Demographic characteristics of participants by categories of A1C are shown in . Participants with A1C ≥5.5% were more likely to be older, African American, and smokers but less likely to be current drinkers as compared with the reference group (A1C 5.0–5.4%). Individuals with A1C 6.0–6.4% at baseline were also more likely to have higher BMI, higher blood pressure, adverse lipid profile, and higher prevalence of CHD and carotid atherosclerosis. A1C and fasting glucose were weakly, but significantly, correlated (r = 0.32, P < 0.001).
Characteristics of participants according to categories of A1C
During a median follow-up time of 14.1 years, there were 841cases of incident heart failure. The overall incidence rate of heart failure was 5.7 per 1,000 person-years. The continuous associations of A1C and fasting glucose levels with incidence rate of heart failure with the adjustment for age, sex, and race are shown in . The incidence rate of heart failure increased linearly above A1C 5.0% (tests for differences in slopes above A1C 5.0% were not statistically significant; data not shown) and was ~2-fold or higher in a range of A1C ≥6.0% as compared with that of A1C 5.0%. Although the incidence rate of heart failure increased at a fasting glucose level of 5.6 mmol/l, the slope was much shallower than that for A1C and was flat at the range of 5.0–5.5 mmol/l. Increased risk of heart failure was observed at the low ranges of A1C (<5.0%) and fasting glucose (<5.0 mmol/l), although 95% CIs were wide, reflecting imprecision of the estimate.
FIG. 1. Incident rates of heart failure (HF) according to A1C and fasting glucose. The graph shows incidence rates (per 1,000 person-years) and 95% CIs (shaded area) of heart failure with spline terms of A1C (knots at 5.0, 5.5, and 6.0%) (A) and fasting glucose (more ...)
We estimated the hazard ratios and corresponding 95% CIs for incident heart failure by categories of A1C using Cox proportional hazards models adjusting for multiple covariates (). As compared with participants with A1C 5.0–5.4, the hazard ratios of heart failure rose progressively from 1.44 (95% CI, 1.24–1.68) to 2.04 (95% CI, 1.63–2.54) across categories of A1C ≥5.5% in the model adjusted for age, sex, and race (model 1). The association among individuals with A1C 6.0–6.4% remained significant even after adjustment for all traditional cardiovascular risk factors (model 2, hazard ratio 1.38 [95% CI, 1.09–1.75]), although the association among participants with A1C 5.5–5.9% was attenuated to borderline significance (hazard ratio 1.16 [0.98–1.36], P = 0.08). The adjustment for fasting glucose did not alter the results (model 3). These associations did not change appreciably after further adjustment for use of antihypertensive drugs (i.e., β-blockers, ACE inhibitors, or diuretics), which might potentially affect both glucose metabolism and risk of heart failure (data not shown).
Adjusted hazard ratios (HRs; 95% CI) for incident heart failure (HF) according to A1C categories
There was no evidence of effect modification by a history of CHD at baseline (P for interaction = 0.83), and similar, but slightly attenuated, associations were observed when we censored participants without prevalent CHD at baseline who developed CHD prior to heart failure (hazard ratio 1.27 [95% CI, 0.95–1.70] for A1C 6.0–6.4% and trend P = 0.095). We obtained similar results even after further adjusting for insulin levels. The exclusion of participants who developed diabetes during the first 6 years or censoring participants who self-reported diagnosed diabetes before heart failure during follow-up did not alter the results (data not shown).
Participants with fasting glucose levels of 6.1–6.9 mmol/l but not 5.6–6.0 mmol/l had an increased risk of heart failure as compared with those with glucose levels of 5.0–5.5 mmol/l in model 1 (). However, the association was greatly attenuated after adjustment for multiple covariates (model 2) and no longer significant when A1C was included in the model (model 3, hazard ratio 1.11 [95% CI, 0.90–1.35]). By contrast, fasting glucose <5.0 mmol/l was associated with higher risk of heart failure as compared with the reference group, even after adjusted for multiple covariates (model 2, hazard ratio 1.51 [1.14–2.00]). This association remained significant even after adjusting for A1C (model 3) or restricting the sample to participants who contribute more than 5 years follow-up time (hazard ratio 1.55 [1.13–2.13]). We repeated the analyses using an average fasting glucose level at visit 1 and visit 2 and obtained similar results (data not shown).
Adjusted HRs (95% CI) for incident HF according to fasting glucose categories
When we compared the quartiles of A1C and fasting glucose in model 2, the highest quartile of A1C (5.7–6.4%) but not fasting glucose (6.0–6.9 mmol/l [108–125 mg/dl]) was associated with heart failure risk as compared with the lowest quartile of A1C (<5.2%) and fasting glucose (<5.3 mmol/l [<95 mg/dl]) (hazard ratio 1.42 [1.13–1.78] and 1.03 [0.84–1.27], respectively). Similar results were observed when we used the second quartile of fasting glucose (5.3–5.6 mmol/l [95–100 mg/dl]) as the reference group (data not shown).
We also examined the joint association of A1C and fasting glucose with heart failure risk (). A1C 6.0–6.4% compared with 5.0–5.4% was significantly associated with increased risk for heart failure at fasting glucose levels of 5.0–5.5 mmol/l with similar association at other fasting glucose levels. In contrast, the association of elevated fasting glucose with heart failure was not significant at A1C 5.0–5.4%. Similarly, there was no consistent increase in heart failure risk associated with higher fasting glucose at other A1C categories. Although the relative risk associated with higher A1C tended to be larger among participants with low/normal fasting glucose levels as compared with those with elevated fasting glucose levels, the interaction of A1C and fasting glucose categories on heart failure risk was not significant (P = 0.257).
Adjusted* HRs (95% CI) for incident HF according to the combination of A1C and fasting glucose categories
Finally, we modeled the association of heart failure risk per 1% unit increase in A1C and examined this association in different subgroups (). Overall, each 1% unit increase in A1C was associated with 39% (95% CI, 13–70%) increased risk of heart failure after adjusted for multiple covariates. These results were largely consistent across the different subpopulations (all Ps for interaction >0.05).
Hazard ratios (HRs) of heart failure per 1% unit increase in A1C. Hazard ratios overall and within subgroups adjusted for the same covariates as model 2 in are shown. Error bars represent 95% CIs. eGFR = estimated glomerular filtration rate.