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Drug review Oral antidiabetic drugs
Oral antidiabetic drugs: their
properties and recommended use
Ian Campbell FRCP
There are now five classes of oral anti-
diabetic drugs available, with metformin
remaining the cornerstone of drug therapy in
type 2 diabetes. Our Drug review considers
their mode of action, properties and
recommended use, followed by sources of
further information, an analysis of prescrip-
tion data and the Datafile.
iabetes mellitus is now recognised as a major
D world-wide public health problem. At present
about 150 million people have diabetes mellitus, a fig-
56 Prescriber 19 March 2007
Skyline Imaging Ltd
ure that is estimated to reach 250-300 million by the
year 2010.
In the UK approximately 3 per cent of the popu-
lation have recognised diabetes mellitus, and another
3 per cent will have unrecognised type 2 diabetes.
This rise in type 2 diabetes is a result of high calorie
intake, limited physical activity and obesity, with about
70-80 per cent of type 2 diabetes patients being over-
weight.
The treatment of type 2 diabetes is not purely a
matter of glucose control, and it is recognised that
morbidity and premature mortality are closely
related to the different components of type 2 dia-
betes, which is now often referred to as the metabolic
syndrome or insulin resistance syndrome. In addi-
tion to hyperglycaemia, these components include
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Review NIDD.qxd 9/3/07 14:32 Page 3
Oral antidiabetic drugs
Class Examples
Sulphonylureas gliclazide, glibenclamide,
glipizide, glimepiride
Postprandial glucose regulators repaglinide, nateglinide
Biguanide metformin
Thiazolidinediones pioglitazone, rosiglitazone
Alpha-glucosidase inhibitor acarbose
Table 1. Available oral antidiabetic agents and their mode of action
central obesity, hypertension, dyslipidaemia (raised
triglycerides and small, dense LDL and lowered
HDL) and a procoagulant state.
Therefore any treatment plan for type 2 diabetes
patients also requires weight loss where obesity
occurs, blood pressure reduction, plasma lipid
abnormalities to be corrected, and antiplatelet
agents to be prescribed according to national
guidelines.1,2 Such an integrated approach will be
beneficial and is now well recognised in clinical
practice.
Oral antidiabetic drugs
As part of this integrated approach to reduce cardio-
vascular risk in type 2 diabetes patients, glycaemic con-
trol is important. There are five classes of oral
antidiabetic drugs available for lowering blood glu-
cose (see Table 1).
Insulin secretagogues: sulphonylureas and postprandial
glucose regulators
Two of the classes, sulphonylureas and postprandial
glucose regulators, are insulin secretagogues. These
agents act at the ATP-dependent potassium channel
in the beta-cell membrane to stimulate insulin secre-
tion from the pancreas. Gliclazide, glibenclamide,
glimepiride and glipizide are the most commonly
used sulphonylureas in the UK, stimulating insulin
secretion for 12-24 hours. Gliclazide and glipizide
are given twice daily, glibenclamide and glimepiride
once daily.
The other group of insulin secretagogues are
known as postprandial glucose regulators or meglin-
itides.3 The former name is used as the insulin secre-
tion profile coincides with meal digestion some one
to two hours after eating.
In the UK there are two postprandial glucose reg-
ulators, repaglinide (Prandin) and nateglinide
58 Prescriber 19 March 2007
Principal mode of action
stimulate insulin secretion (acting 12-24 hours)
stimulate insulin secretion (short acting, <6 hours)
improves insulin action
PPAR-gamma agonists, increase insulin action
slows down rate of carbohydrate ingestion
(Starlix). These two agents are rapidly absorbed and
also quickly eliminated, so that their insulin-secret-
ing effect is short lived, with a maximum effect at
two to four hours and a duration of less than six
hours.
Drugs that reduce insulin resistance: metformin and
thiazolidinediones
Metformin Metformin is the only biguanide in the UK.
It increases insulin action at some unknown intra-
cellular locus, and has no direct action on the pan-
creatic beta-cells. In type 2 diabetes, the main action
of metformin is to potentiate the action of insulin,
thus decreasing hepatic glucose production by reduc-
ing both gluconeogenesis and glycogenolysis. In addi-
tion metformin improves peripheral glucose
utilisation in muscle. Metformin is particularly useful
for obese type 2 diabetes patients as it does not cause
weight gain, but rather a little weight loss.
The United Kingdom Prospective Diabetes Study
(UKPDS) showed that, compared with conventional
treatment with diet, metformin reduced the risk of
diabetes-related deaths by 42 per cent and reduced
myocardial infarction (MI) by 39 per cent over a 10-
year follow-up period.4 These benefits were not seen
in overweight type 2 diabetes subjects given a sulph-
onylurea or insulin therapy. This vascular-protective
effect of metformin has now established it as the drug
of choice in type 2 diabetes patients with a BMI >25
where diet and lifestyle measures fail to achieve gly-
caemic control.
Thiazolidinediones: pioglitazone (Actos) and rosiglita-
zone (Avandia) These drugs are also known as TZDs
or glitazones. They act at the level of the genome,
modifying the transcription of a number of genes that
regulate insulin action and lipid metabolism. The
TZDs are ligands for peroxisome proliferator-acti-
vated receptor gamma (PPAR-gamma). The PPAR-
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Review NIDD.qxd 9/3/07 14:32 Page 4
gamma receptors are located in the nucleus of the
cell and their activation by TZDs improves insulin
action to increase glucose uptake in muscle and sup-
press hepatic glucose output; TZDs also decrease
plasma free fatty acids, decrease plasma triglycerides
(pioglitazone but not rosiglitazone), raise HDL cho-
lesterol by 10-20 per cent, and raise plasma LDL cho-
lesterol by 5-15 per cent but reduce the atherogenic
small, dense LDL particles.
Alpha-glucosidase inhibitors: acarbose (Glucobay)
Acarbose is the only available alpha-glucosidase
inhibitor. It inhibits alpha-glucosidase enzymes, which
break down oligosaccharides into monosaccharides
in the small intestine. Acarbose lowers postprandial
blood glucose by competing with dietar y carbo-
hydrate for the alpha-glucosidase enzymes, hence
delaying glucose absorption. As monotherapy, acar-
bose, like metformin, will not cause hypoglycaemia
or weight gain.
Efficacy
All the oral antidiabetic drugs mentioned above have
about the same blood glucose-lowering effect when
the clinical trial results are reviewed. Within the first
two to three years of diagnosis, they will lower fast-
ing plasma glucose by about 2-4mmol per litre, the
postprandial glucose levels by 4-6mmol per litre and
the glycated haemoglobin (HbA1c) by 1.5-2 per cent.
Type 2 diabetes is a progressive condition. It has
a dual abnormality of insulin resistance (diminished
Side-effect Sulphonylureas Postprandial
glucose regulators
hypoglycaemia ++ +
GI symptoms
weight gain + +
oedema
lactic acidosis
hypersensitivity +
cholestasis +
folate, B12
malabsorption
Table 2. Side-effects of oral antidiabetic agents
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Oral antidiabetic drugs
insulin sensitivity) and beta-cell dysfunction. At
diagnosis in type 2 diabetes, both insulin sensitivity
and beta-cell production of insulin are about 50 per
cent of normal. The latter further declines by 4-5
per cent per year over the next five to six years.
When 80-90 per cent of beta-cell production of
insulin is lost, there is then insufficient endogenous
insulin for the oral antidiabetic drugs to be effec-
tive, even in combination, and it is at this stage that
insulin therapy is necessary to maintain adequate
glycaemic control.
Sulphonylureas, metformin and acarbose have
been available for many years. Postprandial glucose
regulators and TZDs are newer agents, and whether
their earlier use in combination with metformin will
delay insulin therapy remains to be seen (see
below).
Side-effects and drug interactions with
oral antidiabetic drugs
The side-effects of the oral antidiabetic drugs are sum-
marised in Table 2.
Sulphonylureas
Hypoglycaemia and weight gain are the most com-
mon side-effects of sulphonylureas. Sulphonylurea-
induced hypoglycaemia is particularly important in
older people, in whom an incorrect diagnosis of tran-
sient ischaemic attack (TIA) or cerebrovascular acci-
dent may be made. The diagnosis of hypoglycaemia
should be considered in any diabetic subject treated
Metformin TZDs Acarbose
+ ++
+
+
+
+
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Review NIDD.qxd 9/3/07 14:32 Page 5
with a sulphonylurea who develops signs of altered
behaviour.
The action of sulphonylureas may be prolonged in
patients with liver or renal impairment. In these situ-
ations, gliclazide may be preferred as less than 5 per
cent of this drug is excreted unaltered in the urine.
Glibenclamide should be used with caution in older
people as it is the most likely to cause hypoglycaemia.
Postprandial glucose regulators
Hypoglycaemia and weight gain are again the most
significant side-effects of postprandial glucose regu-
lators, although both are less severe than with the
sulphonylureas due to the shorter duration of action
of repaglinide and nateglinide. These can be used in
patients with renal impairment as they are
metabolised in the liver and excreted in the faeces.
Metformin
GI side-effects, with anorexia, abdominal discomfort
and diarrhoea, and a metallic taste in the mouth (due
to the drug being concentrated in salivary glands) can
occur with metformin. If metformin is started at a dose
of 500mg daily and built up slowly, and the tablets taken
after meals, less than 5 per cent will be intolerant of the
drug. A slow-release preparation of metformin is now
available (Glucophage SR) which reduces the fre-
quency of these GI side-effects by up to 50 per cent.
Metformin-associated lactic acidosis is well recog-
nised but rare if the prescribing recommendations are
adhered to, namely to exclude patients with liver and
renal disease and withdrawal of the drug in patients
with severe acute illness that can cause hypoxia, espe-
cially respiratory or acute cardiac failure. The drug
may be used in stable cardiac decompensation. Age is
not a contraindication to metformin use as was once
thought, provided the renal function is satisfactory
with a serum creatinine level below 130mol per litre.
Thiazolidinediones
The original TZD troglitazone was withdrawn because
of hepatotoxicity, but there is no such reported
adverse hepatic effects with either pioglitazone or
rosiglitazone. However it is recommended that liver
function tests (LFTs) are carried out at the start of
therapy. The original recommendation that two-
monthly LFTs should be done for the first year of ther-
apy have now relaxed and it is probably satisfactory to
check the LFTs on an annual basis. If the alanine
transaminase (ALT) is more than twice normal before
therapy, then TZDs should not be started, and they
should be stopped if the ALT rises to more than three
times normal during treatment.
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Oral antidiabetic drugs
Decreased antihyper- Increased antihyper- Blunt hypoglycaemia
glycaemic effect glycaemic effect response
furosemide warfarin beta-blockers
not bumetanide
salicylates clonidine
thiazides
fibrates
steroids
MAOIs
phenytoin
rifampicin
Table 3. Drug interactions with sulphonylureas
The cautious use of glitazone therapy can be con-
sidered in patients with mild hepatic dysfunction as
many of these cases will have nonalcoholic steato-
hepatitis (NASH) and the TZDs can improve hepatic
function in these cases. Regular monitoring of LFTs is
required in these situations, and observance of cur-
rent indications for discontinuation of therapy applied
if necessary.
The other side-effects of the TZDs are weight gain,
usually 3-4kg in the first six months of therapy, mild
peripheral oedema in up to 5 per cent of patients, and
a mild dilutional anaemia in some patients. TZDs
should not be prescribed for patients with congestive
cardiac failure and significant fluid retention.5
Acarbose
The principal side-effects, seen in about 20-25 per cent
of patients, are GI with flatulence, abdominal dis-
comfort and diarrhoea. These side-effects are due to
undigested carbohydrate from the small bowel reach-
ing the colon and may be reduced in frequency with
a low starting dose followed by a gradual increase. In
high doses of 300mg three times daily, there may be a
mild rise in liver transaminases.
Important drug interactions
Of the five classes of oral antidiabetic drugs described,
important drug interactions are only seen with sulpho-
nylureas. The drugs that antagonise and potentiate
the sulphonylureas, as well as drugs that mask the
awareness of impending hypoglycaemic, are sum-
marised in Table 3.
Recommended management of type 2
diabetes
National clinical guidelines have been issued for blood
glucose management using antidiabetic drugs.6 The
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Review NIDD.qxd 9/3/07 14:32 Page 6
Oral antidiabetic drugs
Monotherapy first agent Combination therapy agent to add
metformin pioglitazone+ or rosiglitazone
sulphonylurea, repaglinide or nateglinide
acarbose
sulphonylurea or metformin
postprandial glucose pioglitazone or rosiglitazone
regulator acarbose
pioglitazone or rosiglitazone metformin*
sulphonylurea, repaglinide or nateglinide
acarbose
acarbose sulphonylurea, repaglinide or nateglinide
metformin
+Competact (combination of metformin and pioglitazone) now available
Avandamet (combination of metformin and rosiglitazone) now available
Table 4. Oral antidiabetic drugs that can be used together in combination therapy
(based on current European licensing)
recommendations for the five classes of oral anti-
diabetic drugs will be discussed.
Metformin
The UKPDS has provided evidence that early inten-
sive control with metformin in overweight type 2 dia-
betes subjects is a particularly effective approach to
reduce vascular complications and improve survival.4
Metformin therapy is therefore the cornerstone of
type 2 diabetes management with oral antidiabetic
drugs.
Sulphonylureas
The sulphonylureas have been the most commonly
prescribed antidiabetic agent until the UKPDS results,
but have now been overtaken by metformin as the
first-line drug of choice. However they are still widely
prescribed and a sulphonylurea prescribed with met-
formin is the most commonly used antidiabetic drug
combination at present.
Postprandial glucose regulators
Repaglinide and nateglinide have not been widely pre-
scribed since their introduction compared to the
longer-acting sulphonylureas. They are relatively
expensive drugs and are seen as being very similar to
the older sulphonylureas in terms of their pharma-
cological action. The lesser risk of hypoglycaemia is
not seen to be of major benefit as most GPs do not see
the severe hypoglycaemia when the sulphonylureas
(other than glibenclamide) are prescribed.
62 Prescriber 19 March 2007
However the postprandial glucose regulators may
have a role to play when younger patients have a
lifestyle with variable eating patterns as the drugs can
be taken immediately before a meal, and in older
patients where there may be a risk of hypoglycaemia
with sulphonylureas, especially if there is impaired
renal function.
Thiazolidinediones
The National Institute for Health and Clinical
Excellence (NICE) has recommended that TZDs be
used only as combination therapy, with metformin in
obese patients if a combination of metformin with a
sulphonylurea is not appropriate and with sulphonyl-
ureas if metformin is not appropriate.7 However, since
the NICE guidance was issued, both TZDs have been
granted licences for monotherapy if metformin is
inappropriate. This is likely to confuse prescribers
until NICE updates its guidance, which was expected
in July 2006 but is now not due until early 2008.
The potential value for TZDs is that there is good
scientific evidence that they have pleiotrophic actions
that may prevent the progression of atherosclerosis.8
The NICE guidance in 2003 recommends relatively
limited use of these drugs based on the fact that there
were as yet no end-point studies at that stage to show
that TZDs reduce microvascular or macrovascular
complications or how they will perform in this respect
against metformin or sulphonylureas. In the mean-
time there have been four major new studies involv-
ing TZDs.
The PROspective pioglitAzone Clinical Trial In
macroVascular Events (PROactive) study9 showed that
pioglitazone in type 2 diabetes subjects with macrovas-
cular disease caused a 16 per cent decrease in the prin-
cipal secondary end-point of death, heart attack and
stroke.
The Carotid intima-media tHICkness in
Atherosclerosis using pioGlitazOne (CHICAGO)
study 10 showed that pioglitazone, but not the
Sulphonylureas: recommended use
sulphonylureas should be used with metformin in over-
weight or obese people when glucose control becomes
unsatisfactory
sulphonylureas should be considered as an option for
first-line therapy when metformin is not tolerated or is
contraindicated, and in people who are not overweight
a generic sulphonylurea should normally be chosen
a long-acting sulphonylurea may be useful when com-
pliance is a problem
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Oral antidiabetic drugs
Postprandial glucose regulators: recommended use
the same recommendations as for sulphonylureas are
given for insulin secretagogues in general, but it is
clearly stated that the insulin secretagogue choice
should be a generic sulphonylurea, eg gliclazide or
glipizide
rapidly-acting insulin secretagogues, eg repaglinide or
nateglinide, may have a role in attaining tight glucose
control in patients with nonroutine daily patterns
comparator sulphonylurea agent glimepiride, showed
a regression in carotid atherosclerotic disease using
carotid ultrasonography to measure carotid intima-
media thickness (CIMT).
The Diabetes REduction Assessment with ramipril
and rosiglitazone Medication (DREAM) study 11
showed that rosiglitazone could reduce the progression
to type 2 diabetes in patients with impaired fasting glu-
cose (IFG) or impaired glucose tolerance (IGT).
However, rosiglitazone is not currently licensed for use
in IFG or IGT.
The ADOPT (A Diabetes Outcome Progression Trial)
study12 showed that rosiglitazone as monotherapy sus-
tained glycaemic control better than metformin or
glibenclamide monotherapy over a mean period of four
years. The mean HbA1c was 0.13 per cent less than the
rosiglitazone group at four years compared with the
metformin group and 0.42 per cent less compared with
the glibenclamide group. These small changes in gly-
cated haemoglobin would suggest, in the authors opin-
ion, that metformin should still remain the treatment
of choice when starting drug therapy in type 2 diabetes,
but a TZD would be a preferred combination agent
with metformin.
The DREAM and ADOPT studies support beta-cell
preservation by TZDs in type 2 diabetes with better sus-
tained glycaemic control;13 the PROactive and
CHICAGO studies support a role for TZDs in prevent-
ing macrovascular disease, the principal killer in type 2
diabetes.
Metformin: recommended use
in people who are overweight (BMI >25) and whose
blood glucose is inadequately controlled using lifestyle
interventions alone, metformin should normally be used
as the first-line glucose-lowering therapy
metformin should be considered as an option for first-
line or combination therapy for people who are not
overweight
64 Prescriber 19 March 2007
NICE also highlights that there is no evidence
that TZDs are of added benefit when given as triple
therapy with metformin and a sulphonylurea,
although both pioglitazone and rosiglitazone now
have a licence for triple therapy. In the authors
experience, this triple combination works very well
in some patients but not others, and there is no
harm in giving this therapy a trial if the diabetes
patient is reluctant to consider insulin therapy. The
PROactive study showed that pioglitazone added to
metformin and sulphonylurea therapy could delay
the progression to insulin by up to 50 per cent over
three years.9
The author prefers the Association of British
Clinical Diabetologists (ABCD) position statement in
2004 on glitazones as giving a better guide to the clin-
ical use of these agents,14 with the new approved indi-
cation that pioglitazone may be used in conjunction
with insulin therapy where there is insufficient gly-
caemic control on insulin when metformin is inap-
propriate because of contraindications or intolerance.
The combination of pioglitazone and insulin may
reduce the dosage of insulin required in obese insulin-
resistant type 2 diabetes subjects who require insulin
for glycaemic control.
It is important to remember that after starting
TZDs, there may be a delay of six to eight weeks before
their full effect is seen due to their mode of action of
inducing transcription of genes that regulate proteins
involved in insulin action and lipid metabolism.
Acarbose
Acarbose lowers blood glucose in type 2 diabetes
patients as a single agent or in combination therapy,
but because it has a high incidence of GI side-effects
its use has been much less than metformin and
sulphonylureas.
Achieving best practice
For practical purposes the aim in clinical practice
when treating type 2 diabetes patients is to achieve an
HbA1c of 7 per cent or less, except in older patients or
those with severe co-morbidities where acceptable con-
trol is met by simply keeping the patient free of hyper-
glycaemic symptoms and ignoring tight HbA1c targets.
The UKPDS showed that less than 50 per cent of
patients treated with either metformin or a sulpho-
nylurea will reach a 7 per cent HbA1c target at three
years after diagnosis15 and it is becoming increasingly
recognised that early combination therapy is neces-
sary.16 Table 4 gives a simple outline of those anti-
diabetic drugs that can be used together for
combination therapy.
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Thiazolidinediones (TZDs): recommended use
(adapted from reference 14)
addition of TZD to metformin is preferred second-line
oral antidiabetic therapy in obese type 2 diabetes
TZDs should be considered as monotherapy in those
patients unable to take metformin
consider TZDs in place of metformin in renal impairment
triple therapy with a TZD plus metformin plus a sulph-
onylurea may be considered in obese patients or those
patients unwilling to consider insulin therapy
pioglitazone may be used with insulin where metformin
has contraindications or intolerance; if such treatment
is considered in severe case of insulin resistance,
watch for oedema and heart failure
There are no clinical trials to show which drug
combination is best. Meglitinides and acarbose are not
commonly prescribed and at the present time the
choice lies between the traditional metformin plus
sulphonylurea or the newer combination of met-
formin plus a TZD. The addition of a sulphonylurea
to metformin has been shown in a retrospective analy-
sis to offer maintained control for as little as six
months before deterioration in control occurs. 17
Therefore the combination of a TZD plus metformin
offers an alternative that is being increasingly used.
Pioglitazone has lipid advantages compared with
rosiglitazone, especially with regard to benefits in
triglycerides and HDL,18 which are still seen when
patients are on statin therapy.19
The traditional treatment approach to manage-
ment of newly diagnosed type 2 diabetes has been to
start with diet and lifestyle advice, then when gly-
caemic control is lost to progress to monotherapy, usu-
ally with metformin, and after some years to
combination therapy with a sulphonylurea.
This failure-orientated strategy is better replaced
by an intensive goal-orientated strategy to treat early
for success rather than to await failure.16 In a recent
study performed in the authors unit, a combination
of metformin plus pioglitazone was prescribed in addi-
tion to lifestyle advice for newly diagnosed type 2 dia-
betes subjects at diagnosis (if HbA1c >8 per cent), or
three to six months after diagnosis if HbA1c >7 per
cent. This combination was compared with metformin
plus gliclazide and metformin plus repaglinide. Over
a three-year follow-up period those patients treated
with the metformin/pioglitazone combination
showed a 0.1 per cent increase in HbA1c per year com-
pared with a 0.5 per cent increase seen in the other
two combinations, suggesting there are beta-cell pro-
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Oral antidiabetic drugs
Alpha-glucosidase inhibitors: recommended use
acarbose may be considered as an alternative glucose-
lowering therapy in type 2 diabetes patients unable to
use other drugs
tective properties with the pioglitazone therapy.20 This
is in keeping with the ADOPT trial results mentioned
above.12
The American Diabetes Association (ADA) and
the European Association for the Study of Diabetes
(EASD) have proposed a treatment algorithm for
type 2 diabetes mellitus (see Figure 1),21 advocating
metformin at diagnosis with lifestyle measures. The
authors preference at three to six months after diag-
nosis is to then move on to a metformin/pioglita-
zone combination where the HbA1c is above 7 per
cent, based on experience with other drug combi-
nations followed up for three years after diagnosis
(see above).20 There is no danger of hypoglycaemia
when metformin and a TZD are used in combina-
tion at such an early stage as they are both insulin
sensitisers. When treating to target there is always a
risk of hypoglycaemia where metformin is used in
combination with an insulin secretagogue or insulin
itself.
This is the authors personal view but is a treatment
regimen that will maintain glycaemic control much
longer than that seen in the UKPDS study and sustain
good glycaemic control with a delay in the need for
insulin therapy.
Newer drugs
Newer agents will become available in the UK in
2007 to aid in the management of type 2 diabetes
and these new drugs will need to be evaluated, espe-
cially against metformin, the TZDs and sulphony-
lureas.
Exenatide is an injectable peptide, a glucagon-like
peptide-1 (GLP-1) analogue that is effective against
beta-cell dysfunction and promotes weight loss.
Dipeptidyl peptidase-4 (DPP-4) inhibitors, also
known as gliptins, are oral agents to reduce the degra-
dation of endogenous GLP-1 as well as decreasing
appetite. Two examples of these DDP-4 inhibitors are
sitagliptin and vildagliptin.
Type 2 diabetes subjects are often obese and
rimonabant (Acomplia) is a satiety-inducing
cannabinoid-1 receptor antagonist, now available in
the UK, that can promote weight loss in type 2 dia-
betes subjects and also improve glycaemic and lipid
control.
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Oral antidiabetic drugs

lifestyle + metformin

HbA1c *7%

add sulphonylurea add basal insulin add TZD

HbA1c *7%

add TZD add basal insulin intensify insulin add sulphonylurea add basal insulin

HbA1c *7%

further intensify insulin or add basal

insulin + metformin +/- TZD

Figure 1. Simplified ADA-EASD consensus algorithm for type 2 diabetes (adapted from reference 21)

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13. Leiter LA. Beta-cell preservation: a potential role for thi-
azolidinediones to improve clinical care in type 2 diabetes.

66 Prescriber 19 March 2007 www.escriber.com

Review NIDD.qxd 9/3/07 14:32 Page 10
Diabetic Med 2005;22:963-72.
14. Higgs ER, Krentz AJ, on behalf of the Association of
British Clinical Diabetologists. ABCD position statement on
glitazones. Pract Diab Int 2004;21(8):293-5.
15. Turner RC, Cull CA, et al; for the UK Prospective
Diabetes Study Group. Glycaemic control with diet, sul-
fonylurea, metformin or insulin in patients with type 2 dia-
betes mellitus: progressive requirement for multiple
therapies. JAMA 1999;281:2005-12.
16. Campbell IW. Need for intensive, early glycaemic con-
trol in patients with type 2 diabetes. Br J Cardiol 2000;7:
625-31.
17. Cook MN, Girman CJ, Stein PP, et al. Glycaemic control
continues to deteriorate after sulfonylureas are added to
metformin among patients with type 2 diabetes. Diabetes Care
2005;28:995-1000.
18. Goldberg RB, Kendall DM, Deeg MA, et al. A compari-
son of lipid and glycaemic effects of pioglitazone and rosigli-
tazone in patients with type 2 diabetes and dyslipidaemia.
Resources
Further reading
BMJ Collected Resources. All articles published in
the BMJ on diabetes since January 1998. http://www.
bmj.com/collections.
Management of hyperglycaemia in type 2 diabetes: the
end of recurrent failure. Heine RJ, Diamant M,
Mbanya J-C, et al. BMJ 2006;333:1200-4.
NICE
Technology Appraisal 63. Glitazones in the treatment
of type 2 diabetes. 2003. www.nice.org.uk/cat.
asp?c=83263.
Clinical Guideline E. Management of type 2 diabetes
retinopathy. 2002. www.nice.org.uk/cat. asp?c=
27915.
Clinical Guideline F. Management of type 2 diabetes
renal disease, prevention and early management.
2002. www.nice.org.uk/cat.asp?c=39385.
Clinical Guideline G. Management of type 2 diabetes
blood glucose. 2002. www.nice.org.uk/cat. asp?c=
36733.
Clinical Guideline H. Management of type 2 diabetes
blood pressure and blood lipids. 2002. www.nice.
org.uk/cat.asp?c=38551.
www.escriber.com
Oral antidiabetic drugs
Diabetes Care 2005;28:1547-54.
19. Berhanu P, Kipnes MS, Khan MA, et al. Effects of piogli-
tazone on lipid and lipoprotein profiles in patients with type
2 diabetes and dyslipidaemia after treatment conversion
from rosiglitazone while continuing stable statin therapy.
Diab Vasc Dis Res 2006;3:39-44.
20. Chalmers J, Hunter JE, Robertson SJ, et al. Effects of early
use of pioglitazone in combination with metformin in
patients with newly diagnosed type 2 diabetes. Submitted
for publication, 2007.
21. Nathan DM, Buse JB, Davidson MB, et al. Management
of hyperglycaemia in type 2 diabetes: a consensus algorithm
for the initiation and adjustment of therapy. Diabetologia
2006;49:1711-21.
Professor Campbell is consultant physician at Victoria
Hospital, Kirkcaldy, and honorary professor in the
Department of Biological Sciences, Bute Medical School,
University of St Andrews
Groups and organisations
Diabetes UK offers help and information to diabetes
patients and supports research into the condition.
They also produce publications for patients and health
professionals. Diabetes UK Central Office, Macleod
House, 10 Parkway, London NW1 7AA; tel: 020 7424
1000; fax: 020 7424 1001; e-mail:info@diabetes.org.uk.
Website: www.diabetes.org.uk.
Diabetes Insight (www.diabetes-insight.info) pro-
duces publications and provides support for patients
with diabetes and information for healthcare pro-
fessionals.
Diabetes Monitoring Forum (www.dmforum.org.uk)
helps patients to understand the role of blood glu-
cose and ketone monitoring in diabetes manage-
ment and produces a series of advice leaflets. E-mail:
info@dmforum.org.uk.
Guidance
PRODIGY guidance diabetes type 2 (blood glucose
management). www.prodigy.nhs.uk.
Patient information
Diabetes and oral hypoglycaemic agents. PatientUK
factsheet: www.patient.co.uk/showdoc/40001626/.
Treatments for type 2 diabetes. PatientUK factsheet.
www.patient.co.uk/showdoc/27000260/.
Prescriber 19 March 2007 69
rev.pres anal 9/3/07 14:30 Page 2

Oral antidiabetic drugs

Prescription review metformin combinations have also increased. Sulph-

Prescribing of oral antidiabetic agents has increased sig-
nificantly over the last five years from 2.5 million items
a quarter to 4.5 million (see Figure 2). The biggest
growth has been in the use of metformin, and
prescriptions for the glitazones and the glitazone/
onylurea prescribing has remained steady. Looking at
costs the picture is very different. Despite accounting
for over 80 per cent of items, metformin and sulphonyl-
ureas only make up under 50 per cent of costs (see
Figure 3). The glitazones and glitazone/metformin
combinations are responsible for most of the steep rise
in spending on oral diabetic drugs in recent years.

Items (millions)

5 sulphonylureas biguanides (metformin) pioglitazone and rosiglitazone

nateglinide and repaglinide other antidiabetics rosiglitazone with metformin
4

0
2001 2002 2003 2004 2005 2006
Year, by quarter

Figure 2. Number of prescriptions for oral antidiabetic drugs in England by quarter, 2001-06

NIC (millions)

50 sulphonylureas biguanides (metformin) pioglitazone and rosiglitazone

nateglinide and repaglinide other antidiabetics rosiglitazone with metformin
40

30

20

10

0
2001 2002 2003 2004 2005 2006
Year, by quarter

Figure 3. Cost of prescriptions for oral antidiabetic drugs in England by quarter, 2001-06

70 Prescriber 19 March 2007 www.escriber.com

NIDD datafile.qxd 9/3/07 12:45 Page 1

Oral antidiabetic drugs

Datafile
Oral antidiabetic drugs
Drug group Drug Available as Form/strength Typical dosage Cost1

alpha-glucosidase acarbose Glucobay 50mg, 100mg tabs 50-100mg 3 times 6.16-11.68

inhibitor daily

biguanides metformin Glucophage 500mg sust-rel tabs 1 tab daily, increasing 3.20-12.80
SR dose by 1 tab at
10-15 day intervals
to max. 4 tabs daily
Glucophage 500mg, 850mg tabs 500mg 3 times daily 2.88-3.20
metformin 500mg, 850mg tabs or 850mg twice daily 2.33-2.36

sulphonylureas glibenclamide Daonil 5mg tabs 5-15mg daily 2.69-8.07

Semi-Daonil 2.5mg tabs 3.46-10.38
glibenclamide 2.5mg, 5mg tabs 1.44-4.32
gliclazide Diamicron MR 30mg mod-rel tabs 30-120mg daily 3.08-12.32
Diamicron 80mg tabs 40-320mg daily 1.06-8.51
gliclazide 80mg tabs (in divided doses 0.96-3.88
above 160mg)
glimepiride Amaryl 1mg, 2mg, 3mg, 4mg 2-4mg daily 6.93-13.83
tabs
glimepiride 1mg, 2mg, 3mg, 4mg 6.30-12.61
tabs
glipizide Glibenese 5mg tabs 2.5-20mg daily 1.09-8.72
Minodiab 2.5mg, 5mg tabs (in divided doses 1.48-5.04
glipizide 5mg tabs above 15mg) 1.28-10.24
gliquidone Glurenorm 30mg tabs 45-60mg daily in 7.37-9.82
divided doses
tolbutamide tolbutamide 500mg tabs 500mg-1.5g daily in 2.54-7.62
divided doses

postprandial repaglinide Prandin 0.5mg, 1mg, 2mg tabs 0.5-4mg before each 10.98-21.95
glucose regulators main meal
nateglinide Starlix 60mg, 120mg, 180mg 120mg before meals 22.50
tabs only in combination
with metformin

thiazolidinediones pioglitazone Actos 15mg, 30mg, 45mg 15-30mg once daily 24.14-33.54
tabs
rosiglitazone Avandia 4mg, 8mg tabs 4-8mg once daily or 24.74-50.78
in divided doses

1NHS cost of 28 days treatment at the dosage shown. Prices MIMS/Drug Tariff, January 2007

www.escriber.com Prescriber 19 March 2007 73

NIDD datafile.qxd 9/3/07 12:45 Page 2

Oral antidiabetic drugs

Datafile
Oral antidiabetic drugs (cont.)
Drug group Drug Available as Form/strength Typical dosage Cost1

thiazolidinedione pioglitazone Competact 15mg plus 850mg tabs 1 tab twice daily 31.56
plus biguanide plus metformin
rosiglitazone Avandamet 2mg plus 500mg tabs 1 x 2mg plus 1000mg 27.71-52.45
plus metformin 2mg plus 1000mg tabs tab twice daily; if
4mg plus 1000mg tabs greater glycaemic
control is required
increase to 1 x 4mg
plus 1000mg tab
twice daily after 8
weeks

1NHS cost of 28 days treatment at the dosage shown. Prices MIMS/Drug Tariff, January 2007

Forthcoming events
The Forthcoming events section highlights some of the many courses, meetings and
conferences of interest to the GP and pharmacist planned over the coming months

Postmenopausal Health Second Meeting of the UK conditions and infections and

Date: 16-18 April
Venue: Royal College of
Obstetricians and Gynaecologists
Website (for registration):
www.rcog.org.uk/meetings
Presentations on current issues
relating to postmenopausal health
and management of the menopause.
Follows the recommended syllabus
of the BMS/RCOG Menopause
Special Skills Module.
GP Update Series:
Dermatology
Date: 18 April
Venue: Kings College London
Telephone: 020 7188 7147
Email: cppe-gpcourses@kcl.ac.uk
Website: www.gstt.nhs.uk/cppe
Aiming to provide GPs with current
information on conditions that
commonly require referral advice.
With a focus on relevant QOF tar-
gets, the courses typically comprise
presentations, workshops and Q&A
sessions.
PD Non Motor Group: Non
Motor Symptom Complex of
Parkinsons Disease
Date: 21 April
Venue: Royal Society of Medicine
Website (for registration):
www.pdnmg.com
An international panel will provide
an up-to-date summary of various
aspects of nonmotor symptoms of
PD that affect the day-to-day life
of people with Parkinsons, carers
and the treating healthcare profes-
sionals.
BMJ Masterclass for GPs:
Paediatrics and Womens
Health
Date: 1 May
Venue: Manchester
Email: masterclasses@
bmjgroup.com
Website: www.bmjmaster
classes.com/GPs
Including, in children, constipation,
lactose intolerance, atopic
immunisations; in womens health,
polycystic ovarian syndrome, amen-
orrhoea, contraception and HRT.
BMJ Masterclass for GPs:
Respiratory Medicine
Date: 2 May
Venue: Manchester
Email: masterclasses@
bmjgroup.com
Website: www.bmjmaster
classes.com/GPs
For GPs and nurse prescribers,
including managing asthma and
COPD in primary care; managing
allergic conditions, including
asthma and rhinitis; investigation
and treatment of patients with
pneumonia, bronchiectasis, and
tuberculosis; and the role of oxygen
therapy.
Anyone who wishes to publicise
details of events for GPs and phar-
macists (at no charge) should e-mail
them to: prescriber@wiley.co.uk

74 Prescriber 19 March 2007 www.escriber.com