We read with great interest the letter by Drs. Wang and Hoffman and appreciate the engagement with our research. Our study used a systematic review and meta-analysis methodology to pool published data to examine the relationship between pH, lactate, and mortality in the setting of patients diagnosed with metformin-associated lactic acidosis (MALA). We concluded that the current state of evidence does not support making a prognosis based on pH or lactate [1].
As written in our methods and limitations, our study targeted a specific research question and therefore cannot adequately answer many of the questions asked by Drs. Wang and Hoffman: patient level data regarding disease chronicity, specific treatments, and change in lactate concentration over time are incomplete. As to diagnostic uncertainty, MALA is diagnosed clinically with patient history and ancillary laboratory tests rather than with metformin concentrations; thus, our patient population represents the clinician intention to diagnose MALA and characterizes the case definition [2–4]. Regarding the question of whether mild cases of MALA were missed, our data included a spectrum of severity including mild laboratory derangements: of 170 cases, 42 (24.7%) had a lactate concentration of ≤ 10 mmol/L, and 20 (11.8%) had ≤ 7 mmol/L; 44 (25.9%) had a pH ≥ 7.20, and 94 (55.3%) had a pH of ≥ 7.0.
Although clinicians appropriately use lactate concentration and pH to make prognoses for various disease processes such as sepsis, these laboratory tests have been shown to be insufficient to predict outcome even in scenarios that have markedly abnormal lab parameters [5]. For example, degree of hyperlactatemia does not predict outcomes in diabetic ketoacidosis or trauma [6, 7], nor does significant acidosis imply mortality after seizures or vigorous exercise [8, 9]. Meta-analysis after systematically reviewing the literature failed to yield data demonstrating a correlation between pH, lactate, and death in MALA. The current scarcity of published research in the subject precludes controlling for selection and reporting bias, treatment intensity, and diagnostic uncertainty. To better study MALA would ideally require a prospective randomized multi-center study. Failing that a propensity matched pseudo-randomized retrospective study of complete patient charts or a prospective observational study such as attempted by the ToxIC registry would be needed [10]. Until then, we must take the position of scientific equipoise and affirm our conclusion that the contemporarily available data do not support the role of pH or lactate in prognosticating MALA.
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