The Discovery and Development of Liraglutide and Semaglutide

We describe one such approach, albumin binding, and explain how it was applied in the development of the human GLP-1 analog liraglutide once daily and, subsequently, semaglutide once weekly. The pharmacology of these two long-acting GLP-1 analogs, in terms of improving glycemic control, reducing body weight and decreasing cardiovascular (CV) risk, is also reviewed, together with some novel biology. In addition, we describe the importance of accurate target (GLP-1 receptor) tissue expression analysis. Now an established class of agents, GLP-1-based therapies represent a significant advance in the treatment of T2D. All currently available GLP-1 receptor agonists (GLP-1RAs) are, however, injectable. Ongoing efforts to advance this class of agents include, therefore, attempts to develop an oral formulation. In the final section of this article, we describe an oral formulation of semaglutide that is currently in phase 3 clinical development for the treatment of T2D, as well as summarizing other therapeutic applications—beyond T2D—of liraglutide and semaglutide. Albumin Binding as a Concept for Creating Long-Acting GLP-1 Analogs Human serum albumin (HSA) is among the most stable and abundant of plasma proteins. It comprises three homologous domains assembled into a heart-shaped protein. Approximately 10–15 g is produced by the liver daily, which—owing to its long half-life of several weeks—results in an HSA plasma concentration of 35–50 g/L (~...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research

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In this study, we found that Lnc-OC1 was significantly higher in PCOS granulosa cells (GCs) compared to non-PCOS GCs. Lnc-OC1 knockdown inhibited cell viability and promoted cell apoptosis, expression of aromatase mRNA and production of estradiol in KGN cells. In PCOS mice, Lnc-OC1 promoted the serum insulin release, production of angiogenesis-related factors and IκBα phosphorylation, which could be partially restored by Lnc-OC1 shRNA. These results suggest that Lnc-OC1 plays an important part in the pathogenesis of PCOS.
Source: Molecular and Cellular Endocrinology - Category: Endocrinology Source Type: research
ConclusionsOur study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.Graphical abstract
Source: Molecular Metabolism - Category: Endocrinology Source Type: research
Publication date: Available online 16 February 2020Source: Canadian Journal of DiabetesAuthor(s): Tomoyuki Kawada
Source: Canadian Journal of Diabetes - Category: Endocrinology Source Type: research
This article aims to classify the severity grading assessments for both insulin resistance (IR) syndrome and status of pancreatic beta (β) islet cells’ function using the homeostasis model assessment method (that is; homeostasis model assessment-insulin resistance [HOMA-IR] and homeostasis model assessment-pancreatic beta (β) islet cells’ function [HOMA-B] indices) with the focus of disseminating this information rapidly for clinical use by physicians in their patients with dysfunctional regulation of glucose metabolism. It will also assist clinicians to prevent and screen for these individuals who ar...
Source: Canadian Journal of Diabetes - Category: Endocrinology Source Type: research
In this study, the core-shell polydopamine-coated magnetic nanomaterials were synthesized with one-step approach and applied as magnetic solid phase extraction adsorbents combined with LC-MS/MS for quantification of the diabetes drug glimepiride in beagle dog plasma. The Fe3O4@PDA nanomaterials have strong magnetic response, good dispersibility in aqueous solution, and numerous binding sites for π–π interaction and hydrogen bonding with glimepiride. Based on these merits, glimepiride could be quickly extracted and separated from plasma within 10min. The established method has good linearity (1-2000ng•mL-1)...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 15 February 2020Source: Journal of Pharmaceutical AnalysisAuthor(s): Mahendra Kumar Trivedi, Parthasarathi Panda, Kalyan Kumar Sethi, Mayank Gangwar, Sambhu Charan Mondal, Snehasis JanaAbstractTetrahydrocurcumin (THC) is one of the major metabolites of curcumin (CUR), an ancient bioactive natural polyphenolic compound. This research article described both the solid and liquid state characterization of THC using advanced spectroscopic and thermo-analytical techniques. Anti-inflammatory, anti-oxidant, and neuroprotective activities of THC were investigated using in vitro cell lines. Liquid ...
Source: Journal of Pharmaceutical Analysis - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 16 February 2020Source: International Journal of PharmaceuticsAuthor(s): Namita P. Tipnis, Jie Shen, Derek Jackson, Daniel Leblanc, Diane J. BurgessAbstractThe main objective of the current research was to develop a compendial flow-through cell apparatus based in vitro release testing method for sustained-release triamcinolone acetonide–loaded poly (lactic-co-glycolic) acid (PLGA) microspheres. Media-based and instrument-based parameters, such as surfactant type, concentration, media volume, flow rate, and testing temperature, were investigated. In addition, a detailed exploration w...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 16 February 2020Source: International Journal of PharmaceuticsAuthor(s): L. Simon, V. Lapinte, L. Lionnard, N. Marcotte, M. Morille, A. Aouacheria, K. Kissa, J.M. Devoisselle, S. BéguAbstractNano-sized lipid formulations offer a great potential for topical delivery of active compounds to treat and prevent human skin damages. Of particular importance is the high loading of hydrophobic molecules, the long-term stability and the auspicious penetration capacity especially reached when using lipid nanocapsules (LNC). Unfortunately, their formation currently relies on a phase inversion p...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research
ConclusionsAmong uninsured and underinsured asthma patients with GAD and/or MDD who were initiated on a single antidepressant, those who were titrated to achieve target doses had reduced risk of severe asthma exacerbations and lower number of asthma ÔÇÉrelated outcomes than those who were not optimized to achieve target doses.
Source: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL RESEARCH ARTICLE Source Type: research
Authors: Bartelt A, Widenmaier SB Abstract The proper production, degradation, folding and activity of proteins, proteostasis, is essential for any cellular function. From single cell organisms to humans, selective pressures have led to the evolution of adaptive programs that ensure proteins are properly produced and disposed of when necessary. Environmental factors such as temperature, nutrient availability, pathogens as well as predators have greatly influenced the development of mechanisms such the unfolded protein response, endoplasmic reticulum-associated protein degradation and autophagy, working together in ...
Source: Biological Chemistry - Category: Chemistry Tags: Biol Chem Source Type: research
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