Recently unimolecular multi functional peptides that

Recently, unimolecular, multi-functional peptides that combine GLP-1RA activity with orotic acid and/or GIP activity have been suggested as new therapeutic agents for glycaemic and weight control. In rodents, dual GIP and GLP-1 receptor agonists achieve significantly better glucose control and weight loss compared to selective GLP-1RAs, such as exenatide or liraglutide [31]. To date, clinical data have been reported for two GIPR/GLP-1R co-agonist [31], [35], [36], [37]. A PEGylated dual agonist enhanced insulin secretion, improved glycaemic control, and induced weight loss without causing relevant GI side effects in subjects with T2D [31]. The authors suggest that these results demonstrate the potential of GIP to enhance the pharmacology of selective GLP-1 RAs by strengthening the inherent efficacy and broadening their therapeutic range however, the studies were small and of short duration. Here, we describe a novel, single-peptide, dual GIP and GLP-1 receptor agonist, LY3298176. The dual functionality of the peptide is described in preclinical in vitro and in vivo models, and clinical assessment demonstrates that administration of LY3298176 results in glucose lowering and substantial body weight lowering efficacy in healthy individuals during a multiple ascending dose study, and in a randomized, 4-week, Phase 1b trial in T2DM patients. Based on these findings, this molecule was evaluated in a 26-week, randomized study in T2DM, the results of which are forthcoming [38].
Material and methods
Results
Discussion Based on functional studies in cell culture systems and specific murine gene knockout models, LY3298176 is a dual GIP and GLP-1 receptor agonist. The molecule has greater potency for the GIPR in vitro, but in vivo activity through both incretin pathways is apparent in the glucose lowering by LY3298176 in mice expressing only one or the other receptor. In human subjects with T2DM, LY3298176 had potent effects on both fasting and postprandial glycaemia; the 7-point SMBG profile revealed a nearly flat and well-controlled glucose curve for the highest LY3298176 dose after only four weeks of treatment. Moreover, the significant insulin response seen with LY3298176 during an OGTT speaks to a robust incretin effect. Comparison of these glycaemic results with data from Phase 1 studies of selective GLP-1RAs [47], [48], [49] raises the possibility of additional effects by GIP to overall efficacy. These findings suggest that the combined incretin action of LY3298176 is not subject to the attenuation of GIP-stimulated insulin secretion typically seen in T2DM, and support enhanced glucose-lowering when both the GIPR and GLP-1R are activated [50], [51]. An important finding of these studies is that obese mice administered LY3298176 lost more weight than animals treated with a selective GLP-1RA. There is limited information on the consequences of selective GIPR activation, but available data as well as our own study presented here suggest that chronic administration of a long-acting GIPRA does not reduce body weight [52]. It therefore appears that GIP activation acts synergistically with GLP-1 receptor activation to allow greater weight loss in mice than what can be achieved with single GLP-1 receptor agonism. This observed weight loss appears to be due to both enhanced suppression of calorie intake and a slight but significant increase in energy expenditure. Although additional mechanistic studies are required to fully understand the effects of LY3298176 on energy balance, it seems likely that the synergistic actions of the GIP and GLP-1 receptors occurs at the level of the CNS [32]. The data in this report are consistent with previous findings from combination and dual agonist studies, which show the interaction of GLP-1RA and GIPRA yields better weight control [31], [35]. Our results in obese mice offer further support that the addition of GIPR agonism to GLP-1 enhances weight loss via modulating energy metabolism, an effect that has not been previously reported.