Importance of diabetes as a marker for increased mortality after acute MI

Over 18 million Americans have diabetes, and it is anticipated that the prevalence of diabetes will double by 2050, owing in large part to the obesity pandemic and the aging of the population.1 Moreover, although diabetes is a disorder of glucose metabolism, its complications are largely vascular, with up to 75% of deaths in diabetic patients being attributable to cardiovascular disease.2 In addition, diabetes is a potent risk factor for the development of coronary artery disease (CAD), peripheral arterial disease, and stroke.1,2 The presence of diabetes also has consistently been shown to be a marker for adverse outcomes in patients with acute or chronic cardiovascular conditions, including coronary heart disease.3,4 However, despite the high prevalence of diabetes and its known association with poor prognosis in patients with vascular disease, the mechanisms underlying this association have not been fully elucidated.

Two factors that may contribute to adverse outcomes in diabetic patients with acute myocardial infarction (MI) are a differential ap-

proach to treatment and/or an altered response to therapy in diabetic patients compared with nondiabetic patients. For example, diabetic patients may be less likely to be referred for cardiac catheterization due to preexisting renal insufficiency, and reperfusion therapy may be less efficacious in diabetic patients because of lesion complexity. To address these issues, Timmer and colleagues (page 38) analyzed data from the previously published Zwolle trial, in which 395 patients with acute ST-elevation MI were randomized to receive primary angioplasty or intravenous streptokinase (Kabikinase, Streptase) therapy.5 In the original trial, the authors found that primary angioplasty was associated with reduced mortality and lower rates of stroke and reinfarction compared with streptokinase therapy at 30 days, and that the beneficial effects of angioplasty persisted for up to 5 years.

The analysis by Timmer and colleagues compared long-term outcomes in 74 patients with diabetes (19%) with those in nondiabetic patients over a mean follow-up period of 7.5 years.6 The principal finding was that total mortality was higher among diabetic patients, even after adjusting for baseline differences in left ventricular ejection fraction. In addition, mortality due to heart failure was higher in the diabetic subgroup; however, there was no significant difference between the groups in the incidence of sudden cardiac death. The authors conclude that diabetes is an independent risk factor for mortality following acute ST-elevation MI, even among patients treated with reperfusion therapy, and that most of the excess mortality risk is attributable to heart failure. In addition, the authors found that the benefits of primary angioplasty relative to intravenous streptokinase were at least as great in the diabetic population as they were in the nondiabetic population.

Several important limitations of this study are worth noting. First, a number of variables that may have contributed to the adverse outcomes in diabetic patients were not accounted for in the analysis, including prior history of MI, anemia, baseline renal function, and time to reperfusion. Including these factors in the multivariable analysis may have diminished the apparent impact of diabetes per se on long-term mortality, while simultaneously providing additional insight into the mechanisms whereby diabetes is linked to a worse prognosis.

A second limitation is the relatively small sample size, which reduced the study’s power to detect significant differences between groups with respect to some of the outcomes of interest. Thus, although the risk of sudden death was 60% higher in diabetic patients compared with nondiabetic patients (hazard ratio, 1.6), this difference was not statistically significant (P = .23), most likely reflecting the fact that the number of sudden deaths in the overall sample was small. Because diabetes has detrimental effects on autonomic function and heart rate variability, thereby predisposing diabetic patients to life-threatening arrhythmias, an increased risk of sudden cardiac death might be expected in these patients7,8; this hypothesis, however, awaits testing in a larger patient population.

A third limitation is that the mechanisms underlying the increased risk of death due to heart failure among the diabetic patients in this study remain unknown. As the authors point out, several factors may contribute, including more impaired left ventricular function at baseline (because of prior MI or diabetic cardiomyopathy), diastolic dysfunction, recurrent MI during follow-up, and noncardiac factors, such as renal dysfunction, anemia, obesity, and more severe hypertension.

Conclusion

What are the implications of this study for clinical practice? Most importantly, diabetes is a powerful and readily identifiable marker for increased mortality after acute MI. Therefore, diabetic patients should be selectively targeted for aggressive and intensive therapies designed to minimize risk (see Table for current recommendations).9-11 In addition, because diabetes mellitus is now well-established as a “coronary risk equivalent” (ie, the risk of an incident coronary heart disease event in a diabetic patient without prior CAD is similar to that in a nondiabetic patient with a prior MI),12 appropriate therapy, as recommended by the American Diabetes Association,10 should be implemented in all diabetic adults to minimize the risk of a future MI, which, as the present study shows, is associated with up to 50% mortality at 10 years, even among patients undergoing successful reperfusion.