HFpEF as the Predominant and Underrecognized Heart Failure Phenotype in Type 2 Diabetes: Evidence from the DIABET-IC Study

HFpEF as the Predominant and Underrecognized Heart Failure Phenotype in Type 2 Diabetes: Evidence from the DIABET-IC Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article HFpEF as the Predominant and Underrecognized Heart Failure Phenotype in Type 2 Diabetes: Evidence from the DIABET-IC Study Pedro Gil-Millán, José Antonio Gimeno-Orna, Luis Rodríguez-Padial, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7506485/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Nov, 2025 Read the published version in Cardiovascular Diabetology → Version 1 posted 10 You are reading this latest preprint version Abstract Background : Heart failure (HF) is a major complication of type 2 diabetes (T2D), with HF with preserved ejection fraction (HFpEF) now representing the most frequent phenotype. However, its clinical profile, prognosis, and treatment patterns compared with HF with reduced ejection fraction (HFrEF) remain insufficiently characterized. Objectives : To compare characteristics, outcomes, and longitudinal management of HFpEF versus HFrEF in T2D patients. Methods : This prespecified subanalysis of the nationwide, prospective DIABET-IC cohort included 1,517 patients with T2D recruited across 58 Spanish centers and followed for three years. HF phenotypes were defined according to 2016 ESC criteria. Baseline characteristics, outcomes (mortality, hospitalizations, and progression), and therapeutic patterns were assessed. Results : At baseline, 490 patients had HF (50.2% HFrEF, 30.6% HFpEF, 19.2% HFmrEF). HFpEF patients were older, more often female, and had higher prevalence of obesity, hypertension, and metabolic syndrome, whereas HFrEF was more strongly associated with ischemic heart disease, prior STEMI, and conduction disturbances. During follow-up, HFpEF was the predominant incident phenotype (46.6% of new cases), and 4.7% progressed to HFrEF. Mortality was similarly elevated in both phenotypes; HF hospitalizations tended to be higher in HFrEF, while acute coronary syndromes were more frequent in HFpEF. HFrEF patients more often received guideline-directed therapies, whereas HFpEF remained undertreated, with limited use of SGLT2 inhibitors and GLP-1 receptor agonists. Notably, > 20% of HFpEF patients had natriuretic peptide levels below diagnostic thresholds, highlighting underdiagnosis. Conclusions : HFpEF is the most frequent and incident HF phenotype in T2D, with outcomes comparable to HFrEF yet frequent underdiagnosis and undertreatment. Improved screening strategies and broader adoption of evidence-based therapies—particularly SGLT2 inhibitors—are urgently needed for this high-risk population. Type 2 Diabetes Heart Failure HFpEF HFrEF Cardiometabolic Risk Obesity SGLT2i Finerenone Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 What is currently known about this topic? • T2D markedly increases HF risk, with HFpEF now predominant. • Diagnosis is often missed in obesity due to low natriuretic peptides. • Evidence-based therapies are established for HFrEF, while effective options for HFpEF have only recently emerged with SGLT2i, GLP1RA, and finerenone. What is the key research question? • What are the differences in prevalence, clinical profile, prognosis, and treatment patterns between HFpEF and HFrEF in patients with T2D in real-world practice? What is new? • HF affected ~40% of T2D patients, with HFpEF the leading incident phenotype. • HFpEF showed high comorbidity, arrhythmias, and 4.7% progression to HFrEF. • Despite recent evidence, use of SGLT2i, GLP1RA, and finerenone remained very low. Over 20% had low natriuretic peptides, highlighting underdiagnosis. How might this study influence clinical practice? • Supports systematic HFpEF screening in T2D with weight-independent biomarkers. • Reinforces HFpEF as high-risk and progressive. • Stresses the need to close the treatment gap by expanding SGLT2i, GLP1RA, and finerenone use in routine care. INTRODUCTION Cardiovascular disease has long been the leading cause of morbidity and mortality in type 2 diabetes (T2D), with myocardial infarction and stroke traditionally considered the dominant complications. In recent years, however, heart failure (HF) has emerged as the most frequent and prognostically relevant cardiovascular outcome in this population, conferring a two- to fivefold higher risk compared with individuals without diabetes( 1 – 4 ). Current data indicate that up to 40% of patients with T2D may develop HF, yet nearly one third of cases remain underdiagnosed ( 3 , 5 , 6 ). Among HF phenotypes, HF with preserved ejection fraction (HFpEF) has become the most prevalent presentation in T2D, particularly among women, elderly patients, and those with obesity ( 6 – 9 ). Importantly, HFpEF is not a benign condition: it is associated with a heavy comorbidity burden—including hypertension, atrial fibrillation, obesity, renal dysfunction, and microvascular complications—together with high rates of hospitalizations, arrhythmias, and even progression to reduced ejection fraction in a subset of patients ( 6 , 9 – 13 ). Despite this adverse profile, diagnosis is often missed, since natriuretic peptides may remain below diagnostic thresholds in obese individuals, leading to false negatives and delayed recognition ( 6 , 14 , 15 ). Therapeutic advances have markedly improved outcomes in HF with reduced ejection fraction (HFrEF) through the implementation of evidence-based therapies such as renin–angiotensin system blockers, mineralocorticoid receptor antagonists, beta-blockers, and more recently sodium–glucose cotransporter-2 inhibitors (SGLT2i) ( 16 – 18 ). In contrast, patients with HFpEF have historically remained undertreated, with very low real-world uptake of cardioprotective antidiabetic drugs including SGLT2i and glucagon-like peptide-1 receptor agonists (GLP1RA) ( 12 , 16 , 19 – 23 ). Only recently have randomized trials demonstrated the benefits of SGLT2i in HFpEF, leading to updated international guidelines that now recommend their use irrespective of diabetes status( 6 , 24 – 28 ). Nevertheless, significant evidence practice gap persists in clinical practice( 19 , 29 ). Despite its growing prevalence, the clinical profile, prognosis, and treatment patterns of HFpEF compared with HFrEF in patients with T2D remain insufficiently characterized –( 5 , 6 , 12 , 19 , 28 , 29 ). Understanding these differences is crucial to improve early detection, close diagnostic gaps, and ensure timely initiation of disease-modifying therapies. The present study, a prespecified subanalysis of the nationwide DIABET-IC cohort, sought to (i) compare baseline characteristics of HFpEF and HFrEF in patients with T2D, (ii) evaluate prognosis in terms of mortality, hospitalizations, and disease progression, and (iii) describe longitudinal treatment patterns, with particular focus on cardioprotective therapies. METHODS Study design and participants The DIABET-IC study was a nationwide, multicenter, observational, and prospective cohort conducted in Spain between May 2, 2018, and February 28, 2020, with follow-up until June 30, 2022. It was promoted by the Spanish Society of Diabetes (SED) and the Spanish Society of Cardiology (SEC) and designed to reflect routine clinical practice with a pragmatic, non-interventional approach. After the baseline visit, patients were followed for three years under standard-of-care conditions. The main objective was to evaluate the prevalence and incidence of heart failure in individuals with T2D ( 9 , 12 ). This manuscript reports a pre-specified sub-analysis of the cohort, aimed at characterizing and comparing the clinical, biochemical, and echocardiographic profiles of patients with HFpEF versus HFrEF, evaluating prognosis in terms of hospitalization and mortality, and describing longitudinal treatment patterns with emphasis on disease-modifying therapies. Heart failure phenotypes were defined according to the 2016 ESC guidelines ( 30 ). Due to the small number of HFmrEF (Heart Failure Mildly Reduced Ejection Fraction) cases, analyses were restricted to comparisons between HFpEF and HFrEF. Eligible participants were outpatients aged 18 years or older with a diagnosis of T2D for at least one year, as defined by the 2018 American Diabetes Association criteria ( 31 ). Patients with type 1 diabetes (T1D), end-stage kidney disease (ESKD), or a life expectancy of less than three years were excluded. Recruitment took place during routine visits, without diagnostic or therapeutic interventions mandated by the protocol. All participants provided written informed consent. The study was approved by the Ethics Committee of the Hospital Complex of Toledo on March 28, 2018 (project identification code 243) and conducted in accordance with the Declaration of Helsinki. Variables, data sources, and measurement At baseline, patients underwent a comprehensive evaluation including medical history, physical examination, electrocardiogram, and echocardiography. Demographic variables included age and sex. Clinical assessments recorded systolic and diastolic blood pressure (SBP and DBP), heart rate (HR), and body mass index (BMI). Cardiovascular risk factors and comorbidities were documented, including hypertension, dyslipidemia, atrial fibrillation (AF), ischemic heart disease, peripheral artery disease (PAD), cerebrovascular disease (CVD), chronic kidney disease (CKD), obstructive sleep apnea (OSA), and chronic obstructive pulmonary disease (COPD). The Charlson comorbidity index was calculated for each patient. Information on pharmacological treatment for diabetes and HF was obtained both at baseline and during follow-up. HF was defined as a prior hospitalization with a primary diagnosis of HF or fulfillment of the 2016 ESC guideline criteria ( 30 ). Diagnosis required typical symptoms in addition to echocardiographic (EC), to assess left ventricular ejection fraction (LVEF) and natriuretic peptide (NPs) abnormalities. In HFrEF, a left ventricular ejection fraction 125 pg/mL) and evidence of structural (left ventricular hypertrophy or left atrial enlargement) or functional (diastolic dysfunction) abnormalities were required. All diagnoses were confirmed by the site cardiologist. Laboratory analyses included hemoglobin, fasting glucose, HbA1c, lipid profile, serum creatinine, estimated glomerular filtration rate (eFGR), urinary albumin-to-creatinine ratio (ACR), and NT-proBNP. Coronary artery disease (CAD) was defined as a history of myocardial infarction, acute coronary syndrome (ACS), coronary revascularization, or documented stenosis > 50%. PAD was defined as the presence of lower extremity arterial disease, and cerebrovascular disease as a history of ischemic or hemorrhagic stroke or carotid stenosis > 50%. Clinical outcomes during follow-up included hospitalization for HF, ACS, stroke, progression of CKD, and cardiovascular mortality. All events were validated by investigators and adjudicated according to standardized definitions. Statistical analysis Continuous variables were expressed as mean and standard deviation or as median and interquartile range, while categorical variables were presented as absolute and relative frequencies. Comparisons between groups were performed using the student’s t-test or the Mann–Whitney U test for continuous variables, and the chi-square test for categorical variables. Incidence rates of new events were calculated and expressed as the number of events per 1,000 person-years with 95% confidence intervals. Event-free survival was analyzed with Kaplan–Meier curves, and differences between groups were assessed using the log-rank test. A two-sided p-value < 0.05 was considered statistically significant. RESULTS A total of 1,517 patients with T2D were recruited between January 2018 and December 2019 across 58 Spanish tertiary hospitals, of whom 1,249 (82.3%) completed the 3-year follow-up. At baseline, 490 patients presented with HF (50.2% HFrEF, 19.2% HFmrEF, 30.6% HFpEF). By the end of follow-up, HF prevalence increased to 548 cases (47.4% HFrEF, 20.3% HFmrEF, 32.3% HFpEF) (Fig. 1 a). Among incident HF cases, HFpEF predominated (46.6% vs. 24.1% HFrEF) (Fig. 1 b). Systematic baseline screening identified 22 previously unrecognized HF cases, half corresponding to HFpEF (Fig. 1 c). Subsequent analyses focused on HFpEF vs. HFrEF. Characteristics of the overall population have been previously published ( 9 , 10 , 12 , 22 ) and are summarized in Supplementary Table S1 . Chronic Diabetic Complications Diabetic nephropathy was significantly more common in HFrEF and HFpEF compared to non-HF patients (Table 2 ). Other chronic complications—including retinopathy, neuropathy, and foot lesions—showed no HF-related differences. HF was associated with higher stages of CKD and higher KDIGO risk categories ( Supplementary Table S3 ). Serious hypoglycemia remained rare and hyperglycemic crises did not occur in any group. Table 2 Prevalence of Chronic Diabetic Complications by HF Phenotype Chronic Complication No HF ( 1 ) (n = 759) Total HF (n = 490) HFrEF ( 2 ) (n = 246) HFpEF ( 3 ) (n = 150) p 1 vs 2 p 1 vs 3 p 2 vs 3 Diabetic nephropathy (%) 24.67 39.70 37.21 43.64 0.01 0.01 NS Diabetic retinopathy (%) 14.91 12.20 11.63 13.09 NS NS NS Diabetic neuropathy (%) 5.28 5.83 6.05 5.45 NS NS NS Diabetic foot (%) 1.72 3.55 3.72 3.27 NS NS NS Categorical variables are presented as n (%). (p < 0.05) NS: non-statistical significance. Cardiovascular History History of cardiovascular disease (CVD) was markedly more prevalent in HF patients than in those without HF (Table 3 ). HFrEF patients had higher rates of prior cardiopathy, multivessel CAD, ST-elevation myocardial infarction (STEMI), Ventricular Fibrillation (VF), and device therapy, while HFpEF patients had higher prevalence of aortic valvulopathy, LV hypertrophy due to hypertension, AF, and coronary stents. Rates of ACS were similar across groups, whereas non–ST-elevation myocardial infarction (NSTEMI) was less frequent in HFrEF than in HFpEF or non-HF patients. Table 3 Cardiovascular History among groups History / Event No HF ( 1 ) (n = 759) Total HF (n = 490) HFrEF ( 2 ) (n = 246) HFpEF ( 3 ) (n = 150) p 1 vs 2 p 1 vs 3 p 2 vs 3 Previous cardiopathy (%) 57.05 95.32 99.53 92.00 < 0.001 < 0.001 < 0.001 CVD (%) 43.52 83.70 91.63 77.45 < 0.001 < 0.001 < 0.001 CVD atherosclerosis (%) 43.73 59.42 67.91 52.73 < 0.001 0.010 1) (%) 7.53 16.13 18.60 14.18 < 0.001 0.002 0.003 ACS (%) 71.53 73.66 75.76 72.00 NS NS NS NSTEMI (%) 38.98 36.17 30.30 40.80 0.036 NS NS STEMI (%) 32.54 37.48 45.45 31.20 0.036 NS NS Coronary stents (%) 70.85 67.87 60.61 73.60 0.037 NS 0.027 Cerebro Vascular Disease (%) 6.87 10.20 11.16 9.45 0.039 NS NS PAD (%) 8.06 15.10 15.35 14.91 0.001 0.001 NS Aortic arteriopathy (%) 8.17 13.68 14.42 13.09 0.006 0.002 NS Hypertrophy Cardiac Disease (%) 3.09 4.49 4.67 4.35 NS NS NS Restrictive Cardiac Disease (%) 0.00 0.84 1.40 0.40 0.014 NS NS Congenital cardiopathy (%) 1.16 0.84 1.40 0.40 NS NS NS Aortic valvulopathy (%) 9.72 15.61 9.35 20.55 NS < 0.001 < 0.001 LV hypertrophy due to HTA (%) 22.22 20.21 10.75 27.67 < 0.001 NS < 0.001 AF (%) 21.25 41.83 38.24 44.66 < 0.001 < 0.001 NS VF (%) 18.75 27.69 44.44 14.49 0.033 NS 0.025 Categorical variables are presented as n (%). (p < 0.05). NS: non statistical significance. List of Abbreviations: CVD, cardiovascular disease; CAD, coronary artery disease; ACS: Acute Coronary Syndrome; PAD, peripheral arterial disease; HTA, hypertension; HF, heart failure; HFrEF, HF with reduced ejection fraction; HFpEF, HF with preserved ejection fraction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; LV, Left Ventricular; AF, Atrial Fibrillation; VF, Ventricular Fibrilaltion. Antidiabetic Therapy At baseline, metformin was the most frequently prescribed drug, used more in non-HF patients than in HF subtypes (Fig. 2 a). SGLT2i and GLP1RA were more common in non-HF and HFrEF groups, while pioglitazone use was rare. Insulin use was lower in HFrEF compared with both HFpEF and non-HF groups (Fig. 2 b). Over follow-up, SGLT2i and GLP1RA use increased, sulfonylureas declined, and insulin use remained stable. At final follow-up, SGLT2i was more frequently prescribed in HFrEF, while GLP1RA and metformin remained more common in non-HF patients (Fig. 2 c). Antihyperlipidemic Therapy Statins were widely used across all HF phenotypes at baseline and follow-up, with ezetimibe less frequently prescribed in HFpEF. Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) were rarely used, while fibrates were slightly more common in HFrEF ( Supplementary Figures S4 a–S4b ). Heart Failure Therapy Baseline HF therapy differed significantly between phenotypes (Fig. 3 a). HFrEF patients more frequently received guideline-recommended therapies, including loop diuretics, beta-blocker (BBs), Mineralocorticoid Receptor Antagonists (MRAs), and sacubitril/valsartan. HFpEF patients showed intermediate prescription rates. By the end of follow-up, treatment patterns were largely maintained, with HFrEF patients continuing the highest use of evidence-based therapies and HFpEF showing intermediate use (Fig. 3 b). HF Biomarkers and Echocardiogram NT-proBNP levels were significantly higher in HF patients compared with non-HF patients at baseline and follow-up (Fig. 4 a). HFrEF patients consistently showed the highest levels, whereas HFpEF patients had intermediate elevations. LVEF remained stable in non-HF and HFpEF patients, while it improved in HFrEF patients; 7 HFpEF patients (4.7%) progressed to HFrEF (Fig. 4 b). Electrocardiogram Electrocardiographic characteristics differed significantly across the three groups (no HF, HFrEF, and HFpEF). Sinus rhythm predominated in patients without HF (90.4%) but was significantly less frequent in HFrEF (65.6%) and HFpEF (62.2%) (p < 0.001 for all pairwise comparisons). Atrial fibrillation (AF) was more common in HFpEF (30.0%) and HFrEF (19.5%) compared with the no HF group (7.5%) (p < 0.001). Atrioventricular block (AVB) was uncommon and occurred at similar rates across groups (3.1% in no HF, 2.3% in HFrEF, and 3.0% in HFpEF), with no significant differences. Pacemaker implantation was more frequent in HFrEF (13.9%) compared to HFpEF (4.8%) and no HF (1.5%) (p < 0.001 for all comparisons). Regarding conduction abnormalities, left bundle branch block (LBBB) was significantly more prevalent in HFrEF (21.9%) than in HFpEF (12.6%) and no HF (3.1%) (p < 0.001), whereas right bundle branch block (RBBB) was slightly more common in no HF (7.7%) than in HFrEF (5.6%) and HFpEF (4.4%), without statistical significance. Overall, conduction and rhythm disturbances were more frequent in HF, particularly in HFrEF. Final Clinical Events Hospitalization for HF tended to be higher in HFrEF, whereas ACS incidence was numerically higher in HFpEF. Cardiovascular deaths were slightly more common in HFrEF, though none of these differences reached statistical significance (Fig. 5 ). Summary of Phenotype Differences Detailed comparison of HFpEF vs. HFrEF, including demographics, cardiovascular profile, arrhythmias, biomarkers, LVEF trajectory, renal comorbidity, and outcomes, is summarized in Supplementary Table S5 . DISCUSSION This sub-analysis of the DIABET-IC study provides novel insights into HF in T2D, particularly regarding prevalence, incidence, and prognosis across HF phenotypes. HFpEF emerges as the most frequent and incident form, with outcomes comparable to HFrEF. Despite this, HFpEF remains underdiagnosed and undertreated, with limited use of guideline-directed therapies, underscoring the urgent need for improved recognition and management in this high-risk population. In our study, HF was highly prevalent, affecting nearly 40% of outpatients, with HFpEF emerging as the most frequently newly diagnosed and incident phenotype. At baseline, HFpEF accounted for 30.6% of all HF cases and nearly half (46.6%) of incident HF during follow-up, whereas HFrEF represented 50.2% of prevalent HF but only 24.1% of new cases. Over three years, the cumulative incidence of HF was 7.6% (≈ 3 cases per 100 person-years), underscoring the high cardiovascular burden in this population ( 10 , 12 ). Although prevalence estimates vary across populations and methodologies, similar trends have been reported in European and U.S. cohorts, where HFpEF is consistently identified as the predominant phenotype in T2D, particularly among older and obese individuals ( 5 , 11 , 32 – 34 ). Collectively, these findings reinforce HFpEF as the dominant and emerging form of HF in this high-risk population. The clinical profiles of HF phenotypes observed in DIABET-IC were consistent with contemporary Spanish cohorts: HFpEF clustered with cardiometabolic traits—female sex, obesity, hypertension, AF, and CKD—whereas HFrEF was more strongly linked to ischemic heart disease ( 35 ). Despite these distinct characteristics, outcomes were similarly poor. In the MAGGIC meta-analysis, prognosis worsened progressively across the EF spectrum, with HFrEF showing the highest risk and HFpEF somewhat lower, though still adverse ( 8 ). However, in our cohort of patients with T2D, outcomes were comparably poor in HFpEF and HFrEF, with both phenotypes showing similarly elevated risks of mortality and HF hospitalization relative to T2D patients without HF ( 8 , 11 ). Notably, recent data from Anguita-Gámez et al. in a contemporary general population cohort also found no significant differences in 1-year outcomes across EF categories, suggesting that the prognostic gradient traditionally described may be less pronounced in current clinical practice ( 11 ). Together, these findings reinforce that HFpEF is far from benign, particularly in T2D, and should be recognized as a major prognostic marker. Therapeutic patterns diverged markedly between HF phenotypes. In our cohort, HFrEF patients more frequently received guideline-directed therapies such as MRAs, sacubitril/valsartan, and beta-blockers, whereas HFpEF patients remained undertreated. Cardioprotective antidiabetic drugs, including SGLT2i and GLP1RA, were also underused despite growing evidence of benefit in reducing HF hospitalizations ( 18 , 20 , 21 , 25 , 28 ), and current ESC guidelines now recommend SGLT2i as first-line therapy in HFpEF irrespective of diabetes status ( 28 ). These findings are consistent with Anguita et al., who documented lower use of guideline therapies and SGLT2i in HFpEF compared with HFrEF ( 11 ), and are further confirmed by the RED-HEART registry ( 19 ). Beyond SGLT2i, the FINEARTS-HF trial demonstrated that finerenone significantly reduced HF hospitalizations and cardiovascular death in HFpEF ( 36 ) and recent pooled analyses from SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials further show that semaglutide reduces the risk of the composite endpoint of cardiovascular death or HF events and worsening HF events alone in patients with HFpEF, highlighting its potential as an efficacious therapy in this population with limited treatment options ( 37 ). Collectively, these data underscore both the therapeutic advances and persistent gaps in HFpEF management, emphasizing the urgent need for improved implementation strategies, particularly in patients with T2D. Diagnostic challenges in HFpEF remain considerable, particularly in patients with T2D and obesity. Elevated BMI, highly prevalent in this population, suppresses natriuretic peptide (NP) secretion and clearance, reducing the sensitivity of BNP and NT-proBNP and increasing the risk of false negatives ( 15 , 38 – 40 ). In our cohort, over 20% of HFpEF patients had NP values below conventional diagnostic thresholds, highlighting the potential for underdiagnosis. Echocardiography, while central to HF evaluation, may also be limited in this setting ( 5 , 15 , 41 ), emphasizing the need for weight-independent biomarkers and advanced imaging tools to improve early detection and risk stratification. These diagnostic limitations have important clinical consequences, as high-risk patients may remain unrecognized and deprived of timely, evidence-based therapies. In our cohort, this gap was associated with rising NT-proBNP levels, stable or declining LVEF, and progression to HFrEF in nearly 5% of cases during follow-up. Collectively, these findings underscore that HFpEF in T2D is a dynamic and progressive phenotype that is prone to deterioration when insufficiently recognized and managed. CONCLUSIONS In summary, HF is highly prevalent in patients with T2D, with HFpEF emerging as the most frequent and incident phenotype, and is a high-risk, dynamic, and progressive condition. Despite this, HFpEF is often underdiagnosed due to obesity-related limitations in natriuretic peptide measurement and frequently undertreated, despite evidence supporting the use of SGLT2 inhibitors, GLP1 receptor agonists, and finerenone to improve outcome. The development of weight-independent biomarkers and advanced imaging, coupled with timely initiation of evidence-based therapies, is essential for early diagnosis, improved outcomes, and prevention of disease progression in this high-risk population. Abbreviations AF – Atrial Fibrillation ACS – Acute Coronary Syndrome ACEI – Angiotensin-Converting Enzyme Inhibitor ARA-II – Angiotensin II Receptor Blocker BB – Beta-Blocker BMI – Body Mass Index BNP – B-type Natriuretic Peptide CAD – Coronary Artery Disease CKD – Chronic Kidney Disease COPD – Chronic Obstructive Pulmonary Disease CVD – Cardiovascular Disease DBP – Diastolic Blood Pressure DPP4i – Dipeptidyl Peptidase-4 Inhibitor EF – Ejection Fraction ESC – European Society of Cardiology GDMT : Guideline-Directed Medical Therapy . GLP1RA – Glucagon-Like Peptide-1 Receptor Agonist HF – Heart Failure HFmrEF – Heart Failure with Mildly Reduced Ejection Fraction HFpEF – Heart Failure with Preserved Ejection Fraction HFrEF – Heart Failure with Reduced Ejection Fraction HR – Heart Rate KDIGO – Kidney Disease: Improving Global Outcomes LD – Loop Diuretics LDL-C – Low-Density Lipoprotein Cholesterol LBBB – Left Bundle Branch Block LV – Left Ventricle / Left Ventricular MRA – Mineralocorticoid Receptor Antagonist NPs – Natriuretic Peptides NT-proBNP – N-terminal pro B-type Natriuretic Peptide OSA – Obstructive Sleep Apnea PAD – Peripheral Artery Disease SBP – Systolic Blood Pressure SGLT2i – Sodium-Glucose Cotransporter-2 Inhibitor STEMI – ST-Elevation Myocardial Infarction TG – Triglycerides T2D – Type 2 Diabetes VF – Ventricular Fibrillation WC – Waist Circumference Declarations Ethics approval and consent to participate : The study was approved by the Ethics Committee of the Hospital Complex of Toledo on March 28, 2018 (project identification code 243) and conducted in accordance with the Declaration of Helsinki. Consent for publication Author Contributions (if required): PG-M and AP conceived the study. PG-M, JAG-O, and LR-P contributed to methodology. PG-M and JM curated the data. Formal analyses were performed by PG-M, JM, and VB. PG-M drafted the original manuscript. JAG-O, LR-P, JM, VB, MA, and AP critically revised the manuscript for important intellectual content. AP and MA supervised the study. All authors read and approved the final version of the manuscript. Conflict of Interest Statement: The authors declare no conflict of interest. Funding/Support Statement This research was funded by the Spanish Society of Diabetes (SED) and the Spanish Society of Cardiology (SEC). Availability of data and materials The dataset analysed during the current study is available from the corresponding author on reasonable request. Acknowledgments None. Corresponding Author details Antonio Pérez , Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona; CIBERDEM (Spain); [email protected] Pedro Gil-Millán, Hospital Universitari Vall d´Hebron; [email protected] References Gulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab [Internet]. 2019 [cited 2020 Aug 29];10:2042018819834869. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30944723 Gulsin GS, Brady EM, Swarbrick DJ, Athithan L, Henson J, Baldry E et al. Rationale, design and study protocol of the randomised controlled trial: Diabetes Interventional Assessment of Slimming or Training tO Lessen Inconspicuous Cardiovascular Dysfunction (the DIASTOLIC study). BMJ Open. 2019;9(3). Lorenzo-Almorós A, Tuñón J, Orejas M, Cortés M, Egido J, Lorenzo Ó. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol. 2017;16:28. Park JJ. Epidemiology, pathophysiology, diagnosis and treatment of heart failure in diabetes. Vol. 45, Diabetes and Metabolism Journal. Korean Diabetes Association; 2021. pp. 146–57. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Vol. 145, Circulation. 2022. 895–1032 p. Powell-Wiley TM, Poirier P, Burke LE, Després JP, Gordon-Larsen P, Lavie CJ et al. Obesity and Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation [Internet]. 2021 [cited 2021 Oct 25];143:E984–1010. Available from: http://ahajournals.org Doughty RN, Cubbon R, Ezekowitz J, Gonzalez-Juanatey J, Gorini M, Gotsman I, et al. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: An individual patient data meta-analysis: Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J. 2013;33(14):1750–7. Rodríguez-Padial L, Pérez A, Anguita Sánchez M, Barrios V, Gimeno-Orna JA, Muñiz J. Characteristics of women with type 2 diabetes and heart failure in Spain. The DIABET-IC study. Cardiol J. 2023;XX(X):1–8. Gimeno-Orna JA, Rodríguez-Padial L, Anguita-Sánchez M, Barrios V, Muñiz J, Pérez A. Association of the kdigo risk classification with the prevalence of heart failure in patients with type 2 diabetes. J Clin Med. 2021;10(20). Anguita-Gámez M, Bonilla-Palomas JL, Recio-Mayoral A, González-Manzanares R, Muñiz-García J, Romero-Rodríguez N et al. Differences in clinical features and 1-year outcomes of patients with heart failure and reduced, mildly reduced, and preserved ejection fraction in a contemporary cohort: is the clinical profile changing? Clin Res Cardiol. 2025. Gonzalez-Manzanares R, Anguita-Gámez M, Muñiz J, Barrios V, Gimeno-Orna JA, Pérez A et al. Prevalence and incidence of heart failure in type 2 diabetes patients: results from a nationwide prospective cohort—the DIABET-IC study. Cardiovasc Diabetol. 2024;23(1). Savji N, Meijers WC, Bartz TM, Bhambhani V, Cushman M, Nayor M, et al. The Association of Obesity and Cardiometabolic Traits with Incident HFpEF and HFrEF HHS Public Access. JACC Heart Fail. 2018;6(8):701–9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol [Internet]. 2013 Oct 15 [cited 2020 Aug 28];62(16):e147–239. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0735109713021141 Meijers WC, Bayes-Genis A, Mebazaa A, Bauersachs J, Cleland JGF, Coats AJS, et al. Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC). Eur J Heart Fail. 2021;23(10):1610–32. Steiner S. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. Zeitschrift fur Gefassmedizin. Volume 13. Krause und Pachernegg GmbH; 2016. pp. 17–8. Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP et al. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients with Heart Failure by Baseline Diabetes Status: Results from the EMPEROR-Reduced Trial. Circulation. 2021;337–49. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019;21(11):1402–11. Kocabas U, Ergin I, Yavuz V, Altın C, Kaplan M, Yılmaz Öztekin GM, et al. Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED–HEART study. ESC Heart Fail. 2025;12(1):434–46. Bizino MB, Jazet IM, Westenberg JJM, Van Eyk HJ, Paiman EHM, Smit JWA et al. Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial. [cited 2022 Mar 5]; Available from: https://doi.org/10.1186/s12933-019-0857-6 Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776–85. Diabet-ic T. European Journal of Internal Medicine Risk of cardiovascular events in patients with type 2 diabetes after 3 years of follow-up. Belli M, Barone L, Bellia A, Sergi D, Lecis D, Prandi FR, et al. Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients? Int J Mol Sci. 2022;23(23):14598. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al. Evaluation of the effects of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail. 2019;21(10):1279–87. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine [Internet]. 2021 Oct 14 [cited 2022 Feb 28];385(16):1451–61. Available from: https://www.nejm.org/doi/ 10.1056/NEJMoa2107038 Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089–98. Hasegawa K, Lewis BS. Are SGLT2 inhibitors effective against ‘all’ heart failure with preserved ejection fraction? Eur Heart J Cardiovasc Pharmacother. 2022;9252. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2023;44(37):3627–39. Scheen AJ. Real-life underuse of SGLT2 inhibitors for patients with type 2 diabetes at high cardiorenal risk. Diabetes Epidemiol Manage. 2024;13:100184. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. Volume 37. Oxford University Press; 2016. pp. 2129–m2200. 2. Classification and Diagnosis of Diabetes. Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018;41(Supplement1):S13–27. Hoek AG, Dal Canto E, Wenker E, Bindraban N, Handoko ML, Elders PJM, et al. Epidemiology of heart failure in diabetes: a disease in disguise. Volume 67. Diabetologia. Springer Science and Business Media Deutschland GmbH; 2024. pp. 574–601. Rosano GMC, Seferovic P, Savarese G, Spoletini I, Lopatin Y, Gustafsson F, et al. Impact analysis of heart failure across European countries: an ESC-HFA position paper. ESC Heart Fail. 2022;9(5):2767–78. Abudureyimu M, Luo X, Wang X, Sowers JR, Wang W, Ge J et al. Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics. J Mol Cell Biol. 2022;14(5). Li Z, Shi Y, Xia Y, Wu L, Li H, Zhou R, et al. Disparate Clinical Characteristics and Prognosis of HFpEF versus HFrEF Phenotype of Diabetic Cardiomyopathy. J Clin Med. 2023;12(4):1565. Solomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391(16):1475–85. Kosiborod MN, Deanfield J, Pratley R, Borlaug BA, Butler J, Davies MJ, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet. 2024;404(10456):949–61. Madamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and natriuretic peptides, BNP and NT-proBNP: Mechanisms and diagnostic implications for heart failure. Int J Cardiol. 2014;176(3):611–7. Madamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and natriuretic peptides, BNP and NT-proBNP: Mechanisms and diagnostic implications for heart failure. Int J Cardiol. 2014;176(3):611–7. Mueller C, McDonald K, de Boer RA, Maisel A, Cleland JGF, Kozhuharov N, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21(6):715–31. Pieske B, Tschöpe C, De Boer RA, Fraser AG, Anker SD, Donal E, et al. How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297–317. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS1.docx SupplementaryTableS2.docx SupplementarytableS3.docx SupplementaryTableS5.docx GRAPHICALABSTRACT.pptx SupplementaryFiguresS4a.docx Cite Share Download PDF Status: Published Journal Publication published 03 Nov, 2025 Read the published version in Cardiovascular Diabetology → Version 1 posted Editorial decision: Revision requested 29 Sep, 2025 Reviews received at journal 25 Sep, 2025 Reviews received at journal 21 Sep, 2025 Reviewers agreed at journal 07 Sep, 2025 Reviewers agreed at journal 05 Sep, 2025 Reviewers agreed at journal 05 Sep, 2025 Reviewers invited by journal 05 Sep, 2025 Editor assigned by journal 01 Sep, 2025 Submission checks completed at journal 01 Sep, 2025 First submitted to journal 01 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7506485","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":511357027,"identity":"dd9afac7-231f-4e40-accd-9c76e8547dfa","order_by":0,"name":"Pedro Gil-Millán","email":"","orcid":"","institution":"Vall d'Hebron Hospital Universitari","correspondingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"","lastName":"Gil-Millán","suffix":""},{"id":511357028,"identity":"5bb7cec3-bf01-4ca5-8a3e-b09deb67adc1","order_by":1,"name":"José Antonio Gimeno-Orna","email":"","orcid":"","institution":"Lozano Blesa University Clinical Hospital","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Antonio","lastName":"Gimeno-Orna","suffix":""},{"id":511357029,"identity":"5ca51129-91ff-41d5-84d4-6d15304fae4e","order_by":2,"name":"Luis Rodríguez-Padial","email":"","orcid":"","institution":"University Hospital of Toledo","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"","lastName":"Rodríguez-Padial","suffix":""},{"id":511357030,"identity":"cade6da9-24f3-4693-8a0b-a638adee9303","order_by":3,"name":"Javier Muñiz","email":"","orcid":"","institution":"University of A Coruña \u0026 CIBERCV","correspondingAuthor":false,"prefix":"","firstName":"Javier","middleName":"","lastName":"Muñiz","suffix":""},{"id":511357031,"identity":"50e41d08-6b3e-49fb-8a95-5ebd12084a21","order_by":4,"name":"Vivencio Barrios","email":"","orcid":"","institution":"Hospital Universitario Ramón y Cajal","correspondingAuthor":false,"prefix":"","firstName":"Vivencio","middleName":"","lastName":"Barrios","suffix":""},{"id":511357032,"identity":"b24ae2ec-f7ea-4cbc-b4bf-61e19fd9c694","order_by":5,"name":"Manuel Anguita","email":"","orcid":"","institution":"Reina Sofía University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Anguita","suffix":""},{"id":511357033,"identity":"298e2ab5-4cf8-49fc-86a1-d87cc575867f","order_by":6,"name":"Antonio Pérez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYPACG9K1pAExM5TNRpyWwyRo4Z/dfOzDhz/n7fln9x978LONQZ5/fgN+LRJ3jiXPnMFzO3HGncPshr1tDIYzjhFy0o0cY2YeidsJDDeS2SR42xgSGAhpkb+R/5n5j8E5e3mgFsm/QC3yhLQY3MhhZmZIOMC4AahFGmSLASEthneOGTP2HEhO3Hgj2dxY5pyE4cZjCfi1yN1ufszw44+dvdyNxGcP35TZyMsdPkDAGgkEkw2VS6yWUTAKRsEoGAWYAAAn/EEP9+iy6AAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital de la Santa Creu i Sant Pau, CIBERDEM (Spain)","correspondingAuthor":true,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Pérez","suffix":""}],"badges":[],"createdAt":"2025-09-01 09:08:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7506485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7506485/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12933-025-02995-z","type":"published","date":"2025-11-03T15:57:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91108567,"identity":"fe275be4-4e51-4ecd-aae1-9b090cbc14e1","added_by":"auto","created_at":"2025-09-11 15:57:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44034,"visible":true,"origin":"","legend":"\u003cp\u003e1a. Prevalence of all HF phenotypes in T2D at baseline and during the follow-up. 1b. Incidence of all HF phenotype during the follow-up, all HF case were 58. Distribution among all three different HF forms. 1c. Newly diagnosed HF cases at the baseline visit; all HF cases were 22. List of abbreviations: HFpEF: Heart Failure Preserved Ejection Fraction; HFmrEF: Heart Failure Mildly Reduced Ejection Fraction; HFrEF: Heart Failure Reduced Ejection Fraction.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/ef7e115d7bb2cfc7866099fa.png"},{"id":91108568,"identity":"7e93c8f7-bd06-43df-a499-0258c6dcf393","added_by":"auto","created_at":"2025-09-11 15:57:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":42725,"visible":true,"origin":"","legend":"\u003cp\u003ea. The baseline of antidiabetic treatment among T2D with no-HF, HFrEF and HFpEF. (p \u0026lt;0.05) * → Statistically differences between no-HF vs HFrEF and no-HF vs HFpEF. (p \u0026lt;0.05) # → Statistically differences across all three groups (no-HF, HFrEF, HFpEF). Figure 2.b. The baseline of insulin treatment among T2D with no-HF, HFrEF and HFpEF. (p \u0026lt;0.05) ** Statistically differences between HFpEF vs HFrEF and no-HF vs HFrEF. 2.c. Final antidiabetic treatment among T2D with no-HF, HFrEF and HFpEF. (p \u0026lt;0.05) *Statistically differences (No HF vs HFrEF and HFpEF). # Statistically differences (HFrEF vs no HF and HFpEF).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/63913cf5799137beb2557bca.png"},{"id":91109108,"identity":"bb369ecf-5b41-410b-b56b-d4d9e1806690","added_by":"auto","created_at":"2025-09-11 16:05:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52748,"visible":true,"origin":"","legend":"\u003cp\u003ea. The figure shows the distribution of HF therapy among T2D patients without HF, with HFrEF, and with HFpEF at baseline. (p \u0026lt;0.05) Statistically differences were observed in all HF-related therapy between no-HF and HFrEF groups, and between HFrEF vs HFpEF. Abbreviations: LD, loop diuretics; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARA-II, angiotensin II receptor blocker. Figure 3.b. Percentages of HF therapy at the end of follow-up.The figure shows the distribution of HF-related medications among T2D patients without HF, with HFrEF, and with HFpEF at the end of follow-up. (p \u0026lt;0.05) Statistically differences were observed across groups for all treatments, including loop diuretics (LD), thiazide diuretics, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARA-II), sacubitril/valsartan, beta-blockers (BB), and ivabradine (all p \u0026lt; 0.05 for at least one group comparison) Abbreviations: LD, loop diuretics; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARA-II, angiotensin II receptor blocker.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/2bc69040fac33b2421d21b03.png"},{"id":91108574,"identity":"bb5773f8-e4ee-420e-bfe8-4348e84eebbd","added_by":"auto","created_at":"2025-09-11 15:57:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":49420,"visible":true,"origin":"","legend":"\u003cp\u003ea. Differences in NT-proBNP levels in T2D patients without HF, with HFrEF, and with HFpEF at baseline and final visit. The figure shows NT-proBNP levels measured at baseline and final visit across the three groups. (p \u0026lt;0.05) * Statistically differences intra-group between baseline and final visit. (p \u0026lt;0.05) # Statistically differences in NT-proBNP levels at baseline between the three groups. NS, non-significant differences. 4.b. Differences in left ventricular ejection fraction (LVEF) in T2D patients with no HF, HFrEF, and HFpEF at baseline and final visit. (p \u0026lt;0.05) *** Statistically differences intra-groups at basal and final visit. (p \u0026lt;0.05) * Statistically differences in HFrEF between basal LVEF vs LVEF final. NS, non-significant differences in no-HF and HFpEF groups.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/2002d094a95bdc7e2bfc6858.png"},{"id":91108577,"identity":"c5ee1e82-d1e2-4fd2-8a26-7f6eeeca372d","added_by":"auto","created_at":"2025-09-11 15:57:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":27491,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in Final events: Hospitalization due HF, ACS and Cardiovascular death related in patients T2D with no HF, HFrEF and HFpEF basal and final visit. Non-statistically significant differences were observed between groups and intragroup. List of Abbreviations: HF: Heart Failure; ACS: Acute Coronary Syndrome\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/b6309181aba64978cb42662d.png"},{"id":95564693,"identity":"10fabde4-e926-42f1-b0a1-e1e4c7cf5b03","added_by":"auto","created_at":"2025-11-10 16:10:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1358393,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/90d6c8c5-7c58-4c2c-afb1-42d8f593a3a4.pdf"},{"id":91108572,"identity":"09594dbb-f445-4c46-9ce0-26f89658c8fa","added_by":"auto","created_at":"2025-09-11 15:57:18","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21517,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/b3e5b98d05c895c111250a43.docx"},{"id":91109107,"identity":"b0b9f2d7-d1df-4a1b-8b93-ea52bad237da","added_by":"auto","created_at":"2025-09-11 16:05:18","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18437,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/f53dec4b1aed12e3a1c92f92.docx"},{"id":91109110,"identity":"23fccf45-6fae-48d8-b87c-021b29b512bf","added_by":"auto","created_at":"2025-09-11 16:05:18","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":15607,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarytableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/298d83640adc64e0c3b7a94e.docx"},{"id":91108581,"identity":"ffeb146e-3a53-4560-aa62-667f0e69fc6a","added_by":"auto","created_at":"2025-09-11 15:57:19","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17339,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS5.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/b32dc9325cb8ce6a9f12aa4e.docx"},{"id":91109114,"identity":"6490cb46-f608-46c3-8848-accc771f3b58","added_by":"auto","created_at":"2025-09-11 16:05:19","extension":"pptx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1027972,"visible":true,"origin":"","legend":"","description":"","filename":"GRAPHICALABSTRACT.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/99b9b10b9910cf88e41523d9.pptx"},{"id":91109123,"identity":"5659726e-d0a8-4174-8fce-2a4baa4e5c56","added_by":"auto","created_at":"2025-09-11 16:05:19","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":113349,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiguresS4a.docx","url":"https://assets-eu.researchsquare.com/files/rs-7506485/v1/ff9decd541cec33bdcb153a4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"HFpEF as the Predominant and Underrecognized Heart Failure Phenotype in Type 2 Diabetes: Evidence from the DIABET-IC Study","fulltext":[{"header":"What is currently known about this topic?","content":"\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;T2D markedly increases HF risk, with HFpEF now predominant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Diagnosis is often missed in obesity due to low natriuretic peptides.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Evidence-based therapies are established for HFrEF, while effective options for HFpEF have only recently emerged with SGLT2i, GLP1RA, and finerenone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is the key research question?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;What are the differences in prevalence, clinical profile, prognosis, and treatment patterns between HFpEF and HFrEF in patients with T2D in real-world practice?\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is new?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;HF affected ~40% of T2D patients, with HFpEF the leading incident phenotype.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;HFpEF showed high comorbidity, arrhythmias, and 4.7% progression to HFrEF.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Despite recent evidence, use of SGLT2i, GLP1RA, and finerenone remained very low. Over 20% had low natriuretic peptides, highlighting underdiagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHow might this study influence clinical practice?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Supports systematic HFpEF screening in T2D with weight-independent biomarkers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Reinforces HFpEF as high-risk and progressive.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp; \u0026nbsp;Stresses the need to close the treatment gap by expanding SGLT2i, GLP1RA, and finerenone use in routine care.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eCardiovascular disease has long been the leading cause of morbidity and mortality in type 2 diabetes (T2D), with myocardial infarction and stroke traditionally considered the dominant complications. In recent years, however, heart failure (HF) has emerged as the most frequent and prognostically relevant cardiovascular outcome in this population, conferring a two- to fivefold higher risk compared with individuals without diabetes(\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Current data indicate that up to 40% of patients with T2D may develop HF, yet nearly one third of cases remain underdiagnosed (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAmong HF phenotypes, HF with preserved ejection fraction (HFpEF) has become the most prevalent presentation in T2D, particularly among women, elderly patients, and those with obesity (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Importantly, HFpEF is not a benign condition: it is associated with a heavy comorbidity burden\u0026mdash;including hypertension, atrial fibrillation, obesity, renal dysfunction, and microvascular complications\u0026mdash;together with high rates of hospitalizations, arrhythmias, and even progression to reduced ejection fraction in a subset of patients (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Despite this adverse profile, diagnosis is often missed, since natriuretic peptides may remain below diagnostic thresholds in obese individuals, leading to false negatives and delayed recognition (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTherapeutic advances have markedly improved outcomes in HF with reduced ejection fraction (HFrEF) through the implementation of evidence-based therapies such as renin\u0026ndash;angiotensin system blockers, mineralocorticoid receptor antagonists, beta-blockers, and more recently sodium\u0026ndash;glucose cotransporter-2 inhibitors (SGLT2i) (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In contrast, patients with HFpEF have historically remained undertreated, with very low real-world uptake of cardioprotective antidiabetic drugs including SGLT2i and glucagon-like peptide-1 receptor agonists (GLP1RA) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Only recently have randomized trials demonstrated the benefits of SGLT2i in HFpEF, leading to updated international guidelines that now recommend their use irrespective of diabetes status(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Nevertheless, significant evidence practice gap persists in clinical practice(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDespite its growing prevalence, the clinical profile, prognosis, and treatment patterns of HFpEF compared with HFrEF in patients with T2D remain insufficiently characterized \u0026ndash;(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Understanding these differences is crucial to improve early detection, close diagnostic gaps, and ensure timely initiation of disease-modifying therapies.\u003c/p\u003e\u003cp\u003eThe present study, a prespecified subanalysis of the nationwide DIABET-IC cohort, sought to (i) compare baseline characteristics of HFpEF and HFrEF in patients with T2D, (ii) evaluate prognosis in terms of mortality, hospitalizations, and disease progression, and (iii) describe longitudinal treatment patterns, with particular focus on cardioprotective therapies.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and participants\u003c/h2\u003e\u003cp\u003eThe DIABET-IC study was a nationwide, multicenter, observational, and prospective cohort conducted in Spain between May 2, 2018, and February 28, 2020, with follow-up until June 30, 2022. It was promoted by the Spanish Society of Diabetes (SED) and the Spanish Society of Cardiology (SEC) and designed to reflect routine clinical practice with a pragmatic, non-interventional approach. After the baseline visit, patients were followed for three years under standard-of-care conditions. The main objective was to evaluate the prevalence and incidence of heart failure in individuals with T2D (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This manuscript reports a pre-specified sub-analysis of the cohort, aimed at characterizing and comparing the clinical, biochemical, and echocardiographic profiles of patients with HFpEF versus HFrEF, evaluating prognosis in terms of hospitalization and mortality, and describing longitudinal treatment patterns with emphasis on disease-modifying therapies. Heart failure phenotypes were defined according to the 2016 ESC guidelines (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Due to the small number of HFmrEF (Heart Failure Mildly Reduced Ejection Fraction) cases, analyses were restricted to comparisons between HFpEF and HFrEF.\u003c/p\u003e\u003cp\u003eEligible participants were outpatients aged 18 years or older with a diagnosis of T2D for at least one year, as defined by the 2018 American Diabetes Association criteria (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Patients with type 1 diabetes (T1D), end-stage kidney disease (ESKD), or a life expectancy of less than three years were excluded. Recruitment took place during routine visits, without diagnostic or therapeutic interventions mandated by the protocol. All participants provided written informed consent. The study was approved by the Ethics Committee of the Hospital Complex of Toledo on March 28, 2018 (project identification code 243) and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eVariables, data sources, and measurement\u003c/h3\u003e\n\u003cp\u003eAt baseline, patients underwent a comprehensive evaluation including medical history, physical examination, electrocardiogram, and echocardiography. Demographic variables included age and sex. Clinical assessments recorded systolic and diastolic blood pressure (SBP and DBP), heart rate (HR), and body mass index (BMI). Cardiovascular risk factors and comorbidities were documented, including hypertension, dyslipidemia, atrial fibrillation (AF), ischemic heart disease, peripheral artery disease (PAD), cerebrovascular disease (CVD), chronic kidney disease (CKD), obstructive sleep apnea (OSA), and chronic obstructive pulmonary disease (COPD). The Charlson comorbidity index was calculated for each patient. Information on pharmacological treatment for diabetes and HF was obtained both at baseline and during follow-up.\u003c/p\u003e\u003cp\u003eHF was defined as a prior hospitalization with a primary diagnosis of HF or fulfillment of the 2016 ESC guideline criteria (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Diagnosis required typical symptoms in addition to echocardiographic (EC), to assess left ventricular ejection fraction (LVEF) and natriuretic peptide (NPs) abnormalities. In HFrEF, a left ventricular ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;40% together with symptoms was sufficient. In HFpEF (\u0026ge;\u0026thinsp;50%) and HFmrEF (40\u0026ndash;49%), both elevated N-terminal pro B-type Natriuretic Peptide (NT-proBNP) (\u0026gt;\u0026thinsp;125 pg/mL) and evidence of structural (left ventricular hypertrophy or left atrial enlargement) or functional (diastolic dysfunction) abnormalities were required. All diagnoses were confirmed by the site cardiologist.\u003c/p\u003e\u003cp\u003eLaboratory analyses included hemoglobin, fasting glucose, HbA1c, lipid profile, serum creatinine, estimated glomerular filtration rate (eFGR), urinary albumin-to-creatinine ratio (ACR), and NT-proBNP. Coronary artery disease (CAD) was defined as a history of myocardial infarction, acute coronary syndrome (ACS), coronary revascularization, or documented stenosis\u0026thinsp;\u0026gt;\u0026thinsp;50%. PAD was defined as the presence of lower extremity arterial disease, and cerebrovascular disease as a history of ischemic or hemorrhagic stroke or carotid stenosis\u0026thinsp;\u0026gt;\u0026thinsp;50%.\u003c/p\u003e\u003cp\u003eClinical outcomes during follow-up included hospitalization for HF, ACS, stroke, progression of CKD, and cardiovascular mortality. All events were validated by investigators and adjudicated according to standardized definitions.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were expressed as mean and standard deviation or as median and interquartile range, while categorical variables were presented as absolute and relative frequencies. Comparisons between groups were performed using the student\u0026rsquo;s t-test or the Mann\u0026ndash;Whitney U test for continuous variables, and the chi-square test for categorical variables. Incidence rates of new events were calculated and expressed as the number of events per 1,000 person-years with 95% confidence intervals. Event-free survival was analyzed with Kaplan\u0026ndash;Meier curves, and differences between groups were assessed using the log-rank test. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 1,517 patients with T2D were recruited between January 2018 and December 2019 across 58 Spanish tertiary hospitals, of whom 1,249 (82.3%) completed the 3-year follow-up. At baseline, 490 patients presented with HF (50.2% HFrEF, 19.2% HFmrEF, 30.6% HFpEF). By the end of follow-up, HF prevalence increased to 548 cases (47.4% HFrEF, 20.3% HFmrEF, 32.3% HFpEF) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Among incident HF cases, HFpEF predominated (46.6% vs. 24.1% HFrEF) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Systematic baseline screening identified 22 previously unrecognized HF cases, half corresponding to HFpEF (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Subsequent analyses focused on HFpEF vs. HFrEF. Characteristics of the overall population have been previously published (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and are summarized in \u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e\n\u003ch3\u003eChronic Diabetic Complications\u003c/h3\u003e\n\u003cp\u003eDiabetic nephropathy was significantly more common in HFrEF and HFpEF compared to non-HF patients (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Other chronic complications\u0026mdash;including retinopathy, neuropathy, and foot lesions\u0026mdash;showed no HF-related differences. HF was associated with higher stages of CKD and higher KDIGO risk categories (\u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e\u003c/b\u003e). Serious hypoglycemia remained rare and hyperglycemic crises did not occur in any group.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePrevalence of Chronic Diabetic Complications by HF Phenotype\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic Complication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo HF (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;759)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTotal HF (n\u0026thinsp;=\u0026thinsp;490)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHFrEF (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;246)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHFpEF\u003c/p\u003e\u003cp\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e1 vs 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e1 vs 3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e2 vs 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetic nephropathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e39.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e43.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetic retinopathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e13.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetic neuropathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetic foot (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eCategorical variables are presented as n (%). (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) NS: non-statistical significance.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eCardiovascular History\u003c/h3\u003e\n\u003cp\u003eHistory of cardiovascular disease (CVD) was markedly more prevalent in HF patients than in those without HF (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). HFrEF patients had higher rates of prior cardiopathy, multivessel CAD, ST-elevation myocardial infarction (STEMI), Ventricular Fibrillation (VF), and device therapy, while HFpEF patients had higher prevalence of aortic valvulopathy, LV hypertrophy due to hypertension, AF, and coronary stents. Rates of ACS were similar across groups, whereas non\u0026ndash;ST-elevation myocardial infarction (NSTEMI) was less frequent in HFrEF than in HFpEF or non-HF patients.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCardiovascular History among groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory / Event\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo HF\u003c/p\u003e\u003cp\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;759)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTotal HF (n\u0026thinsp;=\u0026thinsp;490)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHFrEF (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;246)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHFpEF (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e1 vs 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e1 vs 3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ep\u003c/p\u003e\u003cp\u003e2 vs 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious cardiopathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e95.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e99.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e92.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCVD (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e83.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e91.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e77.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCVD atherosclerosis (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e59.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e67.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e52.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCAD (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e52.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e61.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAffected vascular territories\u003c/p\u003e\u003cp\u003e(\u0026gt;\u0026thinsp;1) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e18.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACS (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e71.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e73.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e75.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e72.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNSTEMI (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e38.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSTEMI (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e45.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e31.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoronary stents (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e70.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e67.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e60.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e73.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebro Vascular Disease (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePAD (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e15.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAortic arteriopathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e13.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertrophy Cardiac Disease (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRestrictive Cardiac Disease (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital cardiopathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAortic valvulopathy (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLV hypertrophy due to HTA (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e20.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAF (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e41.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e38.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e44.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVF (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e44.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.033\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eCategorical variables are presented as n (%). (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). NS: non statistical significance. List of Abbreviations: CVD, cardiovascular disease; CAD, coronary artery disease; ACS: Acute Coronary Syndrome; PAD, peripheral arterial disease; HTA, hypertension; HF, heart failure; HFrEF, HF with reduced ejection fraction; HFpEF, HF with preserved ejection fraction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; LV, Left Ventricular; AF, Atrial Fibrillation; VF, Ventricular Fibrilaltion.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eAntidiabetic Therapy\u003c/h2\u003e\u003cp\u003eAt baseline, metformin was the most frequently prescribed drug, used more in non-HF patients than in HF subtypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). SGLT2i and GLP1RA were more common in non-HF and HFrEF groups, while pioglitazone use was rare. Insulin use was lower in HFrEF compared with both HFpEF and non-HF groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Over follow-up, SGLT2i and GLP1RA use increased, sulfonylureas declined, and insulin use remained stable. At final follow-up, SGLT2i was more frequently prescribed in HFrEF, while GLP1RA and metformin remained more common in non-HF patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAntihyperlipidemic Therapy\u003c/h2\u003e\u003cp\u003eStatins were widely used across all HF phenotypes at baseline and follow-up, with ezetimibe less frequently prescribed in HFpEF. Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) were rarely used, while fibrates were slightly more common in HFrEF (\u003cb\u003eSupplementary Figures \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003ea\u0026ndash;S4b\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eHeart Failure Therapy\u003c/h2\u003e\u003cp\u003eBaseline HF therapy differed significantly between phenotypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). HFrEF patients more frequently received guideline-recommended therapies, including loop diuretics, beta-blocker (BBs), Mineralocorticoid Receptor Antagonists (MRAs), and sacubitril/valsartan. HFpEF patients showed intermediate prescription rates. By the end of follow-up, treatment patterns were largely maintained, with HFrEF patients continuing the highest use of evidence-based therapies and HFpEF showing intermediate use (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eHF Biomarkers and Echocardiogram\u003c/h2\u003e\u003cp\u003eNT-proBNP levels were significantly higher in HF patients compared with non-HF patients at baseline and follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). HFrEF patients consistently showed the highest levels, whereas HFpEF patients had intermediate elevations. LVEF remained stable in non-HF and HFpEF patients, while it improved in HFrEF patients; 7 HFpEF patients (4.7%) progressed to HFrEF (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eElectrocardiogram\u003c/h2\u003e\u003cp\u003eElectrocardiographic characteristics differed significantly across the three groups (no HF, HFrEF, and HFpEF). Sinus rhythm predominated in patients without HF (90.4%) but was significantly less frequent in HFrEF (65.6%) and HFpEF (62.2%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all pairwise comparisons). Atrial fibrillation (AF) was more common in HFpEF (30.0%) and HFrEF (19.5%) compared with the no HF group (7.5%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Atrioventricular block (AVB) was uncommon and occurred at similar rates across groups (3.1% in no HF, 2.3% in HFrEF, and 3.0% in HFpEF), with no significant differences. Pacemaker implantation was more frequent in HFrEF (13.9%) compared to HFpEF (4.8%) and no HF (1.5%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all comparisons). Regarding conduction abnormalities, left bundle branch block (LBBB) was significantly more prevalent in HFrEF (21.9%) than in HFpEF (12.6%) and no HF (3.1%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas right bundle branch block (RBBB) was slightly more common in no HF (7.7%) than in HFrEF (5.6%) and HFpEF (4.4%), without statistical significance. Overall, conduction and rhythm disturbances were more frequent in HF, particularly in HFrEF.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eFinal Clinical Events\u003c/h2\u003e\u003cp\u003eHospitalization for HF tended to be higher in HFrEF, whereas ACS incidence was numerically higher in HFpEF. Cardiovascular deaths were slightly more common in HFrEF, though none of these differences reached statistical significance (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eSummary of Phenotype Differences\u003c/h2\u003e\u003cp\u003eDetailed comparison of HFpEF vs. HFrEF, including demographics, cardiovascular profile, arrhythmias, biomarkers, LVEF trajectory, renal comorbidity, and outcomes, is summarized in Supplementary Table \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis sub-analysis of the DIABET-IC study provides novel insights into HF in T2D, particularly regarding prevalence, incidence, and prognosis across HF phenotypes. HFpEF emerges as the most frequent and incident form, with outcomes comparable to HFrEF. Despite this, HFpEF remains underdiagnosed and undertreated, with limited use of guideline-directed therapies, underscoring the urgent need for improved recognition and management in this high-risk population.\u003c/p\u003e\u003cp\u003eIn our study, HF was highly prevalent, affecting nearly 40% of outpatients, with HFpEF emerging as the most frequently newly diagnosed and incident phenotype. At baseline, HFpEF accounted for 30.6% of all HF cases and nearly half (46.6%) of incident HF during follow-up, whereas HFrEF represented 50.2% of prevalent HF but only 24.1% of new cases. Over three years, the cumulative incidence of HF was 7.6% (\u0026asymp;\u0026thinsp;3 cases per 100 person-years), underscoring the high cardiovascular burden in this population (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Although prevalence estimates vary across populations and methodologies, similar trends have been reported in European and U.S. cohorts, where HFpEF is consistently identified as the predominant phenotype in T2D, particularly among older and obese individuals (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Collectively, these findings reinforce HFpEF as the dominant and emerging form of HF in this high-risk population.\u003c/p\u003e\u003cp\u003eThe clinical profiles of HF phenotypes observed in DIABET-IC were consistent with contemporary Spanish cohorts: HFpEF clustered with cardiometabolic traits\u0026mdash;female sex, obesity, hypertension, AF, and CKD\u0026mdash;whereas HFrEF was more strongly linked to ischemic heart disease (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Despite these distinct characteristics, outcomes were similarly poor. In the MAGGIC meta-analysis, prognosis worsened progressively across the EF spectrum, with HFrEF showing the highest risk and HFpEF somewhat lower, though still adverse (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, in our cohort of patients with T2D, outcomes were comparably poor in HFpEF and HFrEF, with both phenotypes showing similarly elevated risks of mortality and HF hospitalization relative to T2D patients without HF (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Notably, recent data from Anguita-G\u0026aacute;mez et al. in a contemporary general population cohort also found no significant differences in 1-year outcomes across EF categories, suggesting that the prognostic gradient traditionally described may be less pronounced in current clinical practice (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Together, these findings reinforce that HFpEF is far from benign, particularly in T2D, and should be recognized as a major prognostic marker.\u003c/p\u003e\u003cp\u003eTherapeutic patterns diverged markedly between HF phenotypes. In our cohort, HFrEF patients more frequently received guideline-directed therapies such as MRAs, sacubitril/valsartan, and beta-blockers, whereas HFpEF patients remained undertreated. Cardioprotective antidiabetic drugs, including SGLT2i and GLP1RA, were also underused despite growing evidence of benefit in reducing HF hospitalizations (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), and current ESC guidelines now recommend SGLT2i as first-line therapy in HFpEF irrespective of diabetes status (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). These findings are consistent with Anguita et al., who documented lower use of guideline therapies and SGLT2i in HFpEF compared with HFrEF (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), and are further confirmed by the RED-HEART registry (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Beyond SGLT2i, the FINEARTS-HF trial demonstrated that finerenone significantly reduced HF hospitalizations and cardiovascular death in HFpEF (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) and recent pooled analyses from SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials further show that semaglutide reduces the risk of the composite endpoint of cardiovascular death or HF events and worsening HF events alone in patients with HFpEF, highlighting its potential as an efficacious therapy in this population with limited treatment options (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Collectively, these data underscore both the therapeutic advances and persistent gaps in HFpEF management, emphasizing the urgent need for improved implementation strategies, particularly in patients with T2D.\u003c/p\u003e\u003cp\u003eDiagnostic challenges in HFpEF remain considerable, particularly in patients with T2D and obesity. Elevated BMI, highly prevalent in this population, suppresses natriuretic peptide (NP) secretion and clearance, reducing the sensitivity of BNP and NT-proBNP and increasing the risk of false negatives (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). In our cohort, over 20% of HFpEF patients had NP values below conventional diagnostic thresholds, highlighting the potential for underdiagnosis. Echocardiography, while central to HF evaluation, may also be limited in this setting (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), emphasizing the need for weight-independent biomarkers and advanced imaging tools to improve early detection and risk stratification. These diagnostic limitations have important clinical consequences, as high-risk patients may remain unrecognized and deprived of timely, evidence-based therapies. In our cohort, this gap was associated with rising NT-proBNP levels, stable or declining LVEF, and progression to HFrEF in nearly 5% of cases during follow-up. Collectively, these findings underscore that HFpEF in T2D is a dynamic and progressive phenotype that is prone to deterioration when insufficiently recognized and managed.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn summary, HF is highly prevalent in patients with T2D, with HFpEF emerging as the most frequent and incident phenotype, and is a high-risk, dynamic, and progressive condition. Despite this, HFpEF is often underdiagnosed due to obesity-related limitations in natriuretic peptide measurement and frequently undertreated, despite evidence supporting the use of SGLT2 inhibitors, GLP1 receptor agonists, and finerenone to improve outcome. The development of weight-independent biomarkers and advanced imaging, coupled with timely initiation of evidence-based therapies, is essential for early diagnosis, improved outcomes, and prevention of disease progression in this high-risk population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAF\u003c/strong\u003e \u0026ndash; Atrial Fibrillation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACS\u003c/strong\u003e \u0026ndash; Acute Coronary Syndrome\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACEI\u003c/strong\u003e \u0026ndash; Angiotensin-Converting Enzyme Inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eARA-II\u003c/strong\u003e \u0026ndash; Angiotensin II Receptor Blocker\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBB\u003c/strong\u003e \u0026ndash; Beta-Blocker\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e \u0026ndash; Body Mass Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBNP\u003c/strong\u003e \u0026ndash; B-type Natriuretic Peptide\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCAD\u003c/strong\u003e \u0026ndash; Coronary Artery Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCKD\u003c/strong\u003e \u0026ndash; Chronic Kidney Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOPD\u003c/strong\u003e \u0026ndash; Chronic Obstructive Pulmonary Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCVD\u003c/strong\u003e \u0026ndash; Cardiovascular Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDBP\u003c/strong\u003e \u0026ndash; Diastolic Blood Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDPP4i\u003c/strong\u003e \u0026ndash; Dipeptidyl Peptidase-4 Inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEF\u003c/strong\u003e \u0026ndash; Ejection Fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESC\u003c/strong\u003e \u0026ndash; European Society of Cardiology\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGDMT\u003c/strong\u003e:\u0026nbsp;\u003cstrong\u003eGuideline-Directed Medical Therapy\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGLP1RA\u003c/strong\u003e \u0026ndash; Glucagon-Like Peptide-1 Receptor Agonist\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHF\u003c/strong\u003e \u0026ndash; Heart Failure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHFmrEF\u003c/strong\u003e \u0026ndash; Heart Failure with Mildly Reduced Ejection Fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHFpEF\u003c/strong\u003e \u0026ndash; Heart Failure with Preserved Ejection Fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHFrEF\u003c/strong\u003e \u0026ndash; Heart Failure with Reduced Ejection Fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e \u0026ndash; Heart Rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKDIGO\u003c/strong\u003e \u0026ndash; Kidney Disease: Improving Global Outcomes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLD\u003c/strong\u003e \u0026ndash; Loop Diuretics\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLDL-C\u003c/strong\u003e \u0026ndash; Low-Density Lipoprotein Cholesterol\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLBBB\u003c/strong\u003e \u0026ndash; Left Bundle Branch Block\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLV\u003c/strong\u003e \u0026ndash; Left Ventricle / Left Ventricular\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRA\u003c/strong\u003e \u0026ndash; Mineralocorticoid Receptor Antagonist\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPs\u003c/strong\u003e \u0026ndash; Natriuretic Peptides\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNT-proBNP\u003c/strong\u003e \u0026ndash; N-terminal pro B-type Natriuretic Peptide\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOSA\u003c/strong\u003e \u0026ndash; Obstructive Sleep Apnea\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePAD\u003c/strong\u003e \u0026ndash; Peripheral Artery Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSBP\u003c/strong\u003e \u0026ndash; Systolic Blood Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSGLT2i\u003c/strong\u003e \u0026ndash; Sodium-Glucose Cotransporter-2 Inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTEMI\u003c/strong\u003e \u0026ndash; ST-Elevation Myocardial Infarction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTG\u003c/strong\u003e \u0026ndash; Triglycerides\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT2D\u003c/strong\u003e \u0026ndash; Type 2 Diabetes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVF\u003c/strong\u003e \u0026ndash; Ventricular Fibrillation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWC\u003c/strong\u003e \u0026ndash; Waist Circumference\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: The study was approved by the Ethics Committee of the Hospital Complex of Toledo on March 28, 2018 (project identification code 243) and conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions (if required):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePG-M and AP conceived the study. PG-M, JAG-O, and LR-P contributed to methodology. PG-M and JM curated the data. Formal analyses were performed by PG-M, JM, and VB. PG-M drafted the original manuscript. JAG-O, LR-P, JM, VB, MA, and AP critically revised the manuscript for important intellectual content. AP and MA supervised the study. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Spanish Society of Diabetes (SED) and the Spanish Society of Cardiology (SEC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset analysed during the current study is available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author details\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAntonio P\u0026eacute;rez\u003c/strong\u003e, Endocrinology \u0026amp; Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona; CIBERDEM (Spain); [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePedro Gil-Mill\u0026aacute;n, Hospital Universitari Vall d\u0026acute;Hebron;\u0026nbsp;\u003c/strong\[email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab [Internet]. 2019 [cited 2020 Aug 29];10:2042018819834869. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/30944723\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/30944723\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGulsin GS, Brady EM, Swarbrick DJ, Athithan L, Henson J, Baldry E et al. Rationale, design and study protocol of the randomised controlled trial: Diabetes Interventional Assessment of Slimming or Training tO Lessen Inconspicuous Cardiovascular Dysfunction (the DIASTOLIC study). BMJ Open. 2019;9(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLorenzo-Almor\u0026oacute;s A, Tu\u0026ntilde;\u0026oacute;n J, Orejas M, Cort\u0026eacute;s M, Egido J, Lorenzo \u0026Oacute;. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol. 2017;16:28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePark JJ. Epidemiology, pathophysiology, diagnosis and treatment of heart failure in diabetes. Vol. 45, Diabetes and Metabolism Journal. Korean Diabetes Association; 2021. pp. 146\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, B\u0026ouml;hm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599\u0026ndash;726.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Vol. 145, Circulation. 2022. 895\u0026ndash;1032 p.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePowell-Wiley TM, Poirier P, Burke LE, Despr\u0026eacute;s JP, Gordon-Larsen P, Lavie CJ et al. Obesity and Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation [Internet]. 2021 [cited 2021 Oct 25];143:E984\u0026ndash;1010. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ahajournals.org\u003c/span\u003e\u003cspan address=\"http://ahajournals.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDoughty RN, Cubbon R, Ezekowitz J, Gonzalez-Juanatey J, Gorini M, Gotsman I, et al. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: An individual patient data meta-analysis: Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J. 2013;33(14):1750\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRodr\u0026iacute;guez-Padial L, P\u0026eacute;rez A, Anguita S\u0026aacute;nchez M, Barrios V, Gimeno-Orna JA, Mu\u0026ntilde;iz J. Characteristics of women with type 2 diabetes and heart failure in Spain. The DIABET-IC study. Cardiol J. 2023;XX(X):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGimeno-Orna JA, Rodr\u0026iacute;guez-Padial L, Anguita-S\u0026aacute;nchez M, Barrios V, Mu\u0026ntilde;iz J, P\u0026eacute;rez A. Association of the kdigo risk classification with the prevalence of heart failure in patients with type 2 diabetes. J Clin Med. 2021;10(20).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnguita-G\u0026aacute;mez M, Bonilla-Palomas JL, Recio-Mayoral A, Gonz\u0026aacute;lez-Manzanares R, Mu\u0026ntilde;iz-Garc\u0026iacute;a J, Romero-Rodr\u0026iacute;guez N et al. Differences in clinical features and 1-year outcomes of patients with heart failure and reduced, mildly reduced, and preserved ejection fraction in a contemporary cohort: is the clinical profile changing? Clin Res Cardiol. 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGonzalez-Manzanares R, Anguita-G\u0026aacute;mez M, Mu\u0026ntilde;iz J, Barrios V, Gimeno-Orna JA, P\u0026eacute;rez A et al. Prevalence and incidence of heart failure in type 2 diabetes patients: results from a nationwide prospective cohort\u0026mdash;the DIABET-IC study. Cardiovasc Diabetol. 2024;23(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSavji N, Meijers WC, Bartz TM, Bhambhani V, Cushman M, Nayor M, et al. The Association of Obesity and Cardiometabolic Traits with Incident HFpEF and HFrEF HHS Public Access. JACC Heart Fail. 2018;6(8):701\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol [Internet]. 2013 Oct 15 [cited 2020 Aug 28];62(16):e147\u0026ndash;239. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://linkinghub.elsevier.com/retrieve/pii/S0735109713021141\u003c/span\u003e\u003cspan address=\"https://linkinghub.elsevier.com/retrieve/pii/S0735109713021141\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeijers WC, Bayes-Genis A, Mebazaa A, Bauersachs J, Cleland JGF, Coats AJS, et al. Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC). Eur J Heart Fail. 2021;23(10):1610\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSteiner S. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. Zeitschrift fur Gefassmedizin. Volume 13. Krause und Pachernegg GmbH; 2016. pp. 17\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP et al. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients with Heart Failure by Baseline Diabetes Status: Results from the EMPEROR-Reduced Trial. Circulation. 2021;337\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcMurray JJV, DeMets DL, Inzucchi SE, K\u0026oslash;ber L, Kosiborod MN, Langkilde AM, et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019;21(11):1402\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKocabas U, Ergin I, Yavuz V, Altın C, Kaplan M, Yılmaz \u0026Ouml;ztekin GM, et al. Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED\u0026ndash;HEART study. ESC Heart Fail. 2025;12(1):434\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBizino MB, Jazet IM, Westenberg JJM, Van Eyk HJ, Paiman EHM, Smit JWA et al. Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial. [cited 2022 Mar 5]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12933-019-0857-6\u003c/span\u003e\u003cspan address=\"10.1186/s12933-019-0857-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKristensen SL, R\u0026oslash;rth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDiabet-ic T. European Journal of Internal Medicine Risk of cardiovascular events in patients with type 2 diabetes after 3 years of follow-up.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBelli M, Barone L, Bellia A, Sergi D, Lecis D, Prandi FR, et al. Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients? Int J Mol Sci. 2022;23(23):14598.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al. Evaluation of the effects of sodium\u0026ndash;glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail. 2019;21(10):1279\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, B\u0026ouml;hm M et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine [Internet]. 2021 Oct 14 [cited 2022 Feb 28];385(16):1451\u0026ndash;61. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nejm.org/doi/\u003c/span\u003e\u003cspan address=\"https://www.nejm.org/doi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2107038\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2107038\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSolomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHasegawa K, Lewis BS. Are SGLT2 inhibitors effective against \u0026lsquo;all\u0026rsquo; heart failure with preserved ejection fraction? Eur Heart J Cardiovasc Pharmacother. 2022;9252.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, B\u0026ouml;hm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2023;44(37):3627\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScheen AJ. Real-life underuse of SGLT2 inhibitors for patients with type 2 diabetes at high cardiorenal risk. Diabetes Epidemiol Manage. 2024;13:100184.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePonikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. Volume 37. Oxford University Press; 2016. pp. 2129\u0026ndash;m2200.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e2. Classification and Diagnosis of Diabetes. Standards of Medical Care in Diabetes\u0026mdash;2018. Diabetes Care. 2018;41(Supplement1):S13\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoek AG, Dal Canto E, Wenker E, Bindraban N, Handoko ML, Elders PJM, et al. Epidemiology of heart failure in diabetes: a disease in disguise. Volume 67. Diabetologia. Springer Science and Business Media Deutschland GmbH; 2024. pp. 574\u0026ndash;601.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosano GMC, Seferovic P, Savarese G, Spoletini I, Lopatin Y, Gustafsson F, et al. Impact analysis of heart failure across European countries: an ESC-HFA position paper. ESC Heart Fail. 2022;9(5):2767\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbudureyimu M, Luo X, Wang X, Sowers JR, Wang W, Ge J et al. Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics. J Mol Cell Biol. 2022;14(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi Z, Shi Y, Xia Y, Wu L, Li H, Zhou R, et al. Disparate Clinical Characteristics and Prognosis of HFpEF versus HFrEF Phenotype of Diabetic Cardiomyopathy. J Clin Med. 2023;12(4):1565.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSolomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391(16):1475\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKosiborod MN, Deanfield J, Pratley R, Borlaug BA, Butler J, Davies MJ, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet. 2024;404(10456):949\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and natriuretic peptides, BNP and NT-proBNP: Mechanisms and diagnostic implications for heart failure. Int J Cardiol. 2014;176(3):611\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and natriuretic peptides, BNP and NT-proBNP: Mechanisms and diagnostic implications for heart failure. Int J Cardiol. 2014;176(3):611\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMueller C, McDonald K, de Boer RA, Maisel A, Cleland JGF, Kozhuharov N, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21(6):715\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePieske B, Tsch\u0026ouml;pe C, De Boer RA, Fraser AG, Anker SD, Donal E, et al. How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297\u0026ndash;317.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 2 Diabetes, Heart Failure, HFpEF, HFrEF, Cardiometabolic Risk, Obesity, SGLT2i, Finerenone","lastPublishedDoi":"10.21203/rs.3.rs-7506485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7506485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Heart failure (HF) is a major complication of type 2 diabetes (T2D), with HF with preserved ejection fraction (HFpEF) now representing the most frequent phenotype. However, its clinical profile, prognosis, and treatment patterns compared with HF with reduced ejection fraction (HFrEF) remain insufficiently characterized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e: To compare characteristics, outcomes, and longitudinal management of HFpEF versus HFrEF in T2D patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This prespecified subanalysis of the nationwide, prospective DIABET-IC cohort included 1,517 patients with T2D recruited across 58 Spanish centers and followed for three years. HF phenotypes were defined according to 2016 ESC criteria. Baseline characteristics, outcomes (mortality, hospitalizations, and progression), and therapeutic patterns were assessed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: At baseline, 490 patients had HF (50.2% HFrEF, 30.6% HFpEF, 19.2% HFmrEF). HFpEF patients were older, more often female, and had higher prevalence of obesity, hypertension, and metabolic syndrome, whereas HFrEF was more strongly associated with ischemic heart disease, prior STEMI, and conduction disturbances. During follow-up, HFpEF was the predominant incident phenotype (46.6% of new cases), and 4.7% progressed to HFrEF. Mortality was similarly elevated in both phenotypes; HF hospitalizations tended to be higher in HFrEF, while acute coronary syndromes were more frequent in HFpEF. HFrEF patients more often received guideline-directed therapies, whereas HFpEF remained undertreated, with limited use of SGLT2 inhibitors and GLP-1 receptor agonists. Notably, \u0026gt; 20% of HFpEF patients had natriuretic peptide levels below diagnostic thresholds, highlighting underdiagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: HFpEF is the most frequent and incident HF phenotype in T2D, with outcomes comparable to HFrEF yet frequent underdiagnosis and undertreatment. Improved screening strategies and broader adoption of evidence-based therapies—particularly SGLT2 inhibitors—are urgently needed for this high-risk population.\u003c/p\u003e","manuscriptTitle":"HFpEF as the Predominant and Underrecognized Heart Failure Phenotype in Type 2 Diabetes: Evidence from the DIABET-IC Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 15:57:13","doi":"10.21203/rs.3.rs-7506485/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-29T04:52:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-25T18:12:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-21T11:32:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"320210163043923806200879891300332908689","date":"2025-09-07T08:07:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63630023680393289957804225062758008761","date":"2025-09-05T08:49:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237910415569159577434068100818768156995","date":"2025-09-05T08:29:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-05T08:04:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-01T19:51:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-01T18:25:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Diabetology","date":"2025-09-01T09:02:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7665934-0f25-4b99-b8d4-bee8d6d3d905","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T16:08:51+00:00","versionOfRecord":{"articleIdentity":"rs-7506485","link":"https://doi.org/10.1186/s12933-025-02995-z","journal":{"identity":"cardiovascular-diabetology","isVorOnly":false,"title":"Cardiovascular Diabetology"},"publishedOn":"2025-11-03 15:57:17","publishedOnDateReadable":"November 3rd, 2025"},"versionCreatedAt":"2025-09-11 15:57:13","video":"","vorDoi":"10.1186/s12933-025-02995-z","vorDoiUrl":"https://doi.org/10.1186/s12933-025-02995-z","workflowStages":[]},"version":"v1","identity":"rs-7506485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7506485","identity":"rs-7506485","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}