Parasympathetic dysfunction assessed by deep‐breathing CVR ‐R is associated with early discontinuation of oral semaglutide in type 2 diabetes: A multicenter retrospective study

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Aims/Introduction Although glucagon‐like peptide‐1 receptor agonists are widely used for type 2 diabetes, gastrointestinal intolerance frequently leads to early discontinuation. Predictors of oral semaglutide discontinuation remain poorly defined, and its formulation‐specific dependence on gastric conditions may influence tolerability. We examined whether the coefficient of variation of R–R intervals (CVR‐R) was associated with discontinuation within 6 months. Materials and Methods In this multicenter retrospective study, 203 consecutive patients initiating oral semaglutide between February 2021 and December 2024 were screened, and 61 were analyzed after exclusions. The Discontinuation Group ( n = 21) discontinued because of nausea and/or vomiting within 6 months, whereas the Maintenance Group ( n = 40) continued for ≥ 6 months. CVR‐R was assessed at rest (CVR‐R_rest) and during deep breathing (CVR‐R_DB). Associations with discontinuation were evaluated using multivariable logistic regression; exploratory machine learning and time‐to‐event analyses were performed. Results CVR‐R_DB was lower in the Discontinuation Group than in the Maintenance Group (median 1.93% vs 3.26%, P < 0.001). CVR‐R_DB remained independently associated with discontinuation after adjustment for age and sex (adjusted OR 0.191; 95% CI 0.071–0.512; P = 0.001; AUC 0.832) and further adjustment for neuropathy stage. The AUC was numerically higher for the age‐ and sex‐adjusted model containing CVR‐R_DB than for that containing CVR‐R_rest (0.832 vs 0.699; DeLong P = 0.085). An internally derived CVR‐R_DB cutoff of 2.55% stratified 6‐month persistence (43.3% vs 87.1%; log‐rank P < 0.001), and machine learning analyses prioritized CVR‐R_DB. Conclusions Lower CVR‐R during deep breathing was associated with early oral semaglutide discontinuation due to nausea and/or vomiting. CVR‐R_DB may support risk stratification at initiation.