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

ABSTRACT 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 2 ; excess gain + 0.6 kg/m 2 ). 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 2 ). 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 2 ; 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.