In this study, we show that serum glucose levels were strongly associated with risk for HF development in elderly who did not have diabetes mellitus at baseline. This risk was independent of other HF risk factors and was consistent in both sexes, and in whites and blacks. Importantly, other glycemic measures did not provide incremental predictive information. With the increasing obesity and metabolic syndrome prevalence in the United States and the related worsening of glycemic abnormalities in the general population, our findings have important clinical implications.
Although various definitions have been developed and modified over time to characterize glycemic status into sub-groups, we and other investigators have shown in the past that the relation between serum glucose levels and incident HF is continuous.5, 12, 13
Notably, previous studies included both subjects with and without clinical DM; in the current study, we found a continuous relation in subjects without history of DM. Moreover, risk increases even within a range of levels that is currently considered normal by all criteria. However, analysis using categorization of glucose levels into normal, pre-diabetes range, and DM-range failed to detect increased risk for incident HF in persons with pre-diabetes range in our study. This most likely represents the effect of sub-group analysis and beta-error related to lack of power to detect a difference. Thus, our results underscore the risk of loss of information associated with categorization of biologically continuous variables. One may contest that the importance of pre-diabetes and cardiovascular risk is primarily shown in younger populations, and part of the risk might be mediated through risk of new onset DM over time. The potent relationship between serum glucose levels as an independent predictor of HF risk even after adjusting for other risk factors makes this assertion less likely.
The biological association of serum glucose levels and HF risk has been studied well in patients with DM; the same mechanisms may underlie this risk association in patients without history of DM and may be mediated through IR. In the presence of IR, the heart rapidly modifies its metabolism, resulting in augmented fatty acid and decreased glucose consumption.6, 21
This alteration is central in the development of diabetic cardiomyopathy, a condition that affects both systolic and diastolic function of the heart and predisposes to HF.22, 23
Additional mechanisms linking IR and HF include adverse effects of hyperglycemia on endothelial function,24
effects of excess circulating glucose and fatty acids on myocyte structure,25
intracellular signaling and gene expression,26
and impaired recruitment of the myocardial insulin-responsive glucose transport system in response to ischemia.27
In line with these findings, we recently reported that fasting glucose is an independent predictor of incident HF prediction in the elderly participants of the Health, Aging, and Body Composition (Health ABC) Study,13
superseding baseline diabetes status (as defined by self-reported history and use of medications).
The WHO definition of glycemic status suggests incorporation of OGTT, which is expected to uncover latent DM (or at risk for DM) subjects based on a challenge as opposed to a fasting value. With respect to prediction of HF risk, we did not detect any incremental value of OGTT over fasting glucose alone. When used as a categorical value, OGTT rather reduced the specificity of the fasting glucose based categorization of glycemic abnormalities, and when studied as a continuous variable, it did not add anything to the prediction of incident HF beyond fasting glucose. Thus, OGTT did not help identify persons at greater risk for subsequent HF. Indeed, neither switching to WHO criteria (which are more liberal on normal fasting glucose values) nor addition of OGTT resulted in net improvement in HF risk classification above ADA fasting glucose based definitions.
Although we found significant unadjusted relations between markers of glycemic status and HF risk, serum glucose levels remained the most potent risk predictor. Once controlled for all other predictors of HF risk including serum glucose, none of the other markers -- fasting insulin, 2 hour post challenge glucose levels. Hemoglobin A1c, and HOMA-based IR and β cell function assessment -- provided additional prognostic information. These results obviously neither test nor suggest any pathophysiologic association of any of these markers with HF risk, but they provide important practical information. Fasting glucose levels may help to identify persons who are at risk for HF, and risk detection with respect to glycemic status may best be achieved with a simple and inexpensive blood test.
Interestingly, in our study fasting glucose was more strongly associated with incident HF with depressed as compared to preserved LVEF. Although some data suggest that the outcomes for these two groups of patients are similar, the distribution of demographic characteristics still differ significantly between the two groups,28
i.e. patients with HF and preserved EF are more likely to be older and women. This may impact on the risk factor profile for incident HF for the two groups, something that is also suggested by our solitary risk factor analysis, i.e. fasting glucose. However, due to the restricted number of patients in our subgroup analysis and the lack of uniform LVEF assessment, these data are preliminary. Differences in risk factors and their population attributable risks for HF with preserved vs. low LVEF need further study.
Our study has several limitations. Diagnosis of incident HF in our study was based on HF hospitalization and therefore we likely underestimated the true incidence of HF. Echocardiography was not performed at baseline in the Health ABC Study. Thus, participants with subclinical prevalent structural heart disease may have been included in the analysis. Ninety-eight participants in this study had fasting glucose in the DM range. We are not certain what proportion of these individuals represents undiagnosed DM vs. spurious finding, what proportion were subsequently clinically diagnosed and treated vs. not; and who required intensive medical therapy vs. just diet control for borderline elevated glucose levels. These issues are however important as undiagnosed and untreated DM would not only heighten the risk for HF development, but it may also represent more complex social (inadequate access to care) and medical (poorly treated comorbidities) issues which may also predispose an individual to develop HF. Because ventricular function during hospitalization for HF was not prospectively assessed, we could not reliably assess the differential impact of fasting glucose on development of HF with preserved vs. reduced LVEF. The available data on LVEF were based on medical record reviews and are not derived from a single modality. Therefore, we cannot be confident that the distribution of LVEF in our data is representative of the investigated population. Finally, the findings of this study are limited to the elderly population and are not transferable to the general population. Further work is needed.
In conclusion, our study demonstrates that simple fasting serum glucose levels were the strongest predictor of incident HF risk among glycemic status markers; that this relationship is continuous; and starts at a level considered normal for serum glucose. This relationship was not affected by either white or black race, or sex. Testing for other glycemic measures did not add to our ability to identify individuals at risk for incident HF. Whether identification of such high-risk individuals and subsequent glucose lowering intervention would reduce HF risk needs further study.