[indices] metformin and lactic acidosis

[offerhausl@euronet.nl]

[Cross posted from e-drug]

Dear  E-Druggers,

- 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 Austr 
2004;180:53-4) .It 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 use in 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