NPC Archive Item: Incretin-based therapies in type 2 diabetes

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24th February 2009

Madsbad S. Treatment of type 2 diabetes with incretin-based therapies. The Lancet 2009; 373:438-39

Incretin-based therapies may offer a new option in the treatment of type 2 diabetes. However, as with many new therapies in this area, their role remains to be clarified by long-term trials measuring cardiovascular endpoints.

Area Prescribing Committees may wish to prepare for the publication of the NICE clinical guideline on newer agents in type 2 diabetes mellitus (T2DM), anticipated in March 2009. This will cover the role of the ‘gliptins’ and one of the incretin- based therapies, exenatide▼.  Liraglutide may be licensed in 2009 and therefore may also require local consideration and planning.

What is the background to this?
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that, in the presence of glucose, stimulates insulin and suppresses glucagon secretion. Native GLP-1 is rapidly degraded in the body by the enzyme, dipeptidyl peptidase-4 (DDP-4) and DDP-4-resistant analogues have been developed. One such, exenatide▼ (Byetta ®), is already on the market. The EMEA is currently reviewing data from the LEAD series of trials for another GLP-1 analogue, liraglutide. Details of the LEAD 2 study can be found in a previous rapid review.

The LEAD 3 mono trial has just been published. This double-blind, randomised trial of 746 patients with early type 2 diabetes compared liraglutide 1.2 or 1.8mg monotherapy with glimepiride 8mg monotherapy. After one year, liraglutide was more effective than glimepiride on the surrogate outcome of HbA1c. More details can be found in an earlier rapid review. An “On the Horizon” bulletin is available about liraglutide (NHSnet connection required).

Liraglutide is given once daily by subcutaneous (s/c) injection whereas exenatide is given twice daily s/c, although a long-acting formulation is in development. The levels of endogenously released GLP-1 can be increased by using oral inhibitors of DDP-4 such as vildagliptin▼ ( Galvus ®, Eucreas ®) and sitagliptin▼ (Januvia ®).

GLP-1 analogues are associated with gastro-intestinal adverse effects, such as nausea, vomiting and diarrhoea. Pancreatitis has been reported with both exenatide▼ and liraglutide (two cases in LEAD 3, one in LEAD 2). Due to their mode of action, the risk of major hypoglycaemia is low. Unlike many commonly used anti-diabetic medicines, GLP-1 analogues tend to lead to weight loss (in the region of 2.0 to 2.5kg in the LEAD-3 mono trial).

So what?
The role of incretin-based products in the management of T2DM remains to be clarified. No data are available on the impact of these agents on cardiovascular endpoints.

Most studies have been of short duration (<30 weeks) and long-term data on the durability of weight loss and the adverse effect profile is required, also. The NICE clinical guideline on T2DM includes a minor role for exenatide▼ and further information is expected in the guideline on newer agents anticipated in March 2009 (although liraglutide will not be part of this due to the fact that it is not licensed). Information on the management of diabetes is available on the cardiovascular section of NPC.

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