The biguanide, metformin (Glucophage®, Novo-metformin, Nu-metformin and Gen-metformin) is an oral antihyperglycemic agent used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Phenformin, another biguanide, was withdrawn from the market in many countries because of the high risk of inducing lactic acidosis; however, metformin is associated with a very low incidence of lactic acidosis because it has different pharmacokinetic properties. For example, metformin is not metabolized by the liver, therefore, there are no high- risk groups demonstrating an impaired metabolism. One benefit of metformin, in contrast to the sulphonylureas, is that hypoglycemia does not occur during monotherapy. Also, obese patients with NIDDM may favour metformin because it does not appear to cause an increase in body weight.
Metformin has been available in Canada since 1972. Since marketing, the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) has received 11 reports (7 women, 4 men) of lactic acidosis associated with the use of metformin.
Summary of cases:
• The mean age was 68 years (range 39 to 91 years).
• Patients, for whom a daily dose was reported, were prescribed 1.5 grams.
• The actual lactate level was provided in only three cases.
• The outcomes were: four people died; four recovered; two patients had not yet recovered at the time of reporting; and one recovered with residual effects.
• In all cases, one or more risk factors for developing lactic acidosis were present: Five cases (3 fatal), had pre-existing renal insufficiency; in four cases, there was implicit evidence of congestive heart failure from the concomitant medications being taken (e.g., digoxin, furosemide); and in one report, the patient consumed an excessive amount of alcohol while on metformin. Finally, one report involved a 91-year-old man who developed lactic acidosis and acute renal failure 2 days after metformin was initiated. The complicating factor, following the onset of the reaction, was that metformin treatment was continued and the patient underwent a diagnostic examination using radiocontrast media.
The Canadian Adverse Drug Reaction Advisory Committee was asked to review the above 11 cases of lactic acidosis. The committee concluded that none of the cases provided evidence that metformin was definitely the cause of the acidosis, but for most patients, it may have been a contributing factor.
The above cases, reported to CADRMP, occurred primarily in patients with explicit or implicit evidence of renal insufficiency or congestive heart failure. The diabetic patient is susceptible to complications that cause morbidity and premature mortality, including cardiovascular and renal impairment. While some evidence suggests that the risk of lactic acidosis with metformin is unrelated to age, elderly diabetic patients will have developed complications that possibly increase this risk. Thus, careful selection of patients and continuous monitoring for any changes in condition that may lead to contraindication of the drug is important.
The contraindications associated with the use of metformin include patients:
a) with hypersensitivity to metformin or related agents
b) with medical conditions, including
- i) renal impairment or unknown renal function
- ii) liver disease
- iii) alcoholism
- iv) intercurrent infection, or
- v) cardiopulmonary insufficiency
c) undergoing medical or diagnostic examinations, e.g., angiography or i.v. pyelography
d) with a history of ketoacidosis or lactic acidosis
Although the development of lactic acidosis is rare, the reported case fatality rate is 30% to 50%. Nevertheless, lactic acidosis is largely preventable by strict observance of such risk factors; therefore, it is important to heed the contraindications, precautions and warnings detailed in the product monograph.