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Background and Importance Metformin belongs among the first-line drugs in patients with type 2 diabetes (T2D). Patient compliance with metformin is not optimal, especially owing to frequent gastrointestinal side effects. However, accurate and objectively validated compliance data are thus far not available.Aim and Objectives The aim of our study was to evaluate the adherence to metformin treatment by determining its plasma concentrations during a routine outpatient control.Material and Methods 641 T2D outpatients from a diabetes centre and outpatient clinic using standard or XR (sustained release) form of metformin were included in the study. Blood sampling for metformin, together with a short questionnaire on its use, was performed during a regular visit. Hydrophilic interaction chromatography (HILIC) and high resolution mass spectrometry (Q Exactive Plus instrumentation) were used to quantify metformin concentrations. Values below 100 ng/ml were deemed subtherapeutic.Results Of the 641 patients, subtherapeutic concentrations were measured in 7.6%, of whom in 1.9% the concentration was not detectable at all (<1 ng/ml). The presence of subtherapeutic concentrations was not affected by the administration of the XR form (7.5 vs. 8.5% for standard vs. XR form, n.s.). With increasing number of metformin doses per day the occurrence of subtherapeutic concentrations decreased (15.1% one dose vs. 2.2% 3 doses, p < 0.001), although these patients reported the highest frequency of dose omitting in the questionnaire. However, fasting blood glucose and glycated haemoglobin increased with increasing number of metformin doses per day (both p < 0.001). Metformin serum concentration increased with increasing duration of diabetes (p < 0.001). No significant relationship was found between metformin concentration and fasting blood glucose, HbA 1c or any of the self-reported demographic and lifestyle factors.Conclusion and Relevance In our study, adherence based on the measurement of metformin concentrations reached 92.4%. The lowest incidence of metformin subtherapeutic levels was detected in patients taking highest number of metformin doses per day. Plasma analysis using LC-MS methods may serve as a robust tool for adherence assessment, identifying patients suitable for more detailed pharmacotherapeutic revision to increase adherence and therapeutic effect of treatment.References and/or Acknowledgements 1. Czech MOH (NU20-01-00186); EXCELES (LX22NPO5104); CZ–DRO (IKEM, IN 00023001); Charles University (SVV 260 785).Conflict of Interest No conflict of interest