Association between Metformin Use and Risk of Lactic Acidosis or Elevated Lactate Concentration in Type 2 Diabetes

Abstract

PurposeMetformin can reduce diabetes-related complications and mortality. However, its use is limited because of potential lactic acidosis-associated adverse effects, particularly in renal impairment patients. We aimed to investigate the association of metformin use with lactic acidosis and hyperlactatemia in patients with type 2 diabetes.Materials and MethodsThis was a cross-sectional study from a tertiary university-affiliated medical center. A total of 1954 type 2 diabetes patients were recruited in 2007–2011, and stratified according to the estimated glomerular filtration rate of 60 mL/min/1.73 m2. Lactic acidosis was defined as plasma lactate levels >5 mmol/L and arterial pH <7.35.ResultsMetformin was used in 61.4% of the patients with type 2 diabetes mellitus. Plasma lactate levels were not different in the patients with and without metformin use. There was no difference in prevalence of hyperlactatemia and lactic acidosis between the patients with and without metformin use (18.9% vs. 18.7%, p=0.905 for hyperlactatemia and 2.8% vs. 3.3%, p=0.544 for lactic acidosis). Similar results were observed in the patients with estimated glomerular filtration rate <60 mL/min/1.73 m2. Most patients with lactic acidosis had at least one condition related to hypoxia or poor tissue perfusion. Multiple regression analysis indicated no association between metformin use and lactic acidosis, whereas tissue hypoxia was an independent risk factor for lactic acidosis [odds ratio 4.603 (95% confidence interval, 1.327–15.965)].ConclusionMetformin use was not associated with hyperlactatemia or lactic acidosis in patients with type 2 diabetes.

Effect of continuous use of metformin on kidney function in diabetes patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

“…Other studies have also shown that metformin concentrations remain in a therapeutic range in mildly to moderately renal impaired patients [40]. At the same time, growing evidence suggests that the underlying disease associated with the tissue hypoxia rather than metformin use is related to lactic acidosis in diabetes [41][42][43]. In the present research, no case of lactic acidosis was observed during hospitalization for both groups.…”

Metformin-associated lactic acidosis refractory to hemodialysis in the setting of concomitant alcohol intoxication

“…Metformin can reduce diabetes-related morbidities by up to 32%, diabetes-related deaths by up to 42%, and all-cause mortality by up to 36%. 1 Metformin inhibits gluconeogenesis by reducing expression of genes encoding gluconeogenic enzymes. Metformin also increases both insulin sensitivity of peripheral tissues and glucose uptake while decreasing fatty acid oxidation.…”

“…Although metformin is also a biguanide, it does not affect anaerobic lactate production, and the incidence of lactic acidosis with metformin treatment is up to 20-fold lower than that for phenformin. 1,4 Metformin is cleared by the kidneys, and its potential for accumulation in patients having decreased renal function could precipitate lactate accumulation. On the other hand, several studies found no association between metformin use and lactic acidosis, although there are reports of increased metabolic acidosis primarily in patients who had at least one condition associated with decreased tissue perfusion (e.g., renal failure, liver disease, heart failure, myocardial infarct, infection, shock, seizure, or alcohol abuse).…”

Metformin treatment for patients with diabetes and chronic kidney disease: A Korean Diabetes Association and Korean Society of Nephrology consensus statement

“…Because of the potential risk of fatal lactic acidosis, metformin has long been under-prescribed, especially for patients with heart failure (HF) [10]. This situation has changed considerably following recent epidemiological studies that showed the risk of lactic acidosis associated with metformin use was not greater than that of other antidiabetic medications, and that metformin use in patients with DM and HF did not necessarily increase the risk of lactic acidosis [11,12]. We also found that the use of metformin was not associated with an increased incidence of HF in a case-control study of patients with T2DM who were first diagnosed with HF between 2013 and 2015 (Supplementary Table 1; available online).…”