Nov 18, 2025

Public workspaceRisk of Acute Pancreatitis with Tirzepatide: A Systematic Review and Meta-Analysis of Randomized and Observational Studies

DOI
https://dx.doi.org/10.17504/protocols.io.5jyl887j9l2w/v1
  • Olivia Benny1,
  • Anurag Agarwal2,
  • Harvey Alecock1,
  • Raksha Ganapathy Subramani1,
  • Anoushka Pawar3,
  • Zubayer Shams4,
  • Mohammad Kermansaravi5,
  • Sjaak Pouwels PhD6,
  • Wah Yang MD7,
  • Chidubem Gerald Obi MD8,
  • Peter Cripps9,
  • Alethea Tang9,
  • Edgar Gelber10,
  • Anil lala10,
  • Khaldoun Nadi9,
  • Adel Mahmoud11,
  • Mohammed Hammoda11,
  • Hashim Al-Sarireh9,
  • Richard Egan11,
  • Daniel Hanratty11,
  • Alexander Drummondh9,
  • Scott Caplin11,
  • Dean Harris9,
  • Jonathan Barry11,
  • Andrew.Beamish 11,
  • Mahmoud Ardah11,
  • Bilal Al-Sarireh11,
  • Samuel Chon Sum Ong9,
  • Shahab Hajibandeh12,
  • Jonathan Roy Honey9,
  • A’mar babneh9,
  • Vincent Ribordy13,
  • Wolf E. Hautz14,
  • Dominik Jakob14,
  • Bijendra Patel15,
  • Isabel Sprackling9,
  • Ayman Ashabi11,
  • Amir Kambal11,
  • Rodolfo J. Oviedo16,
  • Chetan Parmar17,
  • Nicholas Mowbray11,
  • Mohammed Al Hadad18,
  • Khaled Gawdat19,
  • Rebecca Hoffmann20,
  • Sherif Hakky21,
  • Ahmad Al-Sarireh22,
  • Maria Agnieszka Nowak 23,
  • Scott Shikora24,
  • Ahmed R Ahmed21,
  • Suhaib Ahmad9
  • 1School of Medicine, University of Keele, Keele, UK;
  • 2Department of General Surgery, Betsi Cadwaladr University Health Board, Wales, UK.;
  • 3School of Medicine, University of Buckingham, Buckingham, UK;
  • 4Brunel medical school, Brunel University, London, United Kingdom;
  • 5Department of Surgery, Division of Minimally Invasive and Bariatric Surgery, Hazrat-e Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran;
  • 6Department 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;
  • 7Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.;
  • 8Department of Anaesthesia and Critical care, Betsi Cadwaladr University Health Board, Wales, United Kingdom;
  • 9Health Education and Improvement Wales (HEIW), Wales, UK;
  • 10Department of Surgery, Betsi Cadwaladr University Health Board, Wales, United Kingdom;
  • 11Swansea Bay University Health Board, Wales, UK;
  • 12Department of Hepatobiliary and Pancreatic Surgery, Manchester Royal Infirmary Hospital, Manchester, UK.;
  • 13Department of Emergency Medicine, HFR Fribourg – Cantonal Hospital, Villars-sur-Glâne, Switzerland.;
  • 14Department of Emergency Medicine, Inselspital University Hospital of Bern, Bern, Switzerland.;
  • 15Department of General Surgery, Barts Health NHS Trust, London, UK.;
  • 16Department of Surgery, Nacogdoches Medical Center, Nacogdoches, TX 75965, USA;
  • 17Department of Surgery, Whittington Hospital, University College London, London, UK.;
  • 18Metabolic and bariatric surgery centre, Healthpoint Hospital, M42, Abu Dhabi, UAE;
  • 19Department of Surgery, Ain-Shams School of Medicine, Heliopolis, Cairo, Egypt.;
  • 20Coventry University, Coventry, UK.;
  • 21Department of General Surgery, Imperial College London, London, UK.;
  • 22University of Cambridge, Cambridge, UK.;
  • 23School of Medicine, University of Swansea;
  • 24Center for Metabolic and Bariatric Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • NHS
suhaib Ahmad
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DOI: https://dx.doi.org/10.17504/protocols.io.5jyl887j9l2w/v1
Protocol Citation: Olivia Benny, Anurag Agarwal, Harvey Alecock, Raksha Ganapathy Subramani, Anoushka Pawar, Zubayer Shams, Mohammad Kermansaravi, Sjaak Pouwels PhD, Wah Yang MD, Chidubem Gerald Obi MD, Peter Cripps, Alethea Tang, Edgar Gelber, Anil lala, Khaldoun Nadi, Adel Mahmoud, Mohammed Hammoda, Hashim Al-Sarireh, Richard Egan, Daniel Hanratty, Alexander Drummondh, Scott Caplin, Dean Harris, Jonathan Barry, Andrew.Beamish , Mahmoud Ardah, Bilal Al-Sarireh, Samuel Chon Sum Ong, Shahab Hajibandeh, Jonathan Roy Honey, A’mar babneh, Vincent Ribordy, Wolf E. Hautz, Dominik Jakob, Bijendra Patel, Isabel Sprackling, Ayman Ashabi, Amir Kambal, Rodolfo J. Oviedo, Chetan Parmar, Nicholas Mowbray, Mohammed Al Hadad, Khaled Gawdat, Rebecca Hoffmann, Sherif Hakky, Ahmad Al-Sarireh, Maria Agnieszka Nowak , Scott Shikora, Ahmed R Ahmed, Suhaib Ahmad 2025. Risk of Acute Pancreatitis with Tirzepatide: A Systematic Review and Meta-Analysis of Randomized and Observational Studies. protocols.io https://dx.doi.org/10.17504/protocols.io.5jyl887j9l2w/v1
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License,  which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this protocol and it's working
Created: November 18, 2025
Last Modified: November 18, 2025
Protocol Integer ID: 232828
Keywords: estimate of pancreatitis risk, risk of acute pancreatitis, pancreatitis risk, pancreatitis outcome, acute pancreatitis, prior history of pancreatitis, pancreatitis, association between tirzepatide, data on tirzepatide exposure, diabetes mellitus, tirzepatide exposure, tirzepatide, observational studies this systematic review, obesity
Abstract
This systematic review and meta-analysis evaluates the association between tirzepatide and the risk of acute pancreatitis in adults with type 2 diabetes mellitus (T2DM) or obesity. Following PRISMA 2020 guidelines, randomised clinical trials and observational studies were identified through comprehensive searches of MEDLINE and Embase up to August 2025. Eligible studies included adults aged ≥18 years, with obesity or T2DM defined by accepted diagnostic criteria, and no prior history of pancreatitis. Data on tirzepatide exposure, comparators, diagnostic definitions, and pancreatitis outcomes were extracted using a structured template. Risk of bias was assessed using RoB 2.0, ROBINS-I, and JBI tools. Meta-analyses were performed using random-effects models, with heterogeneity quantified using the I² statistic. Subgroup analyses explored dose-dependent effects and risk variation by demographic and clinical features. This review aims to provide an up-to-date, evidence-based estimate of pancreatitis risk associated with tirzepatide to support informed clinical decision-making.
Troubleshooting
Methods
This systematic review and meta-analysis was designed to synthesise evidence from randomised clinical trials (RCTs) and observational studies. The review process followed the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations, which outline 27 essential reporting items to ensure transparency, reproducibility, and methodological rigour [1].
Primary Objective
Following the PICO framework, the primary aim of this review was to quantify the incidence and/or relative risk of acute pancreatitis associated with tirzepatide therapy in adults aged ≥18 years with type 2 diabetes mellitus (T2DM) or obesity. Comparator groups included placebo, no treatment, or alternative glucose-lowering agents such as GLP-1 receptor agonists and SGLT2 inhibitors.
Obesity was defined as a body mass index (BMI) ≥30 kg/m², or ≥27.5 kg/m² for Asian populations, in line with international standards [2,3]. Acute pancreatitis events were included only when explicitly reported by the original studies, either through clinical assessment or via diagnostic coding in administrative datasets.
Secondary Objectives
Secondary analyses aimed to determine:
            •           whether the risk of acute pancreatitis varies according to tirzepatide dose;
            •           whether demographic factors (age, sex, ethnicity) or clinical features (gallstone disease, alcohol consumption, pre-existing pancreatic conditions) modify the association between tirzepatide and acute pancreatitis.
Definitions of Key Concepts
Standardised definitions were applied across all included studies.
 
 
 
Obesity
Obesity was defined as BMI ≥30 kg/m², or ≥27.5 kg/m² for Asian individuals, consistent with WHO recommendations and international consensus guidelines [2,3].
 
Type 2 Diabetes Mellitus
T2DM was defined according to NICE guidance [4], using one or more of the following diagnostic criteria:
            •           HbA1c ≥48 mmol/mol (6.5%);
            •           Fasting plasma glucose ≥7.0 mmol/L;
            •           Random plasma glucose ≥11.1 mmol/L in symptomatic individuals;
            •           2-hour plasma glucose ≥11.1 mmol/L during a 75 g oral glucose tolerance test.
 
Special considerations applied for conditions in which HbA1c may be unreliable (e.g., pregnancy, haemoglobinopathies, anaemia).
 
Acute Pancreatitis
Acute pancreatitis was defined using the Revised Atlanta Classification (2012) and required ≥2 of the following criteria [5]:
            1.         Characteristic abdominal pain (persistent, severe epigastric pain radiating to the back);
            2.         Serum amylase and/or lipase ≥3× upper limit of normal;
            3.         Imaging features consistent with acute pancreatitis on CT, MRI, or ultrasound.
 
Literature Search and Study Selection
A comprehensive search of Ovid MEDLINE and Embase was conducted from database inception to 1 August 2025. Search terms included Medical Subject Headings (MeSH), keywords, and text words relating to tirzepatide, obesity, T2DM, and acute pancreatitis, combined using Boolean operators to maximise study retrieval. Titles and abstracts were independently screened to identify potentially eligible studies. Full-text articles were subsequently assessed against predefined inclusion and exclusion criteria. Only studies reporting populations consistent with the definitions above were retained. Two reviewers (OB and RGS) conducted the screening process independently, with disagreements resolved through consultation with a supervising reviewer (SA).
 

Eligibility Criteria
Inclusion Criteria:
Studies were included if they met all of the following:
            •           Adults aged ≥18 years;
            •           Confirmed diagnosis of T2DM or obesity using accepted criteria;
            •           BMI ≥30 kg/m² (or ≥27.5 kg/m² in Asian participants);
            •           No prior history of pancreatitis;
            •           Tirzepatide used at any dose, frequency, or duration;
            •           Comparator groups comprising placebo, no treatment, or approved glucose-lowering agents (e.g., GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, insulin, sulfonylureas);
            •           RCTs or observational studies;
            •           Published in English.
 
Exclusion Criteria:
Studies were excluded if they met any of the following:
            •           Participants <18 years;
            •           Type 1 diabetes mellitus;
            •           BMI below defined thresholds;
            •           Animal or in vitro studies;
            •           Prior history of pancreatitis;
            •           Non-English publications;
            •           Case reports, case series (<5 patients), dissertations, conference abstracts, or review articles;
            •           Studies without a control group;
            •           Non-randomised trials with inadequate methodological detail;
            •           Follow-up period <4 weeks or unclear treatment duration;
            •           Invalid or inappropriate statistical methods;
            •           Duplicate or non-original research;
            •           Comparator groups or outcomes not aligned with the objectives of this review.
 
Data Extraction
Data extraction was performed using a standardised template, summarised in Table 2. Extracted variables included study characteristics, participant demographics, intervention details, comparator information, outcome definitions, subgroup data, statistical metrics, and follow-up duration.
Data Synthesis
Statistical analysis was conducted using RevMan 5.3. Heterogeneity among studies was quantified using the I² statistic and categorised as low (<50%), moderate (50–69%), or high (≥70%). A fixed-effect model was applied when heterogeneity was low (I² <50%, p >0.1); otherwise, random-effects models were used. Given the variability in study populations and designs, random-effects models were applied for all primary analyses.
 
Where substantial heterogeneity was detected, sensitivity analyses and descriptive comparisons were performed to explore potential contributing factors. Pooled effect estimates were summarised as odds ratios with 95% confidence intervals to evaluate the association between tirzepatide and acute pancreatitis.
Quality Assessment
Risk of bias assessment was carried out using validated tools appropriate to study design: the Cochrane RoB 2.0 tool for RCTs [6], the ROBINS-I tool for non-randomised studies [7], and the JBI checklist for case series [8]. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade overall study quality [9]. Publication bias was evaluated via Egger’s regression test and visual inspection of funnel plot asymmetry, with significance defined as p < 0.05 [10].
Protocol references
1.     https://www.prisma-statement.org/prisma-2020-checklist
2.    WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004 Jan 10;363(9403):157-63. 
3.    Salminen P, Kow L, Aminian A, Kaplan LM, Nimeri A, Prager G, Behrens E, White KP, Shikora S; IFSO Experts Panel. IFSO Consensus on Definitions and Clinical Practice Guidelines for Obesity Management-an International Delphi Study. Obes Surg. 2024 Jan;34(1):30-42.
4. NICE guideline NG28 – Type 2 diabetes in adults: management. (https://www.nice.org.uk/guidance/ng28).
5.  Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. 
6.  Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. 
7.  Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, Carpenter JR, Chan AW, Churchill R, Deeks JJ, Hróbjartsson A, Kirkham J, Jüni P, Loke YK, Pigott TD, Ramsay CR, Regidor D, Rothstein HR, Sandhu L, Santaguida PL, Schünemann HJ, Shea B, Shrier I, Tugwell P, Turner L, Valentine JC, Waddington H, Waters E, Wells GA, Whiting PF, Higgins JP. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;355:i4919. 
8.Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Lisy K, Qureshi R, Mattis P, Mu P. Systematic reviews of etiology and risk (2020). Aromataris E, Lockwood C, Porritt K, Pilla B, Jordan Z, editors. JBI Manual for Evidence Synthesis. JBI; 2024. Available from: https://synthesismanual.jbi.global. https://doi.org/10.46658/JBIMES-24-06
9. Oxford Centre for Evidence-Based Medicine. Levels of Evidence (March 2009) https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009
10.  Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997 Sep 13;315(7109):629-34. doi: 10.1136/bmj.315.7109.629.