European Journal of Cardiovascular Medicine

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two of the most significant and growing public health challenges of the 21st century. Their confluence represents a particularly malignant clinical entity, as they share common risk factors and pathophysiological pathways, creating a vicious cycle of disease progression [1]. The global prevalence of both conditions is rising, and projections indicate that their combined burden on healthcare systems will continue to escalate [2]. T2DM is an independent risk factor for the development of HF, increasing the risk two- to five-fold, even after adjusting for traditional risk factors like hypertension and coronary artery disease (CAD) [3].

The pathophysiological link between T2DM and HF is complex and multifactorial. Beyond accelerating atherosclerosis and increasing the risk of ischemic heart disease, diabetes promotes a specific cardiac condition known as diabetic cardiomyopathy. This is characterized by structural and functional changes in the myocardium, including myocardial fibrosis, hypertrophy, and diastolic dysfunction, driven by mechanisms such as hyperglycemia, hyperinsulinemia, lipotoxicity, oxidative stress, and chronic low-grade inflammation [4, 5]. These processes often manifest clinically as heart failure with preserved ejection fraction (HFpEF), a phenotype increasingly recognized as a hallmark of diabetic heart disease [6].

Recent landmark clinical trials have revolutionized the management of patients with T2DM and HF. The discovery that sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly reduce HF hospitalizations and cardiovascular mortality in patients with and without diabetes has shifted the therapeutic paradigm, highlighting the importance of targeting non-glycemic pathways in this population [7, 8]. These advances have underscored the unique pathophysiology at play when HF and T2DM coexist.

Despite extensive research on the prognostic implications and therapeutic responses, a distinct research gap exists in the comprehensive characterization of the baseline clinical profile of HF patients with T2DM compared to their non-diabetic counterparts in contemporary clinical practice. While large trial datasets provide some insights, they often involve highly selected patient populations. A clearer understanding of the differences in presentation—including functional status, biomarker profiles, cardiac structure, and comorbidity burden—in a real-world setting is crucial for early risk stratification and the implementation of targeted, aggressive management strategies from the outset.

Therefore, the aim of this study was to conduct a detailed comparative analysis of the baseline demographic, clinical, biochemical, and echocardiographic characteristics of patients presenting with heart failure with concomitant T2DM versus those with heart failure in the absence of diabetes.

Study Design and Population

This was a prospective, observational, comparative cohort study conducted at a single, large-volume tertiary care cardiology center. A total of 400 consecutive patients with a primary diagnosis of acute or chronic decompensated heart failure.

Inclusion and Exclusion Criteria

Inclusion criteria were: (1) age ≥ 18 years; (2) a confirmed clinical diagnosis of heart failure based on the European Society of Cardiology (ESC) guidelines, including symptoms and/or signs of HF and elevated natriuretic peptides or objective evidence of cardiogenic pulmonary or systemic congestion; and (3) provision of informed consent.

Exclusion criteria included: (1) type 1 diabetes mellitus; (2) acute coronary syndrome within the past three months; (3) severe valvular heart disease as the primary cause of HF; (4) end-stage renal disease (eGFR < 15 mL/min/1.73m²) or on dialysis; (5) active malignancy or other non-cardiac conditions with a life expectancy of less than one year; and (6) inability to provide consent.

Study Groups

Participants were stratified into two groups based on their diabetic status:

1. HF-T2DM Group (n=185): Patients with a prior diagnosis of T2DM or a glycated hemoglobin (HbA1c) level ≥ 6.5% on admission.
2. HF-non-DM Group (n=215): Patients with no history of diabetes and an HbA1c level < 6.5%.

Data Collection and Procedures

A standardized case report form was used to collect data for each patient upon enrollment.

• Demographic and Clinical Data: Information on age, sex, body mass index (BMI), smoking status, medical history, and current medications was recorded. Blood pressure was measured in a seated position after 5 minutes of rest. Functional status was assessed using the New York Heart Association (NYHA) classification.
• Laboratory Analysis: Venous blood samples were drawn within 24 hours of admission. Laboratory parameters included a complete blood count, renal function panel (creatinine, blood urea nitrogen), electrolytes, HbA1c, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• Echocardiography: A comprehensive transthoracic echocardiogram was performed on all patients during their index hospitalization by an experienced sonographer, according to American Society of Echocardiography guidelines. Left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson's method. Diastolic function was assessed using E/e' ratio and other standard parameters. Based on LVEF, HF was categorized as HF with reduced ejection fraction (HFrEF, LVEF ≤ 40%), HF with mildly reduced ejection fraction (HFmrEF, LVEF 41–49%), or HF with preserved ejection fraction (HFpEF, LVEF ≥ 50%).

Statistical Analysis

All statistical analyses were performed using SPSS for Windows, version 26.0 (IBM Corp., Armonk, NY). Continuous variables were presented as mean ± standard deviation (SD) and compared using the independent samples t-test for normally distributed data or the Mann-Whitney U test for non-normally distributed data. Categorical variables were presented as counts and percentages (%) and were compared using the Chi-square (χ²) test or Fisher’s exact test, as appropriate. A two-sided p-value of < 0.05 was considered statistically significant for all analyses

A total of 400 patients with a diagnosis of heart failure were included in the final analysis, comprising 185 (46.3%) patients in the HF-T2DM group and 215 (53.7%) in the HF-non-DM group.

Baseline Demographics and Clinical Characteristics

The baseline demographic and clinical characteristics of the two study groups are presented in Table 1. The mean age was similar between the groups. However, the HF-T2DM group had a significantly higher mean BMI (31.2 ± 4.5 kg/m²) compared to the HF-non-DM group (28.1 ± 3.9 kg/m²; p<0.001). Patients with T2DM also presented with higher systolic and diastolic blood pressure. A significantly greater proportion of patients in the HF-T2DM group were in NYHA functional class III or IV (65.4%) compared to the non-diabetic cohort (48.8%; p=0.002), indicating more severe symptoms at presentation.

Table 1. Baseline Demographics and Clinical Characteristics

Echocardiographic and Laboratory Findings

Table 2 summarizes the key echocardiographic and laboratory parameters. While the mean LVEF did not differ significantly between the groups, the distribution of HF phenotypes varied markedly. HFpEF (LVEF ≥ 50%) was the dominant phenotype in the HF-T2DM group, present in 61.1% of patients, compared to 42.8% in the HF-non-DM group (p=0.001). Conversely, HFrEF was more common in the non-diabetic cohort.

Biochemically, the HF-T2DM group demonstrated a profile indicative of greater cardiac stress and poorer renal function. Mean NT-proBNP levels were significantly higher in the diabetic group (3450 ± 1280 pg/mL) than in the non-diabetic group (2150 ± 990 pg/mL; p<0.001). As expected, HbA1c was elevated in the T2DM group (8.1 ± 1.3%). Critically, mean eGFR was significantly lower in the HF-T2DM group (55.4 ± 15.2 mL/min/1.73m²) compared to the HF-non-DM group (68.3 ± 16.5 mL/min/1.73m²; p<0.001).

Table 2. Echocardiographic and Laboratory Parameters

Comorbidities and Baseline Medications

The burden of cardiovascular and related comorbidities was significantly higher in the HF-T2DM group, as detailed in Table 3. Hypertension, coronary artery disease, chronic kidney disease (defined as eGFR < 60), and atrial fibrillation were all more prevalent among patients with diabetes (p<0.05 for all). In terms of medication, patients in the HF-T2DM group were more likely to be on diuretics and mineralocorticoid receptor antagonists (MRAs), consistent with a more congested clinical state. As expected, SGLT2 inhibitor use was almost exclusive to the diabetic group at baseline, reflecting contemporary prescribing practices.

Table 3. Prevalence of Comorbidities and Baseline Medication Use

This comparative study provides a detailed snapshot of the clinical differences between heart failure patients with and without T2DM in a real-world setting. Our principal finding is that HF-T2DM patients present with a substantially more adverse clinical, biochemical, and structural phenotype. This population is characterized by worse functional capacity, greater comorbidity burden, higher levels of cardiac biomarkers, and impaired renal function, supporting the concept that diabetes accelerates and modifies the HF disease process.

The significantly higher BMI and blood pressure observed in our HF-T2DM cohort are consistent with the well-established clustering of metabolic risk factors. This metabolic milieu is a key driver of cardiac remodeling and dysfunction [9]. The greater prevalence of NYHA class III/IV symptoms and higher NT-proBNP levels in the diabetic group directly reflect a state of more advanced cardiac decompensation and higher ventricular filling pressures at the time of presentation. NT-proBNP is a robust marker of myocardial wall stress, and its pronounced elevation in diabetic patients likely reflects the cumulative impact of pressure and volume overload, myocardial fibrosis, and systemic inflammation [10].

One of the most striking findings of our study is the strong association between T2DM and the HFpEF phenotype. Over 60% of our diabetic HF patients had a preserved ejection fraction, a significantly higher proportion than in the non-diabetic group. This aligns with a growing body of evidence suggesting that T2DM preferentially promotes diastolic dysfunction and concentric hypertrophy through pathways independent of ischemia, such as advanced glycation end-product accumulation, mitochondrial dysfunction, and microvascular rarefaction [6, 11]. The higher E/e' ratio in our diabetic cohort provides further objective evidence of elevated left ventricular filling pressures and advanced diastolic dysfunction. This finding is clinically important, as HFpEF has historically had fewer evidence-based therapies, although recent trials with SGLT2 inhibitors and MRAs are changing this landscape [12].

The profound impact of T2DM on renal function was also evident, with our HF-T2DM cohort demonstrating significantly lower eGFR. This highlights the critical nature of the cardiorenal syndrome, a condition where cardiac and renal dysfunction mutually exacerbate one another [13]. The coexistence of HF, T2DM, and chronic kidney disease (CKD) forms a triumvirate of risk that portends a particularly poor prognosis [14]. The higher prevalence of CKD in our diabetic group underscores the systemic nature of diabetes-related end-organ damage and complicates management, particularly with respect to dosing of guideline-directed medical therapies and diuretic management.

The higher prevalence of comorbidities like hypertension, CAD, and atrial fibrillation in the HF-T2DM group is expected but reinforces the concept of multimorbidity. HF in diabetic patients is rarely an isolated condition but rather the culmination of multiple interacting pathologies. This complexity necessitates an integrated care model that moves beyond a cardio-centric view to address metabolic, renal, and other systemic issues concurrently [15]. The greater use of diuretics and MRAs in the diabetic cohort at baseline likely reflects both the greater severity of fluid retention and the higher prevalence of resistant hypertension.

This study has several limitations. First, its single-center, observational design precludes the establishment of causality and may limit generalizability. Second, the sample size, while adequate for identifying major differences, may have been insufficient to detect more subtle associations. Third, we did not collect data on long-term outcomes, such as rehospitalization or mortality, which would be a valuable extension of this work. Strengths include the prospective data collection, the use of standardized diagnostic criteria, and the comprehensive assessment of clinical, biochemical, and echocardiographic parameters in a contemporary, real-world cohort.

In conclusion, patients with heart failure and concomitant type 2 diabetes mellitus exhibit a distinct and more severe clinical phenotype compared to their non-diabetic counterparts. This profile is characterized by a higher prevalence of obesity, worse functional status, a predominance of the HFpEF phenotype, greater biomarker evidence of myocardial stress, and a significantly higher burden of renal dysfunction and cardiovascular comorbidities. These findings emphasize the profound systemic impact of diabetes on the heart and vasculature and highlight the urgent need for early, aggressive, and multifaceted management strategies tailored to the unique pathophysiological landscape of this high-risk population

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