Around a quarter of patients presenting to the hospital with chest pain have diabetes. Given the close relationship between these disorders, it is perhaps surprising that the optimal way to manage glycaemia in the coronary care unit remains uncertain. In the current issue of Cardiovascular Endocrinology, Hailpern and colleagues highlight increased mortality among patients with chest pain and diabetes who have HbA1c levels less than 6.5% (48 mmol/mol) on admission to a large municipal hospital in Bronx, New York.
Several studies in recent years have addressed the best way to manage patients with diabetes and myocardial infarction. The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study was one of the first clinical trials to influence clinical decision making. A total of 620 patients with acute myocardial infarction were randomized either to receive an intravenous insulin–glucose infusion for 24 h, followed by subcutaneous insulin treatment, or to receive standard treatment 1. After 3.4 years of follow-up, the relative risk of death was 0.72 (0.55–0.92) (P=0.011) for those treated with insulin; the beneficial effects appeared to be most pronounced in those patients who had not previously been treated with insulin. These findings had an impact on the organization of clinical services, and many additional patients were commenced on insulin treatment.
It was not clear at that time, however, whether survival was improved by acute insulin treatment at the time of myocardial infarction, longer-term subcutaneous insulin administration or a combination of both. A follow-up study, DIGAMI-2, attempted to address this issue but did not recruit the planned numbers of patients and was therefore arguably inconclusive 2. Nevertheless, in response to its findings, enthusiasm for initiating insulin therapy and for tight glucose control around the time of myocardial infarction waned in many centres. This was reinforced by the subsequent HI-5 study, which reported no improvement in short-term mortality with intensive insulin treatment, despite decreased rates of cardiac failure and reinfarction 3.
More recently, the benefits of intensive glycaemic control in type 2 diabetes have been questioned in a more general context. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, published in 2008, enrolled over 10 000 patients with longstanding type 2 diabetes and compared the rates of cardiovascular events among patients randomized to intensive glycaemic control [aiming for HbA1c<6.0% (42 mmol/mol)] or standard treatment [aiming for HbA1c 7.0–7.9% (53–63 mmol/mol)] 4. After 3.5 years of follow-up, those treated intensively were found to have an increased rate of mortality and no reduction in cardiovascular events. Moreover, NICE-SUGAR, which allocated 3000 patients to intensive glycaemic control (81–108 mg/dl, 4.5–6.0 mmol/l) and 3000 to standard care (<180 mg/dl, 10 mmol/l) in an intensive care unit setting, reported higher rates of severe hypoglycaemia and higher mortality rates among those allocated to intensive glycaemic control. There was no difference in the length of intensive care unit stay, time on a mechanical ventilator, or time to renal replacement therapy 5.
In the current study, Hailpern and colleagues examined the outcome of a consecutive series of patients who were admitted to hospital in 2004 with symptoms of acute coronary syndrome (chest pain, dyspnoea, or both) and had their troponin level measured (regardless of whether it was positive). Patients with elevated troponin levels but without symptoms suggestive of acute coronary syndrome, were excluded. HbA1c levels were measured routinely in all patients. An increased risk of in-hospital death [hazard ratio 3.51 (1.25–9.83), P=0.02] and death at 1 year [relative risk 3.5 (1.85–6.64), P<0.001] was observed among patients with diabetes and HbA1c levels less than 6.5% (48 mmol/mol). In contrast, there was no increase in mortality among patients without diabetes who had HbA1c levels less that 6.5% (48 mmol/mol). Patients who showed evidence of low blood glucose [defined as at least one measurement less than 70 mg/dl (3.89 mmol/l)] had a significantly higher rate of in-hospital mortality, regardless of whether or not they were known to have diabetes.
How should these data be interpreted? It should be noted that no overall relationship was observed between HbA1c levels and mortality in the cohort as a whole. The findings reported are therefore based on a subgroup analysis and are hence hypothesis-generating rather than definitive. It is unclear how many patients had a myocardial infarction as opposed to unstable angina (or even pulmonary embolism/pneumonia) and what treatment was administered. The authors suggest a causal link between their finding of increased mortality in the diabetes subgroup and hypoglycaemia, implicating overzealous attempts at blood glucose lowering. They consider the alternative (that lower blood glucose may have reflected general illness or other diseases) to be less likely, as those who died had a higher BMI than those who survived.
One of the issues is that treatment and classification of myocardial infarction has changed significantly over the last decade. Those with positive troponin levels (without ST-segment elevation) are promptly treated with dual antiplatelet therapy and low molecular weight heparin, and often undergo early revascularization. Further, patients with ST-segment elevation myocardial infarction (STEMI) are now less likely to be critically ill as they often undergo primary percutaneous intervention with early discharge. Therefore, if the analysis were repeated in a contemporary population, the results may have been different.
Despite the reservations, support for the findings reported is provided by analyses of other key datasets. In a pooled analysis of data from the Thrombolysis in Myocardial Infarction (TIMI) trial, the Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction (LIMIT-AMI) trial and the Optimal Angioplasty versus Primary Stenting (OPUS-TIMI) trial, Pinto et al. 6 described a J-shaped relationship between glycaemia and mortality, whereby those with low and those with high HbA1c levels had a higher risk of mortality, regardless of diabetes status. A blood glucose level of less than 81 mg/dl (4.5 mmol/l) was seen in 8% of all STEMI patients, but it accounted for 13% of deaths. However, drugs to lower glucose levels were not thought to have caused the increased mortality rates as only 8.7% of those with hypoglycaemia had a prior diagnosis of diabetes.
Hailpern and colleagues therefore provide a thought-provoking observation in relation to mortality and glycaemic control in the setting of acute coronary syndrome, but many questions remain unanswered. The authors go as far as to suggest that adjustments in medication aimed at relaxing glycaemic control may be advisable in the setting of diabetes and acute coronary syndrome, but the paper provides no direct evidence to support this approach. At the time the study was undertaken, glucagon-like 1 peptide receptor agonists had not been introduced into clinical practice. These are currently considered to be promising agents in the acute coronary syndrome setting given their good glucose-lowering efficacy with a low risk for hypoglycaemia 7 and reduction of infarct size by exenatide in STEMI 8. Cardiovascular outcome studies involving these agents (e.g. ELIXA 9) are awaited, which may inform future clinical practice.
The 2009 ACC/AHA and the 2013 ESC/EASD guidelines both recommend that in patients with acute coronary syndrome, treatment should be initiated in those with hyperglycaemia greater than 180 mg/dl (10 mmol/l), while avoiding hypoglycaemia 10, and with an approximation towards normoglycaemia with less stringent targets in those with severe comorbidities 11. In the absence of evidence to the contrary, and while awaiting further data, there are no immediate grounds for changing these approaches.
Conflicts of interest
There are no conflicts of interest.
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