Challenge in identifying MALA without plasma metformin levels

Abstract

Type 2 diabetes mellitus (T2DM) remains a major and steadily growing global public health challenge. Metformin, a biguanide agent, is widely recommended as first-line therapy because of its glycemic efficacy, low risk of hypoglycemia when used as monotherapy, weight neutrality, cardiovascular benefits, and low cost. Nevertheless, metformin-associated lactic acidosis (MALA), although uncommon, is a life-threatening adverse drug reaction with high reported mortality. Diagnosing MALA in real-world practice is particularly challenging because clinical manifestations are non-specific and frequently overlap with comorbid systemic conditions that can independently cause lactic acidosis.

       This article reviews the pathophysiology and clinical evaluation of lactic acidosis in patients receiving metformin, emphasizing contemporary concepts that distinguish metformin-induced lactic acidosis (MILA), metformin-associated lactic acidosis (MALA), and metformin-unrelated lactic acidosis (MULA), as well as the clinical relevance of Type A versus Type B lactic acidosis. Key diagnostic criteria, including lactate elevation and acidemia, are summarized alongside practical considerations in emergency settings where metformin levels are often unavailable. The review also highlights major clinical risk factors—particularly renal dysfunction, sepsis, shock, hypoxia, dehydration, advanced age, and alcohol use—and discusses inter-individual variability in metformin exposure driven in part by transporter gene polymorphisms (e.g., OCT and MATE pathways), which may influence susceptibility and disease severity. In addition, the roles of structured causality assessment tools (WHO–UMC and the Naranjo scale) and pharmacist-led pharmacovigilance are discussed to support consistent case evaluation and adverse event reporting.

       Overall, MALA should not be inferred solely from plasma metformin concentrations, given substantial variability and an inconsistent relationship with clinical severity. In many cases, metformin acts as an “amplifier” of lactic acidosis in the presence of concurrent systemic illness rather than the sole causal agent. An integrated approach combining clinical context and laboratory findings is therefore essential to enable timely recognition, appropriate management, and improved patient safety.

Keywords: type 2 diabetes mellitus; metformin; lactic acidosis; metformin-associated lactic acidosis; pharmacovigilance; causality assessment; emergency medicine