Systematic Reviews
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2025; 16(4): 101731
Published online Apr 15, 2025. doi: 10.4239/wjd.v16.i4.101731
Reasons for discontinuing tirzepatide in randomized controlled trials: A systematic review and meta-analysis
Abul Bashar Mohammad Kamrul-Hasan, Joseph M Pappachan, Deep Dutta, Lakshmi Nagendra, Mohammad Shafi Kuchay, Nitin Kapoor
Abul Bashar Mohammad Kamrul-Hasan, Department of Endocrinology, Mymensingh Medical College, Mymensingh 2200, Dhaka, Bangladesh
Joseph M Pappachan, Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
Joseph M Pappachan, Department of Endocrinology, KMC Medical College, Manipal University, Manipal 576104, India
Deep Dutta, Department of Endocrinology, CEDAR Superspeciality Healthcare, Dwarka New Delhi 110075, India
Lakshmi Nagendra, Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, India
Mohammad Shafi Kuchay, Department of Endocrinology and Diabetes, Medanta the Medicity Hospital, Gurugram 122001, Haryana, India
Nitin Kapoor, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
Nitin Kapoor, Non-Communicable Disease Unit, Melbourne School of Population and Global Health, University of Melbourne, Carlton 3053, Victoria, Australia
Author contributions: Kamrul-Hasan ABM and Pappachan JM contributed to the design, implementation of the study and the writing of the manuscript; Kamrul-Hasan ABM, Pappachan JM, and Dutta D contributed to the statistical analyses and performance of the research; Nagendra L, Dutta D, and Kuchay MS contributed to the quality and professional revision and the writing of the manuscript; Pappachan JM and Kapoor N supervised the manuscript preparation and editing the work in the final form.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Joseph M Pappachan, MD, FRCP, Professor, Senior Researcher, Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom. drpappachan@yahoo.co.in
Received: September 24, 2024
Revised: December 21, 2024
Accepted: January 14, 2025
Published online: April 15, 2025
Processing time: 156 Days and 17.8 Hours
Abstract
BACKGROUND

Despite therapeutic benefits, discontinuation of tirzepatide is common in randomized controlled trials (RCTs) due to adverse events (AEs) and other causes. No previous systematic reviews have explored the reasons for discontinuing tirzepatide in the RCTs.

AIM

To explore the reasons for permanent discontinuation of tirzepatide vs controls [placebo, insulin, and glucagon-like peptide-1 receptor agonists (GLP-1Ras)] in RCTs.

METHODS

Relevant RCTs were systematically searched using related terms through multiple databases such as MEDLINE (via PubMed), Scopus, Cochrane Central Register, and ClinicalTrials.gov from their inception until June 20, 2024. RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).

RESULTS

Seventeen RCTs (n = 14645), mostly having low risks of bias, were analyzed. Compared to placebo, the risk of permanent discontinuation of the study drug was substantially lower with tirzepatide 10 mg (RR: 0.69, 95%CI: 0.51-0.93, P = 0.02) and similar with tirzepatide 5 mg (RR: 0.74, 95%CI: 0.47-1.17, P = 0.20) and 15 mg (RR: 0.94, 95%CI: 0.68-1.31, P = 0.71). Tirzepatide had identical discontinuation risks when compared to insulin at 5 mg (RR: 0.96, 95%CI: 0.75-1.24, P = 0.77) and 10 mg (RR: 1.19, 95%CI: 0.77-1.82, P = 0.44) doses, whereas such risk was higher with tirzepatide 15 mg than insulin (RR: 1.31, 95%CI: 1.03-1.67, P = 0.03). Compared to GLP-1RA, the permanent discontinuation risk was similar with tirzepatide 5 mg (RR: 0.98, 95%CI: 0.70-1.37, P = 0.90) but was higher with tirzepatide 10 mg (RR: 1.40, 95%CI: 1.03-1.90, P = 0.03) and 15 mg (RR: 1.70, 95%CI: 1.27-2.27, P = 0.0004). Tirzepatide, at all doses, had higher risks of AE-related discontinuation than insulin; such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RA. Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin. Compared to the placebo, tirzepatide (all doses) conferred a lower risk of study drug discontinuation due to other causes not specifically mentioned.

CONCLUSION

The discontinuation risk is not higher in tirzepatide group than in the placebo arm. Many factors other than AEs led to drug discontinuation in the included RCTs.

Keywords: Tirzepatide; Drug adherence; Study drug discontinuation; Adverse events; Withdrawal by the study subjects

Core Tip: The reasons for permanent discontinuation of tirzepatide vs controls [placebo, insulin, and glucagon-like peptide-1 receptor agonists (GLP-1Ras)] are not systematically assessed based on data from randomized controlled trials. We studied 17 randomized controlled trials (n = 14645) and found that the risks of study drug discontinuation were greater with higher doses of tirzepatide than with insulin or GLP-1RAs. Tirzepatide, at all doses, had higher risks of adverse event-related discontinuation than insulin. Such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RAs. Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin.