SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY:
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. This 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 study
involved 823 patients who were randomly assigned to one of four treatment
groups ( Diabetes, 19, supp. 2: 747-830, 1970).
UGDP reported that patients treated for 5 to 8 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. A significant increase in total
mortality was not observed, but the use of tolbutamide was discontinued based on the increase
in
cardiovascular mortality, thus limiting the opportunity for the study to show
an increase in overall mortality. Despite controversy regarding the interpretation of these
results, the
findings of the UGDP study provide an adequate basis for this warning. The
patient should be informed of the potential risks and advantages of GLUCOTROL and of alternative
modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included
in this study, it is prudent from a safety standpoint to consider that this warning may also
apply to other
oral hypoglycemic drugs in this class, in view of their close similarities
in mode of action and chemical structure.