GLP-1, Incretin Mimetics and DPP 4 Inhibitors: New Ways in the Treatment of Type 2 Diabetes

Abstract

The incretin hormone glucagon-like peptide 1 (GLP-1) is produced by post-translational processing of the proglucagon gene in intestinal L-cells. Owing to its glucose-dependent insulinotropic effect, a potential in the treatment of type 2 diabetes has been suggested already 20 years ago. However, rapid enzymatic inactivation of GLP-1 in vivo and the need for parenteral administration have obviated its earlier therapeutic application. In addition to its effects on insulin secretion, GLP-1 suppresses glucagon secretion, decelerates gastric emptying and increases satiety leading to reduced food intake and weight loss. In the light of these features, GLP-1 appears to be an ideal candidate for the treatment of type 2 diabetes. Today, a number of different GLP-1 analogues or derivatives (the so called "incretin mimetics") with more favourable pharmacokinetic profiles have been generated. Exenatide (Byetta; Eli Lilly & Co), a synthetic GLP-1 receptor agonist suitable for twice daily s.c. injection, has now been approved by the FDA for the add-on therapy of patients with type 2 diabetes with insufficient metabolic control during metformin and/or sulfonylurea treatment. A number of other incretin mimetics are currently being studied in clinical trials. An alternative strategy to enhance the action of endogenous GLP-1 is inhibition of its enzymatic degradation by specific inhibitors of the protease DPP 4 (DPP 4 inhibitors), which are absorbed after oral ingestion. Reductions in HbA1c-levels during treatment with incretin mimetics and DPP 4 inhibitors were in the order of 0.5-1 %. Major advantages of using incretin mimetics compared to other antidiabetic drugs available include the lack of a risk for hypoglycaemia due to the strict glucose-dependence of insulinotropic and glucagonostatic GLP-1 actions as well as weight reduction by several kg despite their insulinotropic mode of action. Therefore, incretin mimetics and DPP 4 inhibitors seem to be useful new tools for the future treatment of type 2 diabetes. Keywords: Gastric inhibitory polypeptide, antihyperglycaemic, ALBUGON, DPP 4 INHIBITION, Liraglutide, sulfonylureas