The results of our meta-analysis suggest that elevated HbA1c levels predict increased risk of short and long term mortality in patients hospitalized with CAD. Subgroup analyses showed that the impact of HbA1c on mortality seemed to be different between patients with and without diabetes. Elevated HbA1c was associated with a higher risk of mortality in patients without recognized diabetes even after adjusting for other known risk factors, but had a neutral effect on mortality in patients with diabetes.
Diabetes mellitus and acute glycemic control (admission, fasting or preoperative glucose level) are independent prognostic factors for survival following ACS or AMI [1–5, 37, 38]. Although acute hyperglycemia for most patients may be a manifestation of antecedent disturbed glucose metabolism [1, 2], it is also partly caused by the transient stress with release of catecholamines and cortisol [39, 40]. The adverse outcomes associated with acute hyperglycemia may be somewhat attributed to the stress response to a severe disease state. HbA1c level is a stable indicator of unstressed long-term glucose control and is more useful to predict the abnormal glucose tolerance in CAD patients compared with admission glucose . However, recent studies that evaluated the prognostic value of HbA1c in patients hospitalized with advanced atherosclerosis have reported discrepant results. Several studies showed that although crude mortality data was higher in patients with elevated HbA1c following adjustment for many cardiovascular risk factors, HbA1c values failed to predict mortality independently [11, 15, 16, 20, 30, 36]. Others suggested that HbA1c level was a potent predictor of in-hospital and long-term death [13, 14, 21, 23, 29, 31, 34]. After systematically reviewing previous published data and directly comparing the effect of HbA1 on outcomes in patients with and without recognized diabetes, we found that HbA1c levels had different prognostic effects based on patient's diabetes status.
There are several reasons for the discrepant findings between patients with and without diabetes. First, patients with elevated HbA1c but without known diabetes likely have diabetes that was neither diagnosed nor treated, and other relevant cardiovascular risk factors such as hypertension and dyslipidemia that were also untreated before hospitalization; while those with diabetes are more likely to be treated with insulin and control the established risk factors [2, 4]. This therapeutic difference may account in part for the disparity in outcomes. Second, the same cutoff value that defined elevated HbA1c may have been relatively too low to distinguish those with chronic hyperglycemia in diabetic patients compared with in non-diabetic patients. Third, recent studies suggested progress in the reperfusion treatment of patients with AMI improved the outcome of diabetic patients . Effective reperfusion especially PCI might attenuate the adverse effect of elevated HbA1c on outcomes of diabetic patients . Fourth, HbA1c may lose its predictive power in diabetic patients with heart failure as it has been recognized for other cardiovascular risk factors like BMI and total cholesterol . A recent study reported the association between mortality and HbA1C among 5815 diabetic patients with heart failure appeared U-shaped, HbA1c ≤ 7.1 and > 7.8% all associated with higher risk of death . Another cohort study in diabetic patients with advanced heart failure observed an inverse relationship between HbA1c and long-term mortality . Heart failure was present in ~20% of the diabetic patients included in our analysis. Future studies should investigate the impact of HbA1c in different high-risk diabetic populations with CAD. Fifth, the UK Prospective Diabetes Study (UKPDS) showed that although intensive glycemic treatment resulted in a non-significant improvement in macrovascular disease during the 5-year trial period , the 10-year follow-up demonstrated a significant risk reduction for myocardial infarction and death emerged over time . The follow-up periods for diabetic patients in our study were all less than five years. Therefore, if the follow-up periods were longer, more differences in the mortality between diabetic patients with and without elevated HbA1c might have emerged.
Elevated HbA1c level is likely the result of long term insulin resistance; metabolic disturbances associated with insulin resistance including hyperglycemia, dyslipidemia, hypercoagulability and inflammation might the major pathologic mechanism for the adverse impact of elevated HbA1c in the setting of CAD . In risk-adjusted analysis, after adjusted for other prognostic factors such as old age, hypertension, prior myocardial infarction, and hyperlipidaemia, HbA1c remained independently associated with increased mortality risk (except for patients with diabetes), but it was observed that the associations were attenuated. This suggested that the adverse effect of HbA1c on mortality is somewhat attributable to a correlation with other cardiovascular risk factors. The presence of an elevated HbA1c level, through its association with the metabolic syndrome, may potentially predate the development of other risk factors, and hence these risk factors may represent a common biological proatherogenic pathway [49, 50].
Prior clinical trials of intensive glucose control have shown little benefit, and possibly some harm, of lowering the HbA1c level in patients with diabetes to prevent cardiovascular outcomes [46, 47, 51, 52]. The results of two recent meta-analyses suggested that intensive glucose control reduced cardiovascular events with no effect on mortality [53, 54], and subgroup analyses showed participants with a history of cardiovascular disease did not appear to benefit from intensive therapy . The majority of current trials for glycemic control were designed primarily to patients with established diabetes. Our observation support the need for large randomized trials designed to confirm or refute preliminary suggestions that intensive glycemic control may improve outcomes in CAD patients without diabetes and elevated HbA1c level.
Several limitations of this meta-analysis should be noted. First, the pooled studies differed in inclusion and exclusion criteria, cutoffs for elevated HbA1c, definition of diabetes, duration of follow-up and concomitant treatment. These may be the major source of heterogeneity. We used a random effects model in an effort to incorporate heterogeneity between trials in our analysis, but recognize that this does not eliminate the fact that heterogeneities were present. Second, given the lack of data in some studies, less than half the studies were combined for adjusted analysis, which meant that the results of risk-adjusted analysis were less conclusive. And the covariates adjusted in each study were different. Given the limitations, the results should be interpreted cautiously. Third, although we found no significant effect of elevated HbA1c on all-cause mortality in patients with diabetes, recent studies suggested that HbA1c was associated with an increased risk of major adverse cardiac events following stent implantation  and was a predictor of ischemic events in diabetic patients . The prognostic effect of HbA1c on other cardiovascular events in diabetic patients with CAD needs further evaluation. Finally, given that a proportion of studies included are retrospective, a possibility of residual confounding by unmeasured factors cannot be eliminated. This provided associative, not causal, evidence and mandates caution when interpreting these results.