{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:59:38Z","timestamp":1791323978847,"version":"4.3.1"},"reference-count":203,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents to transformative therapies across multiple organ systems. This comprehensive review synthesizes current evidence on the mechanisms, established applications, and emerging therapeutic frontiers of GLP-1 RAs. Methods: We conducted a systematic literature search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception through May 2025, using controlled vocabulary and free-text terms related to GLP-1 RAs, their mechanisms, and clinical applications. Results: GLP-1 RAs demonstrate pleiotropic effects through fundamental cellular mechanisms, including enhanced mitochondrial function, anti-inflammatory actions, improved cellular quality control, and comprehensive metabolic regulation. Established applications demonstrate robust efficacy in diabetes management (HbA1c reductions of 1.5\u20132.0%), obesity treatment (weight loss of 7\u201324%), and cardiovascular protection (14\u201320% reduction in major adverse cardiovascular events, or MACE). Emerging applications span neurological disorders, dermatological conditions, respiratory diseases, and novel applications in addiction medicine and autoimmune disorders. Conclusions: GLP-1 RAs represent a paradigmatic shift toward multi-system therapeutic intervention, with expanding evidence supporting their role as comprehensive metabolic modulators.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081036","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T08:10:32Z","timestamp":1754899832000},"page":"1036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Emerging Frontiers in GLP-1 Therapeutics: A Comprehensive Evidence Base (2025)"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8474-2463","authenticated-orcid":false,"given":"Shikha","family":"Patel","sequence":"first","affiliation":[{"name":"mAbtide Scientific Communications, Ahmedabad 380001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-0336","authenticated-orcid":false,"given":"Sarfaraz K.","family":"Niazi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Illinois, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12933-025-02608-9","article-title":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and cardiometabolic protection: Historical development and future challenges","volume":"24","author":"Westermeier","year":"2025","journal-title":"Cardiovasc. 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