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If the patient is very symptomatic or has a very
high blood glucose level, diet and lifestyle
changes are unlikely to achieve target values.
In this instance, pharmacological therapy should
Algorithms showing the treatment of obese and non-obese individuals
Traditionally, sulphonylureas have been regarded as the
first-line drug treatment in type 2 diabetes patients who
are not very obese; for example: tolbutamide; glibenclamide;
glimepiride; glipizide; gliclazide; gliguidone; chlorpropamide.
Initial and maximum daily dosages will vary between different
countries and ethnic groups. Sulphonylureas can reduce HbA
Biguanides, e.g. metformin and buformin, are useful as first-
line therapy in the obese, and are recommended as first-line
therapy in non-obese subjects in some countries. The UK
Prospective Diabetes Survey (UKPDS) has demonstrated
that metformin is able to reduce HbA1c as effectively as
sulphonylureas and insulin without significant weight gain,
and may have additional cardioprotective properties.
Biguanides also do not cause hypoglycaemia.
α-Glucosidase inhibitors, such as acarbose, miglitol and
voglibose, decrease post-prandial blood glucose and, to a
lesser degree, fasting hyperglycaemia, and thus improve over-
all glycaemic control without mitigation of effect over time.
They have a weight-neutral or weight-reducing effect, and
can be used as first-line therapy in association with diet, or
in combination with sulphonylureas, biguanides and insulin.
These drugs may lower HbA1c by about 1%. In order to minimise thegastrointestinal side-effects of α-glucosidase inhibitors, a low starting doseis recommended followed by a gradual increase. α-Glucosidase inhibitorsare generally well tolerated and do not cause hypoglycaemia.
The thiazolidinediones, such as rosiglitazone and pioglitazone, reduce insulin
resistance in patients with type 2 diabetes, IGT, and those who are insulin
resistant but non-diabetic. Thiazolidinediones increase insulin-stimulated
glucose disposal in people with type 2 diabetes and in obese subjects.
They sensitise the body to its own insulin by improving cellular response
to insulin action; however, they do not enhance insulin production.
Mechanistically and when administered on their own, thiazolidinediones
do not cause hypoglycaemia. When administered as monotherapy or in
conjunction with other antiglycaemic agents, thiazolidinediones improve
glycaemic control in patients with type 2 diabetes. As monotherapy,
thiazolidinediones may decrease HbA1c by 1.5%.
Rosiglitazone has shown some significant changes to surrogate markers
for cardiac disease, suggesting a long-term beneficial effect, and outcome
studies are currently under way to demonstrate this.
Abnormalities in liver function tests (LFTs) were noted in patients treated
with troglitazone and, as a result, it has been withdrawn from the market
worldwide. Adverse LFTs have not been reported as an adverse effect of
rosiglitazone or pioglitazone; nevertheless, it is currently recommended to
monitor liver function periodically. Thiazolidinediones should not be initiated
in patients with active liver disease or increased transaminase levels.
In addition, weight increase and fluid retention may occur as a result of
A new generation of sulphonylurea-like agents has recently become
available in several countries in the region. The compounds, which include
nateglinide and repaglinide, appear to stimulate first-phase insulin secretion.
Glinides may be used as monotherapy or in combination therapy with
biguanides or thiazolidinediones. They reduce post-prandial hyperglycaemia
and, when used as monotherapy, do not usually cause hypoglycaemia.
Insulin is used in patients who present initially with very high blood glucose
levels, especially if associated with weight loss. It is also used in patients
who have failed to respond to oral therapy who have weight loss and/or
persistent hyperglycaemia. Some patients may be asymptomatic. Insulin
should be considered as first-line therapy in lean symptomatic subjects if
there is uncertainty about the diagnosis of diabetes type. Further details
regarding insulin usage appear on page 22. In addition, pages 23 and 24
discuss special situations where temporary insulin therapy may be required.
Biguanides, sulphonylureas, thiazolidinediones and α-glucosidase inhibitorsmay be used in combination as oral therapy, or with insulin when treatment
targets are not achieved with one agent alone, or when there are clinical
reasons for not using insulin. This regimen may also apply to children and
adolescents with type 2 diabetes. Combinations of small doses of each
drug may also be used to avoid the individual side-effects of each agent.
Treatment of type 2 diabetes must also address other
significant cardiovascular disease risk factors, such as
reductions in weight, serum lipids and blood pressure.
The evidence for this comes from recent landmark clinical
trials including the UKPDS, the Scandinavian Simvastatin
Survival Study (4S), the Micro-HOPE study and the
Coronary Artery Recurrent Events (CARE) study.
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