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Glycaemic intervention studies – the case for early and intensive therapy

The recommended targets for HbA1c in people with type 2 diabetes are less tight in the UK than the US or Europe. There is evidence that for each additional reduction in HbA1c of 1%, there is a significant reduction in risk of complications of diabetes. In his presentation, Cliff Bailey recommended more intensive therapy for people with type 2 diabetes.

This report is from a symposium that took place on 18 November 2006 at the Primary Care Diabetes Society conference in Birmingham. The event was sponsored by GlaxoSmithKline.

Treat the disease early, treat it intensively and try to reduce the HbA1c by an extra 1% are the three key points to remember when providing good care for people with type 2 diabetes. This is according to Professor Cliff Bailey, the Head of Diabetes Research and Professor of Clinical Science at Aston University, Birmingham.

HbA1c targets
There are different targets for HbA1c all around the world, he said, so which should we choose? In the UK, we probably have more targets than anywhere else. The favourite target in the world, and the one in use in Europe today, seems to be a HbA1c of about 6.5% (Nathan et al, 2006). There is a lot of published information about a target HbA1c of 7.0%, as this is what the US was working to until recently, although they seem to be moving towards a 6.5% target as well. Professor Bailey then suggested that the National Institute for Health and Clinical Excellence (NICE) target of up to 7.5% (NICE, 2002) is too high. Professor Bailey said there were sensible arguments for pursuing a lower HbA1c.

Reduce HbA1c more
Irrespective of how far you drop the HbA1c (i.e., from 9% to 8%, or 8% to 7%, or 7% to 6%), there is always a substantial reduction in deaths from diabetes, risk of heart attack and microvascular complications (Stratton et al, 2000). Professor Bailey suggested that in poorly motivated patients it would be beneficial to help them to understand these data. Over a 10-year period, a 1% reduction in HbA1c reduces risk of retinopathy by a third and peripheral vascular disease by about half (Stratton et al, 2000). ‘There is no lower threshold for HbA1c[below which we do not see extra benefit], we should aim for as close to normal as possible,’ said Professor Bailey.

Cardiovascular targets
This presentation focused on keeping glucose levels under control as this is the primary driver for microvascular disease, said Professor Bailey. At the same time, he said, we must bear in mind the components of metabolic syndrome which are cardiovascular risk factors. Generally speaking, we are good at achieving these cardiovascular targets. This is demonstrated by the 8-year STENO 2 trial in which the investigators attempted to deal with as many cardiovascular risk factors as possible. They were able to reduce the relative risk of cardiovascular disease by about 50  %. Large numbers of people in this trial reached targets for cholesterol, blood pressure and triglycerides. However, the big problem was HbA1c. Even with intensive therapy, few patients actually reached their target (Gaede et al, 2003).

Lower life expectancy
Diabetes UK has said that 1.8 million people in the UK have been diagnosed with diabetes and a further 0.8 million are unaware that they have the disease (Diabetes UK, 2004). The prevalence appears to be doubled in areas of the country where there are many people of Asian origin (DoH, 2005). This is very significant, suggested Professor Bailey, because the life expectancy of people with diabetes can be reduced by 10 years. Another indication of the significance of the problem is that 40 % of the people on the dialysis register have diabetes [mainly caused by diabetic nephropathy].

The risk of cardiovascular death increases with rising 2-hour post-glucose tolerance test results. In fact, when the result is within the range representing impaired glucose tolerance, the risk of cardiovascular death is almost as high as that for people with newly diagnosed type 2 diabetes (DECODE study group and the European Diabetes Epidemiology Group, 2003). It is important to recognise the increased risk of macrovascular disease which occurs in people with impaired glucose tolerance, said Professor Bailey. In reality, patients may have been experiencing a raised risk of complications for 10 years when diabetes is diagnosed (Diabetes UK, 2000). There is therefore no room to delay treatment when we spot the disease. The UK Prospective Diabetes Study (UKPDS) showed that over a third of people already have raised blood pressure at diagnosis (Turner et al, 1999).

In the US, one-third of people with diabetes are below the target of HbA1c at 7.0% (Saydah et al, 2004). Just under one-third of patients in Europe meet the target of 6.5% (Liebl et al, 2002). Even if we do not always reach the target with all our patients, at least if we are trying to reduce HbA1c further we are moving in the right direction, said Professor Bailey.

Progressive disease
Diabetes is a progressive disease. The UKPDS showed us that, irrespective of the agent used, there is still going to be a gradual increase in hyperglycaemia over time. The percentage of patients on monotherapy that achieve and maintain a target HbA1c of 7.0% 3 years after diagnosis is less than half, at 6 years it is only a third and by 9 years only about a quarter. Therefore, 75% of these patients should be on more than one therapy after 9 years (Turner at al, 1999). In other medical conditions, we routinely give more than one treatment to maintain people within target, but this is the evidence that in diabetes extra treatment should be given, said Professor Bailey.

More intensive treatment
Professor Bailey explained that current treatment practice often involves waiting until the HbA1c has risen above the target before more therapies are added. He suggested a more intensive approach to treatment whereby additional therapy should be started before the HbA1c rises to the target level, so that the person is always able to stay within range. Referring to his earlier comments, he reminded participants that reducing average HbA1c by just 1% can be of significant benefit over time to people with diabetes.


DECODE Study Group, European Diabetes Epidemiology Group. (2003) Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 26: 688–96
DoH (2005) Health Survey for England 2004. Updating of trend tables to include 2004 data. Department of Health, London
Diabetes UK (2000) Diabetes update, winter 2000. Diabetes UK, London
Diabetes UK (2004) Diabetes update, winter 2004. Diabetes UK, London
Gaede P, Vedel P, Larsen N et al (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. New England Journal of Medicine 348: 383–93
Liebl A, Mata M, Eschwege E, ODE-2 Advisory Board (2002) Evaluation of risk factors for development of complications in Type II diabetes in Europe. Diabetologia 45: S23–8
Nathan DM, Buse JB, Davidson MB et al (2006) Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 49: 1711–21
NICE (2002) Inherited clinical guideline G. Management of type 2 diabetes. NICE, London
Saydah SH, Fradkin J, Cowie CC (2004) Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. Journal of the American Medical Association 291: 335–42
Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405–12
Turner RC, Cull CA, Frighi V, Holman RR (1999) Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group Journal of the American Medical Association 281: 2005–12

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