Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41399474 · doi:10.1016/j.eclinm.2025.103680
What was done
This systematic review and meta-analysis searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov through October 17, 2025, for randomized controlled trials assessing GLP-1 receptor agonist (GLP-1RA) discontinuation in adults and adolescents with obesity, type 2 diabetes, or type 1 diabetes with at least 12 weeks of post-cessation follow-up. Random-effects models estimated pooled mean differences in anthropometric, glycemic, cardiovascular, and lipid outcomes between treatment end and follow-up. Risk of bias and evidence certainty were evaluated using Cochrane ROB 2.0 and GRADE.
What was found
Across 18 RCTs (3,771 participants, all rated low risk of bias): - Obesity: Discontinuation led to body weight gain of 5.63 kg (95% CI: 3.52-7.73, I2 = 99.57%, moderate certainty) and an HbA1c increase of 0.25% (95% CI: 0.18-0.32, I2 = 98.45%, moderate certainty), with significant deterioration in waist circumference, BMI, systolic blood pressure (SBP), and fasting plasma glucose (FPG). - Type 2 diabetes: Weight gain was 2.03 kg (95% CI: 1.63-2.42, I2 = 42.28%, moderate certainty) and HbA1c increased by 0.65% (95% CI: 0.22-1.08, I2 = 96.83%, moderate certainty), while FPG remained stable (0.90 mmol/L, 95% CI: -0.36 to 2.17, I2 = 98.81%, moderate certainty). - Modifiers: Weight regain was higher with follow-up >26 weeks (7.31 kg vs. 2.51 kg) and with semaglutide versus liraglutide (8.21 kg vs. 4.29 kg). Semaglutide also showed larger increases in waist circumference (3.80 cm vs. 2.69 cm) and SBP (7.09 mmHg vs. 1.56 mmHg).
Why it matters
These findings show that metabolic and cardiovascular improvements achieved with GLP-1RAs are largely lost following treatment cessation. Clinical practice guidelines must develop structured long-term maintenance and discontinuation protocols rather than treating GLP-1RA use as a temporary intervention.
Limits
Statistical heterogeneity was extremely high for most pooled outcomes (I2 exceeding 96% to 99%). Post-discontinuation follow-up was limited in duration (minimum 12 weeks). Although the review protocol included adolescents and individuals with type 1 diabetes, specific pooled outcomes for these groups were not reported in the abstract. Minor publication bias asymmetry was detected for VLDL in obesity and weight change in type 2 diabetes.
Cited by
- supports Studies show that newer GLP-1 receptor agonists like semaglutide cause more rapid and excessive weight regain after discontinuation compared to older agents like liraglutide and exenatide.