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Postprandial glucose regulators repaglinide, nateglinide stimulate insulin secretion (short acting, <6 hours)
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-
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
hypoglycaemia ++ +
GI symptoms + ++
weight gain + + +
oedema +
lactic acidosis +
hypersensitivity +
cholestasis +
folate, B12 +
malabsorption
lifestyle + metformin
HbA1c *7%
HbA1c *7%
add TZD add basal insulin intensify insulin add sulphonylurea add basal insulin
HbA1c *7%
Figure 1. Simplified ADA-EASD consensus algorithm for type 2 diabetes (adapted from reference 21)
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.
Items (millions)
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)
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
Datafile
Oral antidiabetic drugs
Drug group Drug Available as Form/strength Typical dosage Cost1
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
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
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