The Association of Hemoglobin A1c with Heart Failure among People without Diabetes

Diabetes is one of the most important risk factors for heart failure. Among people with diabetes, a dose relationship between glycemia measured by HbA1c (A1c) and heart failure risk has been reported in observational studies. The risk of hospitalization for heart failure increases 8-32% per 1% unit increase in A1c. In contrast, researchers said, no previous study has investigated the association between A1c and the risk of heart failure in a population without diabetes. In this population, fasting glucose is only marginally or not associated with heart failure risk. This may be partially attributable to relatively high variability in glucose measurements and to the fact that fasting glucose levels do not necessarily reflect postprandial hyperglycemia, a condition potentially contributing to development of cardiovascular disease.

In January 2010, the American Diabetes Association published new clinical guidelines recommending the use of A1c as a diagnostic test for diabetes, with cut-points based largely on the documented association of A1c with microvascular disease. Little is known, however, regarding the risk relationship of A1c levels with heart failure incidence in nondiabetic adults. The objective of the study was to investigate a possible relationship between A1c and the incidence of heart failure in a community-based study of people without diabetes. Researchers also compared the associations of A1c and fasting glucose levels with risk of incident heart failure in this middle-aged nondiabetic population.

The study sought to investigate an association of HbA1c (A1c) with incident heart failure among individuals without diabetes and compare it to fasting glucose.

They studied 11,057 participants of the Atherosclerosis Risk in Communities (ARIC) Study without heart failure or diabetes at baseline and estimated hazard ratios of incident heart failure by categories of A1c (<5.0, 5.0–5.4 [reference], 5.5–5.9, and 6.0–6.4%) and fasting glucose (<90, 90–99 [reference], 100–109, and 110–125 mg/dl) using Cox proportional hazard models.

The results showed a total of 841 cases of incident heart failure hospitalization or deaths occurred during a median follow-up of 14.1 years (incidence rate 5.7 per 1,000 person-years). After the adjustment for covariates including fasting glucose, the hazard ratio of incident heart failure was higher in individuals with A1c 6.0–6.4% (1.40 [95% CI, 1.09–1.79]) and 5.5–6.0% (1.16 [0.98–1.37]) as compared with the reference group. Similar results were observed when adjusting for insulin level or limiting to heart failure cases without preceding coronary events or developed diabetes during follow-up. In contrast, elevated fasting glucose was not associated with heart failure after adjustment for covariates and A1c. Similar findings were observed when the top quartile (A1c, 5.7–6.4%, and fasting glucose, 108–125 mg/dl) was compared with the lowest quartile (<5.2% and <95 mg/dl, respectively).

In contrast to the robust independent association of A1c with increased risk of heart failure, fasting glucose was only weakly associated and no longer significant after adjusting for A1c in the study population. This weak association between fasting glucose and incident heart failure in a nondiabetic population is consistent with the previous literature and may result from relatively high variability in glucose measurements. Superiority of A1c to fasting glucose for disease prediction has also been observed for CHD, stroke, and total mortality. Nevertheless, researchers said, results suggest that A1c is a better risk marker of heart failure as compared with fasting glucose in a nondiabetic population.

Participants with a fasting glucose <90mg/dL.(<5.0 mmol/l) had an increased risk of heart failure compared with individuals with fasting glucose 90-99mg/dL.(5.0–5.5 mmol/l) in the study. Such a J-shaped association has been observed for all-cause or cardiovascular mortality in some studies but not for heart failure. Given that excluding heart failure cases within 5 years of follow-up did not alter findings, reverse causation is unlikely. There remains the possibility that comorbid conditions associated with both lower glucose concentration and risk of heart failure, e.g., liver dysfunction, might account for the observed higher heart failure risk at low serum glucose concentrations.

Researchers concluded that elevated A1c (≥5.5–6.0%) was more strongly associated with increased risk of heart failure as compared with fasting glucose in a middle-aged bi-ethnic population without diabetes and that findings suggested chronic hyperglycemia even before the development of diabetes is an independent risk factor of heart failure and may contribute to the development of heart failure beyond its effect on CHD risk.