Association Between Diabetes, Chronic Kidney Disease, and Outcomes in People With Heart Failure From Asia

Background Diabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF) are pathophysiologically linked and increasing in prevalence in Asian populations, but little is known about the interplay of DM and CKD on outcomes in HF. Objectives This study sought to investigate outcomes in patients with heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF) in relation to the presence of DM and CKD. Methods Using the multinational ASIAN-HF registry, we investigated associations between DM only, CKD only, and DM+CKD with: 1) composite of 1-year mortality or HF hospitalization; and 2) Kansas City Cardiomyopathy Questionnaire scores, according to HF subtype. Results In 5,239 patients with HF (74.6% HFrEF, 25.4% HFpEF; mean age 63 years; 29.1% female), 1,107 (21.1%) had DM only, 1,087 (20.7%) had CKD only, and 1,400 (26.7%) had DM+CKD. Compared with patients without DM nor CKD, DM+CKD was associated with 1-year all-cause mortality or HF hospitalization in HFrEF (adjusted HR: 2.07; 95% CI: 1.68-2.55) and HFpEF (HR: 2.37; 95% CI: 1.40-4.02). In HFrEF, DM only and CKD only were associated with 1-year all-cause mortality or HF hospitalization (both HRs: 1.43; 95% CI: 1.14-1.80), while in HFpEF, CKD only (HR: 2.54; 95% CI: 1.46-4.41) but not DM only (HR: 1.01; 95% CI: 0.52-1.95) was associated with increased risk (interaction P < 0.01). Adjusted Kansas City Cardiomyopathy Questionnaire scores were lower in patients with DM+CKD (HFrEF: mean 60.50, SEM 0.77, HFpEF: mean 70.10, SEM 1.06; P < 0.001) than with no DM or CKD (HFrEF: mean 66.00, SEM 0.65; and HFpEF: mean 75.80, SEM 0.99). Conclusions Combined DM and CKD adversely effected outcomes independently of HF subtype, with CKD a consistent predictor of worse outcomes. Strategies to prevent and treat DM and CKD in HF are urgently required.

H eart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD) are major pandemics of the 21st century. Increasing incidence of obesity and hypertension, alongside aging of the population, means that the prevalence of all 3 conditions is rising, with the most rapid increase in rates in developing countries. 1 In Asia, DM develops at a much younger age and at a lower mean body mass index (BMI) than in the United States. 2 The prevalence of HF in some parts of Asia is 2-to 3-fold that found in the United Kingdom and United States, presenting up to 20 years earlier, 3 and nearly one-third of all cases of CKD are in China or India. 4 HF is often clinically differentiated by ventricular ejection fraction, defined as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). DM and CKD appear to play an important role in the pathogenesis of both HFpEF and HFrEF, 5 albeit with potentially different pathophysiological mechanisms and associated risk factors. While DM [6][7][8][9] and CKD [10][11][12][13] individually worsen prognosis in HF, evidence by HF phenotype is limited and conflicting. [14][15][16][17][18][19][20][21][22][23][24][25] Furthermore, while outcomes for people with HF and DM have improved slightly over the past 2 decades, these improvements appear to be lost once CKD is present. 26 Few studies, if any, have investigated the single and combined effects of these prevalent conditions by HF phenotype. This is important given that, until recently, 27,28 no drug trials had demonstrated a reduction in cardiovascular death or hospitalization for HF in people with HFpEF. Additionally, there is now also an emergence of therapeutic agents that provide cardiorenal protective benefits for people with DM and CKD. [29][30][31][32] This study aimed to investigate the clinical correlates and outcomes of DM and CKD in patients with HFpEF and HFrEF in a multinational cohort in Asia and to disentangle the prognostic implications of DM, CKD, and combined DM and CKD.

METHODS
The data used in this study are not available to other researchers due to legal restrictions imposed by multinational jurisdictions. POPULATION

Diabetes and CKD in Heart Failure
A U G U S T 2 0 2 3 : 6 1 1    Figure 1). There was a pattern of reduced KCCQ score with the most severe CKD severity in those with and without DM and in both the HFrEF and HFpEF groups (Supplemental Table 4). All associations were similar after removing patients with HF and type 1 DM (Supplemental Table 5).

DISCUSSION
The combined presence of DM and CKD was significantly associated with more than 2-fold-higher risk of mortality or HF admission, in both HFrEF and HFpEF, but there were distinct differences in associations between HF subtypes and individual conditions. We Values are n (%), unless otherwise indicated. a Adjusted for age, sex, ethnicity, enrollment type, regional income, systolic BP, heart rate, ejection fraction, coronary artery disease, chronic obstructive pulmonary disease, atrial fibrillation, peripheral arterial vascular disease, use of ACE inhibitors, ARBs, beta-blockers, and diuretics.
HRQoL show that both DM and CKD independently contributed to increased risk in HFrEF, but only CKD, and not DM, was associated with increased risk in HFpEF.
CKD and increasing CKD severity was also the pre- Associations between the exposure groups, diabetes mellitus (DM) only, chronic kidney disease (CKD) only, and DMþCKD, compared with patients with no DM or CKD (reference group), with the primary composite outcome of 1-year mortality or heart failure (HF) admission.
HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction. and monitoring, and participants were representative of single-country registers. 52 We also acknowledge that by including prevalent cases of HF we could not assess the temporal relationship between baseline DM, CKD, and HF, meaning that there is potential for some residual confounding by disease duration and reverse causality, and further work is required to fully understand the interrelationships. Furthermore, we did not have complete data on albuminuria, and patients were studied before the widespread availability of newer antiglycemic agents (eg, sodium-glucose cotransporter 2 inhibitor).

CONCLUSIONS
In a prospective registry of HF in Asia, the combination of DM and CKD posed a major health challenge, modulated by socioeconomic and ethnic differences.
DM combined with CKD was associated with higher rates of most adverse outcomes independent of HF subtype, with increasingly severe renal dysfunction a consistent predictor of worse outcomes and reduced HRQoL. Strategies to optimize the prevention and treatment of DM and CKD in HF and to translate the recent promising sodium-glucose cotransporter 2 trial results into real-world patient benefit are urgently required.
ACKNOWLEDGMENTS The contribution of all the site investigators and clinical coordinators is acknowledged.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
The ASIAN-HF study is supported by grants from Boston Scientific