Semaglutide and Tirzepatide in Type 1 Diabetes: Real-World Insulin-Dose Reduction, Metabolic Outcomes and Safety Assessment

Background: Semaglutide and tirzepatide are not approved for type 1 diabetes (T1D), and their real-world effects on insulin requirements, metabolic outcomes, and safety are uncertain. Methods: Using de-identified electronic health record data from a federated U.S. network (2018–2025), adults with T1D who initiated semaglutide (n = 1447) or tirzepatide (n = 568) were matched 1:1 to unexposed adults with T1D on demographics, comorbidities, glycated hemoglobin (HbA1c), body mass index (BMI), estimated glomerular filtration rate (eGFR), T1D duration, healthcare utilization, and calendar year (Cohort A). Insulin total daily dose (TDD) was analyzed in a second cohort additionally matched on baseline TDD and insulin delivery modality (Cohort B; 337 semaglutide and 117 tirzepatide pairs). Results: At 12 months, TDD changed by −12.9% with semaglutide versus −2.6% in matched controls (difference −10.4 percentage points [pp]; p < 0.001) and by −10.4% with tirzepatide versus +13.3% (difference −23.7 pp; p = 0.02); a ≥10% TDD reduction was reached by 41% versus 21% of patients with semaglutide and 47% versus 11% with tirzepatide (both p < 0.001). Among semaglutide-treated patients, 6-month-TDD reduction was −24.1%, −12.6%, and −5.6% with ≥10% weight loss, 0 to <10% loss, and weight gain (p < 0.001), but did not vary with HbA1c change (p = 0.95) or semaglutide dose (p = 0.50). At 12 months, HbA1c fell 0.31 pp more with semaglutide than in controls (p < 0.001) and 0.19 pp more with tirzepatide (p = 0.07); body weight fell 3.3 pp and 5.1 pp more with semaglutide and tirzepatide, respectively (both p < 0.001). Relative to matched controls, the 365-day risk of nausea or vomiting rose 8.6 pp after semaglutide or tirzepatide initiation (p < 0.001) and constipation rose 3.4 pp (p = 0.003), whereas diabetic ketoacidosis (+0.3 pp; p = 0.63) and severe hypoglycemia (−0.8 pp; p = 0.39) did not change significantly. Conclusion: In routine care, adjunctive semaglutide and tirzepatide were associated with lower insulin requirements, modest HbA1c improvement, and weight loss in adults with T1D, with a gastrointestinal-predominant adverse-event profile. Randomized trials are needed to establish efficacy and safety.