Causes and consequences of discontinuation of GLP1RAs or tirzepatide.
Tirzepatide keeps making waves in peptide research. This dual GLP-1 and GIP receptor agonist is now a mainstay for researchers focused on type 2 diabetes and obesity. Its ability to lower blood glucose and body weight, with added cardiovascular and renal perks, has put it front and center in metabolic studies.
Nat Rev Endocrinol
by Ceriello A, Prattichizzo F, Mastan Sheik Abdullah AR et al.
“Causes and consequences of discontinuation of GLP1RAs or tirzepatide. Ceriello A(#)(1), Prattichizzo F(#)(2), Mastan Sheik Abdullah AR(3), La Grotta R(2), Berra CC(4), McGowan B(5), Jenkins A(6), Cohen N(6), Nauck MA(7)(8), Russo GT(3). Author information: (1)Polo Scientifico e Tecnologico, IRCCS MultiMedica, Milan, Italy. antonio.ceriello@multimedica.it. (2)Polo Scientifico e Tecnologico, IRCCS MultiMedica, Milan, Italy. (3)Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. (4)Department of Endocrinology and Metabolic Diseases, IRCCS MultiMedica, Milan, Italy. (5)Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK. (6)Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. (7)Diabetes, Endocrinology, Metabolism Section, Medical Department 1, St Josef-Hospital, Katholisches Klinikum Bochum gGmbH, Ruhr University Bochum, Bochum, Germany. (8)Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. (#)Contributed equally Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering and weight-lowering effects as well as their cardiovascular and renal benefits. However, data from the past 2 years suggest that real-world persistence on these drug classes is often suboptimal, with many people discontinuing these medications, even within their first year of therapy. Reasons for treatment discontinuation include, but are not limited to, gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear about uncommon or rare adverse effects. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation of these drugs might induce body weight and HbA1c fluctuations - two risk factors for cardiovascular and microvascular events. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control when not on therapy, might increase the long-term risk of complications. The lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, especially acutely following their discontinuation. However, at present, few data are available regarding the incidence of hard outcomes in people discontinuing such drugs. In this Review, we discuss common reasons for GLP1R agonist and tirzepatide discontinuation and examine available evidence related to potential cardiometabolic consequences. We also discuss long-term implications for T2DM care, weight management and, ultimately, cardiorenal disease prevention in patients with T2DM and/or overweight or obesity. © 2026. Springer Nature Limited. Conflict of interest statement: Competing interests: A.C. reports being on the advisory board, consultancy and giving lectures for Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Hikamr Pharma, Guidotti, Eli Lilly, MSD, Merck, Novo, Roche Diagnostics, Sanofi, Servier, and Sun Pharma. G.T.R. is on the advisory board and does consultancy and lectures for NovoNordisk, AstraZeneca, Sanofi, Boehringer, Lilly, Mundipharma and Sankyo. N.C. and A.J. are investigators on an investigator-initiated trial of tirzepatide in Indigenous Australians with T2DM and suboptimal glycaemia with drug provision by Eli Lilly (Australia). M.A.N. has been a member of advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma and Structure Therapeutics (ShouTi, Gasherbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers’ bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. He is on a data monitoring and safety board for Inventiva. The other authors declare no competing interests.”
But here’s the catch: a lot of researchers are seeing early discontinuation when working with GLP-1 receptor agonists and tirzepatide. Real-world data shows that many subjects stop these research compounds within the first year. Why? Several reasons come up:
GI side effects can be tough to manage
Sometimes the results don’t hit expectations
High cost is always a hurdle
Some are cautious about rare side effects
When tirzepatide is pulled from a research protocol, things shift fast. The data points to weight regain and a rise in cardiometabolic risk factors once the peptide is stopped. Repeated on-off cycles? Expect more fluctuations in body weight and HbA1c. These swings aren’t just numbers—they’re tied to increased risk of cardiovascular and microvascular events.
Key takeaway: Consistency in research peptide exposure matters. Interruptions can lead to a loss of those hard-earned gains in glycemic control and weight management.
There’s still a gap in long-term outcome data post-discontinuation, but the trend is clear. Researchers looking to study tirzepatide’s full potential should consider strategies for optimizing protocol persistence.
For more details on the compound, check the tirzepatide page. Need reputable sources for your own studies? Browse the vendor directory.
Stay tuned—tirzepatide’s story in metabolic research is far from over.
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