• Healthy lifestyle advice—healthy eating plan, exercise, and
weight reduction plan.
• Oral hypoglycaemic agents should be given only when
dietary treatment alone has failed after a proper trial period,
usually lasting at least three months. They should not
normally be given as the initial treatment (this is a common
error).
• Sulphonylureas stimulate insulin secretion
• Meglitidine analogues stimulate insulin secretion
• Biguanides (metformin) reduce hepatic gluconeogenesis
and enhance glucose uptake
• Thiazolidinediones enhance insulin sensitivity
• glucosidase inhibitors (acarbose) reduce absorption of
complex carbohydrates.
• Pharmacological agents to assist weight reduction:
• Orlistat inhibits pancreatic lipase and reduces fat
absorption
• Sibutramine is a monoamine reuptake inhibitor, causing
reduced appetite
• Antihypertensive and lipid lowering agents
Sulphonylureas
Seven sulphonylureas are available. They are remarkably safe
and free from side effects, although rare toxic effects have been
reported, including rashes and jaundice.
Only one sulphonylurea should be used at a time since there is nothing
to be gained from any combination of these drugs and there is
no evidence that any one drug is likely to be more successful
than another.
Selecting a sulphonylurea is largely a matter of personal
choice, though it is now usual to use one of the shorter acting,
metabolised drugs such as gliclazide or glipizide, which are
suitable for all ages and for those with renal impairment as
well.
Glibenclamide, which has the advantage of once-daily use,
is still suitable for younger patients, but is contraindicated in
the elderly. Glimepiride is also given once daily and may cause
less hypoglycaemia.
Excessive doses can cause hazardous (even
fatal)
hypoglycaemia, and it is thus usual to start treatment with
the smallest useful dose. If hypoglycaemia does occur in a
patient taking a sulphonylurea, the drug should be stopped or
at the very least the dose substantially reduced.
Chlorpropamide is now obsolete. It has a very long half life,
thus increasing the risk of hypoglycaemia, and many patients
experience an unpleasant facial flush on drinking very small amounts of alcohol.
Meglitidine analogues
The mode of action of this group of drugs is similar to that of
sulphonylureas though acting at a different site.
Their advantages are the rapid onset and short half life, efficacy when
taken just 15 minutes before meals, and a duration of effect of
no more than three hours.
They are omitted if no meal is taken.
There may be some benefit in reducing postprandial glycaemia
and in theory at least there might be less hypoglycaemia
Nateglinide is one of a new class of oral hypoglycaemic
agents, namely an amino acid derivative. Insulin release after
meals is both faster and of shorter duration than that with either
sulphonylureas or repaglinide, giving less postprandial
hyper-insulinaemia and less reactive hypoglycaemia.
It is licensed only for use in combination with metformin, but not for
monotherapy or substitution for conventional sulphonylureas.
Biguanides: metformin
Biguanides act chiefly by reducing hepatic glucose production.
They also enhance peripheral glucose uptake, and to some
extent reduce carbohydrate absorption. Metformin is the only
biguanide available in the United Kingdom. It is the drug of
choice in the treatment of overweight Type 2 diabetic patients
when diet alone has failed.
UKPDS found some evidence for a
reduction in mortality after the use of metformin.
Lactic acidosis is a serious consequence of the
inappropriate use of metformin. It is contraindicated in any
patient with renal failure, and serum creatinine should be
monitored. A creatinine concentration above 150 mol/l
indicates that the drug should be stopped. Metformin should
not be used in any seriously ill or shocked patient, nor in those
with heart failure, serious liver disease or a very high alcohol
intake. It is not appropriate for the treatment of thin diabetic
patients nor for use in frail elderly patients.
Glucosidase inhibitors
These agents block the enzyme responsible for the breakdown
of complex carbohydrates in the gut and can effectively reduce
the increase in blood glucose after a meal. Acarbose acts in this
way and can be used alone or in combination with other oral
hypoglycaemic agents.
Its hypoglycaemic effect is relatively
small and the severe flatulence which develops (to some extent
avoidable by starting with small amounts) deters many patients
from using it.
Thiazolidinediones
This newly introduced group of hypoglycaemic agents act by
reducing insulin resistance and by activation of the peroxisome
proliferator activated receptor expressed predominantly in
adipose tissue.
These drugs are licensed for use with metformin if this
alone has failed to control the diabetes, or with a sulphonylurea
if metformin is either not tolerated or contraindicated (for
example, in renal failure). In the European Union they are not
licensed for use alone or in combination with insulin, and
should not be given to patients with a history of heart failure,
or during pregnancy.
They may cause oedema, a minor
reduction of haemoglobin, and a small increase of HDL
cholesterol. There are very rare reports of liver dysfunction,
and liver function should be monitored before, and every two
months after, starting treatment, for the following 12 months.
Drugs for management of obesity
There is a limited place for the use of medication in assisting
with weight reduction in the obese diabetic patient. The use of
such drugs is restricted to those whose BMI is 28 or more and
who are between the ages of 18 and 65 years; they should only
be prescribed for individuals who have lost at least 2·5 kg body
weight by diet and exercise during the preceding month.
Patients should continue to be supported by their advisers and
counsellors throughout treatment.
Orlistat inhibits fat
absorption by inhibition of pancreatic lipase. Weight red
indicating a successful response should be greater than 5%
after 12 weeks, in which event prescription may be continued
for one year to a limit of two years, otherwise treatment should
cease.
Unpleasant oily leakage and steatorrhoea can occur.
Sibutramine also acts centrally as a serotonin and
noradrenaline reuptake inhibitor and enhances the satiety
response. It is used as an adjunct to weight maintenance after
weight loss. Full details of its use and contraindications are to
be found in the BNF.
Guar gum
Guar gum preparations, taken in adequate quantity three times
daily before meals, can reduce postprandial blood glucose
concentrations. Flatulence is common and often unacceptable.
Guarem is the only available preparation. It has a very limited role
Side effects and risks of treatment:
Hypoglycaemia
Only sulphonylureas and meglitidine analogues cause
hypoglycaemia, but it should not be allowed to occur at all—it
almost invariably indicates excessive dosage. Those most at risk
are elderly people who may make dosage errors or fail to take
their normal meals.
Hypoglycaemia in this situation can be
fatal. The shorter acting sulphonylureas cause the least
hypoglycaemia and are therefore best for older people
Blockers may not only exacerbate
hypoglycaemia, but also occasionally inhibit the early
warning symptoms.
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