Background: Metformin has been available since 1957. Over 50 years later, one can legitimately question whether a clear definition of its "therapeutic concentrations" is available.
Objective: The objective of this systematic review was to establish whether or not there is a literature consensus on the "therapeutic concentrations" of metformin.
Methods: We systematically searched the scientific literature with the keywords "metformin", "therapeutic concentration", "therapeutic level", and "therapeutic range". When the suggested values were defined by citing a literature reference, the types of studies in cited references and the concordance of data between the citations and theirs sources were studied.
Results: We identified 120 documents that reported or cited 65 different "therapeutic" plasma metformin concentrations or ranges. The values ranged from 0.129 to 90 mg/L, and the lowest and highest boundaries were 0 and 1800 mg/L. Only four original research studies determined a "therapeutic concentration". Fifty-four publications cited previous studies as defining the therapeutic concentrations, whereas 62 publications mentioned "therapeutic concentrations" but did not even cite a supporting reference. The supporting references were mostly reviews, pharmacokinetic studies and in vitro studies. In the 54 publications that cited references, concordance between the wording of the citation and the true nature of the source data was observed in only 23 cases (42.6%).
Limitations: Given the nature of a systematic literature search, the only possible limitation would be incomplete identification and retrieval of publications on therapeutic concentrations. An extensive study of the literature has, however, been performed by examining nearly 1000 potentially relevant publications.
Guidance for clinical practice: The only valid way of defining the therapeutic concentration window for metformin would be to relate dose efficacy (in terms of blood glucose control) to the corresponding plasma concentration in long-term treated patients.
Conclusions: Although metformin has been available for over 50 years and it is the key medication in first-line treatment of type 2 diabetes mellitus, major methodological and/or conceptual errors have confounded the literature on its therapeutic concentrations.