice is for women
Surgery in diabetic patients
Principles of management
• Surgery constitutes a major stress.
• Insulin needs will often increase with surgery.
The programme for control should be agreed between
anaesthetist and physician whenever diabetic patients must
undergo general anaesthesia or modify their diets, and most
hospitals/provider trusts have local guidelines for this. There
are many different techniques that can give satisfactory results:
typical guidelines are detailed below.
Type 1 diabetes
The guidelines below may also be useful for insulin-treated
type 2 diabetes, but suggested doses may need modifying
619
Section
|8|
Endocrine system, metabolic conditions
Table 36.3 Sliding scale of insulin doses according to
blood glucose concentrations (not for ketoacidosis)
Blood
glucose
(mmol/L)
Infusion rate (mL/h =
units/h for 50-mL syringe
containing 50 units insulin)
≥22.0
10.0 (and check pump and connections)
19–21.9
8.0
16–18.9
6.0
12–15.9
4.0
8–11.9
2.0
4–7.9
1.0
<3.9
0.5 (and increase glucose infusion)
if patients are insulin resistant with a large constitutive insulin
requirement.
Elective major surgery
• The evening before surgery: give patient’s usual
insulin.
• Day of operation: omit morning s.c. dose; set up i.v.
•
•
•
infusion: 0.45% sodium chloride with 5% glucose
and KCL (0.15% or 0.3%); insulin should be infused
by pump at an approximate rate of 2 units/h and
adjusted according to a sliding scale (variable-rate
insulin infusion, VRII) maintaining a glucose level of
6–10 mmol/L (acceptable range 4–12 mmol/L).
Modify regimen during and after surgery according to
monitoring; insulin doses should be adjusted
according to a similar scale as that in Table 36.3.
Stop i.v. infusion 1 h after first post-surgical s.c. usual
quick-acting insulin (given when eating again).
Insulin requirements may be high, 10–15 units/h, in
cases of major surgery, serious infection,
corticosteroid use or obesity.
Minor surgery/procedures
For example, simple dental extractions or endoscopy. For
short, relatively non-stressful procedures, i.v. insulin is usually
not needed. When nil by mouth, patients should omit
fast-acting insulin normally given for that mealtime.
Emergency surgery
When a surgical emergency is complicated by diabetic ketosis,
an attempt should be made to control the ketosis before
620
surgery. Management during the operation will be similar
to that for major surgery except that more insulin may be
needed.
Type 2 diabetes
For minor procedures when diabetes is well controlled on
oral hypoglycaemics, it should be possible simply to omit
the oral hypoglycaemic agent on the morning of surgery.
Diabetic ketoacidosis
This condition is discussed in detail in medical texts, and
only the more pharmacological aspects will be considered
here.
The best way to consider ketoacidosis is as a severe and
life-threatening metabolic disorder resulting from a lack of
insulin in which hyperglycaemia is present, rather than as
a primary hyperglycaemic disorder. The patient with ketoacidosis often remains critically ill during treatment even after
blood glucose is normalised. Patients are severely dehydrated,
and fluid resuscitation is a major priority. Insulin is needed
not only to lower blood glucose, but also to suppress
ketogenesis. The objective is to supply, as continuously as
possible, a moderate amount of insulin.
Intravenous fluid. A patient with diabetic ketoacidosis
may have a fluid deficit of above 5 L. Usual fluid replacement
is isotonic saline, and a typical regimen might be:
• 1 L in the first hour, followed by
• 2 L in 4 h, then
• 4 L in the next 24 h, watching for signs of fluid
overload.
Note that fluid replacement itself causes a fall in blood
glucose concentration both by dilution and also by restoring
blood volume to perfuse skeletal muscle, a major insulin
target tissue.
Soluble insulin should be given by continuous i.v. infusion
of a 1-unit/mL solution of insulin in isotonic sodium chloride. High doses are needed (e.g. 0.1 U/kg/h), and treatment
needs to be prolonged beyond restoration of blood glucose
to suppress ketogenesis. A reasonable rate of fall of glucose
during treatment is 4–5.5 mmol/L (75–100 mg/100 mL) per
hour. Once the blood glucose has fallen to 10–15 mmol/L,
i.v. dextrose infusion is started to prevent this continued
high-dose insulin resulting in hypoglycaemia (rather than
reducing the insulin infusion rate, which will slow resolution
of the metabolic derangement).
Potassium. Even if plasma potassium concentration is
normal or high, patients have a substantial total body deficit,
and the plasma level will fall briskly with i.v. fluids (dilution)
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
and insulin, which draws potassium into cells within minutes.
Potassium chloride should be added to the second and
subsequent litres of fluid according to plasma potassium
(provided the patient is passing urine).
• <3.5 mmol/L: additional potassium needs to be given
possibly via central line
• 3.5–5.5 mmol/L: add 40 mmol/L.
• >5.5 mmol/L: none.
Bicarbonate is generally not recommended as it may
paradoxically increase intracellular acidosis and delay the
reduction in blood lactate.
Success in treatment of diabetic ketoacidosis and its
complications (hypokalaemia, aspiration of stomach
contents, infection, shock, thromboembolism, cerebral
oedema) depends on close, constant, informed supervision
and repeated monitoring of clinical state and biochemical
parameters.
Euglycaemic ketoacidosis can happen rarely, particularly
where insulin is used in combination with SGLT-2 inhibitor
therapy. Principles of management are the same, although
intravenous glucose along with saline is usually required
from the outset to allow adequate insulin delivery without
hypoglycaemia. Diabetic ketoalkalosis is also possible if
excessive vomiting of gastric acid leads to loss of chloride
(hypochloraemia).
Diabetic ketosis without acidosis. As with full-blown
ketoacidosis, this may develop during intercurrent illness.
Increasingly, patients with type 1 diabetes are given ‘sick
day rules’ for how to manage this when appropriate out of
hospital. This relies on the patient being fully conscious,
not vomiting and being willing and able to drink fluids
and follow instructions, including regular and repeated
monitoring of blood glucose and ketone levels. In general,
insulin doses are increased with additional injections
of soluble insulin (10–20% of total daily insulin dose
every 2 h). The rules include ‘bail out’ instructions on
seeking admission if ketone and glucose levels are not
resolving and/or patients start to vomit or fail to improve
clinically.
Ketosis-prone type 2 diabetes (“Flatbush diabetes”).
Many ketoacidosis cases in people with type 2 diabetes
have been reported, usually in Afro-Carribean individuals.
After an initial aggressive insulin therapy, it may be possible
for them to be in remission without needing insulin for
months and even years. The underpinning mechanism is
unknown but may be related to a reversible glucose toxicity effect on beta cells, so that restoring normoglycaemia
for a period of time allows functional insulin secretion to
recover.
Hyperosmolar Hyperglycaemic State (HHS) occurs
chiefly in type 2 diabetics who fail to compensate for their
Chapter
| 36 |
continuing osmotic glucose diuresis. It is characterised
by severe dehydration, a very high blood sugar level
(>33 mmol/L), and in most cases lack of ketosis and acidosis.
Treatment is with isotonic (0.9%) saline, usually at one-half
the rate recommended for diabetic ketoacidosis, and with
less potassium than in severe ketoacidosis. Insulin requirements are less than in ketoacidosis, where the acidosis causes
resistance to the actions of insulin, and should generally
be one-half of those shown in Table 36.3. Patients may
be profoundly dehydrated and liable to thrombosis so
that prophylactic low molecular weight heparin should be
considered.
Preventing complications other
than by glucose lowering
Diabetes is a condition not just of abnormal glucose but
also of significantly increased cardiovascular risk. Indeed,
most patients with both type 1 and type 2 diabetes succumb
to either the macrovascular or microvascular complications – especially ischaemic heart disease and/or diabetic
nephropathy.
Aggressive treatment of hypertension and hyperlipidaemia
in addition to glycaemia is particularly important in patients
with diabetes. For example, the landmark UK Prospective
Diabetes Study (UKPDS) of type 2 diabetes confirmed that
good glycaemic control and aggressive blood pressure
reduction independently improve outcome.6,7 For every
1% reduction in haemoglobin A1c (HbA1c), there was a
21% reduction in diabetes-related deaths and a 37% reduction
in microvascular disease. Of highest importance was the
finding that effective blood pressure control – regardless of
the type of antihypertensive drug – was more influential
than glycaemic control in preventing macrovascular complications. Reduction of blood pressure in 758 patients to a
mean of 144/82 mmHg achieved a 32% reduction in deaths
related to diabetes and a 37% reduction in microvascular
endpoints, compared with findings in 390 patients treated
to a blood pressure of 154/87 mmHg.
Similarly, aggressive targeting of lipids reduces cardiovascular complications in diabetes. In the Heart Protection
Study, addition of simvastatin 40 mg/day to the treatment
of 4000 patients with diabetes reduced cardiovascular
6
UK Prospective Diabetes Study (UKPDS) Group 1998 Effect of
intensive blood-glucose control with metformin on complications in
overweight patients with Type 2 diabetes (UKPDS 34). Lancet
352:854–865.
7
UK Prospective Diabetes Study (UKPDS) Group 1998 Tight blood
pressure control and risk of macrovascular and microvascular
complications in Type 2 diabetes. British Medical Journal 317:703–713.
621
Section
|8|
Endocrine system, metabolic conditions
complications by 30%. Some guidelines have suggested
that aspirin may be worth using in primary prevention in
diabetes (i.e. in those who have not suffered a cardiovascular
event), although current thinking is that the benefits are
unproven.
Patients with evidence of diabetic nephropathy should
receive either an angiotensin-converting enzyme (ACE)
inhibitor or an angiotensin receptor antagonist; the evidence
Summary
• Diabetes mellitus is important in global terms because
of its chronicity, and high incidence and frequency of
major complications. It is generally divided into two
kinds: type 1 (previously, insulin-dependent diabetes
mellitus) and type 2 (previously, non–insulin
dependent diabetes, essentially an umbrella term for a
group of conditions which are non–type 1).
• Type 1 diabetes is commoner in those with onset
before 30 years of age, whereas type 2 diabetes is
best considered as a heterogenous group of
conditions usually presenting at a later age.
Increasingly, insulin therapy is required in type 2
diabetes when glycaemic control is not optimised by
oral drugs.
• Insulin is usually self-administered subcutaneously to
stable patients, with a variety of regimens which can
be tailored to the needs of a particular patient.
Modern practice in type 1 diabetes is to educate
patients in flexible insulin dosing which is adjusted for
differing meals, activity levels, etc.
• In the treatment of diabetic ketoacidosis, in the
perioperative patient, and during inpatient
management of the critically ill patient with diabetes,
insulin is best given by intravenous infusion of the
soluble form.
• Diet plays a major role in the treatment of type 2
diabetes, particularly when associated with obesity.
• If a drug is required in type 2 diabetes, metformin (a
biguanide) is now widely used as first-line therapy,
especially for the obese. There are many second-line
agents available now, but the increasing focus of
attention is on the cardiovascular outcomes of
antidiabetics. Many patients with type 2 diabetes will
need treatment escalation with time to multiple
combination therapy and/or insulin.
• Aggressive blood glucose–lowering treatment of type
1 and type 2 diabetes reduces the risk of
microvascular complications. Close attention to
associated risk factors, especially hyperlipidaemia and
hypertension, is important in reducing the risk of
macrovascular disease.
622
for the superiority of the latter in reducing progression to
renal failure compared with other antihypertensive agents
is particularly strong.8 Addition of an ACE inhibitor to other
drugs may also improve overall outcome in patients with
diabetes.9 In addition, diabetic nephropathy is independently
associated with an increased risk of macrovascular disease
so that aggressive lipid and blood pressure–lowering therapy,
as described above, should be employed.
Obesity and appetite control
Overweight and obesity are the commonest nutritional
disorders in developed countries. Between 1991 and 2014,
the prevalence of obesity in adults rose from 22.3% to 37.9%
in the USA. Obesity predisposes to several chronic diseases
including hypertension, hyperlipidaemia, diabetes mellitus,
cardiovascular disease and osteoarthritis, and aspects of these
are discussed in the relevant sections of this book.
Individuals whose body mass index10 (BMI) lies between
25 and 30 kg/m2 are considered overweight, and those in
whom it exceeds 30 kg/m2 are defined as obese. Management of the condition involves a variety of approaches from
nutritional advice to lifestyle alteration, drugs and, where
available and appropriate, bariatric surgery. In the UK, an
evidence-based algorithm coordinates these.11 The present
account concentrates on pharmacological interventions.
In general, drugs that have been used for obesity act either
on the gastrointestinal tract, lowering nutrient absorption,
or centrally, reducing food intake by decreasing appetite or
increasing satiety (appetite suppressants). A number of
8
Three trials compared an angiotensin blocker with other blood
pressure–lowering drugs and found a 20% reduction in the proportion
of patients in whom proteinuria worsened or serum creatinine
concentration doubled during follow-up: (1) Parving H H, Lehnert H,
Brochner-Mortensen J et al 2001 The effect of irbesartan on the
development of diabetic nephropathy in patients with Type 2 diabetes.
New England Journal of Medicine 345:870–878; (2) Brenner B M,
Cooper M E, de Zeeuw D et al 2001 Effects of losartan on renal and
cardiovascular outcomes in patients with Type 2 diabetes and
nephropathy. New England Journal of Medicine 345:861–869; (3)
Lewis E J, Hunsicker L G, Clarke W R et al 2001 Renoprotective effect
of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to Type 2 diabetes. New England Journal of Medicine
345:851–860.
9
The HOPE study included patients with diabetes as one of its high-risk
groups of cardiovascular patients, in whom ramipril reduced further
coronary heart disease endpoints by about 30%. Yusuf S, Sleight P,
Pogue J et al 2000 Effects of an angiotensin converting enzyme
inhibitor, ramipril, on cardiovascular events in high-risk patients. The
Heart Outcomes Prevention Evaluation Study Investigators. New
England Journal of Medicine 342:145–153.
10
The weight in kilograms divided by the square of the height in
metres (kg/m2).
11
https://pathways.nice.org.uk/pathways/obesity
Diabetes mellitus, insulin, oral antidiabetes agents, obesity
Chapter
| 36 |
pharmacological agents that have been marketed for obesity
have been withdrawn because of concerns about safety.
Currently, only one agent, orlistat, is available in the UK:
Leptin acts to control satiety via the melanocortin system,
predominantly in the basomedial hypothalamus, and a
number of agents in development aim to target this.
Orlistat
Newer agents
Orlistat is a pentanoic acid ester that binds to and inhibits
gastric and pancreatic lipases; the resulting inhibition of
their activity prevents the absorption of about 30% of dietary
fat compared with a normal 5% loss. Weight loss is due to
calorie loss, but drug-related adverse effects also contribute
by diminishing food intake. The drug is not absorbed from
the alimentary tract.
Clinical trials have shown that patients who adhered to
a low-calorie diet and took orlistat lost on average 9–10 kg
after 1 year (compared with 6 kg in those taking placebo);
in the following year those who remained on orlistat regained
1.5–3.0 kg (4–6 kg with placebo). Orlistat has found a place
in the management of obesity in the UK but, not surprisingly,
this is subject to stringent guidance from NICE, namely that
it be initiated only in individuals with a BMI of 28 kg/m2
or more who also have cardiovascular risk factors, or 30 kg/
m2 or more without such co-morbidity.
The dose is 120 mg, taken immediately before, during or
1 h after each main meal, up to three times daily. If a meal
is missed, or contains no fat, the dose of orlistat should be
omitted.
Treatment should be accompanied by counselling advice
and proceed beyond 3 months only in those who have lost
more than 5% of their initial weight and beyond 6 months in
those who have lost more than 10%. It should not normally
exceed 1 year and should never be more than 2 years.
GLP-1 agonist
Adverse effects include flatulence and liquid, oily stools,
leading to faecal urgency and abdominal and rectal pain.
Symptoms may be reduced by adhering to a reduced-fat
diet. Low plasma concentrations of the fat-soluble vitamins
A, D and E have been found. Orlistat is contraindicated where
there is chronic intestinal malabsorption or cholestasis.
Leptin
The adipocyte-derived hormone leptin (Greek: leptos, thin)
has a limited role in therapeutics for patients with rare genetic
defects in the leptin or leptin receptor genes. Leptin acts on
the brain to reduce appetite. Most obese patients have raised
plasma leptin concentrations, to which they have become
relatively resistant. A small number of patients are genuinely
deficient in leptin, and therapy with recombinant leptin
has had dramatic beneficial effects. Leptin may also be of
benefit in lipodystrophic patients, a rare group of conditions
in which a generalised or partial lack of adipocytes leads
to marked metabolic abnormalities and diabetes.
In addition to being a blood glucose–lowering therapy in
type 2 diabetes as described above, there is interest in whether
GLP-1 agonist therapy should be used for weight reduction
in non-diabetes. High-dose liraglutide 3 mg once a day
(Saxenda) has now been approved in the US and Europe
as a weight-loss agent in patients without diabetes.
Lorcaserin
Lorcaserin is a novel selective agonist of 5-HT2c receptors
in the hypothalamus and increases satiety leading to reduced
food intake. It has been approved by the US FDA for adults
with a BMI over 30 or a BMI over 27 with another weightrelated co-morbidity. It is administered orally, and common
unwanted effects include headache, upper respiratory
infections, nausea and dizziness.
Naltrexone/bupropion (Contrave) and phentermine/
topiramate (Qsymia) have also been approved by the US
FDA, although clinical use is still low.
Obesity and diabetes
Obesity is associated with type 2 diabetes, and weight loss
improves (and in rare cases ‘cures’) diabetes. Weighed against
this is the challenge that certain pharmacologic therapies
for diabetes, particularly sulfonylureas, thiazolidinediones
and insulin, can promote weight gain. The patient and
clinician may find themselves caught in a vicious cycle in
which dose escalation of these agents leads to weight gain,
worsening glycaemic control, which in turn leads to further
dose increments.
As for patients without diabetes, diet and exercise are
critical factors, but diabetes treatment may need to be
adjusted for this (e.g. insulin reductions to avoid hypoglycaemia with increased exercise or reduced carbohydrate
intake). Metformin, either alone or as adjuvant therapy,
especially with insulin as an ‘insulin-sparing’ agent is useful.
GLP-1 analogue therapy offers an alternative to insulin
therapy. Ultimately, as for patients without diabetes, orlistat
and/or bariatric surgery12 may be appropriate.
12
Weight-loss surgery: the procedures include reducing the size of the
stomach by resection, gastric banding and gastric bypass.
623
Section
|8|
Endocrine system, metabolic conditions
Guide to further reading
Chan, J.L., Mantzoros, C.S., 2005. Role
of leptin in energy-deprivation
states: normal human physiology
and clinical implications for
hypothalamic amenorrhoea and
anorexia nervosa. Lancet 366, 74–85.
Cushman, W.C., Evans, G.W., Byington,
R.P., et al., 2010. Effects of intensive
blood-pressure control in type 2
diabetes mellitus. N. Engl. J. Med.
362, 1575–1585.
Dhatariya, K., et al., 2016. JBDS-IP:
Management of adults with diabetes
undergoing surgery and elective
procedures: Improving standards.
Available at: http://www.
diabetologists-abcd.org.uk/JBDS/
Surgical_guidelines_2015_full_
FINAL_amended_Mar_2016.pdf.
(Accessed 21 January 2017.)
Dhatariya, K., et al., 2013. JBDS-IP: The
management of diabetic
ketoacidosis in adults. Available at:
http://www.diabetologists-abcd
.org.uk/JBDS/JBDS_IP_DKA_Adults_
Revised.pdf. (Accessed 21 January
2017.)
Diabetes Control and Complications
Trial/Epidemiology of Diabetes
Interventions and Complications
(DCCT/EDIC) Study Research
Group, 2005. Intensive diabetes
624
treatment and cardiovascular disease
in patients with type 1 diabetes. N.
Engl. J. Med. 353, 2643–2653.
Diabetes Control and Complications
Trial/Epidemiology of Diabetes
Interventions and Complications
(DCCT/EDIC) Research Group,
2009. Modern-day clinical course of
type 1 diabetes mellitus after 30
years’ duration. Arch. Intern. Med.
169, 1307–1316.
Drucker, D.J., Nauck, M.A., 2006. The
incretin system: glucagon-like
peptide-1 receptor agonists and
dipeptidyl peptidase-4 inhibitors in
type 2 diabetes. Lancet 368,
1696–1705.
Eckel, R.H., Grundy, S.M., Zimmet,
P.Z., 2005. The metabolic syndrome.
Lancet 365, 1415–1428.
Gerstein, H.C., Miller, M.E., Genuth, S.,
et al., 2011. Long-term effects of
intensive glucose lowering on
cardiovascular outcomes. N. Engl. J.
Med. 364, 818–828.
Ginsberg, H.N., Elam, M.B., Lovato,
L.C., et al., 2010. Effects of
combination lipid therapy in type 2
diabetes mellitus. N. Engl. J. Med.
362, 1563–1574.
Marso, S.P., et al., 2016. Liraglutide and
cardiovascular outcomes in type 2
diabetes. N. Engl. J. Med. 375,
311–322.
National Institute for Health and
Clinical Excellence, 2015. Diabetes
in pregnancy: Management from
preconception to the postnatal
period. Available at: http://
www.nice.org.uk/guidance/ng3.
(Accessed 21 January 2017).
US Department of Health and Human
Services, Food and Drug
Administeration, Centre for Drug
Evaluation and Research (CEDR),
2008. Guidance for Industry:
Diabetes Mellitus – Evaluating
Cardiovascular risk in New
Antidiabetic Therapies to Treat Type
2 Diabetes. Available at: https://
www.fda.gov/downloads/Drugs/…/
Guidances/ucm071627.pdf.
(Accessed 21 January 2017.)
Wright, J.R., 2002. From ugly fish to
conquer death: J J R Macleod’s fish
insulin research, 1922–24. Lancet
359, 1238–1242.
Zinman, B., et al., 2015. Empagliflozin,
cardiovascular outcomes, and
mortality in type 2 diabetes
(EMPA-REG). N. Engl. J. Med. 373,
2117–2128.