Sustained Low-Dose Semaglutide Is Linked to Broad-Spectrum Cardiometabolic Benefits, and Better Tolerability Profile over Low-Dose Tirzepatide, Motivating Semaglutide Microdosing Studies

Semaglutide and tirzepatide are typically evaluated through dose escalation, yet many patients in routine care do not reach a recommended maintenance dose due to tolerability, access, cost, supply or individualized goals. Here we used sustained 0.25 mg-only semaglutide and sustained 2.5 mg-only tirzepatide exposures as real-world proxies for “microdosing” and analyzed de-identified electronic health records from a federated system of 29 million patients. Among 490,072 semaglutide-treated patients, 814 met stringent sustained low-dose criteria including at least 3 distinct 0.25 mg prescriptions with at least 6 months between the first and last qualifying prescriptions. In a matched head-to-head comparison aided by AI-enabled curation of clinical notes, sustained low-dose tirzepatide showed a worse 24-month adverse event profile (p