Factors potentiating risk of higher lactate level associated with metformin therapy: a cross-sectional study in an ambulatory care setting

Background: Metformin is the first-line pharmacological treatment for type 2 diabetes mellitus. Metformin-associated lactic acidosis is uncommon; however, subclinical increases in lactate levels can yield considerable clinical consequences, warranting regular surveillance in high-risk patients. Limited data exist on the patterns of metformin dosing and specific patient factors that may elevate lactate levels, indicating a critical need for further investigation. Objectives: This study aimed to determine the patterns of metformin dosing and identify patient-specific factors associated with higher lactate levels. Design: A retrospective, cross-sectional study. Methods: Patients who attended the endocrinology and internal medicine clinic between January 2021 and December 2022 were included. Patients’ data, including demographics, comorbidities, prescribed medications, and laboratory tests, were collected from electronic health records. Patients were categorized based on age (middle-aged <65 years and older ⩾65 years) and metformin dosage (low, medium, and high). Univariable analyses were performed to assess the difference between the comparison groups. Multivariable linear regression analysis was performed to identify factors associated with elevated lactate levels. Results: Among 3304 diabetic patients, 2329 were metformin users. Metformin users exhibited significantly higher lactate levels (1.9 vs 1.0 mmol/L, p < 0.001) compared to nonusers. Older patients had a higher prevalence of comorbidities such as heart failure (74 vs 55, p < 0.001) and renal disease (3 vs 1, p = 0.01) but received lower metformin doses compared to middle-aged patients. Increasing metformin dosage (β = 0.66, p < 0.001), renal impairment (β = 0.2, p < 0.001) and co-prescription of diuretics (β = 0.2, p < 0.001) and nonsteroidal anti-inflammatory drugs (β = 0.1, p = 0.001) were associated with elevated lactate level, whereas co-prescription of renin-angiotensin-aldosterone inhibitors showed negative association with high lactate level (β = −0.25, p < 0.001). Conclusion: Metformin users demonstrated higher lactate levels, with increasing doses and renal impairment being key risk factors. This study calls attention to the importance of routine lactate monitoring, particularly in older adults and patients with renal dysfunction or polypharmacy.