Pre-Pregnancy GLP-1 Receptor Agonist or Tirzepatide Use and Gestational Diabetes Risk: Evaluating Pharmacodynamic Carry-Over Versus Post-Discontinuation Metabolic Rebound in a Multinational Federated Cohort.

AIM: To evaluate the association between preconception glucagon-like peptide-1 receptor agonist (GLP-1RA)/tirzepatide use and the risk of gestational diabetes mellitus (GDM). METHODS: This retrospective cohort study (January 1, 2015-April 30, 2025) utilised the TriNetX multinational network. Women (18-45 years) without pre-existing diabetes were propensity score-matched 1:1 on demographics, numerical BMI, HbA1c and comorbidities. The primary cohort examined preconception GLP-1RA/tirzepatide use 6-18 months before index pregnancy encounter with pre-pregnancy (> 90 days pre-index) discontinuation. Secondary analysis evaluated abrupt discontinuation (prescription issuance ≤ 90 days pre-index). Risk ratios (RR) were estimated in matched cohorts. RESULTS: When matched for pre-pregnancy BMI, preconception GLP-1RA/tirzepatide use was associated with a GDM risk comparable to non-users (N = 892; 16.3% vs. 16.8%; RR: 0.967; 95% CI: 0.719-1.315), despite a higher gestational BMI rebound (+1.8 vs. +1.2 kg/m; excess gain + 0.6 kg/m). Conversely, abrupt discontinuation was associated with a 53% increase in GDM risk (N = 578; RR: 1.536; 95% CI 1.020-1.955; p = 0.039), likely driven by a steeper BMI rebound (excess gain + 1.3 kg/m). Sensitivity analysis, matched on pre-treatment window, confirmed similar GDM incidence despite higher residual mean BMI in treated women (37.0 vs. 35.0 kg/m; RR: 0.988, 95% CI 0.701-1.378). CONCLUSIONS: Preconception GLP-1RA or tirzepatide therapy with pre-pregnancy discontinuation was associated with GDM risk comparable to BMI-matched unexposed women despite a modest BMI rebound. However, abrupt discontinuation close to conception conferred a 53% higher GDM risk, indicating that any pharmacodynamic carry-over effect is contingent upon the discontinuation timing and velocity of weight rebound during gestation, rather than preconception exposure itself. Pending confirmation in prospective studies, these findings identify the post-withdrawal window and subsequent weight rebound as targets for preconception care strategies to preserve a potential residual metabolic benefit in women receiving incretin-based therapy.