Metformin-associated lactic acidosis – does severity determine survival?

Metformin is a widely prescribed oral antihyperglycemic drug for the long-term treatment of type 2 diabetes. It is considered a first-line drug treatment for those diabetic patients whose blood glucose remains uncontrolled by dietary and other lifestyle interventions. In addition to this established use, metformin has in recent years been prescribed for treatment of polycystic ovary disease. 

Although a rare occurrence, metformin can cause severe, sometimes fatal, type B (non-hypoxic) lactic acidosis. Intuitively, it would be supposed that the chance of surviving metformin-associated lactic acidosis (MALA) would be related to the severity of the lactate acidosis (i.e. the lower the arterial pH and the higher the blood lactate, the greater the risk of death) or perhaps the degree of metformin accumulation. 

Limited research suggests that is not the case. The issue is revisited in a recently published retrospective study of 56 patients with severe MALA, defined for the purposes of this study as arterial pH <7.0 and blood lactate concentration >10.0 mmol/L. Of the 56 patients, 26 died and 30 survived. 

The mean ±SD of arterial pH among survivors (6.73 ± 0.17) was not significantly different from that of non-survivors (6.79 ± 0.19). Likewise, the mean ±SD of blood lactate concentration among survivors (22.2 mmol/L ± 4.72) was not significantly different from that of non-survivors (24.0 mmol/L ± 8.9). 

Only two patients (one survivor and one non-survivor) had a plasma metformin concentration below the upper limit of the therapeutic range (2.5 mg/L) and most patients (73 %) had marked increase (>25 mg/L). 

Although the mean ±SD plasma metformin concentration among non-survivors (63.3 mg/L ± 47.4) was significantly higher than that among survivors (39.66 mg/L ± 34.22), this difference was accounted for by a single particularly high value (188 mg/L) among the non-survivors. 

Overall the study provides confirmatory evidence that the severity of the lactic acidosis and the degree of metformin accumulation among patients with MALA does not predict survival. Remarkably, this study has demonstrated that it is possible to survive MALA despite arterial blood pH as low as 6.5 and lactate as high as 35 mmol/L; in other circumstances (i.e. non-metformin lactic acidosis) such extreme levels would surely be considered incompatible with life.

The authors of this study also analyzed patient data relating to co-morbidities that are presumed triggering factors for MALA. These triggering conditions, listed by the authors include: renal failure, other organ failure, multi-drug use, sepsis, alcohol abuse among others. The most common MALA triggering condition is renal failure (metformin is contraindicated for patients with reduced renal function because of the risk of lactic acidosis). 

This data revealed that prognosis of MALA is related to the number of triggering co-morbidities. Of 38 patients with just a single triggering medical condition, 25 (68 %) survived and 13 (34 %) died. By contrast, among 15 patients with two or more triggering medical conditions, 3 (20 %) survived and 12 (80 %) died. 

In summary, the authors conclude that prognosis for patients suffering MALA appears to be related to the nature and number of triggering conditions rather than the severity of the acidosis.