DPP-4 inhibitors and GLP-1 analogues: for whom? Which place for incretins in the management of type 2 diabetic patients?

This review tries to delineate how to insert the GLP-1 based agents, DPP4-inhibitors (sitagliptin and vildagliptin) and GLP-1 analogues (exenatide and liraglutide), in the guidelines and the daily practice for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors reduce HbA(1c) by 0.5-1.1%, without hypoglycaemic events and no weight gain. The subcutaneous injected GLP-1 analogues show larger reductions in HbA(1c) by 0.8-1.7% and a weight loss (1.75-3.8 kg) with most gastrointestinal common adverse events contributing to a significant treatment interruption. Regarding the efficacy, the cost and the safety of these drugs they will no challenge the use of metformin as the initial therapy of T2DM. In patients'not tolerating metformin or in older patients, DPP-4 inhibitors seem to be an excellent alternative monotherapy. Several studies argue in favour of the use of DPP-4 inhibitors in combination with metformin as a promising second line treatment. This combination offers advantages when compared to others currently used, particularly if one considers the more stringent guidelines with a higher risk of hypoglycaemic events in patient receiving sulfonylureas and mild hyperglycaemia or weight gain with thiazolidinedione (TZD). Oral triple therapy, metformin + TZD + incretin-based drug, has several theoretical advantages but is not supported by any published trial. Finally, obtaining the acceptance of injections once to twice daily vs. oral administration of OADs will probably remain difficult during the first years of treatment in many patients. Nevertheless a long-acting release exenatide formulation (i.e. once weekly), for subcutaneous injection in patients with type 2 diabetes under development shows promising preliminary results. If confirmed, the use of this new class of drugs should be largely developed from monotherapy to combinations (bitherapy or tritherapy), and even instead of insulin or in association with insulin. The long-term effect of GLP-1 based agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are required and will allow progressively determining the use of incretin-based agents in T2DM treatment strategy. Their efficacy, safety and their cost vs. older strategies, will be really evaluated by physicians in the real daily practice and by large and long term systematic surveys, as recently shown in other therapeutic fields.