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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
While GIP acts nearly exclusively at pancreatic β cells, there are receptors for GLP-1 (GLP-1R) at pancreas (α and β-cells), in peripheral organs (heart, stomach, vagus nerve) and in some regions of the CNS. Thus, GLP-1R agonists (GLP-1 mimetics), formulated as injectable synthetic polipeptides, are commonly used in the treatment Type 2 DM: For instance, exenatide (Amylin Pharmaceuticals, Byetta™/Bydureon™), liraglutide (Novo Nordisk, Victoza™, Saxenda™), lixisenatide (Sanofi, Lyxumia™), albiglutide (GSK, Tanzeum™), dulaglutide (Eli Lilly, Trulicity™), taspoglutide (phase III halted September 2010) or semaglutide (NovoNordisk, Ozempic™) display an advantage over older insulin secretagogues (sulfonylureas or meglitinides) due to their lower risk of causing hypoglycemia (Garber, 2012).
The correlations between steady-state concentration, duration of action and molecular weight of GLP-1RAs and their efficacy and gastrointestinal side effects in patients with type 2 diabetes mellitus: a systematic review and meta-analysis
Published in Expert Opinion on Pharmacotherapy, 2023
Ruoyang Jiao, Chu Lin, Shuzhen Bai, Xiaoling Cai, Suiyuan Hu, Fang Lv, Wenjia Yang, Xingyun Zhu, Linong Ji
Overall, 113 RCTs with 84,475 participants were included in the meta-analysis. Selection process of the studies was shown in Figure 1. GLP-1RAs, including albiglutide, dulaglutide, efpeglenatide, exenatide, liraglutide, lixisenatide, semaglutide, and taspoglutide, were assessed. The baseline characteristics of the included studies were summarized in AppendixTable 1. Among the included RCTs, there were 7 RCTs evaluating albiglutide, 10 RCTs evaluating dulaglutide, 3 RCTs evaluating efpeglenatide, 34 RCTs evaluating exenatide, 29 RCTs evaluating liraglutide, 14 RCTs evaluating lixisenatide, 13 RCTS evaluating semaglutide, and 6 RCTs evaluating taspoglutide. The Cochrane risk-of-bias tool indicated the concerns of bias arising from loss of follow up (2/113), inadequate allocation concealment and blinding (35/113) (Appendix Table 2). The funnel plots also showed uneven distributions, which indicated potential publication bias (AppendixFigure 1).
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
2-Aminoisobutyric acid (Aib, α-aminoisobutyric acid, α-methylalanine, or 2-methylalanine) is a commonly used non-proteinogenic amino acid to replace cleavage site amino acids. Due to the cleavage between positions 2 and 3 by DPP4, native GLP-1 has a very short half-life. Besides, A2G was used in the engineering of exenatide, A2Aib was used to engineer albiglutide, albenatide, lixisenatide, traspoglutide, and semaglutide to eliminate the cleavage by DPP4. Taspoglutide showed outstanding resistance to DPP4 and half-life of 13 h in human plasma upon subcutaneous administration without an acyl chain to bind albumin [104]. Semaglutide containing a fatty acid chain connected to Lys26 through a miniPEG spacer achieved a half-life of 6–7 d in plasma, enabling a once-weekly subcutaneous administration [105].
The cardiovascular effect of incretin-based therapies among type 2 diabetes: a systematic review and network meta-analysis
Published in Expert Opinion on Drug Safety, 2018
Shanshan Wu, Andrea Cipriani, Zhirong Yang, Jun Yang, Ting Cai, Yang Xu, Xiaochi Quan, Yuan Zhang, Sanbao Chai, Feng Sun, Siyan Zhan
Overall, 281 trials met the inclusion criteria (see Web Appendix 2 for full reference list). Flowchart of trials selection was shown in Figure 1. Eight treatments were analyzed, including incretin-based therapies (11 different DPP-4 inhibitors and 6 different GLP-1RAs), six other active antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor [AGI], and sodium-glucose co-transporter 2 [SGLT-2]), and placebo. Of 281 trails, 266 (94.7%) were two-arm studies and only 15 were multiple-arm studies (Appendix 3; Supplemental material). Overall, 180,000 patients contributed to the analysis of cardiovascular events (see Web Appendix 4 for evidence network). Appendix 3 (Supplemental material) summarized the characteristics of the included trials. Publication year varied from 2004 to 2016. Trial duration ranged from 12 to 312 weeks with a median follow-up of 24 weeks (interquartile range [IQR]: 18–48 weeks). The mean age of included patients was 57.0 years (standard deviation [SD]: 4.6), the median duration of diabetes at baseline was 6.7 years (IQR: 4.7–8.8) and the mean baseline HbA1c level was 8.1% (SD: 0.6%). Of the 281 trials included, DPP-4 inhibitors and GLP-1RAs were studies in 195 and 98 trials, respectively, and 12 trials involved both DPP-4 inhibitors and GLP-1RAs simultaneously. Among 195 trials including DPP-4 inhibitors, sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin were the most commonly studied drugs, with 75, 45, 23, 23, and 19 trials, respectively. Out of the 98 RCTs on GLP-1RAs, exenatide, liraglutide, lixisenatide, albiglutide, taspoglutide, dulaglutide, and semaglutide were studied in 35, 31, 12, 8, 7, 5, and 1 trial, respectively.