In April 1977, an advisory committee of the Canadian Diabetic Association recommended to the Health Protection Branch of Health and Welfare Canada the withdrawal from the Canadian market of the oral antidiabetic biguanide phenformin because of worldwide reports of associated lactic acidosis. Phenformin was, in fact, withdrawn from the Canadian market during the summer of 1977. Another recommendation of the advisory committee was that some sort of monitoring program for metformin be instituted in Canada. The Health Protection Branch and the manufacturer of metformin (Glucophage) in Canada, Nordic Laboratories, agreed to the suggestion and since January 1978 I have sent four biannual letters to some 400 diabetologists, endocrinologists and diabetic day-care centres throughout the country, asking them to report any metformin-associated incident of lactic acidoses. Two years and four mailings later, not a single case has been reported in Canada. Also, I wrote a letter of warning in two English- and two French-Canadian medical journals, asking that physicians be alert in detecting such cases and report them at once. Again, not a single case has been reported by the medical community at large.
Metformin has been marketed in Canada since 1972 and at the time of writing, an estimated 9,000 diabetics take this drug. The incidence of lactic acidosis is therefore estimated to be less than one in 9,000 patient-years in this country.
Metformin was first marketed in Europe in 1959; an estimated 600,000 patients are taking the drug throughout the world. Twenty-five cases of lactic acidosis have so far been reported and in each case a contraindication existed. There were 16 survivors and nine deaths. The contraindications are chronic and acute renal failure, chronic and acute hepatic failure, and severe circulatory failure. Aortography, pyelography, or severe dehydration are among the causes of acute renal insufficiency that may lead to metformin-associated lactic acidosis. The risk of lactic acidosis associated with metformin has been estimated at one in 12,500 patient-years in Switzerland and one in 20,000 patient-years in Sweden. These estimates are based, however, on the cases that actually have happened in patients with contraindications. The risk in patients without contraindications is unknown and in all likelihood negligible.
The pharmacodynamics of biguanides are the same; the exact mechanism of blood sugar reduction in diabetics is unknown and there is no hypoglycemia, unlike the situation with sulfonylureas. The pharmacokinetics of metformin are characterized by rapid absorption, absence of biotransformation, and rapid excretion, unchanged by the kidneys. In contrast, phenformin is metabolized in the liver to a hydroxylated derivative to the extent of 30%, the renal elimination is slow, and binding to cell membrane is higher. There are case reports of patients developing lactic acidosis on phenformin who recovered when switched to metformin.
The Metformin Monitoring Program conducted in Canada for the last two years has not revealed a single case of lactic acidosis. These results, and the consideration of the worldwide experience with this drug, suggest that the risk of acidosis is, for practical purposes, negligible when therapeutic doses are given to patients without contraindications. In other words, metformin (Glucophage) appears to be safe when prescribed rationally and in accordance with the guidelines outlined in the present product monograph. The Health Protection Branch of Health and Welfare Canada has no objection to the discontinuation of the Metformin Monitoring Program.