Contraindications to the use of metformin
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7379.4 (Published 04 January 2003) Cite this as: BMJ 2003;326:4All rapid responses
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The contraindications to the use of metformin have been reviewed in a
recent article by Jones et al[1], focusing primarily on the type II
diabetes cohort.
However, pregnancy is one contraindication missing from their table,
and we predict it will gain more importance in the near future. Shifts in
profile of morbidity of type II diabetes will lead to changes in the use
of metformin, as this syndrome is seen in younger people, particularly in
the United States of America. Indeed, recent trends show that younger
adults now declare a non-insulin dependent diabetes, and this trend
includes women in reproductive years.
Polycystic ovary syndrome is the most common endocrinopathy in women
of reproductive years and is the most common cause of endocrine
infertility[2-4]. Central, but not unique, in its physiopathology is
insulin resistance[2, 5], which leads to a rate of obesity, type II
diabetes, and premature coronary disease several folds above that of the
general population[6]. NIDDM in PCOS patients declares itself at a
younger age than in the general population[4, 7].
Despite the fact that oral hypoglycemic agents have been
contraindicated in pregnancy for over twenty years[8-11], metformin has
been used off label by the fertility community to induce ovulatory
menstrual cycles in women with polycystic ovary syndrome[12-16]. This
practice has led to unavoidable fetal exposure.
The Motherisk Clinic in Toronto, Canada has focused on documenting
pregnancy outcome in women with polycystic ovary syndrome exposed to
metformin. Our preliminary data show that metformin does not increase the
risk of major malformations above that of the general population, and is
not associated with an increased rate of obstetrical complications such as
peri-natal hypoglycemia. Other studies have also shown similar results,
although data are still too scarce in the literature to revise the status
of metformin yet[17-20].
As insulin resistance gets growing recognition for its central role
in polycystic ovary syndrome, we predict that metformin will be used more
and more in women of reproductive years, and this cohort should not be
overlooked when we issue recommendations regarding the use of insulin
sensitizers.
Bibliography
1. Jones, G.C., J.P. Macklin, and W.D. Alexander, Contraindications
to the use of metformin. Brit J Med, 2003. 326: p. 4-5.
2. Lobo, R.A. and E. Carmina, The importance of diagnosing the polycystic
ovary syndrome. Ann Intern Med, 2000. 132(12): p. 989-993.
3. Yen, S.S.C., Polycystic ovary syndrome (Hyperandrogenic chronic
anovulation), in Reproductive Endocrinology: Physiology, Pathophysiology,
and Clinical Management., S.S.C. Yen, Jaffe, and Babieri, Editors. 1999.
p. 436-478.
4. Legro, R.S., et al., Prevalence and predictors of risk for type 2
diabetes mellitus and impaired glucose tolerance in polycystic ovary
syndrome: A prospective, controlled study in 254 affected women. J Clin
Endocrinol Metab, 1999. 84(1): p. 165-169.
5. Ciaraldi, T.P., et al., Cellular mechanisms of insulin resistance in
polycystic ovarian syndrome. J Clin Endocrinol Metab, 1992. 75(2): p. 577-
583.
6. Ovalle, F. and R. Azziz, Insulin resistance, polycystic ovary syndrome,
and type 2 diabetes mellitus. Fertility and Sterility, 2002. 77(2): p.
1095-1105.
7. Dunaif, A., Hyperandrogenic anovulation (PCOS): A unique disorder of
insulin action associated with an increased risk of non-insulin-dependent
diabetes mellitus. Amer J Med, 1995. 98(suppl 1A): p. 33S-39S.
8. Meltzer, S., et al., 1998 clinical practice guidelines for the
management of diabetes in Canada. Can Med Ass Jour, 1998. 159(8 suppl): p.
S1-S29.
9. Piacquadio, K., D.R. Hollingsworth, and H. Murphy, Effects of in-utero
exposure to oral hypoglyceamic drugs. The Lancet, 1991. 338(Oct 5): p. 866
-869.
10. Briggf, G., R. Freeman, and S. Yaffe, A reference guide to fetal and
neonatal risk. Drugs in Pregnancy and Lactation. 6th ed. 2002:
Lippincott, Williams, and Wilkins.
11. ASRM, A.S.o.R.M., Use of insulin sensitizing agents in the treatment
of polycystic ovary syndrome - A Practice Committee Report (A Committee
Opinion). 2000.
12. Velazquez, E., et al., Metformin therapy in polycystic ovary syndrome
reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and
systolic blood pressure, while facilitating normal menses and pregnancy.
Metabolism, 1994. 43(5 (May)): p. 647-654.
13. Glueck, C.J., et al., Metformin-induced resumption of normal menses in
39 of 43 (91%) previously amenorrheic women with the polycystic ovary
syndrome. Metabolism, 1999. 48(4 (April)): p. 511-519.
14. Morin-Papunen, L.C., et al., Metformin therapy improves the menstrual
pattern with minimal endocrine and metabolic effects in women with
polycystic ovary syndrome. Fertility and Sterility, 1998. 69(4): p. 691-
696.
15. Nestler, J.E., et al., Effects of metformin on spontaneous and
clomiphene-induced ovulation in the polycystic ovary syndrome. New Eng J
Med, 1998. 338(April 29): p. 1314-1320.
16. Fleming, R., et al., Ovarian function and metabolic factors in women
with oligomenorrhaea treate with metformin in a randomized double blind
placebo-controlled trial. J Clin Endocrinol Metab, 2002. 87(2): p. 569-
574.
17. Glueck, C.J., et al., Pregnancy outcomes among women with polycystic
ovary syndrome treated with metformin. Human Reprod, 2002. 17(11): p. 2858
-2864.
18. Glueck, C.J., et al., Continuing metformin throughout pregnancy in
women with polycystic ovary syndrome appears to safely reduce first-
trimester spontaneous abortion: A pilot study. Fertility and Sterility,
2001. 75(Jan): p. 46-52.
19. Heard, M.J., et al., Pregnancies following use of metformin for
ovulation induction in patients with polycystic ovary syndrome. Fertility
and Sterility, 2002. 77(4): p. 669-673.
20. Pinto, A.B., et al., Pregnancy outcome in clomiphene citrate (CC)-
resistant polycystic ovary syndrome (PCOS) patients treated with and
without metformin (abstr). Fertility and Sterility, 2001. 76(3, suppl 1):
p. S 186.
Competing interests:
None declared
Competing interests: No competing interests
Prescribing practices of doctors may affect outcomes, as follows:
I escorted the patient from the ward to radiology for a CAT scan. In
the preamble, it took about half an hour of “discussion” for the ward
nursing staff to feel comfortable with the “new” idea that Metformin
should have been discontinued. They satisfied themselves that the patient wasn’t
on Metformin anyway, but still didn’t like the new idea - created by some
“researcher” no doubt, merely to interrupt an otherwise healthy schedule.
On arrival, radiology re-explained the new approach to Metformin
being discontinued, and had a look at the patient’s medication sheet, just
in case. The scan went ahead.
On return to the ward, in order to clarify the above-mentioned
"discussion", some computer searching was done via PubMed. This revealed
the usual duplicate names for the same drug – Metformin is also called
Glucophage, though rarely prescribed in the hospital in question as such.
The patient was in fact on Glucophage, and it had not been withheld in the
last 24 hours.
No adverse outcome on that occasion, but using drug names
consistently may help. Sometimes, doctors prescribe existing medications
for new admissions, by writing down exactly what the patient tells them.
And patients love trade names.
PS. Please feel free to comment on any errors.
Competing interests:
None declared
Competing interests: No competing interests
The authors should be congratulated on their review of the relevant
literature about the side effects of metformine. However,their suggestions
for the guidelines about discontinuation of metformin do not stem from the
literature they quote.
The arbitrary limit of serum creatinine ,150 micmol/L for example,is not
born out by the data.
In a randomized prospective study(1) we have followed up, for 4 years, nearly
400 elderly patients with diabetes mellitus and serum creatinine values of
130-220 micmol/L who had been treated with metformin . The drug was
discontinued in half of the patients.
Analysis by intention to treat showed a rise in BMI and in HbA1c in in the
patients who stopped metformin as compared to those who continued the
drug. Serum levels of lactic acid were equal in the two groups. There were
no cases of lactic acidosis.Cardiovascular morbidity and mortality were
identical in the two groups.
More than 200 of the patients had conditions associated with hypoxemia
(e.g. chroic obstructive pulmonary disease ,congestive heart failure).
We have concluded that diabetic patients treated with metformin who
tolerate the drug well my contnue metformin also when mild renal filure
develops possibly to a limit of 220 micmol/L of Serum creatinine.
The limit set by Jones, Macklin and Alexander is arbitrary and may deprive
a substantial number of patients of the benefits of this medication.They
did not find a rise in the rate of side effects in patients with serum
creatinine values of 150-220 micmol/L as compared to thse with values lower
than 150.
Reference
1.Rachmani R, Slavachevski I,Kedar Y, Ravid M
Metformin in patients with type 2 diabetes mellitus:reconsiderations of
traditional contraindications.
Eur J Intern Med 2002;13:428-33
Competing interests:
None declared
Competing interests: No competing interests
We would like to congratulate Jones et al on their timely reminder of
the inappropriately strict contraindications to the use of
metformin(1).The authors have emphasised the justification for using
metformin in patients with type 2 diabetes and its proven effect in
reducing cardiovascular risk in such patients. For many years
Gynaecologists have also found favour with metformin and its emerging role
in the treatment of polycystic ovary syndrome despite not being licensed
for this.
Metformin improves insulin sensitivity and decreases
hyperinsulinaemia,reduces serum androgen levels,restores menstrual
cyclicity and increases the ovulatory and pregnancy rates in patients with
polycystic ovary syndrome who are resistant to clomiphene citrate(2).When
administered during pregnancy it decreases the occurence of first
trimester pregnancy loss(3),and reduces the development of gestational
diabetes in women with polycystic ovary syndrome(4).
Furthermore it has also been suggested as a useful treatment for
obesity(5). We feel that these proven uses have to be formally recognised
in addition to amending the published contraindications list,thereby
eliminating ambiguity in its usage,especially considering the value of
metformin in endocrinopathies like polycystic ovary syndrome.
REFERENCES
1)Jones GC, Macklin JP, Alexander WD. Contraindications to the use of
metformin.BMJ 2003;326:4-5 (4 January)
2)Nestler JE, Stovall D, Akhtar N, Iuorno MJ, Jakubowicz DJ.
strategies for the use of insulin-sensitising drugs to treat infertility
in women with polycystic ovary syndrome. Fertil Steril 2002;77(2):209-15.
3)Jakubowicz DJ,Iuorno MJ,Jakubowicz S,Roberts KA,Nestler JE
Effects of metformin on early pregnancy loss in the poycystic ovary
syndrome.J Clin Endocrinol Metab 2002;87(2):524-9.
4)Glueck CJ, Wang P, Kobayashi S,Philips H, Sieve-Smith L. Metformin
therapy throughout pregnancy reduces the development of gestational
diabetes in women with polycystic ovary syndrome.Fertil Steril
2002;77(3):520-5.
5)Glokcel A, Gumurdulu Y, Karakose H, Melek Ertorer E, Tanaci
N,Bascil TutncuN, Guvener N. Evaluation of the safety and efficacy of
sibutramine,orlistat and metformin in the treatment of obesity.Dibetes
Obes Metab 2002;4(1):49-55
Competing interests:
None declared
Competing interests: No competing interests
Your recent editorial on contraindications to the use of metformin1
did not mention pregnancy, according to the British National Formulary
(http://bnf.org/), another contraindication to its use. In women with
gestational diabetes (GDM), or pre-gestational type 2 diabetes, whose
blood glucose values cannot be controlled by lifestyle measures, insulin
therapy is usually recommended. Given that pregnancy is a state of
insulin resistance, metformin might be a logical alternative: it reduces
hepatic glucose output, improves peripheral glucose uptake and suppresses
fatty acid oxidation, cardinal features of both GDM and type 2 diabetes.
Cohort data support use of metformin in pregnancy2. In a recent report of
women with polycystic ovary syndrome who had become pregnant while taking
metformin, its continuation through pregnancy reduced the incidence of GDM
as well as the frequency of early miscarriage3. One retrospective study4
has reported an increased rate of pre-eclampsia in pregnant women treated
with metformin, but this study was weakened by the lack of matched
controls, while the perinatal losses reported in the metformin group
cannot be attributed to the treatment: two were in non-compliant women
treated with metformin at the end of pregnancy, one was in a woman treated
at 28 weeks who changed to insulin, and one was in a woman treated from 36
weeks who had a stillbirth weighing 1700g at 38 weeks.
We (WMH, PMD, JO) have recently completed a pilot study (The MiG Pilot
trial - MiG = Metformin in Gestational diabetes) in 30 women with GDM
diagnosed by Australasian Diabetes in Pregnancy Society (ADIPS) criteria,
matched for age, parity, BMI, and gestation at entry (Table 1), and
randomised to metformin or insulin treatment. Our hypotheses were that
metformin would be as effective as insulin in reducing maternal
hyperglycaemia and therefore fetal hyperinsulinism, and that perinatal
outcome would be similar. The trial was approved by the local Ethics
Committees and women gave written informed consent. Cord C-peptide
concentration was used as a measure of fetal beta-cell activity: no
difference was detected in the results from the 17 women whose cord blood
was stored (P=0.31: Mann-Whitney) (Figure 1). Perinatal outcomes were not
different between the two groups (Table 1) but numbers are too small to
comment further5.
A larger trial has now been initiated (the MiG Study), with adequate power
to test the hypothesis that, in women with GDM, metformin treatment,
compared with insulin, will have similar perinatal outcomes, improve
insulin sensitivity in both mother and baby, and be associated with
improved treatment acceptability. Funding and ethical approval has been
obtained, and recruitment has commenced (details: WMH/JR).
A follow up
study of the offspring is planned, to study potential effects of metformin
in relation to later insulin sensitivity and subsequent health5.
1. Jones GC, Macklin JP, Alexander WD. Contraindications to the use
of metformin BMJ 2003;326(7379):4-5.
2. Coetzee E, Jackson W. The management of non-insulin-dependent diabetes
during pregnancy. Diab Res Clin Pract 1986;1:281-287.
3. Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin
therapy throughout pregnancy reduces the development of gestational
diabetes in women with polycystic ovary syndrome. Fertility and Sterility
2002;77(3):520-525.
4. Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in
118 diabetic pregnancies. Diabetic Medicine 2000;17:507-511.
5. Barker D. Mothers, babies and health in later life. Edinburgh:
Churchill, Livingstone, 1998.
Table 1. Baseline characteristics and Outcome
data. No significant differences were
found
Insulin (n=14) |
Metformin (n=16) |
|
Maternal Age1 |
34.1 (3.70) years |
33.7 (4.44) years |
Parity2 |
1 (0-5) |
1 (0-4) |
Maternal weight at trial entry1 |
101.2 (22.01) kg |
104.4 (22.28) kg |
Maternal BMI at trial entry1 |
37.9 (6.87) kg/m2 |
39.5 (6.94) kg/m2 |
Gestation at diagnosis of GDM1 |
27.6 (3.80) weeks |
25.8 (5.51) weeks |
Fasting blood glucose at GTT1 |
5.4 (0.52) mmol/L |
5.6 (1.26) mmol/L |
2-hour blood glucose at GTT1 |
9.4 (1.42) mmol/L |
10.0 (2.07) mmol/L |
Gestation at entry into trial1 |
30.4 (4.67) weeks |
29.8 (4.49) weeks |
Vaginal birth |
11 (79%) |
5 (31%) |
Induction of labour |
9 (64%) |
5 (31%) |
Elective Caesarean Section |
2 (14%) |
8 (50%) |
Emergency Caesarean Section |
1 (7%) |
2 (13%) |
Pre-eclampsia |
2 (14%) |
3 (19%) |
Gestation at delivery1 |
38.2 (1.0) weeks |
37.8 (1.5) weeks |
Birth weight1 |
3.45 (0.51) kg |
3.56 (0.50) kg |
Birth weight >4000 g (n) |
2 |
2 |
Cord C-peptide1 |
0.78 (0.62) pmol/ml (n=7) |
0.77 (0.75) pmol/ml (n=10) |
Cord glucose1 |
4.2 (1.1) mmol/l (n=11) |
4.2 (1.9) mmol/l (n=14) |
Cord glucose/C-peptide1 |
5.7 (2.67) |
7.4 (1.69) |
Neonatal IV dextrose (n) |
1 |
4 |
Hours in special care nursery2 |
24 (0 – 102) |
48 (0 – 360) |
Neonatal jaundice (n) |
6 |
3 |
Phototherapy (n) |
0 |
2 |
1Mean
(SD); 2Median (range)
Distribution of cord blood C-peptide concentrations from pregnant
women treated with either insulin or metformin. (P for difference = 0.31:
Mann-Whitney)
W M Hague1
P M Davoren2
J Oliver3
J Rowan4
1Consultant Physician in Obstetric Medicine,
Department of Obstetrics,
University of Adelaide,
The Queen Elizabeth Hospital,
Woodville, SA 5011,
Australia
Email: bill.hague@adelaide.edu.au
2Consultant Physician,
Department of Medicine,
Gold Coast Hospital,
University of Queensland,
Southport, QLD 4215,
Australia
Email: Peter_Davoren@health.qld.gov.au
3Associate Professor,
Department of Physiology,
School of Medicine,
Flinders University,
Bedford Park, SA 5042,
Australia
Email: johnno.oliver@flinders.edu.au
4Consultant Physician in Obstetric Medicine,
National Women's Hospital,
Green Lane,
Auckland,
New Zealand
Email: jrowan@internet.co.nz
Corresponding Author: Dr WM Hague, Department of Obstetrics, Women's
and Children's Hospital, North Adelaide, SA 5006, Australia
Competing interests:
None declared
Competing interests: No competing interests
After an analysis of the editorial “Contraindications to the use of
metformin Evidence suggests that it is time to amend the list” BMJ
2003;326:4-5 (4 January), we want to precise that just after the period of
cited review of cases (May 1995 and January 2000) with “no mortality was
associated with metformin alone”, we notified one case of death with
metformin alone in France in October 1995, this case was published (with
two other different cases of lactic acidosis and metformin implicated) in
: Machet G, Coudray JM. “Lactic acidosis and metformin implicated: why
better information about risk factors?” Therapie 2000 Mar-Apr;55(2):283-
94.
We declared these three cases between October 1995 and May 1997 in the
same General Hospital (Longjumeau, Essonne, France). Metformin was
implicated by plasma and intra-erythrocyte levels.
A woman (68 years old) died with :
1) no contraindications (isosorbidedinitrate [Risordan20LP®] (2/day),
nifédipine [Adalate LP 20®] (2/ day), lévothyroxine sodique
[Levothyrox100®](1/ day) lévothyroxinesodique [Levothyrox25®] (0,5/ day),
metformine [Glucophage850mg®] (2/ day), gliclazide [Diamicron®] (3/ day),
2) no intestinal occlusion,
3) no metformin accumulation : 19 days before the patient saw her doctor,
a verification of metformin plasma level was done after on plasma used for
a usual control of thyroid.
Another patient who died have had an infection problem.
The third patient
was saved, she had contraindication of age and three drug interactions
with metformin but she was rapidly in the hospital after symptoms
beginning (she was living in a house for old people).
Using information given by these cases, we analysed available information
about this risk for healthcare professionals and for patients (in 1999). A
comparison was made of approved labelling information on Glucophage and
its patient leaflets in France and in the USA and an analysis made of the
differences. We concluded that : “In France, Information given to
physicians, pharmacists and patients on the risk of lactic acidosis where
Glucophage is implicated must be improved, and on the interest of the
metformin plasma level in this case. These are primary points because the
issue for the few patients concerned may be fatal. Advice on self-
medication may be introduced. The evolution of information provided on
these risks depends on the pharmaceutical laboratory, government
authorities and healthcare professionals.”
In this article, we wrote on an important point: adverse drug reactions
notifications are usually neglected. In “Adverse drug reactions in a
hospital general medical unit meriting notification to the Committee on
Safety of Medicines.Br J Clin Pharmacol 1996; 42: 429-429. Smith CC,
Bennett PM, Pearce HM et al.” the authors precise that for admissions in a
hospital medical unit during three years (20695 patients) only 30 (6.3 %)
of 477 notifications to do were, in fact, done. So is the estimated
prevalence of lactic acidosis associated with metformin the real one ? An
other difficulty : with a lactic acidosis, healthcare professionals must
act rapidly for a vital problem. With a patient taking metformin, the
implication is given by a plasma level corresponding to an accumulation.
This determination is not usual in hospital laboratories and may be not
see as an important element, useful for possible notification but without
interest to take care.
In conclusion, different effects of metformin have a great interest for
many patients but it is very important to prevent by a good information
the risk of metformin and lactic acidosis, a rare adverse reaction, fatal
in approximately 50 per cent of cases. To amend the list of
contraindications to use metformin is possible but is it the better way to
give a contribution to inform on the good use of this drug and about its’
possible fatal adverse reaction ?
Competing interests:
None declared
Competing interests: No competing interests
Contraindications to the use of metformin.
Jones et al (1) criticise current guidelines, which highlight
possible contraindications to the use of metformin, as too vague and
potentially leading to underuse in patients with type 2 diabetes. Although
their desire for a “less ambiguous” approach seems sensible, their own
guidelines still lack clarity.
They note that any specific value of serum creatinine chosen as a cut
-off for prescription of metformin will be arbitrary, because of
variations in muscle mass and protein turnover. Despite this they then
select – for undefined reasons- a serum creatinine value of 150
micromols/L as the cut-off point in their guideline. They then suggest
“caution should therefore be used in prescribing metformin for elderly
patients”.
This is a vague statement, which could be interpreted as meaning that
metformin shouldn’t be prescribed at all in the elderly; that specialist
opinion should be sought or creatinine clearance calculated before it is
prescribed; or that renal function or serum lactate should be monitored
after it is prescribed.(2)
In addition, we are not informed of the authors' own definition of
“elderly”.
Given that the growing majority of patients with type 2 diabetes are
over the age of 65 years,and that there is already evidence of
undertreatment of such patients (3), it would seem particularly desirable
to be as clear as is possible about this age group, if the full benefits
of treatment are to be attained.
Although the simple formulae that can be used to estimate creatinine
clearance(4) are not completely reliable it may be preferable to suggest
that prescription is related to such a calculated estimate of clearance,
which takes into account patient age, rather than the serum creatinine
value alone.
Andrew T. Elder
Consultant Physician
Western General Hospital,
Edinburgh
1.Jones GC, Macklin JP, Alexander WD. Contraindications to the use of
metformin. BMJ 2003; 326: 4-5
2.Chehade JM, Mooradian AD in Diabetes in old age eds Sinclair
AJ,Finucane P. John Wiley,Chichester. 2001 p 202-3.
3.Hendra TJ,Sinclair AJ (1997) Improving the care of elderly diabetic
patients ; the final report of the St Vincent Joint Task Force for
Diabetes. Age and Ageing, 26 , 3-6.
4.Cockcroft, D.W. and Gault, M.H. (1976). Prediction of creatinine
clearance from serum creatinine. Nephron 16, 31.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
Thank you very much for the excellent article on Metformin.
I have been using this drug for the last fiftten years in my practice to
treat type II DM with or without CAD & HTN & I have experienced
very good results without a single case of Lactic Acidosis.It is a good
drug in the sense that it rarely causes hypoglycemic episodes.Combination
with Glybenclamide is ideal.
DrG.Chidambaram
Competing interests:
None declared
Competing interests: No competing interests
That metformin can cause a “lactic acidosis” on occasions suggests
that it may either induce or compound the severity of anaerobic metabolism
(1). This is important for the development of a tissue acidosis may have
an adverse effect upon outcome (2).
The term “lactic acidosis” is misleading for being a base, not an
acid, an elevated blood lactate per se does not establish the presence of
a tissue acidosis or of anaerobic metabolism. Conversely inhibiting the
generation of lactate with iodoacetate in vitro does not prevent the
development of a tissue acidosis in anerobiosis and any lactate present in
blood in vivo may be removed very rapidly and used as a fuel by the heart
or converted into glucose and hence glycogen by the liver. Thus the
finding of a normal blood lactate does not exclude the presence of
anaerobic metabolism which may exist chronically and only become evident
when the demand for energy from ATP hydrolysis exceeds the capacity for
ATP resynthesis by mitochondrial oxidative phosphorylation (2,3).
A fall in gastric intramucosal pH is a very sensitive predictor of
adverse outcome from the translocation of gut toxins, cytokine release,
and hence organ dysfunctions, nosocomial infections, and organ failures
(2,3). Patients with chronic renal failure on haemodialysis have an
abnormally low gastric intramucosal pH but a normal arterial pH (4). This
means that patients with chronic renal failure are more likely to develop
gut mucosal injury and suffer from the adverse consequences of the
translocation of bacterial toxins, notably endotoxin, the release of
cytokines and the increase in permeability of the mitochondrial membrane
they may induce (5).
An increase in permeability of mitochondrial membranes causes a proton
leak which dissipates the proton gradient thus uncoupling oxidative
phosphorylation. This induces or compounds the severity of any impairment
of mitochondrial oxidative phosphorylation present. The presence of a
compensated metabolic acidosis in patients with chronic renal failure
makes them more likely to develop an uncompensated gastric intramucosal
acidosis and even a systemic tissue acidosis. The metabolic acidosis
might even represent an adaptation by enzymes regulating ATP hydrolysis
and resynthesis to an unappreciated presence of an impairment of
mitochondrial oxidative phosphorylation in patients with chronic renal
failure (6).
Given this pathophysiologic scenario it would seem appropriate to
withhold metformin from any patient who has a gastric intramucosal
acidosis or develops a gastric intramucosal acidosis after the
administration of metformin regardles of whether they have renal failure.
A negative exercise stress test whilst on metformin should increase the
confidence in prescribing metformin without precipitating anaerobiosis. A
negative stress test might not, however, avoid compounding the severity
of a gastric intramucosal acidosis and having an adverse effect upon
outcome should it develop for other reasons during the course of a
critical illness (7).
1. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003
2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.
3. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.
4. Diebel L, Kozol R, Wilson RF, Mahajan S, Abu-Hamdan D, Thomas D.
Gastric intramucosal acidosis in patients with chronic kidney failure.
Surgery. 1993 May;113(5):520-6.
5. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in
stress-induced apoptosis before mitochondrial permeabilization. Science.
2002 Aug 23;297(5585):1352-4.
6. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University
Press, New York, NY, 2002
7. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG.
Increased gastric PCO2 during exercise is indicative of gastric ischaemia:
a tonometric study.
Gut. 1999 Feb;44(2):163-7.
Competing interests:
None declared
Competing interests: No competing interests
Re: metformin drug of choice
I have 10 years to use metformin in my patients and I have not had a
single case of lactic acidosis or another complication. Metformin is a
drug of choice to conserve the pancreatic answer of diabetic patients.
Competing interests:
None declared
Competing interests: No competing interests