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Glitazones are a worthwhile use of NHS money

I read with interest a news article in last week's issue of Pulse and would like to respond with our experience of glitazones.

Most oral antidiabetes agents are initially able to lower HbA1c in the order of 1-2% as monotherapy and the glitazones are no exception.

Given its efficacy, long-term outcome data, and cost-effectiveness, metformin remains first-line therapy for most patients with type 2 diabetes.

However, there are many patients who are unable to take metformin or a sulphonylurea because of contraindications or tolerability problems.

In addition, as recommended by NICE in their draft Type 2 Diabetes (Update), patients with hallmarks of the metabolic syndrome may be suitable candidates for earlier therapy with a glitazone because of beneficial effects on the diabetes lipid profile.

Further evidence supporting earlier treatment with glitazones comes from the ADOPT trial, in which rosiglitazone was more effective than metformin or glyburide in delaying the progressive loss of glycaemic control at five years.

Any agent that can expand the treatment options for type 2 diabetes is therefore of value for our patients.

The glitazones have a unique mode of action. Whereas metformin reduces insulin resistance in the liver and thereby decreases hepatic glucose production, the glitazones act by stimulating insulin action in peripheral tissues.

This complementary mode of action means that glitazones are most often used in combination with other oral agents to provide enhanced glycaemic control.

I disagree with the quote in the Pulse article that 'evidence for their use in triple therapy is also weak'. In our experience many patients prefer to try a third oral agent before going on to insulin, frequently with success.

This is supported by clinical study data.

It is important to keep in mind that the heart failure risks associated with glitazones in general are separate from concerns over the potential increased MI risk associated with rosiglitazone. Outside of this contraindication, the glitazones still have a valuable place in therapy.

As mentioned in the Pulse article, the European Medicines Agency reviewed the available information on the benefits and risks of rosiglitazone and pioglitazone in October 2007 and concluded that both medicines' benefits continue to outweigh their risks, although it recommended that patients with ischaemic heart disease should only be prescribed rosiglitazone after careful evaluation of their individual risk.

Type 2 diabetes is associated with increased cardiovascular risk and there is now considerable evidence to support the benefits of pioglitazone on cardiovascular outcomes independent of glycaemic control.

In addition to favourable effects on surrogate markers of cardiovascular disease such as lipid profiles, urinary albumin excretion and carotid intima media thickness, the recently published data from the PERISCOPE trial, demonstrate a significant reduction in atheroma volume for pioglitazone compared with glimepiride.

Pioglitazone is also the only antidiabetes agent other than metformin to have documented evidence for a reduction in cardiovascular outcomes.

Based on the available evidence and the recommendations from the European Medicines Agency, my local PCTs recommend that when a glitazone is newly prescribed it should be pioglitazone and that patients on rosiglitazone with evidence of cardiovascular disease should be switched to pioglitazone.

It is left to the discretion of clinicians whether to continue with rosiglitazone where there is no evidence of cardiovascular disease. This policy is likely to continue until more rosiglitazone data is available.

Professor Anthony Barnett, Professor of Medicine, University of Birmingham

Type 2 diabetes is a chronic, progressive disease which costs the NHS large amounts of money, mostly on the treatment of complications. The current treatment paradigm for hyperglycaemia in the UK consists of lifestyle changes, monotherapy with an oral antidiabetic agent, combination therapy with two oral antidiabetic agents, then triple therapy, which may comprise three oral agents, or two agents combined with insulin or exenatide.

The recent news article concerning NHS expenditure on glitazones contains several potentially misleading statements that may confuse the reader. It refers to a review in April's Drug and Therapeutics Bulletin which specifically looked at the use of glitazones for monotherapy and triple therapy, acknowledging that evidence already supports the use of glitazones in dual combination with metformin or sulphonylureas1.

When reviewing any drug important considerations include efficacy, safety and cost. The review concluded that pioglitazone and rosiglitazone were equally effective in reducing HbA1c as other oral antidiabetic agents when used as monotherapy, and equally effective as insulin when added as triple therapy to the combination of metformin and sulphonylurea1.

When considering cost there is an obvious difficulty in the area of diabetes management that does not affect other disease areas such as hypertension, where many successful drugs have been introduced to the market over the years.

Insulin, metformin, and sulphonylureas are very old drugs and there have been few if any successful new drugs for diabetes over a 30-year period, so any new therapy is going to be more costly that the older therapies.

That is the explanation why half of the expenditure on oral anti-diabetic drugs is on glitazones, which represent much less than half of the prescriptions. Generic metformin and sulphonylureas are cheap.

It would be perverse if diabetic patients were denied new treatments because of the lack of diabetes drug development in the past. As an example, the review recommends glitazones are reserved as triple therapy for patients in whom insulin is contraindicated or likely to be poorly tolerated, presumably on the basis of equal effectiveness and lower cost of insulin1. This takes no account of the obvious complexities of starting insulin, the resistance to the use of injections by patients and healthcare professionals, or patient preference!

In reality in the UK glitazones are frequently used as triple therapy as an alternative to injections.

With regards to safety the review in the Drug and Therapeutics Bulletin was careful to point out differences between pioglitazone, which in the PROactive study and meta-analysis reduced cardiovascular events2,3, and rosiglitazone, which on meta-analysis has been shown to slightly increase acute cardiac events4,5. This is supported by the results of the recent PERISCOPE study which showed that pioglitazone significantly reduced the rate of progression of coronary atherosclerosis compared to the sulphonylurea glimepiride6.

It should be remembered that only other diabetes treatment proven to reduce acute cardiac events in patients with type 2 diabetes is metformin in the United Kingdom Prospective Diabetes Study7, so pioglitazone remains an evidence-based therapy to reduce vascular events in a diabetic patient with diagnosed vascular disease who is not controlled on metformin monotherapy, or the combination of metformin and a sulphonylurea.

Indeed, the safety and efficacy of pioglitazone combined with insulin in the PROactive study were responsible for it receiving a licence for use in combination with insulin in patients with type 2 diabetes.

Miles Fisher, Consultant Diabetologist,Glasgow Royal Infirmary.

1. Anonymous. Glitazones in type 2 diabetes: an update. Drug and Therapeutics Bulletin 2008;46;25-9.

2. Dormandy JA, Charbonnel B, Eckland DJA et al on behalf of the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.

3. Lincoff AM, Wolski K, Nicholls SJ et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298: 1180-8.

4. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, 2457-71.

5. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone. A meta-analysis. JAMA 2007;298;1189-95.

6. Nissen SE, Nicholls SJ, Wolski K et al for the PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes. The PERISCOPE randmized controlled trial. JAMA 2008; 299:1561-73.

7. 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.

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