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The need for early combination therapy

Good glucose control reduces the risk of the microvascular complications of diabetes, but when should combination therapy be introduced to help achieve target HBA1c levels? Dr Miles Fisher discusses the key issues and the evidence base for treating type 2 diabetes as part of the Diabetes Initiative - Take Control

Diabetes is a serious, chronic disease that causes significant morbidity and mortality. It is the commonest cause of preventable blindness in people aged under 65 and is the single commonest reason for people requiring end-stage renal replacement therapy. As the population eats more and exercises less, more people develop central obesity, insulin resistance, and type 2 diabetes.

People with type 2 diabetes are at a high risk of developing premature cardiovascular disease and diabetes can be considered as 'a state of premature cardiovascular death which is associated with chronic hyperglycaemia and may also be associated with blindness and renal failure'1. Many patients do not survive long enough to develop retinopathy or nephropathy.

Evidence base for treating type 2 diabetes

The existing evidence base for treating type 2 diabetes is surprisingly small and consists principally of the many publications from the United Kingdom Prospective Diabetes Study (UKPDS). Designed in the 1970s, and following a complex study design, the UKPDS was set up to determine whether improved control of type 2 diabetes would prevent complications of diabetes and whether therapy with sulphonylureas, insulin or metformin had any specific advantage or disadvantage.

The principal results of the UKPDS are well known; intensive control with either insulin or sulphonylurea was better than conventional control in reducing the development of microvascular complications (especially retinopathy), and although there was a reduction in myocardial infarctions this did not reach statistical significance2. In overweight patients metformin seemed to convey additional benefit, microvascular complications were reduced, myocardial infarctions were significantly reduced, and there was a significant reduction in diabetes-related deaths3.

Several very useful observational studies have been published from the UKPDS as well as a detailed epidemiological analysis. In the conventional control group, where there was little intervention, the HbA1c rose by nearly 2 per cent during the study, indicating that the natural history of type 2 diabetes is of worsening ?-cell function, so that diabetes does indeed get worse with time.

In the intervention group there was an initial fall in HbA1c with intensive control, but thereafter the HbA1c also rose despite treatment with metformin, sulphonylureas or insulin2,3. Intensive treatment with insulin or a sulphonylurea reduced median HbA1c from 6.9 per cent to 6.1 per cent after one year of the study, but this subsequently increased to 7.1 per cent over the next five years.

Hypoglycaemia limited any further increases in treatment that were contemplated. Similarly, HbA1c fell from 6.9 per cent to 6.4 per cent after one year in obese patients treated intensively with metformin, but increased to 7.4 per cent in the next five years4.

Thus, only 50 per cent of patients on monotherapy with sulphonylurea could achieve HbA1c below 7 per cent by three years after randomisation, and this declined to 24 per cent by nine years5.

In the group of overweight patients receiving metformin, less than half (44 per cent) could achieve HbA1c below 7 per cent by three years, and this reduced to 18 per cent by nine years. In the UKPDS this necessitated the early introduction of combination therapy, which offered better glucose control over the subsequent years than monotherapy6.

Standards of the diabetes NSF

The NSF indicates that optimising the control of blood glucose and reducing cardiovascular risk factors will lead to improved outcomes7. In particular, improving blood glucose control reduces the risk of developing microvascular complications of diabetes, and may reduce the risk of people with diabetes developing cardiovascular disease.

This will require the early introduction of oral hypoglycaemic agents with a target HbA1c of less than 7 per cent. For overweight patients, and also in patients who are not overweight, the drug of first choice based on the results of UKPDS is metformin. Unfortunately, three-quarters of patients on oral hypoglycaemic therapy in the UK do not have good glycaemic contro · 8. There is therefore an urgent need for early combination therapy, and for additional therapy to tackle other cardiovascular risk factors, including therapy with hypotensive agents, statins, ACE inhibitors and anti-platelet agents.

Until recently the second-line agent for overweight patients was sulphonylureas, with potential side-effects of hypoglycaemia and weight gain. The insulin sensitisers (glitazones) offer a suitable alternative for early combination therapy. Recent studies have demonstrated that insulin sensitisers improve several conventional and novel cardiovascular risk factors, including reductions in blood pressure, micralbuminuria and C-reactive protein, with increases in HDL cholesterol.

What does the

future hold?

Several studies with cardiovascular endpoints are currently under way using newer treatments for hyperglycaemia, including the glitazones, to see if improvements in insulin sensitivity may improve outcomes in type 2 diabetes, and the results of these studies will be available in the next few years.

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