The use of glitazones in diabetes

Viewpoint: There has been much discussion over the use of glitazones in diabetes. Dr Mark O'Mahony and Dr Azhar Farooqi offer both sides of the debate.

FOR: The glitazones need to stay by Dr Mark O'Mahony

We started using glitazones five years ago, in the drive to get a greater proportion of our patients with type-2 diabetes to an HbA1c target of less than 7.5 per cent.

Half of our type-2 diabetes patients take glitazones, almost all as metformin-glitazone combination products. Half of our patients have an HbA1c less than 6.5 per cent, and about 70 per cent have an HbA1c less than 7.5 per cent.

We have seen calls from some GPs for glitazones to be withdrawn (GP, 19 October). For those who have not used glitazones, or are anxious about starting them, this may need some explanation.

Combination therapy
Insulin resistance and the metabolic syndrome are the drivers behind type-2 diabetes. It follows that insulin sensitisers are the logical agents to combat this.

 

The UK prospective diabetes study (UKPDS) made clear that monotherapy with any agent, including metformin, failed within a few years and progression to combination therapy was inevitable.

The combination of metformin and glitazone provides a powerful way to reduce HbA1c, with little risk of symptomatic hypoglycaemia. This means that patients can get on with their lives with little need for self-monitoring and little fear that dieting or exercise will provoke hypoglycaemia.

The alternative to glitazone use is to add in a sulphonylurea. This puts the patient at greater risk of hypoglycaemia, and means they will need to have access to, and training in, self-monitoring of blood glucose. The sulphonylurea route is short-lived and if one is aiming for tight glycaemic targets, within a few years, patients will need to convert to insulin.

Consultation on insulin
In our PCT, we were one of the first practices to train up to deliver primary care conversion to insulin.

 

A bonus of using glitazones is that the need for insulin conversion in patients with type-2 diabetes is reduced by about a half - evidence supporting the theory that glitazones help conserve pancreatic function. We have found that our insulin conversion rates (and substantial associated costs) are much lower than in practices where the glitazones are not used.

There are two areas of controversy that have had much publicity this year, and they relate to the separate issues of heart failure and MI.

Heart failure
Glitazones have always been known to cause fluid retention, and it has always been prominent on the product information that glitazones were contraindicated in heart failure. It should therefore come as no surprise that about one in 50 patients will need to have their glitazone withdrawn due to fluid retention, but it should be made clear that myocardial muscle is not impaired by glitazones and ejection fraction is not reduced.

 

The fluid retention of glitazones is not associated with increased mortality, and is quickly reversed by withdrawing the glitazone, or may be countered by use of diuretics.

In this respect, I have no fear of using glitazones, and suggest the situation is analogous to the use of beta-blockers causing asthma, ACE inhibitors causing a rise in creatinine or diuretics causing gout.

If we evaluate the patient properly, counsel them well, and monitor them carefully, we can use these drugs sensibly, and if side-effects arise, withdraw the drugs accordingly. Of course the great majority of our patients will have none of these side-effects.

Myocardial infarction
It was with dismay that I first saw the headlines suggesting rosiglitazone caused a substantial increase in MI and deaths. This gave way to disappointment that the New England Journal of Medicine could have published such a flawed paper.

 

Briefly, a strange mix of ill-matched rosiglitazone trials were fed into unsophisticated meta-analysis software, with some bizarre omissions and inclusions, producing results that ran counter to those found in some large randomised controlled trials.

Balance has been restored by a more rigorous and statistically sound review in the Annals of Internal Medicine. This has shown, when properly analysed, there is statistically no increased risk of MI or death with rosiglitazone.

Furthermore, the regulatory authorities have examined this data, and apart from beefing up the warnings about heart failure and IHD, have not moved against the glitazones.

Indeed the European Medicines Agency (EMEA) stated in October 2007: 'the benefits of these antidiabetic medicines continue to outweigh their risks in the approved indications.'

Conclusion
Diabetes is a challenging disorder, requiring many interventions, behavioural and pharmaceutical. The draft NICE guidelines for type-2 diabetes recommend the use of glitazones in the treatment of type-2 diabetes. They propose a general HbA1c target of 6.5 per cent.

 

It would be hard to achieve this target without the use of glitazones. We should not let ignorance and misinformation cause us to be too hasty.

Dr O'Mahony is GP in Avon

Declaration of interests:
I have received a number of speaker fees from Takeda, GSK, Sanofi, MSD, and other diabetes-related pharmaceutical firms, and have been to the International Diabetes Federation and European Association for the Study of Diabetes conferences, sponsored by Takeda.

AGAINST: Glitazones: useful only as third-line therapy

 

Achieving good glycaemic control helps reduce complications of diabetes and is a key aim of management. We now have a range of interventions that we can use to help patients achieve HbA1c targets.

What is important is that for each patient we are confident that the balance of potential benefit versus harm for any treatment is a positive one.

Increasing research data means we need to review carefully the use of glitazones for patients with type-2 diabetes.

The issues we need to consider to determine the place of glitazones include efficacy in achieving glycaemic control; the likelihood of other effects, either potentially beneficial or harmful to our patients, and ensuring treatment choices are cost-effective.

Glycaemic control
It is clear that older agents such as metformin and the sulphonylureas are as effective in reducing HbA1c as the glitazones.

 

The side-effect and safety profile of older agents is better established, and they cost less than 10 per cent of the price of the glitazones. These are the reasons NICE recommends metformin/sulphonylurea as first and second line, with glitazones as potential third-line agents.

According to Glaxo-SmithKline's A Diabetes Outcome Progression Trial (ADOPT) study, a possible advantage appears to be better durability of glycaemic control with rosiglitazone compared with other single agents. No equivalent study exists for pioglitazone.

ADOPT results do not demonstrate that rosiglitazone (at £50 per month) preserves glycaemic control better than metformin/sulphonylurea in combination (at less than £10 per month).

Cardiovascular risk
One may debate the validity of Nissen and Wolksi's meta-analysis (which showed a 40 per cent excess risk of MI with rosiglitazone); however, the fact remains that the FDA and the EMEA have issued alerts based on these data.

 

Nissen's analysis, together with GSK's data and a further meta-analysis by Ptsaty means the concept of rosiglitazone as a cardioprotective drug is not sustainable.

As far as pioglitazone is concerned, it did not achieve its primary endpoint of reduction of cardiovascular disease mortality in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE study).

Metformin remains the only oral hypoglycaemic agent with proven cardiovascular benefits.

What is beyond dispute is the doubling of risk of heart failure with glitazones compared with the older agents.

Heart failure is not an insignificant condition, but a potentially terminal disease. The fact that a meta-analysis shows glitazone-induced heart failure appears not to result in increased death at two years is hardly reassuring - what about at five or 10 years?

Both US and European licences warn against prescribing glitazones in heart failure.

Given that many of our patients are middle-aged arteriopaths, obese and often breathless on exercise, can we be sure they do not have actual or insipient heart failure?

We must think twice in case our actions increase the risk of heart failure or MI.

Other adverse outcomes
There are other concerns with glitazones. Osteoporosis and risk of fractures is a real concern; preliminary data in ADOPT and other studies suggest significant loss of bone density in patients and double the risk of bone fractures in women. This is only after a few years of glitazone use; what will the situation be after 20 years? The worrying position is that we simply do not know.

 

Weight gain is another problem in these patients, and is a worry in terms of longer term impact on both diabetes and cardiovascular risk.

Conclusion
Diabetes is a challenging disorder that requires many interventions. If we correctly use NICE guidance by promoting patient education and making optimal use of metformin, sulphonylurea and, where needed insulin, we will ensure more of our patients achieve HbA1c targets.

 

Glitazones have a role as a third-choice agent, particularly if insulin is not suitable. This means they will continue to be prescribed for some patients - the physician's role is to choose such patients carefully.

Dr Farooqi is a GP in Leicester

Declaration of interests:
I have sat on advisory boards for GSK and Takeda in the past. I look after people with diabetes.

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