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Tahrani et al[1] present data that question whether conventional
contraindications to metformin use are based on fact versus fiction. The
authors proceed to inform clinicians to individualize the decision to
continue metformin for patients, despite whether the drug may be
contraindicated. This article adds to the longstanding debate surrounding
the appropriateness and relevance of metformin’s contraindications, but
does not provide a verdict that can truly assist clinical decision-making.
We have ample evidence that supports that if a risk of lactic
acidosis with metformin exists, the risk must be extremely small.[2,3]
Available data suggest that metformin may be used safely in patients with
mean creatinine clearances as low as 25 mL/min.[3] There are only very
weak case reports in which underlying hypoxemia confounding concomitant
metformin use led to lactic acidosis.[4,5] Further, there is a
pharmacologic basis for why metformin does not share the same risk as
phenformin.[6] Lastly, it appears that clinicians are not convinced that
there is a significant risk of lactic acidosis with metformin, as
prescribing against the manufacturer’s contraindication may be common.[7]
Then why does the debate continue? We believe there are two reasons.
First, stories or individual cases are given unreasonable credibility.
Newman, in the Journal, neatly describes this as ‘the power of stories
over statistics’ in which he highlights how even a single incident can
support policy change despite analyses to the contrary.[8] Just a single
case report, even if strongly confounded, can counter scientific rigour.
The second factor is fear of litigation. If a metformin-treated
patient with renal impairment coincidentally develops lactic acidosis, the
contraindication and a sample of case reports can easily be distorted to
provide a basis for inappropriate prescribing and malpractice. Regulatory
support to change metformin’s contraindications to precautions would offer
some protection but is unlikely to come.
How do we confidently offer this life-saving therapy to patients with
‘contraindications’? Most importantly, the mortality benefit of metformin
must not be forgotten. The available data suggest this benefit will be
far greater than any increase in death from lactic acidosis.[9] With this
in mind we can separate out hypoxemic patients. This subset of patients
would be unable to compensate for any increase in lactate. A second group
of patients to exclude would be patients with high lactate levels, a group
that is already at a higher risk of lactic acidosis and has already lost
their ability to compensate for increased lactate.
This leaves us with well oxygenated patients with normal lactate
levels. In these patients, even if they have traditional
contraindications, we can make dosage adjustments slowly, monitor lactate
levels shortly after dosage adjustments and advise patients on symptoms
which warrant immediate medical attention.
We would suggest a good population to start with is patients with
moderate renal impairment (25-60 mL/min), good oxygenation and normal
lactate levels. There are good data[3] and logic to support this
practice.
Reference List
(1) Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin,
heart failure, and lactic acidosis: is metformin absolutely
contraindicated? BMJ 2007; 335(7618):508-512.
(2) Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic
acidosis rates in type 2 diabetes. Diabetes Care 1998; 21(10):1659-1663.
(3) Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications
to metformin therapy are largely disregarded. Diabet Med 1999; 16(8):692-
696.
(4) Lalau JD, Lacroix C, Compagnon P, de CB, Rigaud JP, Bleichner G
et al. Role of metformin accumulation in metformin-associated lactic
acidosis. Diabetes Care 1995; 18(6):779-784.
(5) Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin
therapy in patients with NIDDM. Diabetes Care 1997; 20(6):925-928.
(6) Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal
and nonfatal lactic acidosis with metformin use in type 2 diabetes
mellitus: systematic review and meta-analysis. Arch Intern Med 2003;
163(21):2594-2602.
(7) Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD.
Contraindications to metformin therapy in patients with Type 2 diabetes--a
population-based study of adherence to prescribing guidelines. Diabet Med
2001; 18(6):483-488.
(8) Newman TB. The power of stories over statistics. BMJ 2003;
327(7429):1424-1427.
(9) Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). UK
Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):854-865.
Competing interests:
None declared
Competing interests:
No competing interests
21 November 2007
Catherine Goulding
Pharmacy Resident
Suzanne Singh, Pharmacist and Andrew Wyllie, Pharmacist
Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5
The data seems to show measurable evidence for using Metformin in
Type 2 Diabetics and the case that it significantly improves mortality as
compared to Sulphonureas. A recent observational study in Circulation on
16 417 Medicare beneficiaries with diabetes and Heart failure showed that
1 year mortality rates on the 1861 patients treated with Metformin were
24.7 % as compared to thiazolidinedione (30.1%) and neither insulin-
sensitizing drug (36.0%).[1]
This is just an observational study but seems to show that Metformin is
not harmful and in fact beneficial for Heart failure patients with Type 2
DM.
[1]Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM.
Thiazolidinediones, metformin, and outcomes in older patients with
diabetes and heart failure: an observational study. Circulation
2005;111:583-90.[
Competing interests:
None declared
Competing interests:
No competing interests
02 November 2007
Mahmood Ahmad
LAT-ST3
Medway Maritime Hospital, Gillingham, Kent ,ME7 5NY
Reconciling Clinical Decision making and Traditional Contraindications
Tahrani et al[1] present data that question whether conventional
contraindications to metformin use are based on fact versus fiction. The
authors proceed to inform clinicians to individualize the decision to
continue metformin for patients, despite whether the drug may be
contraindicated. This article adds to the longstanding debate surrounding
the appropriateness and relevance of metformin’s contraindications, but
does not provide a verdict that can truly assist clinical decision-making.
We have ample evidence that supports that if a risk of lactic
acidosis with metformin exists, the risk must be extremely small.[2,3]
Available data suggest that metformin may be used safely in patients with
mean creatinine clearances as low as 25 mL/min.[3] There are only very
weak case reports in which underlying hypoxemia confounding concomitant
metformin use led to lactic acidosis.[4,5] Further, there is a
pharmacologic basis for why metformin does not share the same risk as
phenformin.[6] Lastly, it appears that clinicians are not convinced that
there is a significant risk of lactic acidosis with metformin, as
prescribing against the manufacturer’s contraindication may be common.[7]
Then why does the debate continue? We believe there are two reasons.
First, stories or individual cases are given unreasonable credibility.
Newman, in the Journal, neatly describes this as ‘the power of stories
over statistics’ in which he highlights how even a single incident can
support policy change despite analyses to the contrary.[8] Just a single
case report, even if strongly confounded, can counter scientific rigour.
The second factor is fear of litigation. If a metformin-treated
patient with renal impairment coincidentally develops lactic acidosis, the
contraindication and a sample of case reports can easily be distorted to
provide a basis for inappropriate prescribing and malpractice. Regulatory
support to change metformin’s contraindications to precautions would offer
some protection but is unlikely to come.
How do we confidently offer this life-saving therapy to patients with
‘contraindications’? Most importantly, the mortality benefit of metformin
must not be forgotten. The available data suggest this benefit will be
far greater than any increase in death from lactic acidosis.[9] With this
in mind we can separate out hypoxemic patients. This subset of patients
would be unable to compensate for any increase in lactate. A second group
of patients to exclude would be patients with high lactate levels, a group
that is already at a higher risk of lactic acidosis and has already lost
their ability to compensate for increased lactate.
This leaves us with well oxygenated patients with normal lactate
levels. In these patients, even if they have traditional
contraindications, we can make dosage adjustments slowly, monitor lactate
levels shortly after dosage adjustments and advise patients on symptoms
which warrant immediate medical attention.
We would suggest a good population to start with is patients with
moderate renal impairment (25-60 mL/min), good oxygenation and normal
lactate levels. There are good data[3] and logic to support this
practice.
Reference List
(1) Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin,
heart failure, and lactic acidosis: is metformin absolutely
contraindicated? BMJ 2007; 335(7618):508-512.
(2) Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic
acidosis rates in type 2 diabetes. Diabetes Care 1998; 21(10):1659-1663.
(3) Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications
to metformin therapy are largely disregarded. Diabet Med 1999; 16(8):692-
696.
(4) Lalau JD, Lacroix C, Compagnon P, de CB, Rigaud JP, Bleichner G
et al. Role of metformin accumulation in metformin-associated lactic
acidosis. Diabetes Care 1995; 18(6):779-784.
(5) Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin
therapy in patients with NIDDM. Diabetes Care 1997; 20(6):925-928.
(6) Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal
and nonfatal lactic acidosis with metformin use in type 2 diabetes
mellitus: systematic review and meta-analysis. Arch Intern Med 2003;
163(21):2594-2602.
(7) Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD.
Contraindications to metformin therapy in patients with Type 2 diabetes--a
population-based study of adherence to prescribing guidelines. Diabet Med
2001; 18(6):483-488.
(8) Newman TB. The power of stories over statistics. BMJ 2003;
327(7429):1424-1427.
(9) Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). UK
Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):854-865.
Competing interests:
None declared
Competing interests: No competing interests