COMORBIDITIES AND THEIR IMPLICATIONS IN PATIENTS WITH AND WITHOUT TYPE 2 DIABETES MELLITUS AND HEART FAILURE WITH PRESERVED EJECTION FRACTION. FINDINGS FROM THE RICA REGISTRY
ABSTRACT
AIM: to determine if patients with heart failure and preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) have a higher comorbidity burden than those without T2DM, if other comorbidities are preferentially associated with T2DM, and if these conditions confer a worse patient prognosis.
METHODS AND RESULTS: Cohort study based on the RICA Spanish Heart Failure Registry, a multicenter, prospective registry that enrolls patients admitted for decompensated HF and follows them for 1 year. We selected only patients with HFpEF, classified as having or not having T2DM, and performed an agglomerative hierarchical clustering based on variables such as the presence of arrhythmia, chronic obstructive pulmonary disease, dyslipidemia, liver disease, stroke, dementia, body mass index (BMI), hemoglobin levels, estimated glomerular filtration rate, and systolic blood pressure. 1,934 patients were analyzed: 907 had T2DM (mean age 78.4+/-7.6 years) and 1,027 did not (mean age 81.4+/- 7.6 years). The analysis resulted in 4 clusters in patients with T2DM, and 3 in the reminder. All clusters of patients with T2DM showed higher BMI, and more kidney disease and anemia than those without T2DM. Clusters of patients without T2DM had neither significantly better nor worse outcomes. However, among the T2DM patients, clusters 2, 3 and 4 all had significantly poorer outcomes, the worst being cluster 3 (HR 2.0, 95% CI 1.36-2.93, p=0.001).
CONCLUSIONS: Grouping our patients with HFpEF and T2DM into clusters based on comorbidities revealed a greater disease burden and prognostic implications associated with the T2DM phenotype, compared to those without T2DM.
KEY WORDS: Heart failure with preserved ejection fraction; type 2 diabetes mellitus; comorbidity; kidney disease.
WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?
WHAT DOES THIS ARTICLE ADD?
INTRODUCTION
Type 2 diabetes mellitus (T2DM) and heart failure (HF) are closely related. Patients with T2DM have an increased risk of developing HF and vice versa. Some studies report that more than one-third of patients who are hospitalized for heart failure without a diagnosis of diabetes mellitus (DM) exhibit impaired fasting glucose or glucose intolerance [1], and that the prevalence of diabetes in patients with heart failure ranges from approximately 25% to 40%, depending on the population studied [1]. However, few of these studies differentiated between HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a subanalysis of the CHARM program (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity), the prevalence of diagnosed diabetes was higher in patients with HFpEF (40%) than in those with HFrEF (35%) [2]. Furthermore, a number of trials in patients with HF have shown an increased risk of cardiovascular death or hospitalization in men and women with diabetes [3-6]. In the case of HFpEF, patients commonly present other associated comorbidities such T2DM, which may contribute to the pathophysiology of HF and its outcome, since their comorbidities are associated with higher rates of non-cardiovascular hospitalization and death. However, the potential impact of HFpEF on the prognosis of T2DM in these patients is not fully characterized. Although diabetes was associated with a steeper increase in left ventricle mass and wall thickness compared to age and sex-adjusted controls in the Framingham study [7], the overall comorbidity burden in patients with T2DM and HF is usually higher than in patients with HF alone [8]. Our aim in this study was to determine if patients with HFpEF and T2DM have a higher comorbidity burden than those without T2DM, if other comorbidities are preferentially associated with T2DM, and if these conditions confer a worse prognosis.
METHODS
Patients were recruited via the RICA Spanish National Heart Failure Registry, supported by the HF and Atrial Fibrillation Working Group of the Spanish Society of Internal Medicine (SEMI-IC-FA). The RICA registry is an ongoing multicenter, prospective, cohort study that has been described elsewhere [9,10]. This registry includes consecutive and unique patients aged 50 years or older with HF according to the criteria of the European Society of Cardiology [11]. Patients were included at discharge after an acute event of decompensated HF between March 2008 and May2017,and followed up for 1 year.
The study protocol was approved by the Ethics Committee of the University Hospital Reina Sofia, Cordoba, Spain, and all patients gave their informed consent before inclusion in the cohort. Data were collected in the database via a website (https://www.registrorica.org) that was accessed with a personal password. Complete registry data are published elsewhere [9].
In this analysis, we included only patients with HFpEF [left ventricular ejection fraction (LVEF) higher than 50% and elevated natriuretic peptides], and we excluded patients with either reduced or mid-range ejection fraction and HF caused by valvular heart disease (figure 1). Data analyzed comprise past medical history related to HF, Charlson comorbidity index (CCI), Barthel index (BI), Pfeiffer index (PfI), acute HF episode admission clinical data [blood pressure, heart rate (HR), body mass index (BMI)] and blood chemistry values, including kidney function defined by estimated glomerular filtration rate (eGFR) based on the MDRD equation (Modification of Diet in Renal Disease [12]), blood sugar profile, hemoglobin, serum sodium and potassium levels, and natriuretic peptides.
HF was characterized using the New York Heart Association (NYHA) scale and the evaluation of left ventricular ejection fraction (LVEF) by 2-D echocardiography. We also recorded the etiology of HF (ischemic, hypertensive, alcoholic, toxic, hypertrophic, and others) and the potential cause of decompensation when the patients were included. We excluded patients whose clinical or laboratory data were not fully completed, patients without an echocardiographic examination, and patients who either died during hospitalization or did not complete follow-up.
To analyze differences between patients with and without diabetes, we first divided the sample into two groups according to the diagnosis of T2DM (based on patient history and prescription of hypoglycemic agents). In a second step, we sub-divided the patients according to clusters based on the following variables: arrhythmia, chronic obstructive pulmonary disease (COPD), dyslipidemia, liver disease, stroke, dementia (all defined according to investigators’ criteria), BMI, hemoglobin, eGFR, LVEF, and systolic blood pressure (SBP). The primary endpoint was to analyze comorbidities in patients with both HFpEF and T2DM and in patients with HFpEF but without T2DM. Secondary endpoints were to analyze the outcomes of the clusters, firstly in terms of HF mortality and readmissions, and secondly in terms of all-cause mortality and readmissions.