Viewpoint - Safety of metformin

Many clinicians wrongly fear metformin, by Dr Abd A Tahrani.

Metformin was first available in the UK in 1957.

It is used mainly in the treatment of type-2 diabetes, but also in conditions in which insulin resistance is a feature, such as polycystic ovary syndrome and non-alcoholic steatohepatitis.

It improves glycaemic control as monotherapy or in combination and also has a favourable effect on the lipid profile, and causes less hypoglycaemia and weight gain compared with sulphonylureas or insulin treatment.

The UKPDS showed that metformin reduces cardiovascular and all-cause mortality in obese patients with type-2 diabetes, which was not observed in equally well-controlled patients treated with other antidiabetic treatments.1

Lactic acidosis
Despite evidence of the benefits, concerns remain about metformin's side-effects and the perceived risk of associated lactic acidosis, particularly in the presence of a hypoxic condition such as renal, liver or cardiac failure.2,3

This perceived risk stems mainly from historical data in regard to phenformin, which was withdrawn in 1977.

Metformin has a much lower reported incidence of lactic acidosis in comparison with phenformin. In addition, phenformin and metformin have different pharmacological characteristics which would explain the difference in the incidence.

Most case reports of lactic acidosis in patients taking metformin have failed to provide adequate information to assess causation, including lactic acid levels and pH.4

In addition, plasma metformin levels were not related to increased lactic acid concentration; and neither increased levels of lactic acid nor metformin were associated with increased mortality risk.4,5

In contrast, acute cardiovascular events, liver cirrhosis and sepsis were all associated with an increased mortality risk in these patients.4,5

The lack of a relationship between lactic acid and metformin levels and mortality, and the absence of an association between metformin concentration and lactic acid concentration per se suggests that the association might be coincidental.4

Ignoring contraindications
Several reports have found that physicians have increasingly ignored contraindications for metformin prescribing, and yet the incidence of lactic acidosis has remained very low.6,7

A population-based study in Scotland found that 24.5 per cent of patients receiving metformin had relative contraindications to its use.

Despite this, there was only one episode of lactic acidosis in 4,600 patient-years, and this was in a 72-year-old patient with acute MI complicated by acute renal failure.6

The evidence from these reports reinforces the viewpoint that metformin is an extremely rare cause of lactic acidosis in patients with type-2 diabetes, even in the presence of apparent contraindications.

Conclusion
Metformin is a very useful drug in the management of patients with type-2 diabetes. Concerns regarding metformin-associated lactic acidosis are probably exaggerated. The risk of lactic acidosis in metformin- treated patients, if any, is small.

Traditional contraindications to metformin treatment should be reconsidered in the light of emerging evidence.

Further studies, particularly randomised controlled trials, are needed to clarify the safety/benefit of metformin use in the context of stated contraindications.

Dr Tahrani is clinical lecturer in diabetes and endocrinology at the University of Birmingham and Birmingham Heartlands Hospital

Metformin advice

  • Metformin is an extremely useful drug for patients with type-2 diabetes.
  • Metformin reduces cardiovascular disease mortality in obese patients with type-2 diabetes.
  • There is still a perceived risk of metformin-associated lactic acidosis.
  • The risk of lactic acidosis in metformin treated patients, if any, is small.

REFERENCES

1. UKPDS 34. Lancet 1998; 352: 854-65.

2. McCormack J, Johns K, Tildesley H. Metformin's contraindications should be contraindicated. CMAJ 2005; 173: 502-4.

3. Tahrani A, Varughese G, Scarpello J, Hanna F. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ 2007; 335: 508-12.

4. Stades A, Heikens J, Erkelens D, et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004; 255: 179-87.

5. Lalau J, Race J. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999; 20: 377-84.

6. Emslie-Smith A, Boyle D, et al. Contraindications to metformin therapy in patients with type-2 diabetes - a population-based study of adherence to prescribing guidelines. Diabet Med 2001; 18: 483-8.

7. Holstein A, Nahrwold D, Hinze S, Egberts E. Contraindications to metformin therapy are largely disregarded. Diabet Med 1999; 16: 692-6.

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