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(Circulation. 1998;97:709-710.)
© 1998 American Heart Association, Inc.

Correspondence

Sulfonylureas and Mortality in Diabetic Patients After Myocardial Infarction

Peter A Brady, MD; Jassim Al-Suwaidi, MD; Stephen L Kopecky, MD; ; Andre Terzic, MD, PhD

Division of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Rochester, Minn

To the Editor:

A long-standing controversy that relates to the potentially harmful effects of sulfonylurea drugs within the ischemic myocardium was presented recently in Circulation.¹ The controversy arises from the fact that sulfonylurea drugs inhibit ATP-sensitive potassium (K_ATP) channels.² Although blockade of K_ATP channels in the pancreas promotes the release of insulin, conductance through K_ATP channels in the heart is thought to be critical to the protection afforded by ischemic preconditioning, which limits infarct size.^{2 3 4} Yet, despite experimental data that demonstrate that sulfonylurea drugs prevent ischemic preconditioning,^{3 5} increase infarct size,⁴ and may be associated with an increase in in-hospital mortality among patients undergoing direct angioplasty for myocardial infarction,⁶ clinical data on long-term outcome of patients treated with sulfonylurea drugs are sparse.

Therefore, in answer to the plea made by Engler and Yellon,¹ we report findings from a population-based study involving 874 residents of Olmsted County, Minnesota, admitted to the Mayo Clinic Coronary Care Unit between January 1988 and October 1996 with acute myocardial infarction (WHO criteria) that compares long-term outcome of sulfonylurea and insulin-treated patients. In all, there were 102 diabetic patients receiving either insulin (n=56) or a sulfonylurea (n=46) at the time of admission to hospital. Mean age was 70±10 years in the sulfonylurea group versus 68±12 years in the insulin group. As determined by left ventricular ejection fraction, frequency of previous myocardial infarction, and severity of coronary artery disease, differences between the two groups were not significant (P=.28, P=.12, and P=.95, respectively). In addition, the prevalence of hypertension, hypercholesterolemia, and tobacco use was also similar between the two groups (P=.13, P=.15, and P=.54, respectively). During follow-up (mean 2.7±2.3 years, maximum 8.4 years), a total of 24 deaths occurred in the sulfonylurea group versus 20 in the insulin group. Of these, 12 deaths were attributable to cardiac causes in the sulfonylurea group versus 10 in the insulin-treated group (differences not significant: P=.79 for overall survival and P=.54 for survival to cardiac death [Kaplan-Meier estimates]).

Thus, our findings indicate that use of sulfonylurea drugs in diabetic patients at the time of myocardial infarction is not associated with increased long-term mortality. However, our data do not address several important issues, including the impact of sulfonylurea drugs on short-term mortality or cardiac morbidity, which may be increased secondary to impaired cardioprotection.⁶ These findings may be related to the known variable efficacy with which sulfonylurea drugs inhibit cardioprotective K_ATP channels. Indeed, the interaction between sulfonylurea drugs and K_ATP channels during metabolic stress is complex, with various factors governing sulfonylurea-inhibitory gating of the channel,^{7 8} leading to a nonuniform action of sulfonylurea drugs at the cellular level.⁹ Such complexity of regulation of cardiac K_ATP channels warrants further clinical and molecular studies to determine more fully the consequences of sulfonylurea drug use on the human heart.

References

1. Engler RL, Yellon DM. Sulfonylurea K-ATP blockade in type II diabetes and preconditioning in cardiovascular disease: time for reconsideration. Circulation. 1996;94:2297–2301.

2. Terzic A, Jahangir A, Kurachi Y. Cardiac ATP-sensitive K⁺ channels: regulation by intracellular nucleotides and potassium opening drugs. Am J Physiol. 1995;38:C525–C545.

3. Gross G. ATP-sensitive potassium channels and myocardial preconditioning. Basic Res Cardiol. 1995;90:85–88.

4. Grover GJ. Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia. J Cardiovasc Pharmacol. 1994;24:S18–S27.

5. Cleveland JC, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited. Circulation. 1997;96:29–32.

6. Garratt KN, Hassinger N, Grill DE, Terzic A, Srivasta SS, Holmes DR. Sulfonylurea drug use is associated with increased early mortality during direct coronary angioplasty for acute myocardial infarction among diabetic patients. J Am Coll Cardiol. 1997;29:493A. Abstract.

7. Findlay I. Sulphonylurea drugs no longer inhibit ATP-sensitive K⁺ channels during metabolic stress in cardiac muscle. J Pharmacol Exp Ther. 1993;266:456–467.

8. Brady PA, Alekseev AE, Aleksandrova LA, Gomez LA, Terzic A. A disrupter of actin microfilaments impairs sulfonylurea-inhibitory gating of cardiac K_ATP channels. Am J Physiol. 1996;271:H2710–H2716.

9. Brady PA, Zhang S, Lopez JR, Jovanovic A, Alekseev AE, Terzic A. Dual effect of glyburide, an antagonist of K_ATP channels, on metabolic inhibition-induced Ca²⁺ loading in cardiomyocytes. Eur J Pharmacol. 1996;308:343–349.

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