Rapid Responses to:

PRACTICE:
A A Tahrani, G I Varughese, J H Scarpello, and F W F Hanna
Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated?
BMJ 2007; 335: 508-512 [Full text]
*Rapid Responses: Submit a response to this article

Rapid Responses published:

[Read Rapid Response] Metformin in Heart Failure
Mahmood Ahmad   (2 November 2007)
[Read Rapid Response] Reconciling Clinical Decision making and Traditional Contraindications
Catherine Goulding, Suzanne Singh, Pharmacist and Andrew Wyllie, Pharmacist   (21 November 2007)

Metformin in Heart Failure 2 November 2007
Next Rapid Response Top
Mahmood Ahmad,
LAT-ST3
Medway Maritime Hospital, Gillingham, Kent ,ME7 5NY

Send response to journal:
Re: Metformin in Heart Failure

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
Reconciling Clinical Decision making and Traditional Contraindications 21 November 2007
Previous Rapid Response Top
Catherine Goulding,
Pharmacy Resident
Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5,
Suzanne Singh, Pharmacist and Andrew Wyllie, Pharmacist

Send response to journal:
Re: 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