Heart Failure and Comorbidities (Chronic Kidney Disease, Diabetes, Obesity) Management: A Multidisciplinary Approach

Abstract

Background

Heart failure (HF) frequently coexists with chronic kidney disease (CKD), type 2 diabetes (T2D), and obesity, creating a complex clinical landscape that requires integrated, multidisciplinary management. The three main HF phenotypes – HF with reduced ejection fraction (EF ≤40%), mildly reduced ejection fraction (EF 41–49%), and preserved ejection fraction (EF ≥50%) – differ in their underlying pathophysiology and therapeutic approaches. Approximately 20–40% of patients with HF have T2D, 30–40% are obese (body mass index ≥30 kg/m²), and 45–63% have CKD. These comorbidities are interrelated through overlapping mechanisms such as insulin resistance, chronic inflammation, neurohormonal activation, and endothelial dysfunction, which amplify morbidity, mortality, and healthcare costs.

Summary

The interplay between HF, CKD, T2D, and obesity extends beyond hemodynamic compromise, influencing other frequent conditions such as anemia, sleep apnea, and atrial fibrillation. Addressing these interconnected comorbidities can yield cumulative benefits by improving both HF-specific and overall health outcomes. Data from recent clinical trials and observational studies indicate how these conditions modify risk, affect therapeutic response, and influence guideline-directed medical therapy. Optimal care involves timely recognition, evidence-based management, and coordination across specialties. Key contributors to care include cardiologists, primary care physicians, endocrinologists, nephrologists, pharmacists, dietitians, and mental health professionals.

Key Messages

The coexistence of HF with CKD, T2D, and obesity constitutes a major clinical challenge with shared pathogenic pathways. Managing these comorbidities requires an integrated, multidisciplinary strategy to improve outcomes and quality of life. Barriers such as clinical inertia, polypharmacy, and socioeconomic disparities continue to impede effective therapy implementation. Enhanced collaboration and patient-centered care models are essential to optimize management in this high-risk population.

Plain Language Summary

Heart failure (HF) often occurs alongside other major health problems like chronic kidney disease, type 2 diabetes (T2D), and obesity. These conditions worsen each other through shared biological processes like inflammation and hormone imbalances, leading to poorer health outcomes and higher medical costs. Conditions such as chronic kidney disease, diabetes, and obesity also share causal pathways with other closely linked diseases such as atrial fibrillation, sleep apnea, and anemia. Treatment of HF requires addressing all comorbid conditions. Standard heart medications help protect both the heart and kidneys, reducing hospitalizations and other adverse outcomes. Management of obesity and T2D requires lifestyle changes and specific drugs that improve weight and subsequently heart health. Patients with kidney disease benefit from targeted medications that improve kidney function. Sleep apnea is managed with breathing devices and fluid-reducing drugs. Anemia is treated with iron replacement, while irregular heart rhythms need careful medication balancing and procedure considerations. Care teams involving heart doctors, kidney specialists, diabetes experts, nutritionists, and mental health providers are crucial for coordinating treatments and supporting patients. However, challenges like complex medication regimens, healthcare system delays in treatment adjustments, and costs of care often hinder progress. Programs that help patients transition from hospitals to home and improve health literacy show promise, but many still struggle to afford or access needed treatments. Addressing these systemic barriers remains key to improving outcomes for people managing multiple chronic conditions alongside HF.

Epidemiology and Interconnection of Comorbidities

Heart failure (HF) is a common condition that affects approximately 6.7–7 million adults over 20 years of age in the USA [1]. HF is commonly associated with other comorbid conditions such as chronic kidney disease (CKD), type 2 diabetes (T2D), and obesity, which are serious health conditions that share common risk factors and concomitantly pose an increased risk of morbidity and mortality [2]. T2D, which affects over 37 million in the US population [3], is present in approximately 20–40% of the HF population. The coexistence of T2D not only exacerbates symptoms and diminishes the overall quality of life for affected individuals but also contributes to a higher incidence of hospitalization for heart failure (HHF) and mortality. Furthermore, individuals diagnosed with both conditions face significantly increased mortality rates in comparison to those without diabetes [4]. T2D is also a significant risk factor for HF development and progression. Large-scale observational studies have consistently demonstrated a 2- to 4-fold increased risk of HF in individuals with diabetes compared with those without diabetes. For example, the Framingham Heart Study found that diabetes was associated with nearly a 2-fold higher incidence of HF in men and a 4-fold increase in women [5]. Similarly, the Heart and Soul Study (in patients with stable coronary disease) reported a 3.3-fold higher adjusted risk of incident HF in diabetic patients [6]. Other large cohort studies mirror these findings – for instance, analyses from the Multi-Ethnic Study of Atherosclerosis (MESA) and from NHANES have shown substantially greater HF incidence and adjusted HF risk in people with diabetes [7].

Obesity has consistently been associated with HF, with data indicating that up to 40% of patients with HF are categorized as overweight (with a body mass index (BMI) of 25–29.9 kg/m²) [8, 9] and another 30% or greater are classified as obese (with a BMI of 30 kg/m² or greater). Obesity demonstrates an even stronger association with heart failure with preserved ejection fraction (HFpEF), with studies showing that in the USA, more than 80% of HFpEF patients are overweight or obese [10]. Adipose tissue is capable of independently inducing alterations in cardiac muscle and compromising cardiac functions, which places individuals who are overweight or obese at an elevated risk for the development of cardiovascular diseases [11]. Central adiposity may have a greater association than elevated BMI in patients with HFpEF and may be implicated in multiple causal mechanisms for the development of HF [12, 13].

A significant variability in the prevalence of CKD among HF cohorts exists in contemporary clinical trials [14, 15]. Reported rates of comorbid CKD within HF inpatient databases range from 45% to 63% with the majority falling into CKD stages 3a to 3b (estimated glomerular filtration rate between 45–59 and 30–44 mL/min/1.73 m², respectively), reflecting moderate renal impairment [16–19]. Epidemiological data indicate that approximately 50% of patients with CKD stages 4 and 5 suffer from CV disease, with CV mortality accounting for 40–50% of deaths in this group, and new-onset HF occurring in 17–21% of CKD patients [20, 21]. Furthermore, undiagnosed stage 3 CKD is prevalent in HF patients, with nearly half (48.5%) of this population having unrecognized moderate CKD, suggesting underestimation of CKD burden [22].

A comprehensive analysis of 40,230 patients from the Swedish Heart Failure Registry revealed a notable prevalence of CKD across HF phenotypes. CKD was present in 56% of patients with HF with HFpEF, 48% with mid-range ejection fraction (HFmrEF), and 45% with reduced ejection fraction (HFrEF) [18]. Furthermore, CKD was associated with an increased risk of mortality, particularly pronounced in patients with HFrEF and HFmrEF phenotypes.

The coexistence of HF and impaired kidney function correlates with a heightened risk of kidney-related adverse events. Conversely, the occurrence of an incident kidney event, whether a new or worsening condition related to kidney function, elevates the risk of subsequent cardiovascular death, HHF, and all-cause mortality. Together, HF and CKD exacerbate clinical outcomes and incur costs that are twice as high as those associated with these conditions treated separately [15, 17, 18, 23, 24].

To elevate the focus on interrelated cardiovascular comorbidities, the American Heart Association developed the cardiovascular-kidney-metabolic (CKM) syndrome framework [25]. CKM syndrome is common, and comorbidities, including T2D, obesity, and CKD, commonly coexist in patients with HF [26, 27]. Additionally, these comorbidities are commonly associated with other highly prevalent conditions in patients with HF, including hypertension, anemia, sleep apnea, and atrial fibrillation (AF). Among a cohort of 87,709 patients with HF, 40% were diagnosed with CKD only, 12% with T2D only, and 16% with both conditions [28]. Among 26,800 patients with HF, only 13% did not have hypertension, diabetes, or obesity, with the majority of remaining patients having at least one uncontrolled comorbidity [29]. In a cohort of 2,314 patients with HF, over half had a history of AF, and approximately 80% had at least one comorbidity such as obesity, diabetes, CKD, or anemia [30]. Therefore, an appreciation of the prevalence and pathophysiology of the interconnected comorbidities associated with HF is important to optimize management strategies.

Shared Risk Factors and Pathophysiological Mechanisms Linking HF to Multiple Comorbidities

Not only are cardiovascular comorbidities common in patients with HF, but these conditions may also be the primary drivers of the pathophysiology, symptoms, and outcomes associated with a HF diagnosis (shown in Fig. 1) [31]. Regarding T2D, there are multiple mechanisms contributing to diabetes-associated cardiac dysfunction. Potential mechanisms include impaired microvascular endothelial function [32], abnormal cardiac metabolism (specifically, abnormal cardiac handling of glucose and free fatty acids), increased myocardial fibrosis [33], increased oxidative stress, and local activation of neurohormonal systems such as the renin-angiotensin and sympathetic nervous systems, as well as other well-characterized pathways such as endothelin (shown in Fig. 2) [34]. The risk factors for HF in individuals with diabetes encompass various elements, including the duration of diabetes, suboptimal glycemic control, uncontrolled hypertension, hyperlipidemia, elevated BMI, microalbuminuria, renal dysfunction, ischemic heart disease, and peripheral artery disease [35, 36]. Furthermore, obesity contributes to the predisposition of patients to insulin resistance hyperglycemia and a pro-inflammatory state, thereby increasing the likelihood of developing HF, particularly among those diagnosed with diabetes [34].

Fig. 1.

Comorbidity management in heart failure (HF).

Fig. 2.

Complex interaction among HF, CKD, and DM.

Obesity, diabetes, and CKD further contribute to HF pathophysiology and morbidity through their association with other cardiac and non-cardiac comorbidities, including AF, sleep apnea, and anemia [37, 38]. Individuals diagnosed with AF exhibit nearly a five-fold increased risk of developing HF [39]. AF is an important comorbidity in patients with HF, as it is present in approximately 20–40% of patients with HF, with prevalence varying according to the stage of HF [40]. Once AF develops, a bidirectional relationship exists to further complicate both AF and HF, in terms of symptoms and therapeutic management.

Increased left atrial size in AF leads to mechanical and electrical remodeling, promoting atrial fibrosis and electrophysiological changes that perpetuate arrhythmia. These changes reduce atrial contractile function, causing a loss of atrial contribution to ventricular filling, which, along with an irregular ventricular response, decreases cardiac output. Additionally, structural remodeling extends to the ventricles, resulting in ventricular dilation and fibrosis. Prolonged rapid ventricular rates seen in AF can cause tachycardia-related cardiomyopathy, further exacerbating HF [41–43]. Studies report that AF significantly increases the risk of HF development, with one large-scale study indicating a hazard ratio of approximately 1.8 to 2.0 for incident HF in AF patients compared to those without AF, highlighting the strong association between these conditions [42].

Similarly, obesity, diabetes, and CKD have been associated with the development and severity of sleep apnea [44, 45]. Obstructive sleep apnea (OSA) is prevalent among patients with HF, impacting between 20 and 60% of this population, with both central and OSA present in up to 75% of patients with HF [46, 47]. Similar to other comorbidities, OSA and HF have a bidirectional relationship. Congestion in the setting of HF can worsen OSA, while OSA leads to endothelial dysfunction, catecholamine excess, increased afterload, and arrhythmias that may worsen HF [47]. Additionally, HF predisposes to central sleep apnea, which can in turn lead to further negative neurohormonal effects, thus further worsening the HF syndrome [47].

Patients with OSA commonly develop various arrhythmias, including AF and ventricular arrhythmias, which further complicate the management of concurrent HF. AF, the most common sustained arrhythmia, occurs in about 10.4% of patients with OSA and is more prevalent with severe OSA and higher BMI. Patients with both OSA and AF present a 2.47-fold high-risk OSA compared to patients with OSA in non-AF patients [48].

Anemia coexists with HF in nearly 22%–37% of patients with HF [49, 50]. Patients who present with both anemia and HF exhibit diminished functional capacity, poorer quality of life, and higher incidences of major cardiovascular events, hospitalizations, and mortality compared to patients with HF without anemia. The development of anemia in the context of HF can be attributed to various factors, including chronic inflammation, hemodilution, and iron deficiency, with concomitant diabetes and CKD significantly contributing to anemia risk [40, 51].

Comorbidity Management Strategies

Comorbidity management in HF requires a comprehensive approach that integrates multiple therapeutic strategies while carefully monitoring specific biomarkers for optimal patient outcomes.

Chronic Kidney Disease

Given the significant bidirectional relationship between HF and CKD, management of CKD is important to potentially prevent and attenuate clinical HF. Management of comorbidities is essential in both HFrEF and HFpEF; however, the approach and supporting evidence differ between these HF phenotypes. In HFrEF, guideline-directed medical therapy (GDMT) – including renin-angiotensin system inhibitors (ACE inhibitors or angiotensin II receptor blockers), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) – constitutes the cornerstone of care and is underpinned by a robust body of clinical trial data supporting morbidity and mortality benefits [52]. In contrast, while GDMT remains relevant for selected HFpEF patients, the overall level of recommendation is lower due to less conclusive clinical evidence [53]. In this context, management of comorbid conditions such as hypertension, obesity, diabetes mellitus, AF, and chronic kidney disease assumes particular importance in HFpEF, both because comorbidities are central to the underlying pathophysiology and because most pharmacologic intervention trials in this population have yielded neutral outcomes. This distinction should guide individualized treatment strategies, especially in patients with concomitant CKD [52–54], though the landscape of specific pharmacologic therapies is changing with the success of SGLT-2i, nonsteroidal MRA, and GLP-1RAs.

SGLT-2i have demonstrated significant cardioprotective and nephroprotective effects both in HF independent of CKD and CKD independent of HF. Landmark clinical trials provide robust evidence supporting these benefits. The DAPA-HF trial demonstrated that dapagliflozin reduced the primary composite outcome of worsening HF (hospitalization or urgent visit) or CV death by 26% (HR: 0.74; 95% CI: 0.65–0.85, p < 0.001) in patients with heart failure with reduced ejection fraction (HFrEF) [55]. Similarly, the EMPEROR-Reduced trial included patients with HFrEF and reported a 25% relative reduction in the composite of CV death or HHF (HR: 0.75; 95% CI: 0.65–0.86, p < 0.001) [56]. The subsequent EMPEROR-Preserved trial enrolled patients with HFpEF and HFmrEF, who showed a similar 21% risk reduction for the same composite outcome (HR: 0.79; 95% CI: 0.69–0.90, p < 0.001), including patients with CKD [57], with the DELIVER trial demonstrating similar benefit for patients with HFpEF and HFmrEF with dapagliflozin.

The CREDENCE trial evaluated patients with T2D and CKD, showing that canagliflozin reduced the primary composite renal outcome (end-stage kidney disease, doubling of serum creatinine, or renal/CV death) by 30% (HR: 0.70; 95% CI: 0.59–0.82, p < 0.001). It also significantly reduced HHF by 39% (HR: 0.61; 95% CI: 0.47–0.80) [58].

MRAs play a crucial role in HF management, particularly in patients with CKD. The nonsteroidal MRA finerenone, initially approved for the management of CKD in patients with T2D, has demonstrated safety and efficacy compared to traditional steroidal MRAs like spironolactone and eplerenone [59, 60]. The FINE-HEART trial (a pooled analysis of FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF) assessed the cardiovascular and renal advantages of finerenone across 18,991 patients with CKD (with or without diabetes) and those with HFpEF or HFmrEF. Finerenone reduced the primary outcome of CV death (HR: 0.89, 95% CI: 0.78–1.01; p = 0.076), and the composite kidney outcome (HR: 0.80; 95% CI: 0.72–0.90; p < 0.001) compared to placebo. Furthermore, finerenone exhibits higher receptor selectivity compared to steroidal MRAs, leading to potentially reduced risk of hyperkalemia and improved CV outcomes, making it particularly valuable for patients with HF and concurrent CKD [61].

Additionally, large meta-analyses and real-world studies consistently demonstrate that GLP-1 receptor agonists (GLP-1RAs) significantly reduce major adverse CV events by 14% (HR: 0.86, 95% CI: 0.81–0.90), HHF by 14% (HR: 0.86, 95% CI: 0.79–0.93), and composite kidney outcomes by 17% (HR: 0.83, 95% CI: 0.76–0.90) in patients with T2D. Additionally, GLP-1RAs lower all-cause mortality by up to 16% (HR: 0.84, 95% CI: 0.71–1.00) and reduce the risk of major adverse kidney events (RR: 0.82, 95% CI: 0.74–0.90), as well as progression to kidney failure [62, 63]. In individuals with obesity without diabetes, GLP-1RA use is associated with a lower risk of major adverse CV and kidney events, as well as lower risk of all-cause mortality (HR: 0.49, 95% CI: 0.42–0.57) [64].

Diabetes

Management of diabetes, both in terms of blood sugar control and comorbidity management to reduce diabetes-related risk, is important to reduce the burden of HF. Although both SGLT-2i and GLP-1RAs were initially developed and approved as therapies for T2D, the efficacy of these classes on renal and HF outcomes demonstrates the role of multimorbidity among patients with HF. The CANVAS program evaluated canagliflozin versus placebo in patients with T2D and high CV risk. The rate of the primary outcome of CV death, nonfatal myocardial infarction, or nonfatal stroke was lower in the canagliflozin group compared to the placebo group (HR: 0.86, 95% CI: 0.75–0.97, p < 0.001 for non-inferiority, p = 0.02 for superiority) [65]. As previously described, both SGLT-2i and GLP-1RAs have been associated with improved cardiovascular outcomes, including HF outcomes, among patients with diabetes. These results have been demonstrated across different medications within the respective classes, with meta-analyses revealing benefits of both SGLT-2i and GLP-1RAs in improving HF outcomes in patients with diabetes [66, 67].

The role of other DM therapies in HF prevention is less clear. For example, insulin, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, and sulfonylureas have been associated with adverse consequences in the setting of HF, and these agents should be de-prioritized compared to SGLT-2i and GLP-1RAs in patients with HF [36].

Obesity

As previously mentioned, obesity, as part of the multimorbidity of the CKM syndrome, is an important comorbidity among patients with HF. Weight management and lifestyle interventions play a critical role in reducing the risk of HF. Weight loss strategies, particularly with GLP-1RAs but also with surgical approaches [68], play an important role in the management of HF, and obesity remains a key treatment target, particularly given the rising prevalence of obesity. The STEP-HFpEF trial has shown that semaglutide can improve symptoms in HFpEF patients [69]. The SUMMITT trial showed an improvement in cardiovascular death and worsening HF with tirzepatide [70]. These benefits seen with these incretin drugs seem to extend to patients with HFpEF and obesity, where improvements in morbidity and mortality are observed, supporting the multifaceted protective role of GLP-1RAs in both cardiovascular and renal disease settings.

In addition, SGLT-2i have also demonstrated cardioprotective effects in patients with HF while contributing to modest weight reduction. Studies showed a reduction in the risk of HHF by 31–50% and CV death by approximately 24%, with odds ratios indicating a significant cardioprotective benefit in patients with HF, including those with and without diabetes [71, 72].

Hypertension

Effective management strategies for blood pressure (BP) in patients with HF and CKD are crucial. The implementation of combination therapies and individualized treatment plans is essential for optimal patient outcomes.

BP targets in HF populations remain uncertain, as robust evidence from large clinical trials is lacking for both HFrEF and HFpEF. A post hoc analysis from PARAGON-HF (evaluating the BP effects of sacubitril-valsartan in HFpEF) and TOPCAT (highlighting time in BP range) illustrates the complexity of BP management in these cohorts but does not provide definitive guidance [73, 74]. Current major guidelines from AHA/ACC/HFSA (2022) and the ESC emphasize that the optimal BP target and antihypertensive regimen remain undetermined; instead, individualized therapy should be guided by patient age and key comorbidities such as diabetes, CKD, coronary artery disease, and stroke [54, 75]. Therefore, although titrating to evidence-based medication doses in HFrEF is advised even with mild hypotension, caution should be taken in HFpEF – especially in patients with left ventricular hypertrophy and limited preload reserve – to prevent sudden hypotension.

The SPRINT trial evaluated intensive BP control (target systolic BP <120 mm Hg) versus standard care (target <140 mm Hg) in 9,361 nondiabetic patients with elevated cardiovascular risk [76]. The primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, HF, or death from CV causes was significantly lower in the intensive treatment group compared to the standard treatment group (HR: 0.75, 95% CI: 0.64–0.89, p < 0.001). Specifically for HF outcomes, intensive treatment significantly reduced HF events (HR: 0.62, 95% CI: 0.45–0.84) [76]. However, long-term post-trial follow-up revealed a paradoxical finding: when strict BP protocols were discontinued, the cohort previously under intensive management exhibited higher rates of HHF compared to the standard care group. Thus, maintaining tight control is important if CV events need to be avoided – otherwise, a moderate level of control may be acceptable in selected patients [76]. Strict BP control in patients with CKD has been shown to slow the progression of CKD and reduce CV risk, which is critical given the high prevalence of hypertension in this population. Guidelines such as those from KDIGO and the European Society of Hypertension recommend targeting lower BP levels, often below 120 mm Hg systolic, particularly in patients with proteinuria, to effectively delay CKD progression and minimize cardiovascular complications [77–79].

Sleep Apnea Syndromes

Both central and OSA in the setting of HF can be difficult to manage. When tolerated, positive airway pressure therapy results in significant improvements in oxygenation during sleep, alongside reductions in systolic BP and heart rate, in patients with HF presenting with OSA [80, 81]. Beta-blockers and angiotensin-converting enzyme inhibitors enhance cardiac output and may provide symptomatic relief in individuals with both central and OSA [47, 82]. Furthermore, diuretics effectively reduce the severity of OSA, particularly in patients with pulmonary edema, by inhibiting fluid retention and reducing rostral redistribution (refers to fluid shifting from the lower part of the body to the upper part) [83].

The established positive effects of SGLT-2i on sleep among patients with diabetes highlight the necessity for further investigation into their potential benefits within the HF population, thereby uncovering previously unexplored avenues for improving patient well-being. An analysis of the impact of SGLT-2i on the incidence of OSA indicates a possible protective effect against the development of OSA in patients with HF [84]. Tirzepatide, a GLP1/GIP agonist, has been shown to be effective in the treatment of OSA in obese patients, further cementing incretin therapy in the management of multiple HF comorbidities [85].

In addition to pharmacologic, non-pharmacological therapies also play a key role. Weight loss of around 10% body weight can reduce OSA severity by approximately 30–57%, significantly improving apnea-hypopnea index (AHI) [86, 87]. Mandibular advancement devices decrease AHI by about 50% in mild to moderate OSA [88]. Myofunctional therapy, focusing on oropharyngeal muscle strengthening, reduces AHI by nearly 40% [89]. Surgical options like uvulopalatopharyngoplasty, lateral pharyngoplasty, and modified expansion sphincter pharyngoplasty yield AHI reductions between 33% and 60%, providing alternatives for patients intolerant to positive airway pressure or oral devices [90, 91].

Anemia

In patients with HFrEF who exhibit either absolute or functional iron deficiency, with or without concomitant anemia, intravenous iron therapy, rather than oral iron therapy, may improve symptoms and clinical outcomes [92]. Current guidelines from the ACC/AHA/HFSA and the European Society of Cardiology guidelines recognize iron deficiency as a prevalent and clinically significant comorbidity that complicates the disease’s natural progression. These guidelines advise against ESA therapy for anemia in patients with HF or cardiorenal syndromes due to safety concerns and lack of clear benefit [54, 93].

Several landmark trials have established the benefits of intravenous iron therapy, particularly ferric carboxymaltose. The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials enrolled stable, symptomatic patients with LVEF ≤40–45%. They demonstrated significant improvements in functional capacity, symptoms, quality of life, and exercise performance compared to placebo or standard care (shown in Table 1) [94–96]. These studies also suggested a potential reduction in HHF over extended follow-up. The AFFIRM-HF trial extended these findings to a high-risk population hospitalized with acute decompensated HF and LVEF <50%, revealing a favorable trend in reducing HF rehospitalizations and cardiovascular events. However, the primary composite endpoint narrowly missed statistical significance [97].

Table 1.

Key characteristics and outcomes of major IV iron therapy trials in HFrEF patients with iron deficiency

Trial	Inclusion criteria	Baseline characteristics	Primary endpoint outcomes
FAIR-HF	HFrEF with LVEF ≤40%, iron deficiency (ferritin <100 ng/mL or 100–300 ng/mL + TSAT <20%), NYHA II or III; with or without anemia	N = 459; mean LVEF ∼36%; ∼50% anemic; symptomatic with impaired QoL	Significant improvement in NYHA functional class, Patient Global Assessment, and 6-min walk test distance at 24 weeks vs. placebo
CONFIRM-HF	Stable symptomatic HFrEF patients, LVEF ≤45%, iron deficiency (same criteria as FAIR-HF), NYHA II–III	N = 304; mean LVEF 25%; iron deficient, ∼30% anemic; stable HF	Improved 6-min walk distance, NYHA class, QoL scores; reduced risk of HHF over 1 year with IV ferric carboxymaltose
EFFECT-HF	Chronic symptomatic HFrEF patients, LVEF ≤45%, iron deficiency (same criteria), NYHA II–III	N = 172; mean LVEF ∼33%; CPET tested cohort; iron deficient	Change in peak oxygen consumption (VO2 peak) at 24 weeks improved with IV ferric carboxymaltose compared to standard care
AFFIRM-HF	Patients hospitalized for acute HF with LVEF <50%, iron deficiency as above, NYHA class II–IV	N = 1,132; median LVEF 37%; iron deficient; ∼40% anemic, acute decompensated HF	Primary composite of total HHF and CV death not statistically significant; sensitivity analysis suggests CV death and rehospitalization reduction with IV iron therapy

CPET, cardiopulmonary exercise test; CV, cardiovascular; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association Functional Classification; QoL, quality of life.

Atrial Fibrillation

Pharmacological treatment for HF, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, β-blockers, diuretics, mineralocorticoid receptor antagonists, including finerenone, and SGLT-2i, when appropriately administered, can enhance therapeutic outcomes for HF and may reduce the risk of AF [98, 99]. Likewise, GLP-1RAs may influence the burden of AF through the reduction in obesity, hypertension, diabetes, and sleep apnea as AF risk factors. However, the relationship between GLP-1RAs and atrial arrhythmias will require further evaluation [100]. The AF-CHF trial showed no significant difference in CV mortality rate between rhythm control (27%) and rate control (25%) strategies in patients with AF and HF [101]. Similarly, the CHF-STAT trial demonstrated that amiodarone-mediated rhythm control led to a higher rate of maintenance of sinus rhythm (55% vs. 22%) and was associated with a reduction in arrhythmic death, although the overall survival benefit was not definitive. In contrast, catheter ablation has shown increasingly promising results; the AATAC trial demonstrated a clear advantage over amiodarone in patients with persistent AF, congestive HF, and implanted devices. Seventy percent of patients treated with ablation remained free from AF recurrence compared with only 34% in the amiodarone group [102]. Additionally, ablation was associated with a significantly lower rate of unplanned hospitalizations (31% vs. 57%) and a reduction in all-cause mortality (8% vs. 18%) [102].

Psychiatric Disorders

There exists a connection between psychological well-being and cardiovascular conditions, which may be influenced through biological, behavioral, and psychosocial pathways. Individual-level interventions, such as mindfulness-based programs and positive psychological strategies, have demonstrated promise in enhancing psychological well-being, thereby underscoring the importance of mental health professionals in supporting this aspect of patient care [103].

Depression and anxiety are prevalent disorders associated with HF, affecting up to 25% of patients with HF who show symptoms of both conditions [104]. The presence of these psychiatric disorders is frequently linked to increased morbidity and mortality rates. The incidence of depression tends to rise in conjunction with the severity of HF, particularly among hospitalized patients with this condition [105]. The association between GLP-1RAs usage and psychiatric disorders is controversial. There is evidence to suggest that it may increase depression and suicidal ideation [106], but there is contrasting evidence to suggest that GLP1 usage may decrease depression [107]. More studies are needed to elucidate the effects of GLP1 on psychiatric disorders.

Multidisciplinary Team Approach

The management of patients with HF requires a comprehensive approach across the healthcare continuum, necessitating the collaboration of various disciplines, including social work, public health, pharmacy, nursing, and medicine (shown in Fig. 3). The multidisciplinary team tasked with managing HF and its associated comorbidities comprises several essential roles:

• Cardiologists are responsible for overseeing the care of patients with HF and for integrating treatments aimed at related conditions.

• Primary care physicians coordinate overall care and manage chronic conditions. In addition to re-considering the role of the different therapies, their practice will need to evolve to meet the needs of chronic disease management [108].

• Endocrinologists manage diabetes and other endocrine disorders associated with the condition, along with optimizing doses to be appropriate for each patient’s condition and severity [109, 110].

• Nephrologists propose targeted therapeutic management and address kidney disease, adjusting treatments accordingly. In any event, when a patient with HF presents with significant renal dysfunction, they should be considered for referral to a nephrologist for management optimization and tailoring the right doses of medications [111].

• Advanced practice providers, including physician assistants and nurse practitioners, provide patient education and symptom monitoring. Self-management interventions reduce the risk of HF-related hospitalization or all-cause death [112]. Hospitalizations and mortality can be improved with education about HF, usually delivered at a level the patient can understand, usually by specially trained nurses [113, 114].

• Pharmacists can significantly contribute to optimizing patients’ complicated drug regimens. Clinical pharmacists optimize medications, manage drug interactions, and provide pharmacotherapeutic recommendations and monitoring [115]. They also play a central role in compliance and ensuring that medications are filled at affordable prices.

• Dietitians offer guidance on medical nutrition therapy for HF and contributing comorbidities, such as hypertension, disorders of lipid metabolism, diabetes mellitus, and obesity. They individualize energy intake as every patient with HF should have a clear, detailed, and evidence-based plan [116].

• Psychiatrists/psychologists implement interventions for patients experiencing psychiatric disorders that impact their HF management. This requirement underscores the necessity for the inclusion of a psychiatrist or psychologist as part of the multidisciplinary management team for such cases.

Fig. 3.

Multidisciplinary team approach.

Unfortunately, this siloed specialist care model is not ideal, as many diseases cross specialties. Unless clearly defined, a common condition such as hypertension, hyperlipidemia, or chronic kidney disease may be managed by multiple clinicians not working in harmony or, worse yet, by no clinician. It is imperative that all team members communicate and ensure that the standard of care is followed for all of these comorbidities.

Healthcare professionals are encouraged to enhance their communicative strategies and actively engage patients’ social networks on an individualized basis. This approach is particularly important for facilitating shared decision-making and promoting treatment adherence, especially among multimorbid patients who are subjected to polypharmacy [117]. The integration of a diverse healthcare team enables comprehensive and coordinated care, effectively addressing the intricate needs of patients suffering from HF and multiple comorbid conditions.

The patient’s perspective and expectations are also essential elements in multidisciplinary decision-making processes. Patient and caregiver adherence is primarily contingent upon effective communication with the managing team of healthcare professionals, including physicians and nurses. Moreover, considering the social, financial, and psychological circumstances of the patient is critical for achieving successful treatment outcomes in cases of HF [118].

Barriers to Effective Management

HF management faces significant challenges due to barriers at the patient, provider, and system levels that hinder the effective implementation of GDMT (shown in Fig. 4). Addressing these barriers is essential for improving patient outcomes and the overall quality of life for those living with HF.

Fig. 4.

Barriers to effective management.

Patient-Level Barriers: Health Literacy, Adherence, and Socioeconomic Factors

Clinical Characteristics

Clinical characteristics specific to patients with HF can hinder the optimal application of GDMT [119]. HF predominantly affects the elderly population, who undergo various physiological and metabolic alterations. These changes can significantly impact pharmacokinetics and pharmacodynamics, necessitating more conservative dosing strategies for GDMT to mitigate the heightened risk of adverse drug events and intolerance. Additionally, the presence of comorbidities, such as renal dysfunction, metabolic disorders, hypertension, hypotension, and vascular diseases, can further influence the selection and dosing of certain pharmacological interventions [120].

Adherence

In the context of HF care, low adherence to GDMT is a common issue that is frequently associated with adverse outcomes [121]. This challenge is often amenable to intervention through a multidisciplinary approach. Unfortunately, nonadherence negatively impacts patient health by depriving individuals of the therapeutic benefits of prescribed medications while also exacerbating disease progression [121–124]. The primary factors contributing to nonadherence include complicated medication regimens, undesirable side effects, polypharmacy, and financial burdens [80, 81]. Thus, tailored interventions need to be implemented to improve medication adherence [123].

Provider-Level Barriers: Knowledge Gaps and Treatment Biases

Prior surveys have demonstrated that patients often do not receive optimal therapies despite physicians reporting to be adherent to the guidelines due to provider-related causes [92].

Clinical Inertia

Despite high-quality evidence from randomized trials, implementation of GDMT has remained challenging due to physician factors, including pharmacologic inertia, particularly in patients presumed to be clinically stable patients, as well as due to patient factors such as concern about cost, side effects, and polypharmacy [125]. Clinical inertia is defined as the reluctance or delay by healthcare professionals to initiate or intensify treatment when indicated [74]. This issue often arises when a patient’s condition appears stable or shows signs of recent improvement, leading healthcare practitioners to question the necessity of modifying the current treatment regimen. Such reservations may stem from worries about potential adverse effects or complications that might result from increased dosages or the introduction of additional therapeutic agents [126]. Furthermore, healthcare professionals’ reservations about the adverse effects or complications that could arise from increasing dosages or introducing additional therapeutic agents remain significant [127]. Additionally, there are concerns about the effect of polypharmacy and the economic burden on the patient, which can affect adherence and ultimately the outcome [128]. However, reluctance to optimize GDMT in the HF population is not benign, given the morbidity and mortality associated with an HF diagnosis. Appreciation of ongoing risks associated with an HF diagnosis, with morbidity significantly higher than for another common cardiovascular diagnosis (atherosclerotic disease) and on par with many cancer diagnoses, may be important in an effort to tilt physician opinion and discussion of treatment benefits versus risks in the HF population [129, 130].

Delays in Therapy and the Traditional Sequential Approach to GDMT Optimization

Delaying the initiation of the full therapeutic regimen may postpone the synergistic advantages associated with combined therapies, which could be critical for certain patients in achieving optimal cardiac function and symptom relief [122]. A gradual approach may result in extended treatment periods, thereby exposing patients to an increased risk of disease progression, HHF, and mortality [131]. There is a need for a careful evaluation of sequential dosing and gradual titration against the benefits of aggressive optimization of GDMT and the associated risks of delay [122].

Moreover, concerns related to polypharmacy and its economic implications can significantly impact patient adherence and, ultimately, treatment outcomes. The interplay of these factors contributes to a reluctance to fully optimize therapy, which can hinder the effective management of patients’ conditions.

Delays in therapy and adherence to a traditional sequential approach in optimizing GDMT can have serious consequences. Prolonging the initiation of a comprehensive therapeutic regimen may ultimately defer the synergistic benefits that arise from combined therapies, which are often crucial for certain patients in achieving optimal cardiac function and symptom relief. The cautious approach of gradual up-titration and sequential dosing can expose patients to unnecessary risks, including disease progression, hospitalizations due to HF, and increased mortality.

Therefore, while a careful strategy may seem prudent, it is essential to weigh it against the benefits of aggressive optimization of GDMT. Recognizing and addressing clinical inertia is critical to improving patient outcomes and ensuring timely intervention in the management of HF.

Knowledge and Adherence to Guidelines

The complexity of drug prescriptions and polypharmacy contribute to the burden experienced by patients, thereby leading to reduced adherence to prescribed treatments [132, 133]. Also, the intricate nature of clinical guidelines remains a substantial barrier to their effective implementation [134]. Additionally, the availability of continuous medical education and access to updated guidelines is not universally accessible, particularly in remote or resource-limited settings [135].

System-Level Barriers: Resource Limitations and Healthcare Access Issues

Access to GDMT

Cost and socioeconomic factors also limit high-intensity implementation in some parts of the developed world and many underdeveloped regions; those should also be addressed when implementing high-intensity care [136]. The accessibility and affordability of prescribed medications are of paramount importance. The irregular availability of these medications in certain regions may be attributed to supply chain disruptions, import restrictions, or local policies that do not prioritize the acquisition of these specific pharmaceuticals [120]. Furthermore, even individuals with insurance may face significant out-of-pocket expenses in the form of co-payments and deductibles, which can become a substantial financial burden [128].

Transitional Care

Patients with HF often experience recurrent hospitalization due to insufficient knowledge regarding self-care practices and the appropriate timing for communicating with healthcare providers about worsening symptoms. The daily risk of readmission and mortality during the month following HHF stands at 0.7% and 0.2%, respectively [137]. One of the promising strategies to address this issue is the implementation of transitional care programs. These programs are designed to promote the coordination and continuity of care as patients transfer between healthcare settings or providers [138, 139]. Research has shown that such programs not only enhance the quality of life for patients with HF but also lead to a reduction in readmission rates and overall healthcare costs. By facilitating smoother transitions, these programs can effectively address the gaps in patient education and engagement that contribute to rehospitalization.

A key component of successful transitional care is the implementation of discharge planning services, which have proven to yield significant improvements in clinical outcomes compared to standard care [140]. Notably, studies indicate that the most effective form of transitional care in minimizing readmissions involves home visits, either conducted independently or in conjunction with telephone follow-ups.

To further enhance the efficacy of transitional care for patients with HF, it is imperative for nurse researchers to identify and address existing gaps in this area by conducting studies that involve larger randomized clinical trials. Such research should focus on measuring critical outcomes, including readmission rates, at regular intervals throughout the study duration. By systematically evaluating the effectiveness of transitional care interventions, researchers can contribute valuable insights that inform best practices and ultimately improve health outcomes for this vulnerable patient population.

Conclusion

HF management demands recognition of its bidirectional relationships with CKD, diabetes, obesity, and CKM syndrome, driven by shared mechanisms like neurohormonal dysregulation and systemic inflammation. Managing comorbidities in HF requires a comprehensive approach that combines various treatment methods while closely tracking certain biomarkers to ensure the best outcomes for patients.

Multidisciplinary care addressing comorbidities, polypharmacy, and psychosocial factors is essential, yet systemic barriers – clinical inertia, socioeconomic disparities, and fragmented care – delay GDMT optimization. Prioritizing early comorbidity detection, rapid GDMT titration, and policy reforms to improve access and affordability are critical to reducing hospitalizations and enhancing quality of life. Bridging evidence-based strategies with real-world implementation through coordinated, patient-centered approaches remains pivotal to altering HF’s trajectory.

Acknowledgments

The authors would like to acknowledge the medical writing assistance provided by Sherif Shamseldein, MD, MMSc, MPH, and the editorial support, visualizations, and graphical abstract development provided by Aqsa Dar, ScM, both of ILM Consulting Services, LLC. ILM’s services complied with international guidelines for Good Publication Practice (GPP 2022).

Conflict of Interest Statement

D.A. has received speaker fees from Bayer and AstraZeneca. S.V.F. has received research funding from Bayer and Novo Nordisk and speaker fees from Bayer, Novo Nordisk, and Eli Lilly. R.O.M. is an employee of the Veterans Health Administration (VHA) but is not speaking for the VHA in this document.

Funding Sources

Bayer US, LLC funded the article processing charge for this article. Bayer US, LLC also funded ILM Consulting Services, LLC for medical writing, editorial support, graphics, and publication management.

Author Contributions

D.A., R.O.M., and S.V.F. contributed to the writing and reviewing of each draft and reviewing and approving the final draft for submission.

Funding Statement

Bayer US, LLC funded the article processing charge for this article. Bayer US, LLC also funded ILM Consulting Services, LLC for medical writing, editorial support, graphics, and publication management.