Você está na página 1de 12

Review NIDD.

qxd 9/3/07 14:32 Page 2

Drug review Oral antidiabetic drugs

Oral antidiabetic drugs: their


properties and recommended use
Ian Campbell FRCP

Skyline Imaging Ltd


There are now five classes of oral anti- ure that is estimated to reach 250-300 million by the
year 2010.
diabetic drugs available, with metformin
In the UK approximately 3 per cent of the popu-
remaining the cornerstone of drug therapy in lation have recognised diabetes mellitus, and another
3 per cent will have unrecognised type 2 diabetes.
type 2 diabetes. Our Drug review considers
This rise in type 2 diabetes is a result of high calorie
their mode of action, properties and intake, limited physical activity and obesity, with about
70-80 per cent of type 2 diabetes patients being over-
recommended use, followed by sources of
weight.
further information, an analysis of prescrip- The treatment of type 2 diabetes is not purely a
matter of glucose control, and it is recognised that
tion data and the Datafile.
morbidity and premature mortality are closely
related to the different components of type 2 dia-
iabetes mellitus is now recognised as a major betes, which is now often referred to as the metabolic
D world-wide public health problem. At present
about 150 million people have diabetes mellitus, a fig-
syndrome or insulin resistance syndrome. In addi-
tion to hyperglycaemia, these components include

56 Prescriber 19 March 2007 www.escriber.com


Review NIDD.qxd 9/3/07 14:32 Page 3

Oral antidiabetic drugs

Class Examples Principal mode of action

Sulphonylureas gliclazide, glibenclamide, stimulate insulin secretion (acting 12-24 hours)


glipizide, glimepiride

Postprandial glucose regulators repaglinide, nateglinide stimulate insulin secretion (short acting, <6 hours)

Biguanide metformin improves insulin action

Thiazolidinediones pioglitazone, rosiglitazone PPAR-gamma agonists, increase insulin action

Alpha-glucosidase inhibitor acarbose slows down rate of carbohydrate ingestion

Table 1. Available oral antidiabetic agents and their mode of action

central obesity, hypertension, dyslipidaemia (raised (Starlix). These two agents are rapidly absorbed and
triglycerides and small, dense LDL and lowered also quickly eliminated, so that their insulin-secret-
HDL) and a procoagulant state. ing effect is short lived, with a maximum effect at
Therefore any treatment plan for type 2 diabetes two to four hours and a duration of less than six
patients also requires weight loss where obesity hours.
occurs, blood pressure reduction, plasma lipid
abnormalities to be corrected, and antiplatelet Drugs that reduce insulin resistance: metformin and
agents to be prescribed according to national thiazolidinediones
guidelines.1,2 Such an integrated approach will be Metformin Metformin is the only biguanide in the UK.
beneficial and is now well recognised in clinical It increases insulin action at some unknown intra-
practice. cellular locus, and has no direct action on the pan-
creatic beta-cells. In type 2 diabetes, the main action
Oral antidiabetic drugs of metformin is to potentiate the action of insulin,
As part of this integrated approach to reduce cardio- thus decreasing hepatic glucose production by reduc-
vascular risk in type 2 diabetes patients, glycaemic con- ing both gluconeogenesis and glycogenolysis. In addi-
trol is important. There are five classes of oral tion metformin improves peripheral glucose
antidiabetic drugs available for lowering blood glu- utilisation in muscle. Metformin is particularly useful
cose (see Table 1). for obese type 2 diabetes patients as it does not cause
weight gain, but rather a little weight loss.
Insulin secretagogues: sulphonylureas and postprandial The United Kingdom Prospective Diabetes Study
glucose regulators (UKPDS) showed that, compared with conventional
Two of the classes, sulphonylureas and postprandial treatment with diet, metformin reduced the risk of
glucose regulators, are insulin secretagogues. These diabetes-related deaths by 42 per cent and reduced
agents act at the ATP-dependent potassium channel myocardial infarction (MI) by 39 per cent over a 10-
in the beta-cell membrane to stimulate insulin secre- year follow-up period.4 These benefits were not seen
tion from the pancreas. Gliclazide, glibenclamide, in overweight type 2 diabetes subjects given a sulph-
glimepiride and glipizide are the most commonly onylurea or insulin therapy. This vascular-protective
used sulphonylureas in the UK, stimulating insulin effect of metformin has now established it as the drug
secretion for 12-24 hours. Gliclazide and glipizide of choice in type 2 diabetes patients with a BMI >25
are given twice daily, glibenclamide and glimepiride where diet and lifestyle measures fail to achieve gly-
once daily. caemic control.
The other group of insulin secretagogues are Thiazolidinediones: pioglitazone (Actos) and rosiglita-
known as postprandial glucose regulators or meglin- zone (Avandia) These drugs are also known as TZDs
itides.3 The former name is used as the insulin secre- or glitazones. They act at the level of the genome,
tion profile coincides with meal digestion some one modifying the transcription of a number of genes that
to two hours after eating. regulate insulin action and lipid metabolism. The
In the UK there are two postprandial glucose reg- TZDs are ligands for peroxisome proliferator-acti-
ulators, repaglinide (Prandin) and nateglinide vated receptor gamma (PPAR-gamma). The PPAR-

58 Prescriber 19 March 2007 www.escriber.com


Review NIDD.qxd 9/3/07 14:32 Page 4

Oral antidiabetic drugs

gamma receptors are located in the nucleus of the insulin sensitivity) and beta-cell dysfunction. At
cell and their activation by TZDs improves insulin diagnosis in type 2 diabetes, both insulin sensitivity
action to increase glucose uptake in muscle and sup- and beta-cell production of insulin are about 50 per
press hepatic glucose output; TZDs also decrease cent of normal. The latter further declines by 4-5
plasma free fatty acids, decrease plasma triglycerides per cent per year over the next five to six years.
(pioglitazone but not rosiglitazone), raise HDL cho- When 80-90 per cent of beta-cell production of
lesterol by 10-20 per cent, and raise plasma LDL cho- insulin is lost, there is then insufficient endogenous
lesterol by 5-15 per cent but reduce the atherogenic insulin for the oral antidiabetic drugs to be effec-
small, dense LDL particles. tive, even in combination, and it is at this stage that
insulin therapy is necessary to maintain adequate
Alpha-glucosidase inhibitors: acarbose (Glucobay) glycaemic control.
Acarbose is the only available alpha-glucosidase Sulphonylureas, metformin and acarbose have
inhibitor. It inhibits alpha-glucosidase enzymes, which been available for many years. Postprandial glucose
break down oligosaccharides into monosaccharides regulators and TZDs are newer agents, and whether
in the small intestine. Acarbose lowers postprandial their earlier use in combination with metformin will
blood glucose by competing with dietar y carbo- delay insulin therapy remains to be seen (see
hydrate for the alpha-glucosidase enzymes, hence below).
delaying glucose absorption. As monotherapy, acar-
bose, like metformin, will not cause hypoglycaemia Side-effects and drug interactions with
or weight gain. oral antidiabetic drugs
The side-effects of the oral antidiabetic drugs are sum-
Efficacy marised in Table 2.
All the oral antidiabetic drugs mentioned above have
about the same blood glucose-lowering effect when Sulphonylureas
the clinical trial results are reviewed. Within the first Hypoglycaemia and weight gain are the most com-
two to three years of diagnosis, they will lower fast- mon side-effects of sulphonylureas. Sulphonylurea-
ing plasma glucose by about 2-4mmol per litre, the induced hypoglycaemia is particularly important in
postprandial glucose levels by 4-6mmol per litre and older people, in whom an incorrect diagnosis of tran-
the glycated haemoglobin (HbA1c) by 1.5-2 per cent. sient ischaemic attack (TIA) or cerebrovascular acci-
Type 2 diabetes is a progressive condition. It has dent may be made. The diagnosis of hypoglycaemia
a dual abnormality of insulin resistance (diminished should be considered in any diabetic subject treated

Side-effect Sulphonylureas Postprandial Metformin TZDs Acarbose


glucose regulators

hypoglycaemia ++ +

GI symptoms + ++

weight gain + + +

oedema +

lactic acidosis +

hypersensitivity +

cholestasis +

folate, B12 +
malabsorption

Table 2. Side-effects of oral antidiabetic agents

www.escriber.com Prescriber 19 March 2007 59


Review NIDD.qxd 9/3/07 14:32 Page 5

Oral antidiabetic drugs

with a sulphonylurea who develops signs of altered


Decreased antihyper- Increased antihyper- Blunt hypoglycaemia
behaviour.
glycaemic effect glycaemic effect response
The action of sulphonylureas may be prolonged in
patients with liver or renal impairment. In these situ-
furosemide warfarin beta-blockers
ations, gliclazide may be preferred as less than 5 per
not bumetanide
cent of this drug is excreted unaltered in the urine.
salicylates clonidine
Glibenclamide should be used with caution in older
thiazides
people as it is the most likely to cause hypoglycaemia.
fibrates
steroids
Postprandial glucose regulators
MAOIs
Hypoglycaemia and weight gain are again the most
phenytoin
significant side-effects of postprandial glucose regu-
lators, although both are less severe than with the
rifampicin
sulphonylureas due to the shorter duration of action
of repaglinide and nateglinide. These can be used in Table 3. Drug interactions with sulphonylureas
patients with renal impairment as they are
metabolised in the liver and excreted in the faeces. The cautious use of glitazone therapy can be con-
sidered in patients with mild hepatic dysfunction as
Metformin many of these cases will have nonalcoholic steato-
GI side-effects, with anorexia, abdominal discomfort hepatitis (NASH) and the TZDs can improve hepatic
and diarrhoea, and a metallic taste in the mouth (due function in these cases. Regular monitoring of LFTs is
to the drug being concentrated in salivary glands) can required in these situations, and observance of cur-
occur with metformin. If metformin is started at a dose rent indications for discontinuation of therapy applied
of 500mg daily and built up slowly, and the tablets taken if necessary.
after meals, less than 5 per cent will be intolerant of the The other side-effects of the TZDs are weight gain,
drug. A slow-release preparation of metformin is now usually 3-4kg in the first six months of therapy, mild
available (Glucophage SR) which reduces the fre- peripheral oedema in up to 5 per cent of patients, and
quency of these GI side-effects by up to 50 per cent. a mild dilutional anaemia in some patients. TZDs
Metformin-associated lactic acidosis is well recog- should not be prescribed for patients with congestive
nised but rare if the prescribing recommendations are cardiac failure and significant fluid retention.5
adhered to, namely to exclude patients with liver and
renal disease and withdrawal of the drug in patients Acarbose
with severe acute illness that can cause hypoxia, espe- The principal side-effects, seen in about 20-25 per cent
cially respiratory or acute cardiac failure. The drug of patients, are GI with flatulence, abdominal dis-
may be used in stable cardiac decompensation. Age is comfort and diarrhoea. These side-effects are due to
not a contraindication to metformin use as was once undigested carbohydrate from the small bowel reach-
thought, provided the renal function is satisfactory ing the colon and may be reduced in frequency with
with a serum creatinine level below 130mol per litre. a low starting dose followed by a gradual increase. In
high doses of 300mg three times daily, there may be a
Thiazolidinediones mild rise in liver transaminases.
The original TZD troglitazone was withdrawn because
of hepatotoxicity, but there is no such reported Important drug interactions
adverse hepatic effects with either pioglitazone or Of the five classes of oral antidiabetic drugs described,
rosiglitazone. However it is recommended that liver important drug interactions are only seen with sulpho-
function tests (LFTs) are carried out at the start of nylureas. The drugs that antagonise and potentiate
therapy. The original recommendation that two- the sulphonylureas, as well as drugs that mask the
monthly LFTs should be done for the first year of ther- awareness of impending hypoglycaemic, are sum-
apy have now relaxed and it is probably satisfactory to marised in Table 3.
check the LFTs on an annual basis. If the alanine
transaminase (ALT) is more than twice normal before Recommended management of type 2
therapy, then TZDs should not be started, and they diabetes
should be stopped if the ALT rises to more than three National clinical guidelines have been issued for blood
times normal during treatment. glucose management using antidiabetic drugs.6 The

www.escriber.com Prescriber 19 March 2007 61


Review NIDD.qxd 9/3/07 14:32 Page 6

Oral antidiabetic drugs

Monotherapy first agent Combination therapy agent to add


However the postprandial glucose regulators may
have a role to play when younger patients have a
metformin pioglitazone+ or rosiglitazone lifestyle with variable eating patterns as the drugs can
sulphonylurea, repaglinide or nateglinide be taken immediately before a meal, and in older
acarbose patients where there may be a risk of hypoglycaemia
with sulphonylureas, especially if there is impaired
sulphonylurea or metformin renal function.
postprandial glucose pioglitazone or rosiglitazone
regulator acarbose Thiazolidinediones
The National Institute for Health and Clinical
pioglitazone or rosiglitazone metformin* Excellence (NICE) has recommended that TZDs be
sulphonylurea, repaglinide or nateglinide used only as combination therapy, with metformin in
acarbose obese patients if a combination of metformin with a
sulphonylurea is not appropriate and with sulphonyl-
acarbose sulphonylurea, repaglinide or nateglinide ureas if metformin is not appropriate.7 However, since
metformin the NICE guidance was issued, both TZDs have been
granted licences for monotherapy if metformin is
+Competact (combination of metformin and pioglitazone) now available inappropriate. This is likely to confuse prescribers
Avandamet (combination of metformin and rosiglitazone) now available until NICE updates its guidance, which was expected
in July 2006 but is now not due until early 2008.
Table 4. Oral antidiabetic drugs that can be used together in combination therapy The potential value for TZDs is that there is good
(based on current European licensing) scientific evidence that they have pleiotrophic actions
recommendations for the five classes of oral anti- that may prevent the progression of atherosclerosis.8
diabetic drugs will be discussed. The NICE guidance in 2003 recommends relatively
limited use of these drugs based on the fact that there
Metformin were as yet no end-point studies at that stage to show
The UKPDS has provided evidence that early inten- that TZDs reduce microvascular or macrovascular
sive control with metformin in overweight type 2 dia- complications or how they will perform in this respect
betes subjects is a particularly effective approach to against metformin or sulphonylureas. In the mean-
reduce vascular complications and improve survival.4 time there have been four major new studies involv-
Metformin therapy is therefore the cornerstone of ing TZDs.
type 2 diabetes management with oral antidiabetic The PROspective pioglitAzone Clinical Trial In
drugs. macroVascular Events (PROactive) study9 showed that
pioglitazone in type 2 diabetes subjects with macrovas-
Sulphonylureas cular disease caused a 16 per cent decrease in the prin-
The sulphonylureas have been the most commonly cipal secondary end-point of death, heart attack and
prescribed antidiabetic agent until the UKPDS results, stroke.
but have now been overtaken by metformin as the The Carotid intima-media tHICkness in
first-line drug of choice. However they are still widely Atherosclerosis using pioGlitazOne (CHICAGO)
prescribed and a sulphonylurea prescribed with met- study 10 showed that pioglitazone, but not the
formin is the most commonly used antidiabetic drug
combination at present. Sulphonylureas: recommended use

Postprandial glucose regulators sulphonylureas should be used with metformin in over-


Repaglinide and nateglinide have not been widely pre- weight or obese people when glucose control becomes
scribed since their introduction compared to the unsatisfactory
longer-acting sulphonylureas. They are relatively sulphonylureas should be considered as an option for
expensive drugs and are seen as being very similar to first-line therapy when metformin is not tolerated or is
the older sulphonylureas in terms of their pharma- contraindicated, and in people who are not overweight
cological action. The lesser risk of hypoglycaemia is a generic sulphonylurea should normally be chosen
not seen to be of major benefit as most GPs do not see a long-acting sulphonylurea may be useful when com-
the severe hypoglycaemia when the sulphonylureas pliance is a problem
(other than glibenclamide) are prescribed.

62 Prescriber 19 March 2007 www.escriber.com


Review NIDD.qxd 9/3/07 14:32 Page 7

Oral antidiabetic drugs

Postprandial glucose regulators: recommended use


NICE also highlights that there is no evidence
that TZDs are of added benefit when given as triple
therapy with metformin and a sulphonylurea,
the same recommendations as for sulphonylureas are
although both pioglitazone and rosiglitazone now
given for insulin secretagogues in general, but it is
have a licence for triple therapy. In the authors
clearly stated that the insulin secretagogue choice
experience, this triple combination works very well
should be a generic sulphonylurea, eg gliclazide or
in some patients but not others, and there is no
glipizide
harm in giving this therapy a trial if the diabetes
rapidly-acting insulin secretagogues, eg repaglinide or
patient is reluctant to consider insulin therapy. The
nateglinide, may have a role in attaining tight glucose
PROactive study showed that pioglitazone added to
control in patients with nonroutine daily patterns
metformin and sulphonylurea therapy could delay
the progression to insulin by up to 50 per cent over
comparator sulphonylurea agent glimepiride, showed three years.9
a regression in carotid atherosclerotic disease using The author prefers the Association of British
carotid ultrasonography to measure carotid intima- Clinical Diabetologists (ABCD) position statement in
media thickness (CIMT). 2004 on glitazones as giving a better guide to the clin-
The Diabetes REduction Assessment with ramipril ical use of these agents,14 with the new approved indi-
and rosiglitazone Medication (DREAM) study 11 cation that pioglitazone may be used in conjunction
showed that rosiglitazone could reduce the progression with insulin therapy where there is insufficient gly-
to type 2 diabetes in patients with impaired fasting glu- caemic control on insulin when metformin is inap-
cose (IFG) or impaired glucose tolerance (IGT). propriate because of contraindications or intolerance.
However, rosiglitazone is not currently licensed for use The combination of pioglitazone and insulin may
in IFG or IGT. reduce the dosage of insulin required in obese insulin-
The ADOPT (A Diabetes Outcome Progression Trial) resistant type 2 diabetes subjects who require insulin
study12 showed that rosiglitazone as monotherapy sus- for glycaemic control.
tained glycaemic control better than metformin or It is important to remember that after starting
glibenclamide monotherapy over a mean period of four TZDs, there may be a delay of six to eight weeks before
years. The mean HbA1c was 0.13 per cent less than the their full effect is seen due to their mode of action of
rosiglitazone group at four years compared with the inducing transcription of genes that regulate proteins
metformin group and 0.42 per cent less compared with involved in insulin action and lipid metabolism.
the glibenclamide group. These small changes in gly-
cated haemoglobin would suggest, in the authors opin- Acarbose
ion, that metformin should still remain the treatment Acarbose lowers blood glucose in type 2 diabetes
of choice when starting drug therapy in type 2 diabetes, patients as a single agent or in combination therapy,
but a TZD would be a preferred combination agent but because it has a high incidence of GI side-effects
with metformin. its use has been much less than metformin and
The DREAM and ADOPT studies support beta-cell sulphonylureas.
preservation by TZDs in type 2 diabetes with better sus-
tained glycaemic control;13 the PROactive and Achieving best practice
CHICAGO studies support a role for TZDs in prevent- For practical purposes the aim in clinical practice
ing macrovascular disease, the principal killer in type 2 when treating type 2 diabetes patients is to achieve an
diabetes. HbA1c of 7 per cent or less, except in older patients or
those with severe co-morbidities where acceptable con-
Metformin: recommended use trol is met by simply keeping the patient free of hyper-
glycaemic symptoms and ignoring tight HbA1c targets.
in people who are overweight (BMI >25) and whose The UKPDS showed that less than 50 per cent of
blood glucose is inadequately controlled using lifestyle patients treated with either metformin or a sulpho-
interventions alone, metformin should normally be used nylurea will reach a 7 per cent HbA1c target at three
as the first-line glucose-lowering therapy years after diagnosis15 and it is becoming increasingly
metformin should be considered as an option for first- recognised that early combination therapy is neces-
line or combination therapy for people who are not sary.16 Table 4 gives a simple outline of those anti-
overweight diabetic drugs that can be used together for
combination therapy.

64 Prescriber 19 March 2007 www.escriber.com


Review NIDD.qxd 9/3/07 14:32 Page 8

Oral antidiabetic drugs

Thiazolidinediones (TZDs): recommended use Alpha-glucosidase inhibitors: recommended use


(adapted from reference 14)
acarbose may be considered as an alternative glucose-
addition of TZD to metformin is preferred second-line lowering therapy in type 2 diabetes patients unable to
oral antidiabetic therapy in obese type 2 diabetes use other drugs
TZDs should be considered as monotherapy in those
patients unable to take metformin
tective properties with the pioglitazone therapy.20 This
consider TZDs in place of metformin in renal impairment
is in keeping with the ADOPT trial results mentioned
triple therapy with a TZD plus metformin plus a sulph-
above.12
onylurea may be considered in obese patients or those
The American Diabetes Association (ADA) and
patients unwilling to consider insulin therapy
the European Association for the Study of Diabetes
pioglitazone may be used with insulin where metformin
(EASD) have proposed a treatment algorithm for
has contraindications or intolerance; if such treatment
type 2 diabetes mellitus (see Figure 1),21 advocating
is considered in severe case of insulin resistance,
metformin at diagnosis with lifestyle measures. The
watch for oedema and heart failure
authors preference at three to six months after diag-
nosis is to then move on to a metformin/pioglita-
There are no clinical trials to show which drug zone combination where the HbA1c is above 7 per
combination is best. Meglitinides and acarbose are not cent, based on experience with other drug combi-
commonly prescribed and at the present time the nations followed up for three years after diagnosis
choice lies between the traditional metformin plus (see above).20 There is no danger of hypoglycaemia
sulphonylurea or the newer combination of met- when metformin and a TZD are used in combina-
formin plus a TZD. The addition of a sulphonylurea tion at such an early stage as they are both insulin
to metformin has been shown in a retrospective analy- sensitisers. When treating to target there is always a
sis to offer maintained control for as little as six risk of hypoglycaemia where metformin is used in
months before deterioration in control occurs. 17 combination with an insulin secretagogue or insulin
Therefore the combination of a TZD plus metformin itself.
offers an alternative that is being increasingly used. This is the authors personal view but is a treatment
Pioglitazone has lipid advantages compared with regimen that will maintain glycaemic control much
rosiglitazone, especially with regard to benefits in longer than that seen in the UKPDS study and sustain
triglycerides and HDL,18 which are still seen when good glycaemic control with a delay in the need for
patients are on statin therapy.19 insulin therapy.
The traditional treatment approach to manage-
ment of newly diagnosed type 2 diabetes has been to Newer drugs
start with diet and lifestyle advice, then when gly- Newer agents will become available in the UK in
caemic control is lost to progress to monotherapy, usu- 2007 to aid in the management of type 2 diabetes
ally with metformin, and after some years to and these new drugs will need to be evaluated, espe-
combination therapy with a sulphonylurea. cially against metformin, the TZDs and sulphony-
This failure-orientated strategy is better replaced lureas.
by an intensive goal-orientated strategy to treat early Exenatide is an injectable peptide, a glucagon-like
for success rather than to await failure.16 In a recent peptide-1 (GLP-1) analogue that is effective against
study performed in the authors unit, a combination beta-cell dysfunction and promotes weight loss.
of metformin plus pioglitazone was prescribed in addi- Dipeptidyl peptidase-4 (DPP-4) inhibitors, also
tion to lifestyle advice for newly diagnosed type 2 dia- known as gliptins, are oral agents to reduce the degra-
betes subjects at diagnosis (if HbA1c >8 per cent), or dation of endogenous GLP-1 as well as decreasing
three to six months after diagnosis if HbA1c >7 per appetite. Two examples of these DDP-4 inhibitors are
cent. This combination was compared with metformin sitagliptin and vildagliptin.
plus gliclazide and metformin plus repaglinide. Over Type 2 diabetes subjects are often obese and
a three-year follow-up period those patients treated rimonabant (Acomplia) is a satiety-inducing
with the metformin/pioglitazone combination cannabinoid-1 receptor antagonist, now available in
showed a 0.1 per cent increase in HbA1c per year com- the UK, that can promote weight loss in type 2 dia-
pared with a 0.5 per cent increase seen in the other betes subjects and also improve glycaemic and lipid
two combinations, suggesting there are beta-cell pro- control.

www.escriber.com Prescriber 19 March 2007 65


Review NIDD.qxd 9/3/07 14:32 Page 9

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)

References lidinediones and risk for atherosclerosis : pleiotrophic


1. British Cardiac Society, British Hypertension Society, effects of PPar gamma agonism. Diab Vasc Dis Res
Diabetes UK, et al. JB2: Joint British Societies guidelines on 2006;3:65-71.
prevention of cardiovascular disease in clinical practice. 9. Dormandy JA, Charbonnel B, Eckland DJ, et al.
Heart 2005;91(suppl 5):V1-V52. Secondar y prevention of macrovascular events in
2. NICE. Clinical Guideline H. Management of type 2 diabetes: patients with type 2 diabetes in the PROactive study
management of blood pressure and lipids. London: NICE, 2002. (PROspective pioglitAzone Clinical Trial In macro-
3. Dornhorst A. Insulinotropic meglitinide analogues. Lancet Vascular Events): a randomised controlled trial. Lancet
2001;358:1709-16. 2005;366:1279-89.
4. United Kingdom Prospective Diabetes Study Group. 10. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of piogli-
Effect of intensive blood-glucose control with metformin on tazone compared with glimepiride on carotid initima-media
complications in overweight patients with type 2 diabetes thickness in type 2 diabetes: a randomised trial. JAMA
(UKPDS 34). Lancet 1998;352:854-65. 2006;296:2572-81.
5. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione 11. The DREAM (Diabetes REduction Assessment with
use, fluid retention, and congestive cardiac failure. A con- ramipril and rosiglitazone Medication) Trial Investigators.
sensus statement from the American Heart Association and Effect of rosiglitazone on the frequency of diabetes in
American Diabetes Association. Diabetes Care 2004;27: patients with impaired glucose tolerance or impaired fasting
256-63. glucose: a randomised controlled trial. Lancet 2006;368:
6. NICE. Clinical Guideline G. Management of type 2 diabetes: 1096-105.
management of blood glucose. London: NICE, 2002. 12. Kahn SE, Haffner SM, Heise MA, et al. Glycaemic dura-
7. NICE. Technology Appraisal 63. Guidance on the use of gli- bility of rosiglitazone, metformin or glyburide monother-
tazones for the treatment of type 2 diabetes. London: NICE, apy. N Eng J Med 2006;355:2427-43.
2003. 13. Leiter LA. Beta-cell preservation: a potential role for thi-
8. Patel CB, De Lemos JA, Wyne KL, et al. Thiazo- 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

Oral antidiabetic drugs

Diabetic Med 2005;22:963-72. Diabetes Care 2005;28:1547-54.


14. Higgs ER, Krentz AJ, on behalf of the Association of 19. Berhanu P, Kipnes MS, Khan MA, et al. Effects of piogli-
British Clinical Diabetologists. ABCD position statement on tazone on lipid and lipoprotein profiles in patients with type
glitazones. Pract Diab Int 2004;21(8):293-5. 2 diabetes and dyslipidaemia after treatment conversion
15. Turner RC, Cull CA, et al; for the UK Prospective from rosiglitazone while continuing stable statin therapy.
Diabetes Study Group. Glycaemic control with diet, sul- Diab Vasc Dis Res 2006;3:39-44.
fonylurea, metformin or insulin in patients with type 2 dia- 20. Chalmers J, Hunter JE, Robertson SJ, et al. Effects of early
betes mellitus: progressive requirement for multiple use of pioglitazone in combination with metformin in
therapies. JAMA 1999;281:2005-12. patients with newly diagnosed type 2 diabetes. Submitted
16. Campbell IW. Need for intensive, early glycaemic con- for publication, 2007.
trol in patients with type 2 diabetes. Br J Cardiol 2000;7: 21. Nathan DM, Buse JB, Davidson MB, et al. Management
625-31. of hyperglycaemia in type 2 diabetes: a consensus algorithm
17. Cook MN, Girman CJ, Stein PP, et al. Glycaemic control for the initiation and adjustment of therapy. Diabetologia
continues to deteriorate after sulfonylureas are added to 2006;49:1711-21.
metformin among patients with type 2 diabetes. Diabetes Care
2005;28:995-1000. Professor Campbell is consultant physician at Victoria
18. Goldberg RB, Kendall DM, Deeg MA, et al. A compari- Hospital, Kirkcaldy, and honorary professor in the
son of lipid and glycaemic effects of pioglitazone and rosigli- Department of Biological Sciences, Bute Medical School,
tazone in patients with type 2 diabetes and dyslipidaemia. University of St Andrews

Resources
Further reading Groups and organisations
BMJ Collected Resources. All articles published in Diabetes UK offers help and information to diabetes
the BMJ on diabetes since January 1998. http://www. patients and supports research into the condition.
bmj.com/collections. They also produce publications for patients and health
professionals. Diabetes UK Central Office, Macleod
Management of hyperglycaemia in type 2 diabetes: the House, 10 Parkway, London NW1 7AA; tel: 020 7424
end of recurrent failure. Heine RJ, Diamant M, 1000; fax: 020 7424 1001; e-mail:info@diabetes.org.uk.
Mbanya J-C, et al. BMJ 2006;333:1200-4. Website: www.diabetes.org.uk.

Diabetes Insight (www.diabetes-insight.info) pro-


NICE duces publications and provides support for patients
Technology Appraisal 63. Glitazones in the treatment with diabetes and information for healthcare pro-
of type 2 diabetes. 2003. www.nice.org.uk/cat. fessionals.
asp?c=83263.
Diabetes Monitoring Forum (www.dmforum.org.uk)
Clinical Guideline E. Management of type 2 diabetes helps patients to understand the role of blood glu-
retinopathy. 2002. www.nice.org.uk/cat. asp?c= cose and ketone monitoring in diabetes manage-
27915. ment and produces a series of advice leaflets. E-mail:
info@dmforum.org.uk.
Clinical Guideline F. Management of type 2 diabetes
renal disease, prevention and early management. Guidance
2002. www.nice.org.uk/cat.asp?c=39385. PRODIGY guidance diabetes type 2 (blood glucose
management). www.prodigy.nhs.uk.
Clinical Guideline G. Management of type 2 diabetes
blood glucose. 2002. www.nice.org.uk/cat. asp?c= Patient information
36733. Diabetes and oral hypoglycaemic agents. PatientUK
factsheet: www.patient.co.uk/showdoc/40001626/.
Clinical Guideline H. Management of type 2 diabetes
blood pressure and blood lipids. 2002. www.nice. Treatments for type 2 diabetes. PatientUK factsheet.
org.uk/cat.asp?c=38551. www.patient.co.uk/showdoc/27000260/.

www.escriber.com 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-


onylurea prescribing has remained steady. Looking at
costs the picture is very different. Despite accounting
Prescribing of oral antidiabetic agents has increased sig- for over 80 per cent of items, metformin and sulphonyl-
nificantly over the last five years from 2.5 million items ureas only make up under 50 per cent of costs (see
a quarter to 4.5 million (see Figure 2). The biggest Figure 3). The glitazones and glitazone/metformin
growth has been in the use of metformin, and combinations are responsible for most of the steep rise
prescriptions for the glitazones and the glitazone/ 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 PD Non Motor Group: Non immunisations; in womens health,
Venue: Royal College of Motor Symptom Complex of polycystic ovarian syndrome, amen-
Obstetricians and Gynaecologists Parkinsons Disease orrhoea, contraception and HRT.
Website (for registration): Date: 21 April
www.rcog.org.uk/meetings Venue: Royal Society of Medicine BMJ Masterclass for GPs:
Presentations on current issues Website (for registration): Respiratory Medicine
relating to postmenopausal health www.pdnmg.com Date: 2 May
and management of the menopause. An international panel will provide Venue: Manchester
Follows the recommended syllabus an up-to-date summary of various Email: masterclasses@
of the BMS/RCOG Menopause aspects of nonmotor symptoms of bmjgroup.com
Special Skills Module. PD that affect the day-to-day life Website: www.bmjmaster
of people with Parkinsons, carers classes.com/GPs
GP Update Series: and the treating healthcare profes- For GPs and nurse prescribers,
Dermatology sionals. including managing asthma and
Date: 18 April COPD in primary care; managing
Venue: Kings College London BMJ Masterclass for GPs: allergic conditions, including
Telephone: 020 7188 7147 Paediatrics and Womens asthma and rhinitis; investigation
Email: cppe-gpcourses@kcl.ac.uk Health and treatment of patients with
Website: www.gstt.nhs.uk/cppe Date: 1 May pneumonia, bronchiectasis, and
Aiming to provide GPs with current Venue: Manchester tuberculosis; and the role of oxygen
information on conditions that Email: masterclasses@ therapy.
commonly require referral advice. bmjgroup.com
With a focus on relevant QOF tar- Website: www.bmjmaster Anyone who wishes to publicise
gets, the courses typically comprise classes.com/GPs details of events for GPs and phar-
presentations, workshops and Q&A Including, in children, constipation, macists (at no charge) should e-mail
sessions. lactose intolerance, atopic them to: prescriber@wiley.co.uk

74 Prescriber 19 March 2007 www.escriber.com