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  • The findings in mice were echoed in the


    The findings in mice were echoed in the human studies, in which the effects of higher doses of LY3298178 caused greater weight loss than the selective GLP-1RA dulaglutide. In patients with T2DM, LY3298176 demonstrated meaningful weight loss after only four weeks of treatment. This was consistent with subject reports of decreased appetite during treatment with the dual agonist. Although several factors likely contribute, the beneficial effects of LY3298176 may in part be attributed to its greater potency at the GIPR versus GLP-1R. While further investigation is needed to determine the optimal properties of a dual agonist, this profile differentiates LY3298176 from another dual GIP-GLP-1 receptor agonist, NNC0090-2746, that displays balanced activity at the receptors [31], [35]. Other functional dual agonists, which combine a GLP-1RA with lrrk2 activity, have recently reported four week data on weight loss; in comparison with these previous studies, LY3298176 appears to provide similar (SAR425899) or greater weight loss (MEDI0384) than these compounds [53], [54]. The safety characteristics of lrrk2 LY3298176 were similar to selective GLP-1RAs. The most frequently reported AEs were gastrointestinal (nausea, vomiting, and diarrhoea) that were of mild to moderate in severity. Gastrointestinal AEs with LY3298176 were dose limiting, similar to what has been universally observe with other drugs with potent GLP-1RA activity. However, titration decreased gastrointestinal AEs, and the simple titration regimens tested in these studies helped subjects tolerate higher doses (up to 15 mg) during the MAD Phase 1 b PoC and Phase 2 b studies [38]. It is important to note that our titration paradigm was not optimised, and slower titration with smaller steps may enable an even more favorable tolerability profile. Similar to effects seen with GLP-1RAs, increases in mean concentrations of lipase and amylase with the dual agonist were observed. The frequency of reporting of hypoglycaemia, hypersensitivity events, and injection site reactions was low across the treatment groups, and we did not observe important differences between LY3298176 and placebo or dulaglutide. Although increased pulse rate is a known effect of GLP-1RA therapy, there was not a consistent dose effect and the maximum increase observed with LY3298176 was similar to dulaglutide.
    Author contributions J.A-F. was responsible for molecule design. T.C. was responsible for design, data collection and analysis in DIO mice studies. D.A.B. was responsible for data collection and analysis in preclinical ipGTT studies. O.C. was responsible for data collection and analysis in islet studies. W.C.R. was responsible for data collection in preclinical adipose studies. J.S.M. and K.W.S. were responsible for data collection and analysis of in vitro characterization studies. X.C. was responsible for the statistical considerations in the analysis. C.L. and S.U. were responsible for data analysis and interpretation. R.E.G., T.C. and A.H. are the guarantors of this work and, as such, take responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in critical review and interpretation of the data for the manuscript. All authors had full access to the data related to these studies and approved the final version submitted for publication. A portion of the preclinical data was presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes in Lisbon, Portugal, held September 11–15, 2017.
    Data sharing statement Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request in a timely fashion after the indication studied has been approved in the US and EU and after primary publication acceptance. No expiration date of data requests is currently set once Repressor protein are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment for up to 2 years per proposal. For details on submitting a request, see the instructions provided at