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The New England Journal of Medicine --
June 13, 1996 -- Vol. 334, No. 24
The data submitted for the approval of metformin for use in the United States were from two 29-week clinical trials involving patients with non-insulin-dependent diabetes mellitus (NIDDM), reported by DeFronzo et al. (Aug. 31 issue), (1) and one 2-year, unreported, open-enrollment study. (2) One of the clinical trials was placebo-controlled, with 143 patients assigned to receive metformin and 146 to receive placebo. In the second trial, 210 patients were assigned to monotherapy with metformin, 213 to metformin plus glyburide, and 209 to glyburide alone.
Six hundred two of these patients chose to enroll in the open study to receive metformin with or without a sulfonylurea drug: 75 patients from the placebo group, 142 from the glyburide group, 217 from the metformin groups, and 168 from the metformin-plus-glyburide group. With the open study, the total duration of metformin treatment during all U.S. open and controlled studies was increased to 1136 patient-years.
There was one death in the controlled trials, and there were six additional deaths in the open study. All seven deaths occurred among the patients who had initially been assigned to metformin therapy; no deaths occurred among those initially assigned to glyburide or placebo. A comparison of the survival distributions in the treatment groups by the log-rank test revealed a significant difference from the expected distribution of 4.4 deaths in the metformin group and 2.6 deaths in the control group (P = 0.04). Moreover, all seven deaths occurred among 423 patients (1.7 percent) randomly assigned to therapy with metformin in the second study. An analysis of survival in this subgroup revealed no statistically significant difference from an expected distribution of 4.9 deaths in the metformin group and 2.1 in the control group (P = 0.09). The shortest duration of treatment resulting in a death was 97 days, and the longest was 825 days (mean [±SD], 463±242 days).
Five of the seven deaths were from cardiovascular causes (including one case of lactic acidosis and another of sudden death after newly developed glomerular dysfunction). Another death was ascribed to suicide. A 1994 review of 255 cases of metformin-associated lactic acidosis (2) revealed a significant proportion of cases due to suicidal overdose (4.7 percent; 95 percent confidence interval, 2.5 to 8.1 percent; P<0.01). The seventh death was ascribed to pulmonary fibrosis in a patient with a small-cell carcinoma of the lung.
Morbidity and mortality in patients with NIDDM are primarily from cardiovascular complications, which have not been found to be correlated with glucose control in any well- designed studies. (3) Because of the substantial morbidity and mortality from cardiovascular causes in patients with this disorder, it is difficult to discern drug-induced cardiovascular toxicity. Wishing to monitor potential metformin-associated mortality, and without the benefit of the data on excess metformin-associated mortality noted above, the Endocrinologic and Metabolic Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended on March 18, 1994, that a registry be established for all patients given metformin in the United States, should the drug be approved. (4) So far, the FDA has not acted on this recommendation. A one-year study of 8000 patients receiving metformin alone or combined with a sulfonylurea drug and 2000 control patients has been requested by the FDA. This marketing study should allow the detection of differences in the rates of clinically important adverse events but will not detect small differences in overall mortality or mortality from cardiovascular causes.
Ronald Jay Innerfield, M.D.
Dorothy Bullock Memorial National Diabetes Center
Olney, MD 20832-1002
References
1. DeFronzo
RA, Goodman AM, Multicenter Metformin Study
Group. Efficacy of metformin in patients with
non-insulin-dependent diabetes mellitus. N Engl J
Med 1995;333:541-9.
Return to Text
2. Innerfield RJ.
Medical officer safety review of an NDA
submission. Metformin. (NDA 20-357.) (On file at
FDA, Bethesda, Md., May 1994 [FOI].)
Return to Text
3. Lebovitz HL. The DCCT
and its implications for NIDDM. Clin Diabetes
1994;12(1):3-4.
Return to Text
4. FDC Reports.
Glucophage Rx registry to track adverse events
recommended by FDA cmte. The Pink Sheet. March
21, 1994.
Return to Text
Slide 61
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.
