Abstract
To the Editor,
We read with interest the recent article by Alqurain et al. on factors associated with higher lactate levels among ambulatory patients receiving metformin. The study addresses a clinically relevant question; however, we believe two aspects of the paper warrant closer scrutiny before its findings are translated into practice. 1
First, the authors’ conclusion appears to move beyond what their data can support. Their analysis identified higher lactate levels among metformin users and associations with higher dose, renal disease, diuretics, and NSAIDs. However, lactate testing in this study was not protocolized; it was performed during routine outpatient care or at physician discretion, and the timing relative to the most recent metformin dose was not standardized. In addition, lactate was measured only once, and the study detected no direct short-term clinical consequences attributable to lactate elevation. Under these conditions, the data support an observational signal, not a practice recommendation for routine lactate monitoring. That distinction is important because mildly higher lactate does not necessarily imply clinically meaningful toxicity, particularly when values remain largely borderline rather than frankly pathologic.1,2
Second, several key associations may have been interpreted too confidently in the presence of substantial residual confounding. The inverse association with renin-angiotensin-aldosterone system inhibitors is a clear example. Although the authors appropriately acknowledged possible confounding by indication, the overall discussion still leaves room for a biologically protective reading. Yet the baseline data already show that metformin nonusers had a higher Charlson Comorbidity Index and a markedly higher prevalence of renal disease than users, suggesting strong channeling in prescribing. More importantly, within the multivariable model, “renal disease” was associated with higher lactate, whereas creatinine clearance was not. This internal inconsistency should have prompted a more cautious interpretation of renal vulnerability and medication-related effects, rather than a relatively direct clinical message. In observational pharmacoepidemiology, such discrepancies often signal residual confounding, phenotype misclassification, or limitations in the timing of exposure and laboratory ascertainment rather than a stable mechanistic relationship.1,3
We therefore suggest that the article’s take-home message be narrowed. A more defensible conclusion would be that this study identifies outpatient characteristics associated with slightly higher lactate values during metformin therapy, but does not yet establish that routine lactate surveillance improves clinical decision-making. Framed this way, the article would remain valuable while avoiding overextension from association to monitoring policy. Elevated lactate is a context-dependent biomarker whose interpretation depends heavily on timing, comorbidity burden, renal physiology, and concurrent illness, not medication exposure alone.4,5
