We found that the prevalence of diagnosed diabetes was higher in patients with HFpEF (40%) in CHARM than in those with HFrEF (35%). However, the novel data in the present report relate to the prevalence of undiagnosed diabetes and prediabetic dysglycemia, each of which were more common than a normal HbA1c in both HFpEF and HFrEF. Indeed, when undiagnosed and diagnosed diabetes were combined, a remarkable 62% of patients with each type of HF had diabetes. An additional fifth or so of patients had prediabetes, leaving just approximately one in six patients with a normal HbA1c, an observation that was true for both HFrEF and HFpEF. In comparison 26% had a normal HbA1c and 49% had either diagnosed or undiagnosed diabetes in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF), and corresponding numbers were 30 and 41%, respectively, in the Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial [10]. One explanation for the higher prevalence in CHARM (irrespective of HF type) is that HbA1c was only measured in North American patients where the prevalence of diabetes is high, with the latest reports estimating that in the general population almost 10% have diagnosed or undiagnosed diabetes and another 34% of the population have prediabetes [11].
As was recently reported for patients with HFrEF, undiagnosed diabetes and prediabetic dysglycemia in patients with HFpEF (and HFrEF) in the present study were associated with worse outcomes than observed in patients with a normal HbA1c. Although this pattern was very similar to that reported in the PARADIGM-HF trial, no elevated risk was reported for patients with prediabetes in GISSI-HF. The difference in risk in the present study was not statistically significant, probably because of the smaller number of subjects with a HbA1c measurement in CHARM [7]. Although we found relative similar prevalences of dysglycemia in patients with HFpEF and HFrEF in the current study, the patients with these two phenotypes differed in respect of many of their baseline characteristics. Patients with HFrEF were more likely to have ischemic etiology, worse NYHA class and were less likely to be female. To some extent, the finding of a similarly high rate of dysglycemia in these two quite distinct phenotypes suggests that the syndrome of HF per se plays some role in the development of prediabetes and diabetes. Notably, insulin resistance is present in patients with idiopathic dilated cardiomyopathy as well as in those with ischemic cardiomyopathy, and it is greater in patients with coronary artery disease and HF than in patients with coronary artery disease without HF and is not correlated with ejection fraction [12,13,14]. These findings suggest that the high prevalence of dysglycemia in HF is not explained by recognized associations, e.g. with atherosclerosis and is related to HF per se, independently of ventricular function.
Like PARADIGM-HF, our study has the limitation of a single HbA1c value without a confirmatory measurement and the additional limitation of only including patients from North America where the prevalence of diabetes is higher than in other geographic regions, which may introduce a selection bias and impair applicability of our results to other regions of the world.
However, even with these limitations, our data confirm the remarkably high prevalence of dysglycemia in HFrEF and show that a similarly high prevalence is found in HFpEF (with only 16–18% of patients having a normal HbA1c). In both types of HF, dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes. These findings raise questions about the potential value of screening (for undiagnosed diabetes) and treatment targeted at correcting dysglycemia in patients with both HF phenotypes [15].