Combined therapy in diabetes

Diabetes, the fastest-growing disease in the UK, requires comprehensive management, says Dr Colin Kenny.

Type-2 diabetes is a disease of carbohydrate metabolism involving insulin resistance and eventual pancreatic beta-cell exhaustion.

It is characterised by a dual defect in insulin secretion and insulin action. While insulin resistance plays a major role in the accompanying metabolic syndrome, the defect in insulin secretion appears to be crucial for the development of hyperglycaemia.

A defect in first-phase insulin secretion is present very early in the natural history of the disease and is considered to play a crucial role in post-prandial hyperglycaemia.

Lifestyle changes

People diagnosed with type-2 diabetes should be encouraged to make lifestyle changes through education, including weight control and physical activity. The multi-disciplinary diabetes healthcare team may work to help patients to develop an individualised care plan that clearly defines treatment objectives and targets, including self monitoring of blood glucose, HbA1c, cholesterol, BP, weight control and smoking cessation.

This should involve a structured program of diabetes education at either a group or individual level and which respects cultural differences.

The healthcare team should be aware that people from Afro-Caribbean and Asian backgrounds tend to develop type-2 diabetes five years earlier than other populations and that the prevalence is at least five times higher in these communities.

There are several targets for HbA1c representing the heterogeneity of the disease and the population involved. The GMS contract has an HbA1c indicator of <7.4 per cent and NICE gives a target range of 6.5-7.5 per cent.

An HbA1c of 6.5 per cent should be the diabetes care gold standard and healthcare professionals should engage with people with diabetes to achieve this threshold.

Glycaemic control

In some patients, especially the elderly and those with associated co-morbidity, such tight glycaemic control may not be appropriate because of the risk of hypoglycaemia. Any reduction in HbA1c is beneficial to patients in terms of reducing the risk of vascular disease.

The effective management of people with diabetes should address both treatment of the diabetes and its complications, as well as examining cardiovascular risk.

The UKPDS study showed that a reduction in HbA1c of 0.9 per cent in the intensively treated arm led to a reduction of risk of 12 per cent for any diabetes-related end points and 25 per cent for microvascular end-points.

Type-2 diabetes has functional disturbances in the pancreas (beta-cell defect leading to impaired insulin secretion), liver (increased glucose production) and skeletal muscle (decreased glucose uptake).

There is a rationale for using combined therapy with pharmacological agents primarily acting in the pancreas (sulphonylureas), in the liver (metformin) and in the skeletal muscle (thiazolidinediones).

Combined therapy

Metformin should be first-line therapy in patients with type-2 diabetes, especially if they are overweight because this agent conferred cardiovascular benefit to patients in the UKPDS study.

Metformin should not be used in those with a serum creatinine over 130micromol/l. It is not able to maintain adequate glycaemic control over many years in most patients. The most common combined therapy, therefore, is that which supplements the action of metformin in the liver by stimulating insulin secretion.

Insulin secretagogues include sulphonylureas and the rapid acting insulin secretagogue repaglinide and nataglinide. These agents may be used in combination with metformin when levels of HbA1c become unsatisfactory.

They may be used as monotherapy when metformin is not tolerated. Both metformin and sulphonylureas, such as gliclazide, have additive antihyperglycaemic effects, without increasing the side-effects of either pharmacological class.

The available thiazolidinediones are rosiglitazone and pioglitazone. NICE guidance restricts their use to those unable to take other combinations or where HbA1c targets are not being met. The drugs have acquired a triple therapy license and may be used as monotherapy within restricted areas.

As beta-cell failure progresses with all oral therapies, exogenous insulin will be required to compensate for defective insulin secretion in many patients with type-2 diabetes.

Many patients continue to have weight loss or osmotic symptoms in spite of maximal oral hypoglycaemic therapy.

The most commonly used insulin regimens in the type-2 diabetes patients are the biphasic preparations that contain short and intermediate acting insulins. Patients and their carers need to be made aware of the risks of hypoglycaemia.


- Regular physical activity and weight loss improve glycaemic control in people with diabetes.

- Intensive blood glucose control reduces the microvascular complications of diabetes.

- Management should extend beyond blood glucose control to address cardiovascular risk factors.

- Diabetes is progressive and combination treatment should be considered early in the illness.

- Methods to improve patient compliance should be considered at all drug changes.

- Once-daily formulations are available for the sulphonylureas and metformin.

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