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

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.