8 The median lactate concentrations were similar in patients who survived and those who died. Similar results were described by Lalau et al, who showed that neither lactate nor metformin concentrations were prognostically related to mortality and that death seemed to be related to other hypoxic disease or underlying ill health. Creatinine concentrations, however, did not correlate with lactic acid concentrations, metformin concentrations, or mortality. Most of the patients developed lactic acidosis in the presence of acute or worsening renal failure. 7 Interestingly, all but one of the cases in this review had at least one risk factor (renal failure, cardiovascular events, pulmonary failure, hepatic failure, alcohol excess, or sepsis) for the development of lactic acidosis independent of metformin use. 7 In contrast, acute cardiovascular events, liver cirrhosis, and sepsis were all associated with an increased mortality risk. 7 In addition, increased concentrations of neither lactic acid nor metformin were associated with increased mortality risk. 7 In a review of published case reports, Stades et al showed that plasma concentrations of metformin were not related to increased lactic acid concentration. Most case reports of lactic acidosis in people taking metformin have failed to provide adequate information to permit assessment of causation, including lactic acid concentrations and pH. Table 1 1 summarises some of these differences. Metformin and phenformin have different pharmacological characteristics that could explain the much lower incidence of lactic acidosis associated with metformin. However, despite increased disregard of contraindications to metformin, as discussed below, the incidence of lactic acidosis has not increased. 3 6 w3 w6 w10-w12 This difference in the incidence of lactic acidosis between metformin and phenformin could be due to more stringent contraindications applied after the experience with phenformin. Phenformin related lactic acidosis had an estimated incidence of 0.25-1 case per 1000 patient years compared with an estimated incidence of 0-0.09 case per 1000 patient years with metformin.
6 w7 w8 Metformin is less likely than phenformin to cause lactic acidosis. 4 5 w4 w7-w9 Most of the evidence for the association between metformin and lactic acidosis is historical data for phenformin (withdrawn in 1977). An increasing body of evidence challenges the so called “contraindications” to metformin. The perceived risk of developing lactic acidosis with metformin is high, particularly in the United States. Metformin and risk of lactic acidosis: what evidence?
In this article we review the evidence for the use of metformin in the presence of stated contraindications and especially for patients with heart failure. 3 w6 w7 The box summarises the current contraindications to metformin use. 2 w4 w5 Perhaps as a result of this, many suitable patients with type 2 diabetes are denied metformin treatment. 1ĭespite the evidence base for the benefits of metformin, concerns remain about its side effects and especially the perceived risk of lactic acidosis in the presence of renal, hepatic, respiratory, or cardiac failure.
1 It was also associated with reduced all cause mortality, which was not seen in patients with equally well controlled blood glucose treated with sulphonylureas or insulin. w2 w3 The UK prospective diabetes study showed that metformin was associated with a lower mortality from cardiovascular disease than sulphonylureas or insulin in obese patients with type 2 diabetes mellitus.
w1 The mechanism of action has been extensively reviewed. Metformin first became available in the United Kingdom in 1957 but was first prescribed in the United States only in 1995. Further studies are needed to assess the risk of lactic acidosis in patients with type 2 diabetes and traditional contraindications to metformin
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