Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and the dual GIP/GLP-1 RA tirzepatide, are widely prescribed for type 2 diabetes mellitus (T2DM). Their musculoskeletal adverse events (AEs) remain underexplored. We analyzed FAERS reports (Q1 2004-Q2 2024) for musculoskeletal and connective tissue disorders. After de-duplication, 15,052 reports were subjected to disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM), and information component (IC). Differences between serious and non-serious events were assessed, and time to onset was examined by cumulative curves and Weibull models. No signals were detected at the SOC level. At the PT level, GLP-1 RAs were linked to back pain, myalgia, and neck mass, while tirzepatide was associated with muscle atrophy and neck mass. Among DPP-4is, sitagliptin, linagliptin, and alogliptin showed signals for osteoarthritis, rhabdomyolysis, and arthritis. Sex-, age-, and weight-related differences were noted for dulaglutide, liraglutide, semaglutide, sitagliptin, linagliptin, alogliptin, and saxagliptin. Median onset was shorter for GLP-1 RAs and tirzepatide (≤ 30 days) and longer for DPP-4is (55-132 days), with vildagliptin latest. Weibull analysis indicated an early-failure pattern for most agents, except saxagliptin, which suggested a borderline wear-out trend. Musculoskeletal AEs associated with incretin therapies differ by drug class and onset timing. Vigilant monitoring is needed during early GLP-1 RA or tirzepatide therapy and later during DPP-4i use to optimize patient safety.
