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Glitazones: tackling killers in diabetes

The National Institute for Clinical Excellence guidance on the use of glitazones is

out of date and GPs will have to use their own clinical judgment, says Dr Peter Stott

A few years ago type 2 diabetes was just a sugar disease. Today we recognise it as a syndrome of increased cardiovascular risk in which resistance to the effects of insulin produces a highly atherogenic patient profile. Attention has now shifted to the significant role the two insulin sensitisers ­ thiazolidinediones (TZDs), pioglitazone and rosiglitazone ­ can play not only in reversing the basic physiological defect but also in preventing the long-term complications of diabetes, CHD and stroke.

The atherogenic patient profile begins many years before formal diabetes develops. While insulin resistance is genetically inherited and can be identified in childhood, its pathological effects do not usually become significant until it is combined with obesity.

The combination of insulin resistance and obesity leads to hyperinsulinaemia resulting in dyslipidaemia and hypertension. Some individuals simply develop premature coronary artery disease. Others develop diabetes.

Insulin resistance can be reduced by weight loss and exercise. Where these lifestyle changes fail insulin sensitisers, metformin and the TZDs, have a role. While metformin reduces insulin resistance via a central effect, mostly via liver enzymes, TZDs have a peripheral action by facilitating insulin utilisation and glycogen deposition in muscle and fat.

In contrast insulin over-drivers sulphonylureas and insulin, can increase insulin resistance and thus paradoxically may increase the long-term risk of CHD.

The difference between the effects of insulin sensitisers and the insulin over-drivers is not just theoretical.

In the UK Prospective Diabetes Study (UKPDS)1 over 10 years, a reduction of HbA1c by 0.9 per cent with sulphonylureas or insulin was associated with a 12 per cent reduction in risk of any diabetes-related endpoint, a 10 per cent reduction in risk for any diabetes-related death and 6 per cent for all-cause mortality.

But therapy with the insulin sensitiser metformin had an even more pronounced effect2. With a mean reduction of HbA1c of only 0.6 per cent there was risk reduction of 32 per cent for any diabetes-related end-point, 42 per cent for a diabetes-related death, and a 36 per cent reduction in all-cause mortality. So it would seem that reduction of insulin resistance may have an effect quite distinct from that achieved by simple reduction of hyperglycaemia.

The two available members of the TZD family ­ pioglitazone (Actos) and rosiglitazone (Avandia) ­ differ pharmacologically only in subtle ways. They are both activators of membrane receptor systems (called PPARg), sensitising the receptors and making it easier for insulin to drive glucose into muscle and fat cells.

NICE guidelines

As recently as August, the National Institute for Clinical Excellence published new guidelines on the use of both TZDs in type 2 diabetes3. Although the guidelines replaced the institute's earlier guidance they only reaffirmed the use of the two TZDs as second-line agents for dual therapy in combination with metformin or sulphonylureas where there is a contraindication or intolerance to either of these alternative agents.

The very next week, the European Agency for the Evaluation of Medicinal Products announced a new licence for both products. The licence included the use of both TZDs as monotherapy where metformin was inappropriate and their use particularly for overweight patients. Since 15-20 per cent of patients are intolerant of metformin at adequate doses, this was a major change.

It remains uncertain why NICE chose to ignore the imminent change in product licence, especially since the monotherapy indication was widely known to all concerned. But the confusion has left UK clinicians poorly served, particularly since NICE does not intend to revise its guidance until 2006.

The monotherapy licence was based upon new data which showed the effect of the TZDs in reducing HbA1c and achieving a fasting plasma glucose equivalent to that of monotherapy with metformin or a sulphonylurea. Data also showed TZDs had an acceptable safety and tolerability profile. Oedema and weight gain are the main adverse effects of the TZDs; weight gain is a result of their effect upon peripheral glucose utilisation but is rarely more than 2kg.

More importantly, the TZDs have been shown to affect more than just glycaemia. Both drugs improve lipid profiles (cholesterol and triglycerides), reduce insulin resistance and even lower blood pressure.

These additional effects have only been demonstrated in relatively short-term (up to two-year) studies. But these measures are also surrogate markers for longer-term outcomes like stroke and myocardial infarction ­ the major killers in diabetes. Only longer-term studies will demonstrate whether this potential is achieved in practice.

Where this fits with the new contract

The new GP contract4 places major responsibility upon us to improve morbidity in diabetes through intensive management of hyperglycaemia, hyperlipidaemia and blood pressure.

The targets will not be easy to achieve. The highest level target is to achieve HbA1c 7.4 per cent or less and maximum payment if this target is achieved in 50 per cent of diabetic patients. No diabetes service that cares for a mixed population with type 2 diabetes has published figures in which more than 50 per cent have reached a HbA1c target of less than 7.5 per cent5.

But because they have such numerous effects the TZDs may help us in other ways. Their unique combination of effects upon hyperglycaemia, dyslipidaemia and blood pressure may assist us in achieving associated lipid and BP targets.

In the US, the TZDs are widely used as monotherapy, as combination oral therapy, and in combination with insulin. In the UK, perhaps because of cost considerations, the TZD have been mostly used in secondary care where, interestingly, the most common use is still off-licence as triple therapy. But their real potential will only be seen if they are used early in the disease process, before insulin resistance has resulted in cardiovascular damage.

NICE guidance now appears to have been superseded by events and UK clinicians will need to use their clinical judgment if patients are to achieve the potential benefits.

Certainly TZDs will be useful in dual therapy. They will be useful as monotherapy where metformin is inappropriate. The relative inclusion of overweight in the new product licence is helpful. But the benefits the TZDs have on surrogate markers for CHD are unique and may have significant benefits for prevention of CHD and stroke.

Is it reasonable to expect UK patients to wait 10 or 15 years until longer-term results are available? If I had diabetes and I was offered a TZD or a sulphonylurea, I know which I would choose.

New contract target standards in diabetes8

 · Top HbA1c target Ã7.4 per cent

 · Lower HbA1c target Ã10 per cent

 · Cholesterol Ã5.0mm/l

 · Systolic BP Ã145mmHg

 · Diastolic BP Ã85mmHg

 · Smoking status in the last 15 months

 · Retinal screening in the last 15 months

 · Record of peripheral pulses in the last 15 months

 · Record of neuropathy testing in the last 15 months

 · Record of microalbuminuria testing in the last 15 months

 · Record of serum creatinine in the last 15 months

 · Influenza vaccination in the preceding year


1 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53

2 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65

3 National Institute for Clinical

Excellence. Technology appraisal

guidance No 63, 2003

4 The NHS Confederation/BMA. New GMS Contract. February 2003

5 Winocour PH. Effective diabetes care:

a need for realistic targets.

BMJ 2002;324:1577-80

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