[e-drug] Metformin and lactic acidosis

["Leo Offerhaus" <offerhausl@euronet.nl>]

E-DRUG: Metformin and lactic acidosis
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Dear  E-Druggers,

       This is especially important because metformin is on the WHO List of Essential
         Medicines and therefore widely used in developing countries ......    

- Metformin and lactic acidosis - an almost forgotten but potentially lethal side effect.

 Recently the Dutch Medical Journal (Nederlands Tijdschrift voor Geneeskunde 2007;151:977-980 and 981-4) published two fatal cases of lactic acidosis due to metformin; one in an elderly woman where renal function was misjudged, and one due to a suicidal attempt with a massive dose (100 tablets) metformin. 

Lactic acidosis due to metformin is said to be very rare, but available data were extracted from large trials in selected patients (Wiholm et al. Eur J Clin Pharmacol 1993;44:589-91). Incidence from spontaneous reports seems to be much higher (Nisbet et al. Med J Aust 2004;180:53-4) . 

Metformin is the successor of two ill-fated biguanides, phenformin and buformin, which were both removed from the market in the late fifties after large numbers of patients had died as a consequence of the complication, resp. in the USA and in Switzerland. 

It has been on the European market since 1979, but was held up by the FDA until 1994 because of doubts about its safety. The risk was well known and comprehensively described in Australia, but less attention was paid to it in the European and American press. 

Bochner et al. in their Clinical Pharmacology Handbook as early as 1978/1979 warned against usein the elderly, because the majority of cases of lactic acidosis were described in patients over 60, and in patients with decreased renal function, and even then the warning was given that a 
"normal" level of serum creatinine in elderly patients does not exclude substantial impairment of renal function because of a much lower muscle mass - a warning which was repeated in the recent 
article in the Dutch Medical Journal. 

PPI warnings that regular monitoring of renal function is mandatory are rather useless if no facilities to measure creatinine CLEARANCE are available. This is especially important because metformin is on the WHO List of Essential Medicines and therefore widely used in developing countries where such monitoring is impracticable or impossible. The early symptoms of lactic acidosis are vague, but a characteristic laboratory sign is the existence of a so-called "anion gap", i.e. severe unexplained acidosis combined with a marked disparity of serum sodium and chloride levels. The complication ends in death in 30-50% of cases.

It is regrettable that in most data sheet texts this complication is more or less "buried" between enumerations of scores of other possible adverse reactions. Metformin is a useful additive 
antidiabetic and this complication can be avoided, preferably by keeping to the original recommendation of avoiding use of the drug in patients over 60 or to those where realistic monitoring of renal function is impossible.

In the Netherlands the drug is at the moment ("Kompas 2007") being reviewed by the reimbursement authorities.

Best wishes,

Dr.Leo Offerhaus, Bussum, the Netherlands
Leo Offerhaus <offerhausl@euronet.nl>