This is the largest contemporary study of the prognostic correlates of stress hyperglycaemia in acute coronary syndromes and the first to include patients with unstable angina. The data show that the relation between admission blood glucose and risk of adverse outcomes is graded across quartile groups without any detectable threshold. Importantly, there was no significant interaction with discharge diagnosis in the associations between glycaemia and adverse outcomes, which were similar for patients with unstable angina and acute myocardial infarction.
The large number of patients enrolled in this study allowed us to explore the relation between admission glycaemia and outcomes across a broad range of glucose concentrations. We found clear evidence of a linear trend between admission glycaemia and major complications, particularly LVF and cardiac death, without a threshold effect. Even in the lower quartile groups, risk was closely related to blood glucose concentrations near to or within the normal range, and certainly below concentrations for which insulin is usually recommended.22
Nevertheless, risk was greatest for patients with admission glucose concentrations > 10.0 mmol/l, although within this upper quartile group the relation with adverse outcomes remained linear with no evidence of a critical concentration above which risk increased abruptly.
An important finding in the present study was that the prognostic correlates of admission glycaemia did not differ significantly between patients with acute myocardial infarction and those with unstable angina. This bears comparison with the findings of Savonitto and colleagues,23
who reported that the prognostic significance of increases in creatine kinase extended across the whole spectrum of acute coronary syndromes and included patients with unstable angina, with event rates beginning to rise for creatine kinase concentrations that were within the normal range. Thus, our own study showed the increasing risk of LVF with glucose quartile applied equally to patients with unstable angina and those with myocardial infarction. Indeed, in multivariate analysis, glycaemia was incrementally associated with LVF across quartile groups independently of admission diagnosis. For cardiac death, the picture was less clear partly because event rates were low, particularly in the group with unstable angina, only seven of whom died. Thus, while the risk of death increased progressively with glucose quartile for patients with acute myocardial infarction, there was no pattern for patients with unstable angina. Nevertheless, our interaction analysis provided no evidence that the effects of admission glycaemia on cardiac death were different for the two groups.
The prognostic correlates of admission glycaemia also applied equally to diabetic and non-diabetic subgroups. In both subgroups, the risk of LVF and cardiac death increased across the glucose quartile groups. This contrasts with the findings of a recent meta-analysis,13
which found significant associations between admission glycaemia and LVF in non-diabetic but not in diabetic patients. In the same study, associations between admission glycaemia and hospital death were severely attenuated in diabetic patients. The authors suggested that this may reflect difficulty in defining threshold concentrations for hyperglycaemia in diabetic subjects, a difficulty avoided in our own study by analysing relations between glycaemia and outcome across the full distribution of admission glucose concentrations. Of course the distinction between diabetic and non-diabetic patients in studies of this type is not always straightforward and particularly in the upper quartile group diabetes may be have been undiagnosed in an unknown proportion of patients. Nevertheless, our data strongly suggest that relations between admission glycaemia and adverse outcomes were not confined to non-diabetic patients, there being no evidence of significant interaction with diabetic status.
Multivariate analysis of the independent association of admission glycaemia with adverse outcomes showed that the association with LVF was graded and highly significant. However, despite close univariate associations of admission glycaemia with both age and LVF—the major determinants of prognosis in acute coronary syndromes24–28
—an independent association with cardiac mortality was not confirmed. This is at variance with some reports1
but agrees with the findings of those investigators who, as we did, included LVF in the regression model.4
It is clear, therefore, that the major association of admission glycaemia is with the development of LVF, which, together with age, is the most potent determinant of death in acute coronary syndromes.
Mechanisms of the adverse effects of hyperglycaemia cannot be deduced from our data, although there was a clear association with the extent of myocardial injury. Thus, peak creatine kinase increased incrementally across glucose quartile groups, as did the frequency of acute myocardial infarction and Q wave development, all of which are well recognised markers of injury. Adrenergic stress is itself related to the severity of myocardial injury,16
and our finding of increasing tachycardia across glucose quartile groups presumably reflects this. Certainly, therefore, our data are consistent with the view that acute phase hyperglycaemia in acute coronary syndromes is a response to adrenergic stress as determined by the extent of myocardial injury, which accounts for its relation with adverse outcomes. As others have argued, however, this does not discount a role for relative insulin deficiency,13
which would exaggerate glycaemic responses to adrenergic stress and account for the benefits of insulin administration in patients with acute myocardial infarction and other critically ill patients.18,22
In conclusion, we found that admission glycaemia stratified patients with acute coronary syndromes according to their risk of in-hospital LVF and cardiac mortality. There was no detectable glycaemic threshold for these adverse effects. The prognostic correlates of admission glycaemia were unaffected by diabetic status and did not differ significantly between patients with acute myocardial infarction and those with unstable angina. If relative hyperinsulinaemia contributes to acute phase hyperglycaemia, our data suggest that current recommendations for insulin administration in acute coronary syndromes may be too restrictive.