Dose-response analysis of tirzepatide and acute pancreatitis: An international systematic review and quantitative meta-analysis of randomised trials.

“Dose-response analysis of tirzepatide and acute pancreatitis: An international systematic review and quantitative meta-analysis of randomised trials. Benny O(1), Agarwal A(2), Alecock H(1), Subramani RG(1), Pawar A(3), Shams Z(4), Kermansaravi M(5), Pouwels S(6), Yang W(7), Obi CG(8), Cripps P(9), Tang A(9), Gelber E(2), Lala A(2), Nadi K(9), Mahmoud A(10), Hammoda M(10), Al-Sarireh H(9), Egan R(10), Hanratty D(10), Drummond A(9), Caplin S(10), Harris D(10), Barry J(10), Beamish A(10), Al-Ardah M(10), Al-Sarireh B(10), Sum Ong SC(9), Hajibandeh S(11), Honey JR(9), Dababneh A(9), Ribordy V(12), Hautz WE(13), Jakob D(13), Patel B(14), Sprackling I(9), Ashabi A(10), Kambal A(10), Oviedo RJ(15), Parmar C(16), Mowbray N(10), Al Hadad M(17), Gawdat K(18), Hoffmann R(19), Hakky S(20), Al-Sarireh A(21), Nowak MA(22), Shikora S(23), Ahmed AR(20), Ahmad SJ(24). Author information: (1)School of Medicine, University of Keele, Keele, UK. (2)Department of General Surgery, Betsi Cadwaladr University Health Board, Wales, UK. (3)School of Medicine, University of Buckingham, Buckingham, UK. (4)Brunel Medical School, Brunel University, London, UK. (5)Department of Surgery, Division of Minimally Invasive and Bariatric Surgery, Hazrat-e Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. (6)Department of Surgery, University Hospital OWL of Bielefeld University, Campus Klinikum Lippe, Detmold, NRW, Germany/Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands. (7)Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China. (8)Department of Anaesthesia and Critical Care, Betsi Cadwaladr University Health Board, Wales, UK. (9)Health Education and Improvement Wales (HEIW), Wales, UK. (10)Swansea Bay University Health Board, Wales, UK. (11)Department of Hepatobiliary and Pancreatic Surgery, Manchester Royal Infirmary Hospital, Manchester, UK. (12)Department of Emergency Medicine, HFR Fribourg - Cantonal Hospital, Villars-sur-Glâne, Switzerland. (13)Department of Emergency Medicine, Inselspital University Hospital of Bern, Bern, Switzerland. (14)Department of General Surgery, Barts Health NHS Trust, London, UK. (15)Department of Surgery, Nacogdoches Medical Center, Nacogdoches, TX, 75965, USA. (16)Department of Surgery, Whittington Hospital, London, UK; University College London, London, UK. (17)Metabolic and Bariatric Surgery Centre, Healthpoint Hospital, M42, Abu Dhabi, United Arab Emirates. (18)Department of Surgery, Ain-Shams School of Medicine, Heliopolis, Cairo, Egypt. (19)Coventry University, Coventry, UK. (20)Department of General Surgery, Imperial College London, London, UK. (21)University of Cambridge, Cambridge, UK. (22)School of Medicine, Swansea University, Wales, UK. (23)Center for Metabolic and Bariatric Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (24)Health Education and Improvement Wales (HEIW), Wales, UK; Inselspital, University Hospital of Bern, University of Bern, Switzerland. Electronic address: Suhaibsami94@gmail.com. BACKGROUND: Tirzepatide, a dual GIP/GLP-1 receptor agonist for type 2 diabetes and obesity, carries a theoretical risk of pancreatitis. Whether risk varies by dose is uncertain. METHODS: Randomised controlled trials (RCTs) reporting outcomes from Tirzepatide 5, 10, and 15 mg once weekly were systematically reviewed. The primary outcome was acute pancreatitis, interpreted against the Revised Atlanta criteria where available. Pooled risk ratios (RRs) were calculated using Mantel-Haenszel random-effects models with a small continuity correction for single-zero trials; double-zero trials were excluded as non-informative. Sensitivity analyses excluded single-zero studies. Poisson generalised linear mixed models (GLMMs) with study-level random intercepts assessed robustness and explored age/sex as moderators. Risk of bias used RoB 2.0. RESULTS: Nineteen RCTs (n = 15,471) met inclusion criteria. Acute pancreatitis was exceedingly rare (0.22%). Head-to-head dose comparisons showed no significant differences: 10 mg vs 5 mg (RR 0.78, 95% CI 0.29-2.09), 15 mg vs 5 mg (RR 0.70, 0.27-1.82), and 15 mg vs 10 mg (RR 1.13, 0.42-3.02); sensitivity analyses were concordant. GLMMs yielded similar inferences; age and sex did not materially modify risk. Most RoB 2.0 domains were low risk, with some concerns for missing data/selective reporting. All trials were industry-funded with short-to-moderate follow-up; funnel plots were underpowered. CONCLUSIONS: Across RCTs, acute pancreatitis with Tirzepatide is rare and shows no demonstrable dose-response between 5 and 15 mg. Precision remains limited; clinicians should maintain vigilance, optimise modifiable risks, individualise dosing, and contribute to post-marketing surveillance. Copyright © 2026 IAP and EPC. Published by Elsevier B.V. All rights reserved. Conflict of interest statement: Declerations competing interest The authors declare no conflict of interest. Data are available on reasonable request from corresponding author.”