Type 2 diabetes mellitus (T2DM) is driven by progressive pancreatic β-cell failure, and few glucose-lowering agents demonstrably modify this defect. This systematic review assessed whether tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, improves β-cell function in adults with T2DM. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, PubMed, Web of Science, Scopus and Embase were searched from inception to July 29, 2026, with citation searching. Eligible reports were original peer-reviewed primary human studies reporting a quantitative measure of β-cell function in adults receiving subcutaneous tirzepatide; preclinical and non-original reports were excluded. Risk of bias was appraised with risk of bias 2 (RoB 2) tool and The Risk Of Bias In Non-randomized Studies of Interventions, Version 2 (ROBINS-I). Heterogeneity of outcome metrics precluded meta-analysis, so findings were synthesised narratively. Eight reports representing six distinct populations and 3,442 unique participants were included. Tirzepatide 5-15 mg weekly raised the Homeostasis Model Assessment 2 of Beta-cell Function (HOMA2-B) by 77% to 163% from baseline, exceeding placebo, dulaglutide and semaglutide 1 mg; fasting intact proinsulin and the intact proinsulin/C-peptide ratio fell by up to 55% and 49%; and the clamp disposition index rose approximately six-fold. Fasting insulin and C-peptide fell in parallel, indicating reduced secretory demand. Risk of bias was low in four reports, of some concern in one, high in two and serious in one. Tirzepatide improves β-cell function indices beyond selective GLP-1 receptor agonism, but the evidence rests largely on post hoc, industry-funded analyses and no study examined function after drug withdrawal. This review was unfunded and unregistered.
