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Executive Summary

Oral hypoglycemic drug labeling that states there is a "reported" link between the drugs and increased cardiovascular mortality will be required by FDA, the agency said in a final rule published in the April 11 Federal Register. Under the heading "SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY," the labeling states: "The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin." The label change become effective in six months. The labeling notes that the warning is "based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes." The UGDP study, involving 823 patients randomly assigned to one of four treatment groups, found that "patients treated for five to eight years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone," the labeling states. The warning culminates a 14-year debate over how the FDA should handle the UGDP findings. FDA announced its basic agreement with the UGDP study in May 1970 and proposed labeling requirements in July 1975. In 1972 the Cmte. on the Care of the Diabetic filed suit asking that FDA be enjoined from requiring labeling changes based on the UGDP study and was granted a temporary restraining order. Additional proceedings by the cmte. led to a preliminary injunction restraining implementation of the labeling changes. In view of criticism of the UGDP study's design and statistical analysis, the Natl. Institute of Arthritis, Metabolism, & Digestive Diseases financed an assessment by the Biometric Society. FDA later conducted its own audit for the study, which was made available in November 1978. After consideration of the entire record, FDA said it believes "the findings reported by UGDP constitute reasonable evidence of an association between the use of oral hypoglycemic drugs and increased cardiovascular mortality." The revised labeling notes that "despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning." FDA will not require, as originally proposed, that use of oral hypoglycemic drugs be limited to patients who cannot take insulin, nor is the warning statement required to be enclosed in a box. In addition, the statement that administration of oral hypoglycemic drugs "may be" associated with increased cardiovascular mortality has been changed to "has been reported to be" associated with increased cardiovascular mortality. Labeling also advises that "the patients should be informed of the potential risks and advantages of (name of drug) and of alternative modes of therapy." FDA noted that the labeling proposed in 1975 applied to two classes of oral hypoglycemics, the sulfonylurea class which includes tolbutamide, chlorpropamide, acetohexamide, and tolazamide, and the biguanide class which at that time included only phenformin. FDA withdrew the NDA for phenformin in November 1978 under the imminent hazard clause of the FD&C Act because of its association with lactic acidosis. Therefore, the agency said, the regulation and guideline labeling are specific for the sulfonylureas.

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