{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:21:19Z","timestamp":1792264879570,"version":"4.4.0"},"reference-count":97,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: Type 2 diabetes and obesity present escalating global health and economic challenges, highlighting the need for therapies that can effectively manage glycemic levels and reduce excess adiposity. Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist available in subcutaneous or oral formulation, has quickly evolved from a theoretical concept to a crucial component of modern metabolic care. This review explores the comprehensive development journey of semaglutide, drawing on evidence from medicinal chemistry, animal studies, initial human trials, the pivotal SUSTAIN and STEP programs, and real-world post-marketing surveillance. Methods: We conducted a detailed analysis of preclinical data sets, Phase I\u2013III clinical trials, regulatory documents, and pharmaco-epidemiological studies published between 2008 and 2025. Results: Through strategic molecular modifications, such as specific amino-acid substitutions and the addition of a C18 fatty-diacid side chain to enhance albumin binding, the half-life of the peptide was extended to approximately 160 h, allowing for weekly dosing. Studies in rodents and non-human primates showed that semaglutide effectively lowered blood glucose levels, reduced body weight, and preserved \u03b2-cells while maintaining a favorable safety profile. Phase I trials confirmed consistent pharmacokinetics and tolerability, while Phase II trials identified 0.5 mg and 1.0 mg once weekly as the most effective doses. The extensive SUSTAIN program validated significant reductions in HbA1c levels and weight loss compared to other treatments, as well as a 26% decrease in the relative risk of major adverse cardiovascular events (SUSTAIN-6). Subsequent STEP trials expanded the use of semaglutide to chronic weight management, revealing that nearly two-thirds of patients experienced a body weight reduction of at least 15%. Regulatory approvals from the FDA, EMA, and other regulatory agencies were obtained between 2017 and 2021, with ongoing research focusing on metabolic dysfunction-associated steatohepatitis, cardiovascular events, and chronic kidney disease. Conclusions: The trajectory of semaglutide exemplifies how intentional peptide design, iterative translational research, and outcome-driven clinical trial design can lead to groundbreaking therapies for complex metabolic disorders.<\/jats:p>","DOI":"10.3390\/medsci13040265","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:59:09Z","timestamp":1763027949000},"page":"265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Semaglutide from Bench to Bedside: The Experimental Journey Towards a Transformative Therapy for Diabetes, Obesity and Metabolic Liver Disorders"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"first","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9886-0698","authenticated-orcid":false,"given":"Amedeo","family":"Lonardo","sequence":"additional","affiliation":[{"name":"Ospedale Civile di Baggiovara (-2023), Department of Internal Medicine, AOU Modena, 41100 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","unstructured":"Goyal, R., Singhal, M., and Jialal, I. (2025, October 25). Type 2 Diabetes, StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK513253\/."},{"key":"ref_2","unstructured":"World Health Organization (2025, October 25). Diabetes. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/diabetes#:~:text=Factors%20that%20contribute%20to%20developing%20type%202,and%20blood%20tests%20with%20a%20healthcare%20provider."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rodriguez-Gutierrez, R., Gonzalez-Gonzalez, J.G., A Zu\u00f1iga-Hernandez, J., and McCoy, R.G. (2019). Benefits and harms of intensive glycemic control in patients with type 2 diabetes. BMJ, 367.","DOI":"10.1136\/bmj.l5887"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.14309\/ajg.0000000000003288","article-title":"Global, Regional, and National Burden of Primary Liver Cancer Attributable to Metabolic Risks: An Analysis of the Global Burden of Disease Study 1990\u20132021","volume":"120","author":"Wu","year":"2025","journal-title":"Am. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., Ostolaza, H., and Mart\u00edn, C. (2020). Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176275"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4891","DOI":"10.1007\/s00210-024-03713-4","article-title":"The dual challenge of diabesity: Pathophysiology, management, and future directions","volume":"398","author":"Sindhwani","year":"2025","journal-title":"Naunyn-Schmiedeberg's Arch. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lonardo, A., and Weiskirchen, R. (2025). Liver and obesity: A narrative review. Explor. Med., 6.","DOI":"10.37349\/emed.2025.1001334"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chandrasekaran, P., and Weiskirchen, R. (2024). The signaling pathways in obesity-related complications. J. Cell Commun. Signal., 18.","DOI":"10.1002\/ccs3.12039"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wentworth, B.J. (2025). Metabolic dysfunction-associated steatotic liver disease throughout the liver transplant cycle: A comprehensive review. Metab. Target Organ. Damag., 5.","DOI":"10.20517\/mtod.2025.73"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lonardo, A. (2024). Association of NAFLD\/NASH, and MAFLD\/MASLD with chronic kidney disease: An updated narrative review. Metab. Target Organ Damage, 4.","DOI":"10.20517\/mtod.2024.07"},{"key":"ref_11","first-page":"e984","article-title":"American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. Obesity and cardiovascular disease: A scientific statement from the American Heart Association","volume":"143","author":"Poirier","year":"2021","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ylli, D., Sidhu, S., Parikh, T., Burman, K.D., Feingold, K.R., Ahmed, S.F., Anawalt, B., Blackman, M.R., Boyce, A., and Chrousos, G. (2025, October 25). Endocrine Changes in Obesity, Endotext [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK279053.","DOI":"10.2174\/0118715303319530240703111013"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhou, X.-D., Chen, Q.-F., Yang, W., Zuluaga, M., Targher, G., Byrne, C.D., Valenti, L., Luo, F., Katsouras, C.S., and Thaher, O. (2024). Burden of disease attributable to high body mass index: An analysis of data from the Global Burden of Disease Study 2021. eClinicalMedicine, 76, Erratum in eClinicalMedicine 2024, 78, 102958.","DOI":"10.1016\/j.eclinm.2024.102958"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.gtc.2016.07.012","article-title":"Obesity epidemiology worldwide","volume":"45","author":"Mincey","year":"2016","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_15","first-page":"s176","article-title":"Obesity: Definition, comorbidities, causes, and burden","volume":"22","author":"Apovian","year":"2016","journal-title":"Am. J. Manag. Care"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, H., Zhou, X.D., Shapiro, M.D., Lip, G.Y.H., Tilg, H., Valenti, L., Somers, V.K., Byrne, C.D., Targher, G., and Yang, W. (2024). Global burden of metabolic diseases, 1990\u20132021. Metabolism, 160.","DOI":"10.1016\/j.metabol.2024.155999"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1152\/physrev.00034.2006","article-title":"The physiology of glucagon-like peptide 1","volume":"87","author":"Holst","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.amjmed.2025.01.021","article-title":"Mechanisms of GLP-1 receptor agonist-induced weight loss: A review of central and peripheral pathways in appetite and energy regulation","volume":"138","author":"Moiz","year":"2025","journal-title":"Am. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shilleh, A.H., Viloria, K., Broichhagen, J., Campbell, J.E., and Hodson, D.J. (2024). GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells. Peptides, 175.","DOI":"10.1016\/j.peptides.2024.171179"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhao, X., Wang, M., Wen, Z., Lu, Z., Cui, L., Fu, C., Xue, H., Liu, Y., and Zhang, Y. (2021). GLP-1 receptor agonists: Beyond their pancreatic effects. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.721135"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Friedman, J.M. (2024). The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity. Proc. Natl. Acad. Sci. USA, 121.","DOI":"10.1073\/pnas.2415550121"},{"key":"ref_22","unstructured":"Collins, L., and Costello, R.A. (2025, October 25). Glucagon-like peptide-1 receptor agonists, StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK551568\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12793\/tcp.2025.33.e3","article-title":"Clinical development of oral semaglutide for the treatment of type 2 diabetes mellitus: Focusing on early phase clinical trials","volume":"33","author":"Won","year":"2025","journal-title":"Transl. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"525","DOI":"10.4093\/dmj.2025.0242","article-title":"Exploring the side effects of GLP-1 receptor agonist: To ensure its optimal positioning","volume":"49","author":"Kim","year":"2025","journal-title":"Diabetes Metab. J."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ayoub, M., Chela, H., Amin, N., Hunter, R., Anwar, J., Tahan, V., and Daglilar, E. (2025). Pancreatitis risk associated with GLP-1 receptor agonists, considered as a single class, in a comorbidity-free subgroup of type 2 diabetes patients in the United States: A propensity score-matched analysis. J. Clin. Med., 14.","DOI":"10.3390\/jcm14030944"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1111\/bph.70003","article-title":"How \u2018miracle\u2019 weight-loss semaglutide promises to change medicine but can we afford the expense?","volume":"182","author":"Weiskirchen","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1111\/dom.16600","article-title":"Shifting obesity treatment paradigms: Trends of glucagon-like peptide-1 receptor agonists and bariatric surgery in the United States","volume":"27","author":"Dawwas","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Barrett, T.S., Hafermann, J.O., Richards, S., LeJeune, K., and Eid, G.M. (2025). Obesity treatment with bariatric surgery vs. GLP-1 receptor agonists. JAMA Surg.","DOI":"10.1001\/jamasurg.2025.3590"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Knudsen, L.B., and Lau, J. (2019). The Discovery and Development of Liraglutide and Semaglutide. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00155"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tamayo-Trujillo, R., Ruiz-Pozo, V.A., Cadena-Ullauri, S., Guevara-Ram\u00edrez, P., Paz-Cruz, E., Zambrano-Villacres, R., Simancas-Racines, D., and Zambrano, A.K. (2024). Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1398059"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"65","DOI":"10.15605\/jafes.037.02.14","article-title":"Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis","volume":"37","author":"Tan","year":"2022","journal-title":"J. ASEAN Fed. Endocr. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7370","DOI":"10.1021\/acs.jmedchem.5b00726","article-title":"Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide","volume":"58","author":"Lau","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s40262-018-0728-4","article-title":"Safety and pharmacokinetics of single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 diabetes","volume":"58","author":"Granhall","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2337\/dc15-0165","article-title":"A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes","volume":"39","author":"Nauck","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and cardiovascular outcomes in obesity without diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2403347","article-title":"Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes","volume":"391","author":"Perkovic","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41366-024-01473-y","article-title":"What is the pipeline for future medications for obesity?","volume":"49","author":"Melson","year":"2025","journal-title":"Int. J. Obes."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1111\/dom.14794","article-title":"In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist","volume":"24","author":"Jones","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lucey, M., Pickford, P., Bitsi, S., Minnion, J., Ungewiss, J., Schoeneberg, K., Rutter, G.A., Bloom, S.R., Tomas, A., and Jones, B. (2020). Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists. Mol. Metab., 37.","DOI":"10.1016\/j.molmet.2020.100991"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gabery, S., Salinas, C.G., Paulsen, S.J., Ahnfelt-R\u00f8nne, J., Alanentalo, T., Baquero, A.F., Buckley, S.T., Farkas, E., Fekete, C., and Frederiksen, K.S. (2020). Semaglutide lowers body weight in rodents via distributed neural pathways. J. Clin. Investig., 5.","DOI":"10.1172\/jci.insight.133429"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jensen, M.H., Sanni, S.J., Riber, D., Holst, J.J., Rosenkilde, M.M., and Sparre-Ulrich, A.H. (2024). AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys. Mol. Metab., 88.","DOI":"10.1016\/j.molmet.2024.102006"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14514","DOI":"10.3390\/cimb46120872","article-title":"Spotlight on the Mechanism of Action of Semaglutide","volume":"46","author":"Papakonstantinou","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wasilewska, B., and Petruczynik, A. (2025). Semaglutide\u2014Properties, action and chromatographic analysis. J. Diabetes Metab. Disord., 24.","DOI":"10.1007\/s40200-025-01711-8"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Mao, T., Zhang, C., Yang, S., Bi, Y., Li, M., and Yu, J. (2024). Semaglutide alters gut microbiota and improves NAFLD in db\/db mice. Biochem. Biophys. Res. Commun., 710.","DOI":"10.1016\/j.bbrc.2024.149882"},{"key":"ref_46","unstructured":"(2025, October 25). Highlights of Prescribing Information. Ozempic Safety and Effectively, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/209637lbl.pdf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.2337\/db13-1087","article-title":"The human GLP-1 analogs liraglutide and semaglutide: Absence of histopathological effects on the pancreas in nonhuman primates","volume":"63","author":"Gotfredsen","year":"2014","journal-title":"Diabetes"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Feier, C.V.I., Vonica, R.C., Faur, A.M., Streinu, D.R., and Muntean, C. (2024). Assessment of thyroid carcinogenic risk and safety profile of GLP1-RA semaglutide (Ozempic) therapy for diabetes mellitus and obesity: A systematic literature review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084346"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1111\/dom.15624","article-title":"A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects","volume":"26","author":"Xie","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2147\/DDDT.S470826","article-title":"Clinical pharmacokinetics of semaglutide: A systematic review","volume":"18","author":"Yang","year":"2024","journal-title":"Drug Des. Devel Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s13300-019-0581-y","article-title":"Population pharmacokinetics of semaglutide for type 2 diabetes","volume":"10","author":"Overgaard","year":"2019","journal-title":"Diabetes Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1007\/s12325-020-01548-y","article-title":"Pharmacokinetics, safety and tolerability of once-weekly subcutaneous semaglutide in healthy Chinese subjects: A double-blind, phase 1, randomized controlled trial","volume":"38","author":"Shi","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/dom.14551","article-title":"Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal AE and weight loss","volume":"24","author":"Wharton","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/dom.13120","article-title":"Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity","volume":"20","author":"Hjerpsted","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0140-6736(18)31773-2","article-title":"Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: A randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial","volume":"392","author":"Birkenfeld","year":"2018","journal-title":"Lancet"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Karimi, M.A., Gholami Chahkand, M.S., Dadkhah, P.A., Sheikhzadeh, F., Yaghoubi, S., Esmaeilpour Moallem, F., Deyhimi, M.S., Arab Bafrani, M., Shahrokhi, M., and Nasrollahizadeh, A. (2025). Comparative effectiveness of semaglutide versus liraglutide, dulaglutide or tirzepatide: A systematic review and meta-analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1438318"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1111\/dom.14725","article-title":"Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension","volume":"24","author":"Wilding","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_58","unstructured":"medwireNews (2025, October 25). A Quick Guide to the SUSTAIN Trials. Available online: https:\/\/www.medwirenews.com\/showcase\/a-quick-guide-to-the-sustain-trials\/#:~:text=The%20SUSTAIN%2010%20findings%20favor,SUSTAIN%20%E2%80%93%20CHINA%20MRCT:%20Published."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1111\/dom.13396","article-title":"Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme","volume":"20","author":"DeVries","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Alenzi, S., Alzahrani, A., Aljaloud, A., Alanazi, K., and Alarfaj, S.J. (2024). The effectiveness of 0.5 mg and 1mg of semaglutide in patients with type two diabetes and predictors of response: A retrospective cohort study. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1395651"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1038\/s41591-024-02996-7","article-title":"Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial","volume":"30","author":"Ryan","year":"2024","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1210\/jc.2018-00070","article-title":"Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomized, controlled trial","volume":"103","author":"Rodbard","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Leiter, L.A., Bain, S.C., Hramiak, I., J\u00f3dar, E., Madsbad, S., Gondolf, T., Hansen, T., Holst, I., and Lingvay, I. (2019). Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: A post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc. Diabetol., 18.","DOI":"10.1186\/s12933-019-0871-8"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1111\/dom.14990","article-title":"Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes","volume":"25","author":"Aroda","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"(2025). Ruseva A, Wojcich M, Fabbricatore A, Hartaigh BO, Wang BJ, Zhao Z1733-P: Two-year real-world effectiveness of semaglutide in patients with obesity or overweight. Diabetes, 74.","DOI":"10.2337\/db25-1733-P"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/dom.14863","article-title":"Semaglutide for the treatment of overweight and obesity: A review","volume":"25","author":"Bergmann","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.cgh.2014.04.014","article-title":"Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: A systematic review and meta-analysis of paired-biopsy studies","volume":"13","author":"Singh","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_68","unstructured":"Girish, V., and John, S. (2025, October 25). Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK541033\/."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Younossi, Z.M., Mangla, K.K., Chandramouli, A.S., and Lazarus, J.V. (2024). Estimating the economic impact of comorbidities in patients with MASH and defining high-cost burden in patients with noncirrhotic MASH. Hepatol. Commun., 8.","DOI":"10.1097\/HC9.0000000000000488"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1053\/j.gastro.2015.04.005","article-title":"Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis","volume":"149","author":"Friedman","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3390\/livers4010010","article-title":"Resmetirom: Finally, the light at the end of the NASH tunnel?","volume":"4","author":"Lonardo","year":"2024","journal-title":"Livers"},{"key":"ref_72","unstructured":"FDAUS Food & Drug Administration (2025, October 25). FDA Approves Treatment for Serious Liver Disease Known as \u2018MASH\u2019. Action Will Proide New Therapy for Growing Public Health Issue, Available online: https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-treatment-serious-liver-disease-known-mash."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Katrevula, A., Kalapala, R., Agrawal, S., Jagtap, N., Chhabra, P., Kulkarni, A.V., Merugu, C., Katukuri, G.R., and Duvvur, N.R. (2025). Oral semaglutide for weight loss and liver fibrosis in overweight and obesity: A randomized controlled trial. Indian J. Gastroenterol., Epub ahead of print.","DOI":"10.1007\/s12664-025-01856-7"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Nitze, L.M., Ratziu, V., Sanyal, A.J., Wong, V.W., Balendran, C., Fleckner, J., Skalsh\u00f8i Kj\u00e6r, M., Krarup, N., and Anstee, Q.M. (2025). Exploration of multiple non-invasive tests for assessing response to treatment in a semaglutide phase 2b trial in patients with MASH. Aliment Pharmacol Ther.","DOI":"10.1111\/apt.70376"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"John, B.V., Bastaich, D., Marchetti, D., Perumalswami, P., Mustafa, M.Z., and Dahman, B. (2025). Veterans Analysis of Liver Disease (VALID) Group of Investigators. Association of glucagon-like peptide-1 receptor agonists with liver-related outcomes and all-cause mortality in patients with harmful alcohol use: A target trial emulation study. Am. J. Gastroenterol., 2022.","DOI":"10.14309\/ajg.0000000000003585"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Golub, I.S., Manubolu, V.S., Aldana-Bitar, J., Dahal, S., Verghese, D., Alalawi, L., Krishnan, S., Kianoush, S., Benzing, T., and Ichikawa, K. (2025). The impact of semaglutide on liver fat assessed by serial cardiac CT scans in patients with type 2 diabetes: Results from STOP trial. Nutr. Metab. Cardiovasc. Dis., 35.","DOI":"10.1016\/j.numecd.2025.104036"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/HEP.0000000000000723","article-title":"Artificial intelligence scoring of liver biopsies in a phase II trial of semaglutide in nonalcoholic steatohepatitis","volume":"80","author":"Ratziu","year":"2023","journal-title":"Hepatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S2468-1253(23)00068-7","article-title":"Semaglutide 2\u00b74 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: A randomised, placebo-controlled phase 2 trial","volume":"8","author":"Loomba","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1111\/apt.16608","article-title":"Randomised clinical trial: Semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging","volume":"54","author":"Flint","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1056\/NEJMoa2028395","article-title":"A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1080\/14796678.2025.2511412","article-title":"Semaglutide: A key medication for managing cardiovascular-kidney-metabolic syndrome","volume":"21","author":"MacIsaac","year":"2025","journal-title":"Future Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1161\/CIRCULATIONAHA.121.055459","article-title":"Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: Pooled analysis of SUSTAIN 6 and LEADER","volume":"145","author":"Shaman","year":"2022","journal-title":"Circulation"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","article-title":"Semaglutide in patients with heart failure with preserved ejection fraction and obesity","volume":"389","author":"Kosiborod","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/oby.24222","article-title":"Safety profile of semaglutide versus placebo in the SELECT study: A randomized controlled trial","volume":"33","author":"Kushner","year":"2025","journal-title":"Obesity"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Chiappini, S., D\u2019andrea, G., Cavallotto Mosca, A., Carlo, F.D., Pettorruso, M., Martinotti, G., and Schifano, F. (2025). Pharmacovigilance signals of semaglutide and other GLP-1 receptor agonists: An analysis of the food and drug administration (FDA) adverse events reporting system (FAERS) datasets. Int. J. Neuropsychopharmacol., 28.","DOI":"10.1093\/ijnp\/pyae059.533"},{"key":"ref_86","unstructured":"European Medicines Agency (2025, October 25). PRAC Concludes Eye Condition NAION Is a Very Rare Side Effect of Semaglutide Medicines Ozempic, Rybelsus and Wegovy. Available online: https:\/\/www.ema.europa.eu\/en\/news\/prac-concludes-eye-condition-naion-very-rare-side-effect-semaglutide-medicines-ozempic-rybelsus-wegovy."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1007\/s00125-017-4289-0","article-title":"Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: A randomised, double-blind, placebo-controlled trial","volume":"60","author":"Kapitza","year":"2017","journal-title":"Diabetologia"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Yaribeygi, H., Maleki, M., Jamialahmadi, T., and Sahebkar, A. (2024). Anti-inflammatory benefits of semaglutide: State of the art. J. Clin. Transl. Endocrinol., 36.","DOI":"10.1016\/j.jcte.2024.100340"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1186\/s40001-025-03124-y","article-title":"Effect of semaglutide on arrhythmic, major cardiovascular, and renal outcomes in patients with overweight or obesity: A systematic review and meta-analysis","volume":"30","author":"Wu","year":"2025","journal-title":"Eur. J. Med Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2337\/dc22-1889","article-title":"Effects of semaglutide on albuminuria and kidney function in people with overweight or obesity with or without type 2 diabetes: Exploratory analysis from the STEP 1, 2, and 3 trials","volume":"46","author":"Heerspink","year":"2023","journal-title":"Diabetes Care"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Alfaris, N., Waldrop, S., Johnson, V., Boaventura, B., Kendrick, K., and Stanford, F.C. (2024). GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: A narrative review. eClinicalMedicine, 75.","DOI":"10.1016\/j.eclinm.2024.102782"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Wei, T., Ma, J., Cui, X., Lin, J., Zheng, Z., Cheng, L., Cui, T., Lin, X., Zhu, J., and Ran, X. (2025). AI-driven de novo design of ultra long-acting GLP-1 receptor agonists. Adv. Sci., 12.","DOI":"10.1002\/advs.202507044"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1097\/CRD.0000000000000513","article-title":"Cagrilintide: A long-acting amylin analog for the treatment of obesity","volume":"32","author":"Mullally","year":"2024","journal-title":"Cardiol. Rev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1056\/NEJMe2509700","article-title":"Expanding the treat-to-target toolbox for obesity and diabetes care","volume":"393","author":"Hales","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jhep.2022.04.003","article-title":"Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial","volume":"77","author":"Alkhouri","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/14737159.2025.2467969","article-title":"Unraveling the future: Hot topics shaping molecular diagnostics today","volume":"25","author":"Weiskirchen","year":"2025","journal-title":"Expert. Rev. Mol. Diagn."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.annepidem.2025.09.003","article-title":"Artificial intelligence and natural language processing of patient narratives to evaluate semaglutide for weight loss","volume":"111","author":"Bhagavathula","year":"2025","journal-title":"Ann. 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