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| |  DG DISPATCH - EASD: Controversy Remains Over Sulfonylurea-Metformin Combination Therapy By Cameron Johnston Special to DG News BRUSSELS, BELGIUM -- October 1, 1999 -- Do overweight patients with type 2 diabetes who take a combination of metformin and sulfonylurea therapy have a higher risk of cardiac mortality than those who use metformin alone? The question appeared to have been answered positively in the United Kingdom Propective Diabetes Study (UKPDS) - yes the combination does lead to an increase in cardiac and diabetes-related deaths.
Now, a second study from researchers in Sweden appears to confirm that finding. The issue is highly controversial, however, and even one of the principal authors of the UKPDS still supports the use of metformin as a useful therapy for many type 2 diabetics. Speaking at the European Association for the Study of Diabetes’ annual meeting, in Brussels, Belgium, Dr. Arne Melander said there is an effect, as yet unknown, between sulfonylureas and metformin that increases the risk of cardiovascular events, including death, among overweight patients who use the two drugs in combination. "I believe the high cardiac mortality and morbidity reflects the insufficient efficacy of sulfonylurea and metformin dosing," said Dr. Melander, who is affiliated with University Hospital and the University of Uppsala, in Sweden. Dr. Melander’s study involved analyzing the health records of all type 2 diabetics who lived in two areas of Sweden between 1984-94, and who used either metformin alone, or metformin in combination with sulfonylurea during that time. Researchers then followed the patients out until the end of 1996 or until they died. In all, 171 patients used the combination regimen and 872 used sulfonylurea alone. All-cause mortality, stroke mortality and ischemic heart disease were all significantly higher among the patients who took the combination therapy. There were no differences in other causes of death for patients in the two groups. The death rate from stroke for those in the combination therapy group was 23.9 per thousand patient-years whereas for those in the sulfonylurea alone group, the death rate was 17.9 per thousand patient-years. Those in the combination therapy group had ischemic heart disease at the rate of 52.9 per thousand patient-years, while for those in the monotherapy group, the rate was 47.9 per thousand patient-years. Adjusted odds ratios were 2.16 and 1.95 respectively, meaning those who took the combination therapy were more than twice as likely to suffer a fatal stroke, and had a 90 percent greater chance of developing ischemic heart disease. Dr. Melander stressed that this was an observational study and not a randomly controlled, clinical trial, and that it merely pointed out that an association existed, not that there was a cause and effect. However, Dr. David Matthews, one of the lead authors for the UKPDS, disputed any link between the two drugs, saying that there were too many unanswered questions in the UKPDS to draw any kind of conclusion. "We should be finding out more about this in real life, looking at real treatments," he said. "We are still quite uncertain about whether sulfonylureas are good or bad." The UKPDS did appear to show greater mortality among patients taking the two drugs - a 1.79 risk ratio for fatal myocardial infarction, a 1.61 risk ratio for sudden death and a 5.25 risk ratio for fatal stroke. However, Dr. Matthews said the variables that could have influenced the data include the patients’ age, the fact that some of them added metformin to their regimens at later stages of the disease and that they were more hyperglycemic to begin with. Metformin has been in use for more than 40 years now, he said, and is still an important tool for doctors to use in treating type 2 diabetes. Compared with other drugs, it is equally effective, it does not cause the patient to gain weight the way sulphonylurea does, and is associated with fewer hypoglycemic attacks than either sulphonylurea or insulin.
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