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Issue No 41 September 2009        

Interaction between clopidogrel and PPIs

HbA1c reporting in different units

NICE updates guidance on management of type 2 diabetes

Insulin glargine and possible cancer link

Interaction between clopidogrel and PPIs

Concomitant use of a proton pump inhibitor (PPI) with clopidogrel should be avoided unless considered essential. This is due to concerns that PPIs may reduce the effectiveness of clopidogrel.^1,2

Action
In the UK, the MHRA has issued the following advice:²

This new advice presents an opportunity to review people on clopidogrel and a PPI. Healthcare professionals should consider stopping either the clopidogrel, if it is being used outside NICE guidance (see below) or beyond the recommended period, or stopping the PPI, or stopping both, unless considered essential. If the original reason for using clopidogrel was due to GI intolerance on aspirin alone, switching to aspirin plus a PPI would seem a reasonable approach. For patients who need to continue taking clopidogrel and also require gastroprotection, there is currently insufficient evidence to recommend H2-receptor antagonists (H2RAs) or other GI therapies as alternatives to PPIs.³

What is the background to this?
Clopidogrel can cause GI symptoms and is associated with an increased risk of GI bleeding. It is, therefore, frequently prescribed with a PPI.² The EMEA’s Committee for Medicinal products for Human Use (CHMP) has concluded, mainly on the basis of observational studies, that a significant interaction might occur when clopidogrel and a PPI are taken together.¹ The consequence of this is that, while some protection against cardiovascular (CV) thrombotic events (e.g. myocardial infarction [MI]) is provided by the combination of clopidogrel plus a PPI, it appears that this may be slightly less than that provided when clopidogrel is taken without a PPI.

Neither the EMEA statement¹ nor recently updated information from the US Food and Drug Administration (FDA)⁴ makes reference to any individual PPI being any more or less likely to interact with clopidogrel than any other. The outcome studies do not fully reflect the known pharmacokinetics of PPIs so there may be more than one explanation for this apparent effect on clopidogrel. More evidence is required before any specific recommendations can be made on the risk associated with individual PPIs.² Although, on the basis of pharmacokinetic data, H2RAs (except cimetidine) and antacids would not be expected to interact with clopidogrel, there are currently no substantial data from outcome studies to support this.² The CHMP has recommended that product information for all clopidogrel-containing medicines should be amended to discourage concomitant use of a PPI and clopidogrel unless absolutely necessary.¹

What does NICE say?
NICE guidance on the use of clopidogrel in non-ST elevation acute coronary syndrome⁵ (ACS) recommends clopidogrel, in combination with low-dose aspirin, in patients who have non-ST elevation ACS who are at moderate to high risk of MI or death. The guidance defines this group on the basis of clinical signs and symptoms with ECG changes and/or raised cardiac markers.

NICE guidance on clopidogrel in the prevention of occlusive vascular events,⁶ which applies to patients who have had an occlusive vascular event or have symptomatic peripheral arterial disease, recommends clopidogrel alone only for those who are intolerant of low-dose aspirin. Aspirin intolerance is defined as proven hypersensitivity to aspirin-containing medicines or a history of severe dyspepsia induced by low-dose aspirin.

For more details see MeReC Stop Press Blog Nos. 271, 354, and 372. Further information on the use of clopidogrel is available on the cardiovascular floors of NPCi.

References

1. EMEA. Public statement on possible interaction between clopidogrel and proton pump inhibitors. 29th May 2009
2. MHRA. Drug Safety Update 2009;2(12):2–3
3. MHRA. Interactions between the use of clopidogrel and proton pump inhibitors. Questions and answers for patients. 7th July 2009
4. FDA. Early Communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). 13th May 2009
5. NICE. Technology appraisal 80. Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. July 2004
6. NICE. Technology appraisal 90. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. May 2005

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HbA1c reporting in different units

The Department of Health has announced¹ that from 1st June 2009, glycated haemoglobin (HbA1c) will be measured in millimoles per mole (mmol/mol) as well as by percentage (%) in all people with diabetes. Measurements will be reported in both ways until 31st May 2011 and only in mmol/mol thereafter.

This change will standardise the reporting of HbA1c results between laboratories throughout the UK and worldwide. The Diabetes UK website (www.diabetes.org.uk) has some useful information about the change, including an online converter and leaflets for health professionals, for patients, and for laboratory staff, which includes a table of some common values. More information on the management of people with type 1 diabetes and type 2 diabetes can be found on the relevant floors of NPCi.

References

1. Department of Health. News release. Change in measurement of HBA1C for people with diabetes. 29th May 2009

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NICE updates guidance on management of type 2 diabetes

NICE clinical guideline (CG87)¹ partially updates recommendations for the management of type 2 diabetes, with new recommendations on blood glucose control with sitagliptin▼, vildagliptin▼, pioglitazone▼, rosiglitazone, exenatide▼ and insulin therapy. This updates and replaces CG66.²

What has changed?
Most of CG66 remains unchanged. Only the sections on the use of newer drugs to control blood glucose (sitagliptin▼, vildagliptin▼, pioglitazone▼, rosiglitazone, exenatide▼) and insulin therapy have new recommendations. The same level of HbA1c is advocated, above which the addition of extra glucose-lowering drugs are appropriate, as defined in the earlier guideline. That is a value of >6.5% (48 mmol/mol), or other higher level agreed with the individual, for people on one glucose-lowering drug and >7.5% (59 mmol/mol), or other higher level agreed with the individual, for people on two or more glucose-lowering drugs or insulin (see previous article for details on new reporting of HbA1c). The role of tight glycaemic control in type 2 diabetes remains controversial (see previous MeReC Blogs) and most patients may benefit most from interventions to reduce CV risk (e.g. smoking cessation, eating healthily, increasing exercise, lowering blood pressure and lowering cholesterol). The new recommendations are discussed in more detail in MeReC Stop Press Blog No. 355, and the quick reference guide³ contains a helpful updated algorithm for blood-glucose lowering therapy.

References

1. NICE. Clinical guideline 87. Type 2 diabetes. May 2009
2. NICE. Clinical guideline 66. Type 2 diabetes. May 2008
3. NICE. Quick reference guide. Clinical guideline 87. Type 2 diabetes. May 2009

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Insulin glargine and possible cancer link

Following an initial observational study signaling a possible association between the long-acting human insulin analogue, insulin glargine (Lantus®) and an increased risk of developing cancer, a series of papers has been published.¹ The results of these observational studies are inconsistent and due to methodological limitations, can neither confirm nor exclude a relationship between insulin glargine and cancer. However, the CHMP has asked the manufacturer of insulin glargine to develop a strategy for further research in this area.²

Action
The EMEA has advised² that no changes to prescribing advice are necessary at present, and patients being treated with insulin glargine can continue their treatment (in accordance with NICE guidance on type 1³ and type 2 diabetes⁴).

NICE does not recommend that insulin analogues are used routinely, but in specific patient circumstances. However, prescribing data for England shows that insulin glargine and insulin detemir are now prescribed extensively. Based on figures for the quarter from October to December 2008, about 1.2 million items of insulin glargine and 400,000 items of insulin detemir are prescribed annually. This equates to approximately 40% of all intermediate/long-acting insulin items. Whether or not a link between an increased risk of cancer and insulin glargine is established, given that the costs per Quality Adjusted Life Year (QALY) are so large for these analogue insulins, prescribers and prescribing managers may wish to review if their use is in line with NICE guidance. See MeReC Rapid Review Blog No. 374, for more details.

References

1. Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia DOI 10.1007/s00125–009–1441–5
2. EMEA. Press release: European Medicines Agency update on safety of insulin glargine. 23rd July 2009
3. NICE. Clinical guideline 15. Type 1 diabetes. July 2004 (Update June 2009)
4. NICE. Clinical guideline 87. Type 2 diabetes. May 2009
5. NHS Business Services Authority. Personal Communication. July 2009

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The National Institute for Health and Clinical Excellence (NICE) is associated with MeReC Publications published by the NPC through a funding contract. This arrangement provides NICE with the ability to secure value for money in the use of NHS funds invested in its work and enables it to influence topic selection, methodology and dissemination practice. NICE considers the work of this organisation to be of value to the NHS in England and Wales and recommends that it be used to inform decisions on service organisation and delivery. This publication represents the views of the authors and not necessarily those of the Institute.

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