1802 which is widely expressed throughout the CNS and peripheral tissues (56). GLP-1 receptors in peripheral tissues, including the stomach, may also be important in meal termination and possibly satiety. Administration of GLP-1 causes a dose-dependent reduction of food intake in experimental animals and in both lean and obese humans. Two main strategies are being followed to combat the extremely short half-life of native GLP-1. The first is by producing more stable GLP-1 analogues; the second is by inhibiting DPP IV, which is catalyzing the GLP-1 break- down. For weight management, stable GLP-1 has so far produced the best results. A first breakthrough was the discovery of the natural GLP-1 analogue exendin-4 in the venom of a lizard called Gila monster. Based on this molecule, Amylin Pharmaceuticals and Eli Lilly developed exenatide (Byetta®), which is already on the market as an adjunct to current diabetes therapies. The observation that the drug not only improved glycemic control, but also caused a reduction in body weight, stimulated further research in this direction. An unpleasant side effect of Exenatide is nausea, in particular during the initial phase of treatment. Furthermore, patients can develop antibodies to the drug, which sometimes leads to reduced efficacy. Exenatide needs to be administered twice daily by subcuta- neous injection, which is also a disadvantage. To overcome this, a once-weekly injection preparation named exenatide LAR (Amylin/Lilly/Alkermes) is currently under develop- ment. Phase III trial results have demonstrated good blood sugar control and weight loss, especially in patients for whom metformin or sulphonylureas are not effective (95). As expected, exenatide LAR has a side-effect profile similar to Byetta®. A promising alternative is liraglutide (Novo Nordisk), a GLP-1 analogue with 97% similarity to human GLP-17–37 (96). Due to the addition of a side chain, liraglutide binds to albumin, leading to a half-life of about 13 hours. Liraglutide has already been approved for use in diabetes. Recently, the NN8022-1807 Study Group (96) reported the results of a double-blind, placebo- controlled 20-week trial, with open-label orlistat comparator in 19 sites across Europe. In total, 564 non-diabetic individuals with a BMI between 30 and 40 kg/m2 participated. Mean weight loss with the different doses of liraglutide was between 4.8 and 7.2 kg, compared to 2.8 kg with placebo and 4.1 kg with orlistat. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3.0 mg than with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide also showed beneficial effects on blood pressure and pre-diabetes symptoms. Although nausea and vomiting occurred at higher frequency in the liraglutide groups, these side effects were considered transient and rarely led to discontinuation of treatment. As liraglutide still needs to be administered by injection, Novo is developing a long-acting oral GLP-1 analog (NN9924) that utilizes Witkamp sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) carrier technology (97). A phase I trial was started early 2010. Oxyntomodulin (OXM) OXM consists of 37 amino acids of which 29 are in common with GLP-1. Levels peak at 30 min and in proportion to caloric intake, remaining elevated for several hours (56). Although OXM has a 50-fold lower affinity for binding at the GLP-1 receptor, it has an equal potency for inhibiting food intake. Studies have shown that OXM reduces food intake and causes reduced weight gain in rodents. Acute OXM administration reduced food intake in lean volunteers, and chronic OXM subcutaneous injections in obese individuals induced an average weight loss of 2.3 kg after 4 weeks, compared to 0.5 kg in the control group (56). Despite this, only a small number of develop- ment projects appear to be in an advanced stage. Thiakis Limited (London, UK) started in March 2008 investigating the potential of their OXM analogue, TKS1225. Following the take-over of Thiakis by Wyeth in December 2008, which was in turn acquired by Pfizer in 2010, the present status of this molecule is unknown. Cholecystokinin-1 (CCK) Agonists CCK is secreted by I-cells in the proximal part of the small intestine. The hormone is formed by post-translational cleavage of the pre-pro-CCK polypeptide, which undergoes further proteolysis to a cocktail of active peptides with varying numbers of amino acids (see (98) for review). Following nutrient ingestion, circulating CCK levels start to increase bi-phasically at 15 min, reaching a peak at around 25 min, and remain elevated for approximately 3 h (56). Presently, there are two G-protein-coupled CCK receptors known. CCK-1 receptors are mainly present in the gastrointestinal tract, myenteric plexus and Vagal afferents, while CCK-2 receptors are predominantly expressed in the brain. It is widely accepted that CCK-induced satiation is largely mediated by the CCK-1 receptors (56). Although administration of CCK has shown to cause a reduction of food intake, its value for anti-obesity therapy has proven to be limited so far. It appears that CCK is more important in satiation than satiety, which could lead to compensation through increasing meal frequency. GSK has stopped the development of their compound GI 181771 after phase II clinical trials failed to show any significant weight loss (99). A limitation of that study might have been that participants were allowed to eat ad libitum and might have compensated their energy intake by increasing meal frequency. At the end of 2008, Pfizer also discontinued development of a CCK agonist (CE-326597) after phase II.