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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 Sulphonylureas
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
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
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. Thiazolidinediones
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 Glinides
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.
Combination therapy
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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