Incidence of new coronary events in older persons with diabetes mellitus and prior myocardial infarction treated with sulfonylureas, insulin, metformin, and diet alone

T are conflicting data as to whether or not oral sulfonylureas increase the incidence of new coronary events in persons with diabetes mellitus.1–11 We report on data from an observational study investigating the incidence of new coronary events in older persons with diabetes mellitus and prior myocardial infarction (MI) treated with sulfonylureas, insulin, metformin, and diet alone. • • • Two hundred five men and 431 women (mean age 80 6 9 years; range 60 to 100) with diabetes mellitus and prior MI were followed in a long-term health care facility for the incidence of new coronary events. Patients were considered to have prior MI if they had a documented clinical history of MI or electrocardiographic evidence of Q-wave MI. Diabetes mellitus was diagnosed according to the American Diabetes Association new criteria.12 New coronary events were diagnosed if the patient developed nonfatal or fatal MI13 or sudden coronary death14 as previously described. Systemic hypertension was diagnosed according to the criteria of the Sixth Joint National Committee (JNC VI) Report on the Detection, Evaluation, and Treatment of Hypertension.15 Fasting serum lipids were drawn in all subjects after a 12to 14-hour overnight fast. A serum low-density lipoprotein cholesterol level $125 mg/dl was considered to be elevated. A serum high-density lipoprotein cholesterol level #35 mg/dl was considered to be decreased. A serum triglyceride level $190 mg/dl was considered to be increased. The weight and height of each person were correlated with the average weight–height table for persons aged 65 to 94 years.16 A subject was considered obese if he or she was $20% above ideal body weight. In this study, the full-time staff physicians treated the 636 patients as follows: 278 patients (44%) received sulfonylureas, 272 patients (43%) received insulin, 9 (1%) received metformin, and 77 patients (12%) were treated with diet alone. Persons were followed until the time of a new coronary event, death, or the cut-off date for analysis of the data. Follow-up was 30 6 21 months (range 1 to 163). Analysis of variance tests and Student’s t tests were used to examine if there were significant differences in coronary risk factors among the 4 different groups. The stepwise Cox regression model was used to identify significant independent predictors of new coronary events. Table 1 shows the baseline characteristics of the subjects treated with sulfonylureas, insulin, metformin, and diet alone, and lists levels of statistical significance. Table 2 shows the incidence of new coronary events at follow-up in the patients treated with sulfonylureas, insulin, metformin, and diet alone and lists levels of statistical significance. Table 3 shows the prognostic variables for new coronary events and their regression coefficients in the stepwise Cox regression model. • • • The University Group Diabetes Program (UGDP) concluded that compared with a placebo group, a standard insulin dose group, and a variable insulin dose group, phenformin and tolbutamide caused an increased incidence of cardiovascular mortality.1 Although the findings and conclusions of the UGDP were criticized,2 these data led the Food and Drug Administration to require a warning in sulfonylurea packaging. Sulfonylureas inhibit membrane-associated potassium channels in the heart and have been shown to impair ischemic preconditioning3 and prevent coronary vasodilation in response to ischemia.4 Sulfonylurea drug action within the myocardium may increase its vulnerability to ischemia.5 Sulfonylureas also impair ischemic preconditioning during coronary angioplasty, resulting in increased clinical manifestations of ischemia.6 Sulfonylurea drug use was found to be associated with an increased risk of in-hospital mortality among diabetic patients who underwent coronary angioplasty for acute MI (odds ratio 2.77). O’Keefe et al8 also demonstrated that sulfonylurea therapy exerted an independent adverse outcome after elective coronary angioplasty. However, Jollis et al9 did not find an association between sulfonylurea treatment and adverse outcomes in older persons who had diabetes mellitus and acute MI. The United Kingdom Prospective Diabetes Study (UKPDS) also found that sulfonylurea treatment was not harmful and raised the question whether metformin was superior to other therapy in treating obese patients with diabetes mellitus.10 However, this study also observed a 96% increase in diabetes-related death in a group of patients that received additional metformin after beginning sulfonylurea therapy.11 The data from the present observational study From the Department of Medicine, New York Medical College, Valhalla, New York; and the Division of Clinical Epidemiology, University of Texas Medical School at Houston, Houston, Texas. Dr. Aronow’s address is: 23 Pebble Way, New Rochelle, New York 10804. E-mail: WSAronow@aol.com. Manuscript received and accepted February 10, 2001.