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Independents' Day

Ten tips on using incretin drugs for type 2 diabetes

GP and committee member of the Primary Care Diabetes Society Dr Colin Kenny gives his pointers to using the newest treatments for type 2 diabetes

GP and committee member of the Primary Care Diabetes Society Dr Colin Kenny gives his pointers to using the newest treatments for type 2 diabetes

1. The incretin drugs act in a totally novel way. The incretin effect was first described in 1964. It is a protective effect and refers to the hormones produced by the GI tract in response to eating, which then stimulate insulin secretion in a glucose-dependent manner.

This means that when the body's insulin response to oral and intravenous glucose loads is compared, an enhanced response is seen with oral glucose.

2. Two therapeutic approaches have been adopted to exploit this effect. One group of incretin drugs – the incretin mimetics – copy the effect of the glucagon-like peptide 1(GLP-1) hormone that mediates the incretin effect. The second way of exploiting this effect is the dipeptidyl peptidase – IV (DPP-IV) inhibitors (also called gliptins) which work by blocking DPP-IV mediated inactivation of GLP-1.

3. The first incretin mimetic available in the UK was exenatide (Byetta), a GLP-1 analogue. Exenatide slows gastric emptying and promotes satiety centrally.

These mechanisms of action are associated with diminished calorie intake and subsequent weight loss. Severe hypoglycaemia is not commonly seen unless it is used in combination with a sulphonylurea.

4. Exenatide is administered as a twice-daily subcutaneous injection. The starting dose is 5µg bd, increasing to 10µg bd to gain maximal therapeutic effect. Several other longer-acting incretin mimetics are in the pipeline, including a once-weekly formulation of exenatide and another once-daily mimetic, liraglutide. These are being submitted to the European Medicines Agency for review. Other incretin mimetics (taspoglutide, albiglutide, AVE-10010) are now entering phase three clinical trials.

5. Exenatide may need to be injected – like insulin – but there is no dose titration beyond getting patients to the therapeutic dose of 10µg bd. Also glucose self-monitoring is not required with the GLP-1s – whether used alone or with metformin – unless there is another indication for doing so.

6. DPP-IV inhibitors prolong the action of endogenous GLP-1, allowing higher plasma levels of the hormone, and affect other peptides within the body. Sitagliptin was the first of this type of agent launched in the UK. It has been shown to be safe with sulphonylureas and has an enhanced effect with metformin. Vildagliptin has been launched recently and has similar effects and actions. Saxagliptin and alogliptin are in phase three trials.

7. NICE recommends that the current two available gliptins be used in combination with metformin where sulphonylureas are unsuitable for defined reasons or when metformin is not tolerated. This guidance was released as a supplement to NICE's 2008 type 2 diabetes guidance. The institute has also recently published draft guidance for consultation on the use of these new agents. Exenatide is only recommended by NICE for patients who have been tried on metformin and sulphonylureas and who have a BMI greater than 35.

8. Concerns about the safety of thiazoladinediones may make the DPP-IVs an acceptable alternative after metformin and sulphonylureas. The recent NICE guidance places these agents in context for primary care teams. Many are now initiating insulin in the community and this may enhance their confidence in initiating the injectable GLP-1s, as little dose titration is needed.

9. The principal concern about the GLP-1 agents is the small reported incidence of pancreatitis with exenatide. But when compared with long-acting insulin analogues they appear to offer much more weight loss than these agents, although this does come at the cost of some nausea, which usually settles with time.

10. GPs are aware that they prescribe from quite a restricted range of products for those with type 2 diabetes. But when the NICE guidance is eventually published next year, I'm sure it will enhance confidence in these agents, which act in distinct ways to exploit the therapeutic usefulness of the incretin effect.

Dr Colin Kenny is a member of the steering group of the Primary Care Diabetes Society and a GP in Dromore, County Down

Competing interests: Dr Kenny has given independent professional advice to Eli Lilly, Novo Nordisk and MSD


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