Causes and consequences of discontinuation of GLP1RAs or tirzepatide

This review finds that many people stop taking GLP1 receptor agonists or tirzepatide within their first year in real-world use, often due to side effects, cost, or unmet expectations. Stopping is linked to weight regain, worsening cardiometabolic risk factors, and potentially harmful HbA1c and body-weight fluctuations with repeated restart cycles.

Narrative review. Population: people with type 2 diabetes mellitus and/or overweight or obesity. Interventions: GLP1 receptor agonists; tirzepatide. Cited by 1 other paper.

The review reports that data from the past 2 years indicate suboptimal real-world persistence, with discontinuation often occurring within the first year. Common reasons include gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear of uncommon or rare adverse effects. After discontinuation, weight regain and deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation may induce body weight and HbA1c fluctuations, which are risk factors for cardiovascular and microvascular events. The authors note that few data are available on the incidence of hard outcomes in people who discontinue these drugs.

For researchers studying tirzepatide, this review highlights that discontinuation is a common real-world problem that may blunt long-term cardiovascular and metabolic benefits. It also clarifies that the paper does not establish a causal link between discontinuation and hard outcomes, because such evidence is currently lacking.

Key findings

Real-world persistence on GLP1R agonists and tirzepatide is often suboptimal, with many people discontinuing within the first year.
Discontinuation commonly results in weight regain and deterioration of multiple cardiometabolic risk factors.
Repeated initiation, interruption and re-initiation can induce body weight and HbA1c fluctuations.
These fluctuations, plus re-development of obesity and poor glycaemic control off therapy, may increase long-term complication risk.
Few data are available on hard outcomes after discontinuation, although incretin-based medications lack proven anti-atherosclerotic effects.

Limitations

Authors state that few data are available regarding hard outcomes after discontinuation.
Review article without systematic methodology, so conclusions rely on selected evidence.
Observational real-world studies cited are prone to confounding and bias.
No original patient-level data are presented.

The record

Journal: Nature reviews. Endocrinology 22(9): 530-542
Published: 2026-05-21
PMID: 42168641 — DOI: 10.1038/s41574-026-01258-5
MeSH terms: Humans, Diabetes Mellitus, Type 2, Obesity, Hypoglycemic Agents, Treatment Interruption, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide
Author countries: Australia, Germany, Italy, UK

Peptide profiles: Tirzepatide.

All indexed evidence: Tirzepatide trials & papers.