The underestimated risk of prediabetes on cardiovascular outcomes in heart failure with reduced left ventricular function

Abstract Background The global prevalence of prediabetes and diabetes is increasing, highlighting an urgent public health challenge. While the cardiovascular (CV) risk of diabetes is well studied, profound data on the CV risk of prediabetes in patients with heart failure (HF) remain scarce in current literature. Therefore, we aimed to investigate the relationship of prediabetes and diabetes with common HF associated events such as all-cause, CV death and hospitalization for HF (HHF) in patients with HF with reduced ejection fraction (HFrEF). Methods Patients with HFrEF who were admitted to a tertiary academic center between 01/2005 and 07/2019 were included in the present analysis and then stratified according to their glycemic state. Prediabetes was defined as an HbA1c value between 5.7% and 6.4% and the absence of diabetes mellitus. The primary outcome was a composite of CV death and HHF. Secondary outcomes were the individual components of the primary outcome and all-cause death. We used cox regression models adjusted for age, sex, chronic kidney disease, body mass index, prior myocardial infarction, hypertension, CRP, and LDL-C. Results In total, 1,777 patients (median age 69 years, 24.3% female) were included in the present analysis and followed over a median of 4 years. Among them, 35.2% were diabetic, 18.7% prediabetic, and 46.1% showed non-impaired glucose metabolism. NT-proBNP levels were comparable between all glycemic groups. Both prediabetes and diabetes were found to significantly increase the risk of CV-death or HHF compared to those with normal glucose metabolism, with adjusted hazard ratios (HR) of 1.41 (95% Confidence Interval [CI]: 1.05-1.89) and 1.52 (95% CI: 1.17-1.97), respectively. This elevated risk applied to both components of the primary outcome, as illustrated in Figure 1. Notably, the increased risk of all-cause mortality was statistically significant only among diabetic patients (adj. HR 1.75; 95%CI: 1.30-2.36), with prediabetic patients showing a trend towards increased risk but not reaching statistical significance (adj. HR 1.40; 95%CI: 0.99-1.97). Conclusion The findings of this study underscores the independent associations between both prediabetes and diabetes with increased risks of cv-death and HHF in patients diagnosed with HFrEF. This emphasizes the critical role of glycemic status in the prognostication and management of HFrEF. The associations suggest that prediabetes is not merely a transient or benign state but has significant implications for cardiovascular health, particularly in the context of HF. In light of these findings, screening of prediabetes in patients with HFrEF might help to identify patients at risk who are susceptible for the development of HF related adverse events.Forest plot for all study endpointsKaplan-Meier curves for CV-death/HHF