Q J Med 2003; 96: 315-316
© 2003 Association of Physicians
Correspondence |
Metformin-associated lactic acidosis in a patient with liver disease
Department of Diabetes and Endocrinology Department of Gerontology Department of Intensive Care, Central Middlesex Hospital, London Department of Diabetes and Metabolism, The Royal London Hospital, London e-mail: Tahseen.Chowdhury{at}bartsandthelondon.nhs.uk
Sir,
Metformin is an orally active biguanide, and was found to reduce mortality and complications in obese diabetic patients in the UK Prospective Diabetes Study.1 As a result, the drug is widely used as first-line therapy for patients with obesity and type 2 diabetes. We would like to remind prescribers of a rare, but commonly fatal complication of metformin therapy in patients with liver or renal disease.
A 40-year-old Gujerati man was admitted through accident and emergency. On admission, little history was available from the patient, and no corroborative history was available, apart from the fact that he was diabetic and on metformin. He was short of breath at rest, with oxygen saturation of 84% on air, and had a Glasgow Coma Score of 13/15. Capillary blood glucose was 1.7 mmol/l. Arterial blood gas analysis on 60% oxygen revealed severe metabolic acidosis: pH 6.62, pCO2 8.3 kPa, pO2 47.8 kPa, base excess -31.2, bicarbonate 6.4 mmol/l, anion gap 37 mmol/l. Serum lactate was extremely high at >20 mmol/l. He had a low urea of 2.4 mmol/l, normal creatinine of 63 µmol/l, a raised aspartate transaminase (110 IU/l, NR 10–50), bilirubin (64 µmol/l, NR 2–17) and alkaline phosphatase (323 IU/l, NR 40–135). He had a macrocytic anaemia (haemoglobin 9.7 g/dl, NR 13.0–17.0; MCV 99.0 fl, NR 76.0–96.0), and deranged clotting (PT 30 s, control 12 s; KPTT 65 s, control 35 s), but normal platelet count (152x109/l, NR 135–450). Hypoglycaemia was confirmed by a venous plasma glucose of 1.9 mmol/l.
On review of his medical notes, he had been diagnosed with type 2 diabetes 3 years prior to admission. He had not been seen at diabetic clinic for over 2 years, when his diabetes was well controlled with metformin 850 mg twice daily. Eighteen months previously, he was admitted with alcoholic hepatitis, his metformin was not stopped, and he subsequently failed to attend the gastroenterology clinic.
The hypoglycaemia was rapidly treated with intravenous 50% dextrose. The patient subsequently deteriorated into pulseless electrical activity and cardiopulmonary resuscitation was initiated. He was intubated and intravenous dextrose, 8.4% sodium bicarbonate and inotropes were administered. Cardiac output was regained, but despite further sodium bicarbonate, haemofiltration, inotropic support and mechanical ventilation over the course of the next 40 h, the patient developed multi-organ failure and died. Post-mortem examination revealed alcoholic cirrhosis.
A high incidence of lactic acidosis was seen with phenformin therapy (40–60/100 000 patient-years), and led to withdrawal of the drug in 1976.2 In contrast to metformin, phenformin was associated with lactic acidosis in the absence of other precipitating factors.3 Whilst the term ‘metformin-associated lactic acidosis (MALA)’ is commonly used to describe cases of lactate acidosis seen with metformin therapy, true MALA has rarely been reported to cause mortality without other precipitating factors (predominantly renal or liver failure).4 The incidence of lactic acidosis is around 3/100 000 patient-years, with a mortality of about 50%.4 A recent large population-based study, using the Diabetes Audit and Research in Tayside Scotland (DARTS) database, indicated that approximately 25% of patients taking metformin had at least one contraindication to its use, suggesting that metformin may be safe in mild renal or liver dysfunction.5 Contraindications to metformin therapy are outlined in the box.
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At a time when prescribing of metformin is likely to increase, due to the increasing prevalence of diabetes and obesity, it is important for all prescribers to remember that concurrent liver, renal or cardiac disease can occasionally lead to the disastrous complication of MALA, which carries an extremely poor prognosis.
References
1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854–65.[CrossRef][Web of Science][Medline]
2. McGuiness ME, Talbert RC. Phenformin induced lactic acidosis: a forgotten adverse drug reaction. Ann Pharmacother 1993; 27:1183–7.[Abstract]
3. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574–9.
4. Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic acidosis rates in type 2 diabetes. Diab Care 1998; 21:1659–63.[Abstract]
5. Emslie-Smith AM, Boyle DIR, Evans JMM, Sullivan F, Morris AD for the DARTS/MEMO collaboration. contraindications to metformin therapy in patients with type 2 diabetes—a population-based study of adherence to prescribing guidelines. Diab Med 2001; 18:483–8.[CrossRef][Web of Science][Medline]
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