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Published: July 1998
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Metformin and Fatal Lactic Acidosis

Prescriber Update 16: 22–24
July 1998

Dr P Pillans,former Medical Assessor,
Centre for Adverse Reactions Monitoring (CARM), Dunedin

Metformin is a useful anti-hyperglycaemic agent but significant mortality is associated with drug-induced lactic acidosis. Significant renal and hepatic disease, alcoholism and conditions associated with hypoxia (eg. cardiac and pulmonary disease, surgery) are contraindications to the use of metformin. Other risk factors for metformin-induced lactic acidosis are sepsis, dehydration, high dosages and increasing age.

Metformin remains a major reported cause of drug-associated mortality in New Zealand. Of the 12 cases of lactic acidosis associated with metformin reported to CARM since 1977, 2 occurred in the last year and 8 cases had a fatal outcome.

Metformin useful but small risk of potentially fatal lactic acidosis

Metformin is a useful therapeutic agent for obese non-insulin dependent diabetics and those whose glycaemia cannot be controlled by sulphonylurea monotherapy. Lactic acidosis is an uncommon but potentially fatal adverse effect. The reported frequency of lactic acidosis is 0.06 per 1000 patient-years, mostly in patients with predisposing factors.1

Examples of metformin-induced lactic acidosis cases reported to CARM include:

Contraindicated in marked renal disease

Ninety percent of metformin is excreted unchanged by the kidneys and lactic acidosis typically occurs in patients with renal insufficiency.2 Significant renal impairment (serum creatinine >0.16 mmol/L) is a contraindication to the use of metformin, and mild renal disease increases the risk of lactic acidosis.

Metformin is also contraindicated in chronic hepatic disease because of the increased risk of metformin-associated lactic acidosis. Patients with diabetes frequently have abnormal liver function tests secondary to fatty liver which in itself is not a contraindication. Other contraindications include conditions associated with hypoxia (e.g. recent myocardial infarction, cardiac failure, pulmonary disease and surgery3) and alcoholism.

Not recommended in pre and post-operative period

Other risk factors for metformin-associated lactic acidosis include sepsis, high dosage, increasing age, and dehydration.4 In situations predisposing to dehydration such as fasting for surgery or contrast radiography, metformin should be ceased at least 48 hours prior to the procedure (or on admission for an emergency procedure), and not restarted until the patient has fully recovered and is eating and drinking normally. The glucose levels of patients in catabolic states, e.g. sepsis or in the post-operative period, should be monitored. Short-term insulin therapy is strongly advised.

Biguanide interference: ↑ lactate production and ↓ clearance

Lactic acidosis appears to result from biguanide interference causing an increase in production and decrease in clearance of lactate leading to higher cellular lactate levels. Intracellular redox potential then shifts from aerobic to anaerobic metabolism. A decrease in pyruvate carboxylase activity, the rate limiting enzyme in the formation of glucose from lactate, can also decrease hepatic metabolism of lactate.

Symptoms nonspecific: anorexia, hyperpnoea, altered consciousness

Signs and symptoms of biguanide-induced lactic acidosis are nonspecific and include anorexia, nausea, vomiting, altered level of consciousness, hyperpnoea, abdominal pain and thirst. Doctors should suspect lactic acidosis in patients presenting with acidosis, but without evidence of hypoperfusion or hypoxia.

Treatment involves biguanide withdrawal, adequate hydration/circulatory support and correction of the acidosis. Haemodialysis may be useful for both acid/base control and drug clearance.

Increase dosage beyond 1.7g/day with caution

A metformin dosage of 850mg twice a day, or 500mg three times a day, usually gives good diabetic control. Caution is needed when increasing the daily dosage beyond 1.7g, especially in the elderly and those with mild renal disease.

Significant mortality (reported as high as 50%3) is associated with biguanide-induced lactic acidosis and attention should be focused on prevention through awareness of the risk factors.

References
  1. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol 1993;44:589-91.
  2. Gan SC, Barr J, Arieff AI, Pearl RG. Biguanide-associated lactic acidosis. Arch Intern Med 1992;152:2333-6.
  3. Gowardman JR, Havill J. Fatal metformin induced lactic acidosis: case report. NZ Med J 1995;108:230-1.
  4. Bartley PC. Caution in use of metformin. Fellowship Affairs (Royal Australasian College of Physicians) 1996;(Nov):5.