BJA Education, 17 (6): 198–207 (2017)

doi: 10.1093/bjaed/mkw075
Advance Access Publication Date: 22 February 2017
Matrix reference
1A02, 2A03, 3A06

Diabetes medication pharmacology

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Daniel J Stubbs BA BMBCh MRCP FRCA1, Nicholas Levy MBBS BSc FRCA
FFICM2,* and Ketan Dhatariya MBBS MSc MD MS FRCP3
1
Department of Anaesthesia, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK, 2Department of
Anaesthesia, West Suffolk Hospital, Hardwick Lane, Bury St Edmunds IP33 2QZ, UK and 3Elsie Bertram
Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich NR4
7UY, UK
*To whom correspondence should be addressed. E-mail: Nicholas.levy@wsh.nhs.uk

Diabetes mellitus (DM) is a group of metabolic conditions

characterized by hyperglycaemia. It is the most common meta-
Key points
bolic condition in the world, and the incidence is increasing. In
• People with Type1 Diabetes must always have a England, it is estimated that there are 2.8 million people over
constant source of exogenous insulin, otherwise the age of 16 who have diabetes.1 There are several forms/
diabetic ketoacidosis (DKA) will result. causes of diabetes. These include:
• People with Type 2 Diabetes can be managed (i) Type 1 diabetes (T1DM) is characterized by an absolute
either with diet alone, or a combination of diet lack of insulin.
and non-insulin glucose lowering drugs with or (ii) Type 2 diabetes mellitus (T2DM) is the most common
without insulin. form and is characterized by insulin resistance.
• Multiple formulations of insulin exist with markedly (iii) Gestational diabetes occurs during pregnancy and is asso-
ciated with conditions including pre-eclampsia, neonatal
diverse pharmacokinetic profiles. These diverse prep-
hypoglycaemia, and fetal abnormality.
arations are used by people with diabetes in a variety
(iv) Genetic defects of b-cell function (e.g. maturity-onset dia-
of different regimens with the aim of both ensuring
betes of the young).
sufficient background insulin, and to minimise pran-
(v) Endocrinopathies (e.g. Cushing syndrome and
dial hyperglycaemia. An understanding of the differ- phaeochromocytoma).
ent formulations and regimens is required to facili- (vi) Pancreatic disease (e.g. cystic fibrosis and chronic
tate safe perioperative use of insulin and to prevent pancreatitis).
complications from perioperative dysglycaemia. (vii) Drugs (e.g. glucocorticoids and b-adrenergic agonists).2
• Insulins must be prescribed by the brand name, the
The terms ‘insulin dependent’ and ‘non-insulin dependent’,
word units must be written in full, and when admin- or ‘juvenile-onset’ or ‘maturity-onset diabetes’ are no longer
istering, an insulin syringe must always be used. used. This is because a large number of people with T2DM re-
• There are currently eight different classes of non- quire insulin to maintain glycaemic control, and there are also
insulin glucose lowering medication, each with an increasing number of children (who are often obese) who
their own mechanism of action and side effects. have T2DM. Thus the terms ‘Type 1 DM’, ‘Type 2 DM’, and ‘Type
An understanding of the pharmacology is essen- 2 DM on insulin’, are now preferred.
tial to facilitate safe perioperative manipulation Unless the patient’s diabetes can be treated with diet, the
patient will require medication to control the hyperglycaemia.
and to promote optimal perioperative outcomes.
In the last 30 years, insulin pharmacology has been
revolutionized by the introduction of recombinant DNA

Editorial decision: October 19, 2016; Accepted: December 6, 2016

C The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
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198
 Diabetes medication pharmacology

technology and genetically engineered human insulin, which Naturally occurring short-acting insulin, be it of human or ani-
has replaced the animal-derived insulin preparations. In more mal origin, is known as soluble insulin.
recent years, the human insulins produced by recombinant
DNA technology, have been further modified by subtle molecu- Very rapid-acting insulin analogues
lar changes to produce insulins that have different systemic ab- Examples: insulin aspart (Novorapid), insulin lispro (Humalog),
sorption from the s.c. site of injection. These are known as insulin glulisine (Apidra).
insulin analogues. As these biological analogues come off pa- Very rapid-acting insulin analogues have had a small num-
tent, generic drugs are being marketed. These biological generic ber of amino acid substitutions made to the human insulin
drugs (which are known as ‘biosimilars’) are not identical in molecule that allow them to be absorbed at a faster rate than
their purity to the initial analogue preparation, and so to be human insulin when injected s.c. Their onset of action is within
licensed need to go through safety and comparative studies. 10–15 min of initial s.c. injection, and they have a peak of action
These studies have not demonstrated clinically important phar- within an hour and last for up to 4 h. They are usually given to
macokinetic or pharmacodynamic differences between the bio- cover the glucose excursion associated with meals (prandial in-

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similar and the original analogue preparation. In 2015, sulin) as part of a basal bolus regimen. The rapid onset of action
Abasaglar, the first biosimilar, was licensed, which is the biosi- means that they can be administered immediately before or
milar of insulin glargine, a long-acting insulin analogue. within 30 min of a meal.
There are currently eight different classes of non- Owing to these pharmacokinetic properties, these are the in-
insulin glucose-lowering agents,3 with the majority being intro- sulins that the Joint British Diabetes Societies (JBDS) and the
duced in the last 20 years. The term ‘oral hypoglycaemic agents’ Association of Anaesthetists of Great Britain and Ireland
to describe the non-insulin glucose-lowering drugs has been (AAGBI) now recommend to treat transient hyperglycaemia in
rendered obsolete, as the relatively new glucagon like peptide-1 the surgical patient.4,5
analogues (GLP-1 analogues) are peptides, and thus need to be
injected. Human soluble insulin
Patients with diabetes require surgery more often than the Examples: Actrapid; Humulin S; Insuman rapid (Human Insulin
general population, and recent studies suggest that  15% of the rDNA).
surgical population has diabetes. Anaesthetists need to have an Human soluble insulins start working within half an hour of
understanding of the pharmacology of these agents to allow the s.c. injection and last for between 4 and 8 h. Even though they
safe use and modification of the diabetes medication during the are an exact clone of human insulin their use is declining. This
surgical period.4,5 is because of their slow onset of action after s.c. administration.
If they are administered immediately before a meal, patients
will be prone to postprandial hyperglycaemia owing to the
Insulin length of time to reach peak action.
Insulin is a peptide hormone produced by the b-cells in the pan- These are the insulins that are recommended to be used in
creas. Within vertebrates the amino acid sequence is strongly the fixed rate and variable rate i.v. insulin infusions. To reduce
conserved. Bovine insulin differs to human insulin by only the incidence of error, it is recommended that the insulin is ad-
three amino acids, whilst in porcine insulin the difference from ministered via a commercially prepared prefilled syringe with a
human insulin is only one amino acid. Most patients are now concentration of 1 unit/ml.6
on human insulin produced by recombinant DNA technology.
There are many types of insulin commercially available. Background insulins
Insulins can be classified by:
There are two types of background human insulin:
(i) The speed of onset and length of action after s.c. injection
(i.e. short-acting insulin or background insulin). (i) Intermediate-acting insulin, also known as NPH (Neutral
(ii) The type of the insulin (i.e. bovine, porcine, or obtained Protamine Hagedorn [NPH]).
from human insulin using recombinant DNA technology). (ii) Long-acting insulin analogues.
(iii) Whether the preparation contains a single type of insulin These insulins are designed to ensure a steady systemic in-
or a mixture of different insulins. sulin concentration, to ensure that insulin is constantly acting
Table 1 summarizes the different insulin preparations and and to promote continuous cellular glucose uptake. The admin-
their pharmacokinetics. istration of these agents averts the use of fatty acids as a cellu-
lar energy substrate and thus prevents subsequent diabetic
ketoacidosis (DKA). There is little to choose between ‘old’ NPH
The different types of insulin insulin and the ‘new’ longer acting insulin analogues in terms
of glycated haemoglobin (HbA1c) reduction. However, there are
Short-acting insulins
suggestions that the rates of severe hypoglycaemia (i.e. requir-
There are three types of short acting insulin: ing help from a third party) are lower with the long-acting ana-
logue insulins. The newer long-acting insulin analogues are
(i) Very rapid-acting insulin analogues.
significantly more expensive than NPH.
(ii) Human soluble insulin.
(iii) Animal soluble insulin.
NPH insulin/intermediate-acting insulin
The short-acting insulins are usually given to cover the glu- Examples: Insulatard (NPH Insulin), Humulin I (Isophane insu-
cose excursion associated with meals (prandial insulin) as part lin); Insuman basal (Isophane insulin).
of a basal bolus regimen. The dose can be adjusted according to With the addition of the protamine molecule, these insulins
the size of the meal, the amount of carbohydrate in the meal, have delayed absorption and are clinically effective 90–120 min
the current glucose reading, and the planned activity levels. after s.c. injection, and exert their effect for 8–10 h. These

BJA Education | Volume 17, Number 6, 2017 199

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Table 1 Summary of different types of insulin and their pharmacokinetic profiles

Type of insulin Onset (min) Peak activity Duration Pharmacokinetic profile Clinical use

• Rapid-acting analogue in- 10 min 15 min to 1 h 3–4 h • Bolus part of basal bolus regimen
sulins, e.g. • Bolus part of twice daily
• Novorapid (aspart) separate injections (rarely used
• Humalog (lispro) in this combination)
• Apidra (glulisine) • CSIIs pump therapy
Diabetes medication pharmacology

• Short-acting soluble 30 min 1–3 h 6–8 h • Bolus part of basal bolus regimen
human insulins, e.g. • Variable rate and fixed rate

BJA Education | Volume 17, Number 6, 2017

• Actrapid i.v. insulin infusions
• Humulin S
• Velosulin
• Short-acting animal 30 min Within 60 min 6–8 h Reduced use in 21st century
(Bovine or Porcine), e.g.
• Hypurin

• NPH insulin/Intermediate- 120 min 4–6 h 8–10 h • Basal part of twice daily
acting insulin, e.g. separate injections
• Humulin I • Basal part of basal bolus
• Insultard regimen—can be given once
• Hypurin (Bovine or or twice in this regimen
Porcine) Isophane

• Long-acting analogue in- 120 min No peak 18–24 h • Once daily regimen for T2DM
sulins, e.g. • Part of basal bolus regimen
• Levemir (detemir)

(continued)

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 Table 1. (continued)
Type of insulin Onset (min) Peak activity Duration Pharmacokinetic profile Clinical use

• Lantus (glargine)
• Tresiba (degludec)

• Biphasic insulin As per Two peaks As per Twice daily regimen, although
(Combinations of either components components occasionally given three
rapid-acting or short- times per day
acting soluble with an
intermediate-acting in-
sulin), e.g.
• Humalog Mix 25 or Mix
50
• Humulin M3
• Insuman comb 15,
comb 25
• NovoMix 30

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Diabetes medication pharmacology

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Diabetes medication pharmacology

insulins are commercially available either alone or in combin- properties as human insulin, but are far more immunogenic,
ation with either a rapid acting (e.g. NovoMix 30), or a soluble and are subsequently associated with immune-mediated lipo-
insulin (e.g. Humulin M3). hypertrophy and lipoatrophy.

Human biphasic/mixed insulins Insulin regimens

Examples: NovoMix 30, Humulin M3, Insuman Comb 25. There are many different regimes depending on the need of the
There are some commercial preparations of premixed inter- patient, ranging from one injection a day to up to five injections
mediate- with a short-acting insulin. The short-acting insulin a day. The idea is to try to mimic the normal physiological con-
may be either a soluble insulin or a very rapid-acting insulin centrations of insulin. They are displayed graphically in Figures
analogue. The number in these insulin names refers to the pro- 1–4.
portion of short-acting insulin in the combination (e.g. NovoMix The different types of insulins can be given in any different
30 comprises 30% Insulin aspart (rapid-acting analogue) and combination.

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70% Insulin aspart complexed with protamine (intermediate- Commonly used regimens:
acting). These mixed insulins are usually given twice daily, first
before breakfast and second before the evening meal. The (i) Once daily.
breakfast dose allows the short-acting insulin to cover the (ii) Twice daily.
increase in blood glucose associated with breakfast, with the (iii) Basal bolus.
intermediate-acting insulin covering the increasing glucose (iv) Three times per day regimen.
that would be associated with lunch. The second dose is usually (v) Continuous s.c. insulin infusions (CSIIs).
taken with the evening meal, with the short-acting insulin cov-
ering the increasing glucose concentration associated with the Once daily
evening meal and the intermediate insulin covering the over-
This is almost always used in people with T2DM where the indi-
night period.
vidual uses a once daily long-acting or intermediate-acting in-
sulin at night in addition to their oral medication to overcome
Long-acting insulin analogues the high hyperglycaemia associated with inappropriate hepatic
Examples: insulin glargine (Lantus), insulin detemir (Levemir), gluconeogenesis (see Fig. 1).
and insulin degludec (Tresiba).
Insulin glargine was the first of these long-acting analogues
and became available in 2003, whilst degludec only became
Twice daily
available in 2013. These insulins have a very long duration of This is a very commonly used regimen in both T1DM and T2DM
action—between 18 and 36 h. They take 2–3 days to reach a where a premixed insulin is injected at breakfast and evening
steady state. They are usually injected once or twice a day. meal (see Fig. 2).
They have relatively ‘flat’ profiles, and often described as
‘peakless’. Basal bolus
Four injections a day regimen is also called the basal bolus. This
Animal insulin
is composed of a longer acting either intermediate- or long-act-
Example of short-acting (soluble) animal insulins: Hypurin neu-
ing insulin analogue given once daily, most frequently at night.
tral (bovine or porcine).
The additional three doses are normally composed of a very
Example of intermediate-acting animal insulin: Hypurin bo-
rapid-acting insulin analogue given at the time of the meal
vine protamine zinc; Hypurin isophane (bovine or porcine).
(however, some patients may use soluble). The basal dose usu-
Examples of mixed animal insulins: Hypurin 30/70 mix
ally equates to 50% of the total daily insulin dose (see Fig. 3).
(porcine).
Occasionally, the long-acting or intermediate insulin is split to
The number of patients on animal insulin (bovine, porcine)
be given 12 h apart; therefore the individual gives themselves
is diminishing. These are available as soluble (short-acting) or
five injections a day.
isophane (intermediate-acting) insulin. These are extracted
from the pancreas of slaughtered animals. It used to take 2 tons
of animal pancreases to produce 200 g of purified insulin. Three times per day
Animal insulin was the initial type of insulin after insulin was Although rarely used, this is the use of a premixed insulin given
identified in the 1920s. With the advent of human insulins in with each meal.
the 1980s, animal insulin is now rarely used. The few patients
who have continued to use it, do so because of patients’ fear of
hypoglycaemic unawareness on human insulins, but this fear
Continuous s.c. insulin infusions (CSII)
has never been substantiated. Hypoglycaemic unawareness is CSIIs (‘pumps’) are becoming more frequent. The UK National
the loss of symptoms of sympathetic overdrive (e.g. sweating, Institute for Health and Care Excellence guidelines7 state that
hunger, shaking, palpatations) when glucose levels drop. In for individuals with T1DM aged >12 yr, pumps are recom-
people without diabetes, or where the diabetes is well con- mended as a treatment option for those attempting to achieve
trolled, symptoms often start to occur when glucose concentra- target HbA1c concentrations <69 mmol mol1 (8.5%), but experi-
tions decline to approximately <3.8 mmol litre1, although it is ence disabling hypoglycaemia with multiple daily injections
very person specific. Hypoglycaemic unawareness most fre- despite intensive education. An insulin pump delivers a fixed
quently occurs in those who have long-standing insulin-treated hourly basal rate of a very rapid-acting insulin analogue. This
diabetes. rate can be changed on an hourly basis. The individual gives
Many people on these animal insulins will be on mixtures themselves bolus doses to cover their carbohydrate intake dur-
twice a day. They have essentially the same pharmacokinetic ing individual meals or snacks (see Fig. 4).

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 Diabetes medication pharmacology

Insulin
activity

Breakfast Lunch Evening meal Bedtime

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Fig 1 Insulin activity profile with a once daily injection of long-acting insulin.

Insulin
activity

Breakfast Lunch Evening meal Bedtime

Fig 2 Insulin activity profile with twice daily injection of mixed (biphasic) insulin.

Insulin
activity

Breakfast Lunch Evening meal Bedtime

Fig 3 Insulin activity profile using a ‘basal bolus’ regimen.

A pump should only be used with close collaboration be- insulins; these include: the risk of inhaling a growth factor onto
tween the patient and the specialist diabetes team. a thin epithelium; the difficulty of prescribing in ‘milligrams’
not ‘units’; and unpredictable absorption in lung disease.
Whether or not this route of administration becomes viable re-
Inhaled insulin mains to be seen.

Administration of insulin via the inhaled route has been diffi-

cult to achieve. The first inhaled insulin, Exubera (Pfizer Ltd),
was withdrawn within a few months of launch—partly because
of very poor sales, but also because of a spike in lung cancers
Safe use of insulin
being reported in users of the drug.8 Newer inhaled insulins are Whilst insulin has the potential to be a life-saving drug, its pre-
in development and the first of these, ‘Afrezza’, was launched scription and administration, and its subsequent use is associ-
in the USA in 2015. There remain many challenges with inhaled ated with iatrogenic harm. Consequently, the national patient

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Diabetes medication pharmacology

Insulin
activity

Breakfast Lunch Evening meal Bedtime

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Fig 4 Insulin activity profile using a CSII. Width of CSII activity shows programmable range of basal infusion. Boluses can be adjusted to carbohydrate load of individual
meals.

safety agency issued specific guidance to improve its safety in Essentially, these drugs work via four broad mechanisms:
2010.6 The guidance included the following facts:
(i) Increase release of endogenous insulin and cause a genu-
• All regular and single insulin (bolus) doses are measured ine reduction in the blood glucose (the sulphonylureas
and administered using an insulin syringe or commercial in- and meglitinides).
sulin pen device. I.V. syringes must never be used for insulin (ii) Affecting gastro-intestinal absorption and renal reabsorp-
administration. tion of glucose (intestinal alpha-glucosidase inhibitors
• The term ‘units’ is used in all contexts. Abbreviations, such and the SGLT-2 inhibitors).
as ‘U’ or ‘IU’, are never used. (iii) Drugs that alter effector site sensitivity to endogen-
• An insulin syringe must always be used to measure and pre- ous insulin and reduce gluconeogenesis/glycogenolysis
pare insulin for an i.v. infusion. Insulin infusions are admin- or endogenous metabolism (metformin and the
istered in 50 ml i.v. syringes or larger infusion bags. thiazolidinediones).
Consideration should be given to the supply and use of (iv) Drugs acting on the incretin pathway (GLP-1 analogues
ready to administer infusion products (e.g. prefilled syringes and the DPP4 inhibitors).
of fast-acting insulin 50 units in 50 ml 0.9% sodium chloride
It is vital to note that only the sulphonylureas and megliti-
solution).
nides are associated with hypoglycaemia in the starved state,
• Policies and procedures for the preparation and administra-
whilst the others are not. Thus the sulphonylureas and megliti-
tion of insulin and insulin infusions in clinical areas are re-
nides should always be omitted in the perioperative period for
viewed to ensure compliance with the above.
this reason.
Additionally, it is vital that the insulin is prescribed by the
brand name rather than the generic name. Furthermore, newer
formulations of insulin are available that have different concen- Sulphonylureas
trations. Previously, the concentration was 100 units per ml, but Examples: glibenclamide, gliclazide, glimepiride, glipizide,
insulins are now available with concentrations 200 units per ml; tolbutamide.
300 units per ml and 500 units per ml in an attempt to help Sulphonylureas are insulin secretagogues and have been in
those who require large doses because of their extreme insulin the armamentarium of the diabetologist since the 1950s. They
resistance. Care needs to be taken to ensure that the correct act by binding on the sulphonylurea receptor in the pancreatic
dose is given when prescribing and administering these b-cell, closing KATP channels, which depolarizes the b-cell and
concentrated formulations. It is essential that insulin is causes an influx of calcium. This ultimately leads to exocytosis
never withheld from a patient with T1DM, otherwise DKA of insulin-containing vesicles and an increase in peripheral in-
will ensue. sulin concentration. The maximum HbA1c reduction is up to
13–14 mmol mol1 (1.5%).
The sulphonylureas rely on adequate b-cell function.
The non-insulin glucose-lowering drugs Additionally, because of the increase in insulin secretion there
is the risk of hypoglycaemia in the starved state. There are data
There are currently eight different classes of non-insulin glu-
to show that the rate of severe hypoglycaemia (i.e. needing
cose-lowering drugs. These are:
third party assistance) for those on sulphonylureas is 0.1 per pa-
(i) Sulphonylureas. tient year.9
(ii) Meglitinides. Sulfonylureas can have a very long half-life and some are
(iii) Intestinal alpha-glucosidase inhibitors. renally excreted, therefore their use in the elderly and in pa-
(iv) Sodium-glucose linked transporter inhibitors (SGLT-2 tients with renal impairment is discouraged. The older agents,
inhibitors). e.g. glibenclamide (half-life 10 h), should no longer be pre-
(v) Biguanides. scribed because of this increased risk, whilst the short-acting
(vi) Thiazolidinediones. and hepatic metabolized gliclazide is considered safer.
(vii) Incretin mimetics/GLP-1 analogues. Sulphonylureas are widely used as second-line agents after
(viii) The gliptins/dipeptidyl peptase-4 inhibitors (DPP4 metformin. This is because they are cheap and effective.
inhibitors). However, as there is now evidence that the long-term use of

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 Diabetes medication pharmacology

sulphonylureas is associated with deterioration of glycaemic Biguanides

control, weight gain, and increased risk of cardiovascular harm,
Example: metformin.
other drugs are now advocated as second-line agents.10
Metformin is the biguanide that is advocated by several
international guidelines as the first-line treatment of people
Meglitinides with T2DM.3 This is because until recently, it was the only oral
hypoglycaemic agent that had evidence of cardiovascular
Examples: nateglinide, repaglinide. benefit.
These agents are short-acting insulin secretagogues. They Metformin will only work when there is circulating insu-
work in a similar manner to sulphonylureas but are rarely used lin present and it can be used in combination with other
because they are short acting and thus require more frequent oral agents or insulin. It is one of the few oral glucose-
dosing. They have a more rapid onset and shorter duration of lowering agents which is weight neutral, and the maximum
action than the sulphonylureas, which could have beneficial ef- HbA1c reduction is most studies is up to 13 or 14 mmol mol1
fects on decreasing late hypoglycaemia. Furthermore, repagli-

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(1.5%).
nide is non-renally excreted.11 The use of metformin was first described in animals in the
1920s and was eventually licensed in Europe for use in humans
in the late 1950s. Despite this long history of use, the exact
Intestinal alpha-glucosidase inhibitors
mechanism of action of metformin remains elusive, although
Examples: Acarbose. several mechanisms have been proposed.
The human gut is not designed to absorb disaccharides such Normally, in the fed state, there is suppression of endogen-
as sucrose and therefore an enzyme in the brush border called ous hepatic gluconeogenesis owing to activation of adenosine
alpha-glucosidase cleaves the disaccharides into its component monophosphate (AMP)-activated protein kinase. However, in
monosaccharides, which can then easily be absorbed. T2DM there is a failure to suppress hepatic gluconeogenesis in
Inhibition of this enzyme inhibits the absorption of monosac- the fed state, leading to inappropriate gluconeogenesis in the
charides, therefore limiting the rate of rise of plasma glucose face of hyperglycaemia. Metformin reactivates hepatic AMP kin-
concentrations and reducing the total quantity of carbohydrate ase and inhibits glucagon signalling, leading to a reduction in
absorbed. Acarbose also inhibits pancreatic alpha-amylase, glycogenolysis and endogenous glucose production. This is im-
which hydrolyses complex carbohydrates into oligosaccharides. portant because the predominant action of metformin is not to
The HbA1c reduction achieved with acarbose is limited, about 8 lower blood glucose but to stop glucose from increasing.
mmol mol1 (0.75%). Metformin also has an ‘acarbose-like’ action. It inhibits in-
Acarbose can be used in combination with sulphonylureas, testinal disaccharidase, which leads to a delay in absorption of
metformin, or insulin. Its use is however limited by its gastro- monosaccharides and a reduction in the rate of increase of
intestinal side-effects. The flora that inhabit the large bowel blood glucose. The resultant disaccharide load to the large
lumen ferment the carbohydrate load, resulting in the common bowel and subsequent micro-organism fermentation causes
side-effects of bloating, diarrhoea, abdominal pain, and nausea. many of the gastrointestinal side-effects of metformin, includ-
It is for this reason, therefore, that the dose of the drug must be ing nausea, diarrhoea, bloating, and wind. Normally, the gastro-
built up gradually. It is contraindicated in those individuals intestinal upset does resolve; however, should it continue to be
with inflammatory bowel disease or history of previous abdom- a problem then the use of modified release metformin has been
inal surgery. shown to reduce the rate of incidence of gastrointestinal side-
effects by 50%.
Metformin has also been shown to work by increasing insu-
Sodium-glucose transporter 2 inhibitors lin receptor expression and tyrosine kinase activity, thereby
Examples: canagliflozin, dapagliflozin, empagliflozin. increasing insulin sensitivity. This results in a reduction of
Glucose is filtered freely through the kidneys at about blood glucose but this effect is relatively minor compared with
180 g day1. Normally, very little glucose is lost in the urine be- the effect on suppression of hepatic gluconeogenesis. The in-
cause it is actively reabsorbed in the proximal convoluted renal crease in insulin sensitivity can be seen in patients treated with
tubule by a transport mechanism linking sodium and glucose, both insulin and metformin who need to stop their metformin;
SGLT2. This actively reabsorbs almost all the glucose that is the dose of insulin rapidly increases by between 25 and 35%,
filtered. showing the insulin-sparing effect of the drug.
The SGLT2 inhibitors are a class of drug which prevent glu- The feared complication of lactic acidosis is rare and most
cose reabsorption from the proximal convoluted tubules in an frequently occurs in patients who have contraindications to the
insulin-independent manner and give rise to the osmotic symp- use of metformin (e.g. renal and severe heart failure with low
toms of uncontrolled diabetes: polyuria, dehydration, subse- peripheral perfusion).14 It is postulated that it is not the metfor-
quent polydipsia, and candidiasis. They result in the loss of min that causes the lactic acidosis but the associated comorbid-
several grams of glucose in the urine every 24 h. There is a sub- ity. The dose of metformin should be reviewed if the eGFR <45
sequent reduction in HbA1c of about 11 mmol mol1. They are ml/min/1.73 m2 and should be stopped if the eGFR is <30 ml/
also associated with a modest weight loss, as well as a reduc- min/1.73 m2.
tion in cardiovascular mortality.12 Because they work independ- The summary of product characteristics for metformin15
ently of insulin there are currently studies looking at the use of suggests that that it should be stopped 48 h before surgery and
this drug in people with T1DM. the administration of iodinated contrast owing to the fear of the
Although the risk of hypoglycaemia in the starved state is metabolic complications of lactic acidosis and AKI. It is now
low, it is now advised that these drugs are stopped before sur- appreciated that this advice may deny many patients the bene-
gery, as there have sporadic cases of DKA that have been attrib- fits of glycaemic control that can be achieved with the use of
uted to the SGLT2 inhibitors.13 metformin, as metformin is not as toxic as once thought.

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Diabetes medication pharmacology

In the perioperative period, the fact that metformin does not is produced by the L cells of the upper GI tract in response to
cause hypoglycaemia and is safer than previously thought glucose in the gut lumen. It has multiple effects including:
allows for the JBDS and the AAGBI to recommend its continu-
(i) Enhancing glucose dependent insulin secretion from b-
ation in elective surgery with short fasting times, as long as
cells.
other risk factors for acute kidney injury are not present (e.g.
(ii) Inhibits glucagon secretion from a-cells.
the use of contrast medium, or other nephrotoxic agents).4,5
(iii) Reduces gastric emptying, slowing the rise in postprandial
The anaesthetic technique must be renoprotective (e.g. main-
glucose.
tain normal blood pressure, maintain normovolaemia, and
(iv) Promotes satiety and reduces appetite.
avoid other potential nephrotoxins).
People with T2DM have very low concentrations of GLP-1
compared with those without the condition.18
Thiazolidinediones Endogenous GLP-1 has a circulating half-life of 2 min be-
Examples: pioglitazone. cause it is broken down by an endogenous circulating enzyme

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The thiazolidinediones act on the peroxisome proliferator- called DPP-4. Greater understanding of this pathway has led to
activated receptor-c, a transcription factor altering multiple two new drug classes to treat diabetes; the GLP-1 analogues and
genes that are involved in glucose and other substrate metabol- the DPP-4 inhibitors (see Fig. 5). The overall HbA1c reduction
ism. They increase the sensitivity of naturally released insulin, with both these classes of drug is in the region of 11 mmol
and so again the risk of hypoglycaemia in the starved state is mol1 (1%). They are frequently used in combination with many
low. other medications, such as metformin, sulphonylureas, and in-
The use of this class of drug has been severely limited over sulin. Both GLP-1 analogues and DPP-4 inhibitors are currently
the last few years owing to the development of potential com- contraindicated in renal failure. The gastric emptying rate may
plications including increased risk of cardiovascular death, be significantly prolonged, and has been reported to nearly dou-
macular oedema, and bladder cancer.16–19 The use of this class ble. This may have important implications for the choice of an-
of drug is reducing, with only pioglitazone now available in the aesthesia and preoperative fasting times.19
UK.
Pioglitazone works very slowly and needs to be given for at
least 4–6 months for maximum benefit. It is most frequently
used in combination with other agents, and the overall im- Glucagon-like peptide-1 (GLP)-1 analogues
provement in control is modest at 8–11 mmol mol1 (0.75–1%). Examples: dulaglutide, exenatide, liraglutide, lixisenatide.
These drugs are peptides and thus must be administered by
the s.c. route to avoid degradation by intestinal peptidases.
The incretin pathway These GLP-1 analogues are resistant to degradation by DPP-4,
Incretin hormones, such as glucagon-like peptide-1, are se- and thus have a longer half-life than endogenous GLP-1. The
creted from the gastrointestinal tract and cause a glucose-de- fact that exenatide can be given by weekly s.c. injection as an
pendent increase in the secretion of insulin from b-cells. GLP-1 extended release form has the potential to aid in patient

GLP-1 analogues
e.g. exenatide

Supra-normal levels of GLP-1

resistant to DPP4

Stimulate insulin release in response to food

Reduce hepatic gluconoeogenesis
ACTIVE GLP-1 Decreased blood glucose
Reduce gastric emptying
Promote satiety

Increased active
GLP-1

DPP-IV
DPP4 inhibitors
(breaks down
e.g. sitagliptin
GLP)

Deactivated GLP-1

Fig 5 Pharmacological action of GLP-1 analogues and DPP-4 inhibitors (orange arrows/boxes) on endogenous incretin pathway (blue arrows/boxes).

206 BJA Education | Volume 17, Number 6, 2017

 Diabetes medication pharmacology

compliance. Owing to their mechanism of action they can aid sa.nhs.uk/alerts/?entryid45¼74287 (accessed 28 December
with weight loss.20 2016)
7. National Institute for Clinical and Healthcare Excellence.
Type 2 diabetes in adults: management. NICE guideline
Dipeptidyl peptidase- 4 (DPP-4) inhibitors
NG28. 2015. Available from https://www.nice.org.uk/guid
Examples: alogliptin, linagliptin, saxagliptin, sitagliptin, ance/NG28 (accessed 28 December 2016)
vildagliptin. 8. Al-Tabakhah MM. Future prospect of insulin inhalation for
The incretin pathway can also be modified by inhibition of diabetic patients. The case of Afrezza versus Exubera. J Con
the enzyme DPP-4 by the DPP-4 inhibitors. Whilst these agents
Rel 2015; 215: 25–38
can improve glycaemic control, they do not have the weight
9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in
loss benefits of the GLP-1 analogues and they have been associ-
types 1 and 2 diabetes: effects of treatment modalities and
ated with pancreatitis and pancreatic cancer.21
their duration. Diabetologia 2007; 50: 1140–7

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10. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of
Conclusion hyperglycemia in type 2 diabetes, 2015: a patient-centered
The pharmacological management of diabetes has progressed approach: Update to a position statement of the American
exponentially in recent years, with multiple new formulations Diabetes Association and the European Association for the
of insulin and new non-insulin glucose lowering agents now Study of Diabetes. Diabetes Care 2015; 38: 140–9
available. A thorough understanding of the pharmacokinetic 11. Guardado-Mendoza R, Prioletta A, Jimenez-Ceja LM et al.
and pharmacodynamic properties of these drugs is vital for the “The role of nateglinide and repaglinide, derivatives of
anaesthetist to ensure safe perioperative care of the surgical pa- meglitinide, in the treatment of type 2 diabetes mellitus”.
tient on glucose-lowering medication. Arch Med Sci 2013; 9: 936–43
12. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardio-
vascular outcomes, and mortality in type 2 diabetes. N Eng J
Declaration of interest Med 2015; 373: 2117–28
None declared. 13. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB.
Euglycemic diabetic ketoacidosis: a potential complication
of treatment with sodium-glucose cotransporter 2 inhib-
MCQs ition. Diabetes Care 2015; 38: 1687–93
The associated MCQs (to support CME/CPD activity) can be 14. Eppenga WL, Lalmohamed A, Geerts AF et al. Risk
accessed at https://access.oxfordjournals.org by subscribers to of lactic acidosis or elevated lactate concentrations
BJA Education. in metformin users with renal impairment: a
population-based cohort study. Diabetes Care 2014; 37:
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