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      The Discovery and Development of Liraglutide and Semaglutide

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          Abstract

          The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

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          Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

          The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.
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            Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

            Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.
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              Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

              Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                12 April 2019
                2019
                : 10
                : 155
                Affiliations
                [1] 1Global Drug Discovery, Novo Nordisk A/S , Måløv, Denmark
                [2] 2Global Research Technology, Novo Nordisk A/S , Måløv, Denmark
                Author notes

                Edited by: Milka Vrecl, University of Ljubljana, Slovenia

                Reviewed by: Jean Albert Boutin, Servier, France; Bruce Welsh Bode, Emory University, United States

                *Correspondence: Lotte Bjerre Knudsen lbkn@ 123456novonordisk.com

                This article was submitted to Molecular and Structural Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00155
                6474072
                31031702
                ef38fe10-fe44-4af9-927c-9e3c5df6b119
                Copyright © 2019 Knudsen and Lau.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 December 2018
                : 21 February 2019
                Page count
                Figures: 13, Tables: 2, Equations: 0, References: 266, Pages: 32, Words: 24645
                Funding
                Funded by: Novo Nordisk 10.13039/501100004191
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                glp-1,liraglutide,semaglutide,type 2 diabetes,obesity,albumin,once-weekly
                Endocrinology & Diabetes
                glp-1, liraglutide, semaglutide, type 2 diabetes, obesity, albumin, once-weekly

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