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?
- Heart Failure with preserved ejection fraction is influenced for
comorbidities.
- Diabetes mellitus (DM) is one of the most important comorbidities
associated.
- The value of the remainder comorbidities in this setting is not fully
understood.
WHAT DOES THIS ARTICLE ADD?
- Patients grouped comorbidities revealed a bigger disease burden in the
case of DM.
- Comorbidity groups with DM had prognostic effects compared to those
without DM.
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.