Metformin and lactic acidosis: cause or coincidence? A review of case reports

Abstract

. Objective. Metformin has been associated with the serious side‐effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis. Design. A literature search of the Index Medicus (1959–66) and of the databases Embase, Medline, Medline Express (1966–99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin‐induced lactic acidosis (MILA) were cross‐referenced. Subjects. Cases were included for analysis if they met the following criteria: serum pH ≤7.35, lactate concentration ≥5 mmol L−1. Intervention. A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2). Main outcome measures. Statistical analysis included the paired interobserver agreement (κ) and multivariate regression analysis. Results. Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2–10). The κ‐value was 0.041 (SD = 0.24, range −0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations. Conclusions. Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.

Contraindications can damage your health—is metformin a case in point?

“…Notwithstanding, neither serum lactate concentrations nor the prognosis of lactic acidosis appear to be determined by the serum concentration of metformin, but rather by the severity of the underlying hypoxic disease and comorbidities [24,30,31]. This indicates that neither lactate nor metformin levels can predict the risk of lactic acidosis in a given patient, and is compatible with the hypothesis that metformin does not play a causative role.…”

“…These patients were mostly elderly and had multiple comorbidities, including advanced renal failure, hepatic failure, heart failure, myocardial infarction and septicaemia [22][23][24]. The mortality of cases of metformin-associated lactic acidosis published before 1996 was 40-50% [23].…”

Metformin in advanced chronic kidney disease: are current guidelines overly restrictive?

“…62 Indeed, case reports have frequently identified kidney failure (both acute and chronic) as a risk factor. [63][64][65] Despite this, only a few experimental studies have tried to establish whether reduced metformin clearance in CKD is associated with an increased serum lactate level. In the only randomised control trial, Rachmani et al randomly assigned 393 type 2 diabetics with a serum creatinine of 130-200 μmol/L to continue or stop metformin.…”

Les nouvelles promesses de la metformine

“…À cause du risque d'acidose lactique, la metformine est contre-indiquée dans toutes les situations pathologiques pouvant provoquer, soit une hypoxie tissulaire ou une ischémie (comme en cas d'insuffisance cardiaque ou pulmonaire), soit une accumulation de metformine dans l'organisme par défaut d'élimination (comme en cas d'insuffisance rénale ou hépatique). Toutefois, le rôle causal de la metformine dans la plupart des cas d'acidoses lactiques rapportés n'est pas totalement avéré [4]. La metformine n'expose pas au risque d'hypoglycémie par interaction médicamenteuse.…”