It is well known that both prior diabetes diagnosis and admission blood glucose concentration are associated with adverse outcome after AMI. In this report, we compared the relative association of these two measures of dysglycaemia with survival after STEMI as well as NSTEMI. Irrespective of the type of AMI, the univariate association with mortality risk for antecedent diabetes (40% excess at 30 days, 55–65% thereafter) was no longer apparent after adjustment for relevant covariates including admission glucose concentration. In contrast, the excess risk associated with increasing glucose was not reduced after adjustment, was similar in those with and without known diabetes, and remained relevant in patients discharged alive from the index event.
In our previous report of over 4000 patients with STEMI, admitted in 1993–2004,9
the 50% increase in 30-day and 1-year mortality risk associated with known diabetes was attenuated by half on covariate adjustment and removed completely when admission blood glucose concentration was included in the analysis. The current report confirms these observations and extends them to a contemporary period, and to patients with NSTEMI as well as STEMI, in whom the strength of association between admission blood glucose concentration and 30-day mortality risk was similar, and concentration dependent. Importantly, the excess risk, around 7% for each 1 mmol/l increase in admission glucose concentration, was maintained up to and beyond 1 year from the index infarction. Further, this phenomenon was attenuated with time only for patients with NSTEMI, and was evident even in those patients who survived to discharge from hospital, two potentially important clinical observations. These findings are in contrast to one previous report which reported the association between admission glucose and mortality to be confined to in-hospital deaths following either STEMI or NSTEMI.8
They are however in keeping with the vast majority of reports in this area.1–7
In contrast to most previous reports,1–9
we observed no independent association between diabetes and mortality risk after AMI. However, to our knowledge and unlike the present report, none of these studies adjusted for admission blood glucose, and each reported individual relationships between mortality after AMI and either diabetes diagnosis1
or blood glucose concentration.3–8
The current analysis and our previous study9
are the only reports to compare the relative association with outcome of both diabetes and blood glucose concentration. Both studies demonstrate a much stronger relationship between survival and blood glucose, and the loss of association between mortality and diabetes when blood glucose is considered. Owing to incomplete data and lack of power, we could not assess whether outcomes varied by diabetes therapies. However, previous studies have reported an independent association of admission blood glucose with mortality regardless of diabetic therapy used.2
These observations are of potential clinical significance. While admission blood glucose concentration after AMI is on average higher in patients with, compared to those without, known diabetes,4
there is considerable overlap, as seen in the current report (). While many patients presenting with AMI will have previously undiagnosed diabetes,22
blood glucose at the time of admission with AMI is not a reliable indicator of the subsequent diagnosis of diabetes.23
In routine practice, the management of hyperglycaemia after AMI is influenced by the presence of prior diabetes diagnosis.5
In both European14
and North American6
settings, the majority (>65%) of patients presenting with hyperglycaemia in the context of AMI, and not previously known to have diabetes, do not receive active management of blood glucose. In the presence of a true, direct toxic effect upon prognosis of elevated blood glucose, failure to correct hyperglycaemia may represent suboptimal clinical care, and patients without known diabetes may be particularly disadvantaged. In particular, our demonstration that the relationship between glucose concentration and subsequent outcome is evident in NSTEMI as well as STEMI is of clear clinical relevance in terms of the overall management of patients presenting with AMI.
The strength of association between diabetes and mortality risk after AMI has been reported to increase with time from the event.25
While we observed such a trend on univariate analysis, this was attenuated in multivariate analysis, an observation which may relate to our inclusion of blood glucose as a covariate. A previous meta-analysis suggested a stronger association between admission blood glucose and adverse outcome.4
While we could not demonstrate formal statistical evidence of such a phenomenon, our data show convincingly that the relationship between glucose and outcome is at least as powerful in patients without known diabetes. Blood glucose soon after admission represents an easily identified, clinically relevant marker of risk after AMI, which should be assessed routinely irrespective of diabetes status.
An important observation from this study is the persisting association between admission blood glucose concentration and mortality risk in patients surviving to discharge, in both NSTEMI and STEMI. While in keeping with the possibility that blood glucose concentration at admission reflects the degree of individual physiological stress, or is a marker of the extent of infarction, our findings are as much in keeping with a direct, adverse influence on prognosis of acute hyperglycaemia. The mechanisms by which elevated glucose may be directly cardiotoxic have been summarised elsewhere10
and include attenuation of ischaemic preconditioning, QT prolongation, increased thrombophilia and endothelial dysfunction. Furthermore, clinical studies overwhelmingly support a possible causal link between hyperglycaemia and adverse prognosis after AMI. Hyperglycaemia persisting at 24 h after admission is associated with adverse outcome.12
While observational studies show consistently the adverse association between hyperglycaemia and outcomes post-AMI, results of the RCTs of active management of blood glucose have been inconsistent.16
However, in such trials, effective reduction in blood glucose with an intervention after AMI was associated with improved prognosis.16
The guidelines from professional societies in this area differ in their recommendations.26
In the North American guidelines, intensive glucose control is recommended in patients with AMI and significant hyperglycaemia (blood glucose levels >10.0 mmol/l) admitted in an intensive care unit.27
In contrast, the National Institute for Health and Clinical Excellence guidance recommends against routine use of intensive insulin therapy to manage hyperglycaemia (blood glucose levels >11.0 mmol/l) in patients with acute coronary syndrome.26
The latter guidelines highlighted a need for randomised controlled trials addressing specific gaps in knowledge this area.
Our report is subject to the limitations inherent in all observational cohort studies. Our results are from a single-centre study. In the early years of the MINAP project, data on only STEMI were collected. Furthermore, data collected for MINAP was gathered mainly from a setting of coronary care unit. Selection bias could be the reason behind the overall low numbers of AMI cases (4111) recruited in our study over a 6-year period in a catchment population of one million. However, baseline and clinical outcome parameters in our study are similar to previous studies. Selection bias could also explain relatively high proportion of patients with STEMI (58.4%) compared to NSTEMI in our cohort. We therefore conducted subgroup analysis for people with STEMI and NSTEMI and compared their outcomes. Blood glucose concentration used in this analysis was that first recorded for the index admission, and is likely to have varied in timing relative to symptom onset. Our database lacks information on left ventricular (LV) ejection fraction, evidence of heart failure and a number of other potentially relevant variables. Information on body mass index, an indicator of underlying metabolic syndrome and associated dysglycaemia, was not available. Further, we have no information regarding the number of patients who were given a diagnosis of diabetes during, or subsequent to, the index admission. However, if elevated glucose contributes directly to prognosis, active management is likely to confer greater benefit when delivered as early as possible, irrespective of subsequent diabetes status. Thus, we suggest the first-recorded blood glucose concentration to be highly relevant to guiding appropriate management in individual patients, irrespective of residual LV function. While we have no information on interventions or changes to therapy after discharge, it is unlikely that these impacted on outcome in a major way, as the strongest association between mortality and glucose was in the first 30 days. Findings of our study based on real-life practice are applicable to other populations treated in similar setting.
In summary, admission blood glucose concentration is a powerful, routinely available marker of mortality risk after AMI. After adjustment for admission blood glucose, known diabetes is not associated with adverse outcome. The association between blood glucose concentration and mortality risk is of similar magnitude in patients with and without known diabetes, is evident for NSTEMI as well as STEMI, and persists beyond 1 year from the index event, including in patients surviving to discharge. Future studies are merited of the impact of active management of blood glucose in patients with all presentations of acute coronary artery disease, irrespective of diabetes diagnosis.