Pharmacotherapy for comorbidities in chronic heart failure: a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia

ABSTRACT

Introduction: Chronic heart failure (HF) is frequently accompanied by one or more comorbidities. The presence of comorbidities in chronic HF is strongly correlated to HF severity and impaired outcome.

Areas covered: This review will address several comorbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these comorbidities will be discussed. For this review, a MEDLINE search was performed.

Expert opinion: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of comorbidities. Although several comorbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these comorbidities will improve patient outcome in chronic HF.

KEYWORDS:

• Heart failure
• comorbidities
• anemia
• iron deficiency
• diabetes mellitus
• hyperkalemia
• hematinics
• vitamin B12
• folic acid

1. Introduction

Chronic heart failure (HF) is the inability of the heart to meet the oxygen demand of body tissues [1]. Clinically, this syndrome is characterized by an impaired quality of life, frequent (re)hospitalizations (>1 million HF hospitalizations annually in both Europe and the United States), and high mortality rates (i.e. 5-year survival rate of ~50%) [1–5]. In developed countries, the prevalence of HF among adults is 1–2%, increasing to >10% in subjects >70 years of age [1,5]. Current management of chronic HF is focused on symptom relieve, delaying disease progression, and improving event-free survival (both rehospitalizations and mortality). An update on the outpatient pharmacological management of chronic HF was recently provided in detail by Kaldara et al. [6].

2. Comorbidities in chronic HF

During the past decade, chronic HF is increasingly considered a multimorbid syndrome. Traditionally, the cornerstone of HF pathophysiology has been neurohormonal activation. However, the pathophysiology of HF (especially in HF with preserved ejection fraction) is more complex and also includes inflammatory and metabolic pathways. Systemic metabolic derangements and chronic low-grade inflammation might contribute to the progression of HF and to the development or worsening of comorbidities [7]. Comorbidities in patients with chronic HF have increasingly received attention. Virtually every HF patient has at least one comorbidity. Braunstein et al. demonstrated that almost half of all chronic HF patients have at least five non-cardiac comorbidities (most commonly hypertension, diabetes mellitus (DM), and chronic obstructive pulmonary disease) [8]. Several studies demonstrated a strong association between the number of comorbidities in HF patients, HF severity, and adverse prognostic consequences [9,10]. Comorbidities in chronic HF are important for several reasons. First, comorbidities may inhibit optimal treatment of HF (for example suboptimal dosage of renin–angiotensin–aldosterone (RAAS) inhibitors in patients with renal dysfunction and/or hyperkalemia, or beta-blockers in patients with severe asthma). Second, pharmacological management of chronic HF and comorbidities may interact with each other (e.g. beta-adrenergic agonist for chronic obstructive pulmonary disease and beta-blockers for chronic HF). Moreover, polypharmacy, as a consequence of the treatment of chronic HF and one or more concomitant diseases, might decrease therapy compliance. Finally, several comorbidities are associated to an impaired clinical and prognostic outcome in patients with chronic HF. Adequate screening and management of comorbidities is, therefore, invaluable when treating patients with chronic HF. In this review, we will focus on the following comorbidities in chronic HF, together with potential pharmacotherapeutic approaches: DM, anemia, hematinic deficiencies (including iron deficiency (ID), vitamin B₁₂, and folate deficiency), and hyperkalemia.

3. DM

Being a major cardiovascular risk factor [11], DM is present in up to half of all chronic HF patients [9,10,12]. It has been recognized that DM is associated with myocardial dysfunction and the development of HF, independent of ischemic heart disease [13–16]. Key DM-related pathophysiological mechanisms are all related to glycemic dysregulation and include oxidative stress, mitochondrial dysfunction, endothelial dysfunction, (micro)vascular abnormalities (e.g. microvascular rarefaction), autoimmunity, and deposition of advanced glycation end-products [13,15]. HF patients with concomitant DM have an increased risk of HF rehospitalization and mortality. There might be a differential impact of DM on prognosis between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) [12]. Some studies showed a similar mortality risk for diabetic patients with HFrEF versus HFpEF, whereas another study showed different short-term mortality and rehospitalization rates for HFrEF versus HFpEF patients (in favor of HFpEF; P for interaction = 0.0012) [17–19]. There is a bidirectional association between HF and DM, as HF is also a risk factor for the development of DM [20,21]. Because of the relationship between HF and DM, McMurray et al. stated that HF hospitalization should always be included as a predefined endpoint in trials assessing new glucose-lowering therapy [22].

3.1. Glucose-lowering therapy

3.1.1. Current therapies

Although there are several pharmacotherapeutical approaches to DM in general (e.g. biguanides, sulfonylureas, insulin), the treatment algorithm for DM in HF is currently unclear. There are conflicting data on the effect of glucose-lowering therapy on cardiovascular event rate [23]. For example, observational research has shown that insulin therapy is a risk factor for HF compared to other glucose-lowering drugs [24,25]. However, a randomized trial assessing the effect of insulin therapy versus standard care on cardiovascular outcome in more than 12,000 diabetic subjects demonstrated similar HF hospitalization risks for both treatment arms (hazard ratio [HR] insulin vs. standard care, 0.90; 95% confidence interval [CI], 0.77–1.05; P = 0.16). Cardiovascular death risk was not increased in the insulin group (HR, 1.00; 95% CI, 0.89–1.13; P = 0.98) [26]. Another drug type, thiazolidinediones, decreases insulin resistance by activating peroxisome proliferator-activated receptors. The incidence of HF events (first hospitalization and death) was significantly increased in diabetic subjects treated with rosiglitazone (thiazolidinedione) compared to either monotherapy with metformin or sulfonylurea, or a combination of metformin and sulfonylurea (HR, 2.10; 95% CI, 1.35–3.27) [27]. Due to this increased risk of adverse HF events, thiazolidinediones are contra-indicated for the treatment of diabetes in symptomatic HF patients [1,28]. The only glucose-lowering drug, which appears to be beneficial in HF is metformin, showing even improved outcome compared to other glucose-lowering drugs (thiazolidinediones, sulfonylurea, or insulin) [29]. More novel glucose-lowering drugs and their cardiovascular effects are discussed in the following paragraphs.

3.1.2. Dipeptidyl peptidase 4 (DDP-4) inhibitors

DDP-4 inhibitors prevent hydrolysis of incretins (glucagon-like peptide 1 and gastric inhibitory polypeptide), thereby inhibiting glucagon release and increasing insulin levels. There are conflicting data on the effect of DDP-4 inhibitors on HF-related events. For example, both alogliptin and sitagliptin did not show any significant effects on major cardiovascular events and hospitalization for HF in large, randomized, double-blind studies comprising diabetic subjects with established cardiovascular disease [30,31]. However, an earlier randomized trial assessing saxagliptin in more than 16,000 diabetic patients with cardiovascular risk factors showed an increased HF hospitalization rate in the saxagliptin arm compared to placebo (3.5% vs. 2.8%; HR, 1.27; 95% CI, 1.07–1.51; P = 0.007) [32]. Interestingly, DDP-4 inhibitor use was associated with a lower HF-hospitalization risk compared to sulphonylurea therapy in a large observation study with long-term follow-up [33]. Whether this difference is due to beneficial effects of DDP-4 inhibitors or detrimental consequences of sulfonylureas is unknown. A recent meta-analysis of randomized clinical trials on DDP-4 inhibitors confirmed the increased risk of HF-related events in patients receiving saxagliptin, especially in patients with high cardiovascular risk (relative risk, 1.22; 95% CI, 1.03–1.44; P = 0.022), whereas such an association was not observed for other DDP-4 inhibitors (alogliptin, linagliptin, sitagliptin, and vildagliptin) [34]. In contrast with these data, a second meta-analysis comprising both randomized clinical trials and observational studies concluded that DDP-4 inhibitor use may be related to an increased risk of HF hospitalization, especially in patients with established cardiovascular disease [35]. With respect to the randomized clinical trials, HF-related events were not adjudicated by independent endpoint committees in most of these trials. Although the increased risk of HF-related events might not be related to each DDP-4 inhibitor, the prognostic consequences of DDP-4 inhibitors use in HF patients are currently unknown. Larger studies using adjudicated HF-related endpoints and long-term follow-up are definitely warranted.

3.1.3. Glucagon-like peptide 1 (GLP-1) receptor agonists

GLP-1 receptor agonists are parenterally administered glucose-lowering drugs, mainly acting by stimulating insulin release and inhibiting glucagon secretion. Moreover, both appetite and gastric emptying are reduced. Although several GLP-1 receptor agonists significantly improve glycemic control, data on long-term cardiovascular endpoints are scarce [36]. Only one large randomized clinical trials focused on cardiovascular event rate of a GLP-1 receptor agonist. In this trial, 6068 patients with type 2 diabetes and established cardiovascular disease were randomized to either lixisenatide or placebo. After a median follow-up of more than 2 years, the primary endpoint rate (a composite of cardiovascular mortality, myocardial infarction, stroke, or hospitalization for unstable angina) was comparable between lixisenatide and placebo (HR, 1.02; 95% CI, 0.89–1.17). Moreover, no difference with respect to HF hospitalizations was observed between treatment arms (HR lixisenatide, 0.96; 95% CI, 0.75–1.23) [37]. A second large long-term trial involving semaglutide demonstrated non-inferiority of major cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the semaglutide arm compared to placebo. Moreover, a significant reduction of cardiovascular risk was observed in the actively treated group. Although semaglutide needs to be administered subcutaneously, an oral tablet variant is currently being developed [38]. A trial on the cardiovascular effects of liraglutide in diabetic patients with and without cardiovascular disease will provide more data on the cardiovascular safety profile of GLP-1 receptor agonists (NCT01179048) [39]. As it stands now, the role of GLP-1 receptor agonists in the treatment of diabetes in HF patients definitely needs to be elucidated further, as there are currently no data available on the safety and efficacy of GLP-1 receptor agonists in this patient group.

3.1.4. Sodium-glucose cotransporter 2 (SGLT2) inhibitors

SGLT2 inhibitors target the renal sodium-dependent glucose transporter, thereby promoting urinary glucose excretion and lowering blood glucose levels. Besides a significant reduction of glycated hemoglobin (HbA1_c), SGLT2 inhibitors promote weight loss and improvement of several other cardiovascular risk factors (e.g. visceral obesity, albuminuria, blood pressure, higher levels of high-density lipoprotein cholesterol, and decreasing body fat). Weight loss is initially achieved by osmotic diuresis, and on the long-term by means of urinary glucose, and thereby caloric, loss [40–43]. Only very recently, the safety profile and effect on cardiovascular prognosis of the SGLT2 inhibitor empagliflozin were assessed in diabetic patients with a high cardiovascular risk profile in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). The EMPA-REG OUTCOME trial was a randomized, placebo-controlled double-blind study, which enrolled 7020 subjects with type 2 DM and established cardiovascular disease. Subjects received either empagliflozin 10 or 25 mg, or placebo once daily. The primary study endpoint was a composite of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction. All cardiovascular events were adjudicated by a clinical event committee. HF events (both hospitalizations and death) alone were not part of the formal study endpoints. After a median follow-up period of 3.1 years, the primary endpoint was reached in 10.5% of the empagliflozin group versus 12.1% in the placebo group (P = 0.04 for superiority). Cardiovascular death rate was significantly lower in the treatment group (HR, 0.62; 95% CI, 0.49–0.77; P < 0.001). Focusing on HF, there was a 35% reduction in the risk of HF hospitalization in the empagliflozin group compared to placebo (HR, 0.65; 95% CI, 0.50–0.85; P = 0.002). No distinction was made between HFrEF and HFpEF [40]. A very recent paper by Fitchett et al. further elaborates on the influence of empagliflozin on HF outcomes in the EMPA-REG OUTCOME trial. On baseline, 706 patients (10.1% of total study cohort) had HF. The effect of empagliflozin on cardiovascular events was consistent in patients with and without HF at baseline [44]. The mechanisms by which empagliflozin improves outcome in DM patients with established cardiovascular disease are still hypothetical, but are most likely multidimensional (e.g. improvement of cardiovascular risk factors, cardiorenal function, vascular resistance, and arterial stiffness) [45]. These multidimensional beneficial effects might also be produced by other SGLT2 inhibitors, such as dapagliflozin and canagliflozin [42,43]. Unfortunately, data on long-term cardiovascular effects and HF-related events are currently lacking. Moreover, there is some evidence that SGLT2 inhibitors may increase the risk of diabetic ketoacidosis [46,47]. Treatment of diabetic ketoacidosis using fluid resuscitation might have deleterious effects in chronic HF patients [48]. Several large randomized trials on different SGLT2 inhibitors and cardiovascular safety are currently ongoing and will provide more insight in the long-term safety of SGLT2 inhibitors other than empagliflozin [45]. Of these trials, the CREDENCE trial (canagliflozin vs. placebo; NCT02065791) and the DECLARE-TIMI 58 trial (dapagliflozin vs. placebo; NCT01730534) are especially of interest, because of their pre-specified secondary adjudicated HF-related endpoints (HF hospitalization). Finally, it is important to notice that the EMPA-REG OUTCOME trial included patients with established cardiovascular disease. It is currently unknown whether comparable beneficial effects of empagliflozin on HF-related events can be observed in patients without established cardiovascular disease.

4. Anemia

The role of anemia in chronic HF patients has been investigated for more than a decade. Traditionally, anemia is defined by the World Health Organization as an Hb level <12 g/dL in women and <13 g/dL in men [49]. Anemia is prevalent in 37% of HF patients [50], but definitions and HF severity in the literature vary and consequently, reported prevalence varies from 4% to 61% [51]. Hb levels are inversely associated with risk of hospitalization and mortality [50,52–54]. The etiology of anemia in chronic HF is often multifactorial and includes hemodilution [55], ID, decreased erythropoietin (EPO) production (due to renal insufficiency or RAAS-inhibitor use) [56], and resistance to endogenous EPO [57]. ID is present in ~60% of patients with anemia and in ~40% of patients without, and is associated with unfavorable prognosis independent of Hb status [58,59]. Hence, ID could be considered a separate comorbidity, and is discussed in Section 5.1 as such. Erythropoiesis-stimulating agents (ESA) might have beneficial effects by increasing the Hb level [52]. Several small studies addressing the use of ESA in HF patients with anemia showed an improvement in clinical outcome and reduction in (re)hospitalizations [60–62], while other studies reported more neutral results [63,64]. All studies reported a significant increase in Hb levels. The largest study evaluating the effect of ESA in chronic HF is the reduction of events by darbepoetin alfa in heart failure (RED-HF) [65]. In this study, 2278 symptomatic chronic HF patients with a LVEF ≤40% and anemia (Hb: 9.0–12.0 g/dL) were randomly assigned to receive either ESA (darbepoetin alfa) or placebo. Subjects assigned to darbepoetin alfa were dosed according to an Hb-driven algorithm until normalization of Hb levels. The primary outcome measure of the RED-HF consisted of a combined endpoint of all-cause mortality and HF hospitalization. Although Hb levels significantly increased in the darbepoetin alfa group, no difference in the primary endpoint rate was observed between both groups (50.7% in the darbepoetin alfa group vs. 49.5% in the placebo group; HR, 1.01; 95% CI, 0.90–1.13; P = 0.87). Among subjects receiving darbepoetin alfa, significantly more thromboembolic adverse events were observed compared to the placebo group (13.5% vs. 10.0%; P = 0.009). Stroke rate was similar between both groups (3.7% in treatment group vs. 2.7% in placebo group; P = 0.23). The authors conclude that their findings do not support the assumed clinical benefits of darbepoetin alfa in patients with HFrEF and mild-to-moderate anemia. The findings regarding adverse events were comparable to the results of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), a randomized trial assessing the clinical benefits of darbepoetin alfa in diabetic patients with chronic renal failure and anemia (without ID) [66]. However, the authors reported an almost twofold increase in the risk of fatal and nonfatal stroke in the darbepoetin alfa group compared to placebo (HR, 1.92; 95% CI, 1.38–2.68; P < 0.001) and a higher incidence in venous and arterial thromboembolic events (41 [2.0%] vs. 23 [1.1%]; P = 0.02; and 178 [8.9%] vs. 144 [7.1%]; P = 0.04). Proposed mechanisms for these adverse event findings include increased blood pressure and/or increased blood rheology [67]. Two randomized controlled trials in chronic kidney disease assessed various Hb targets and suggested that aiming at higher targets was associated with higher rates of cardiovascular events [68,69]. However, a sub-analysis of the TREAT assessed the erythropoietic response to darbepoetin alfa and found that not the achieved Hb level but a lack of erythropoietic response was associated with the highest adverse event risk [70]. It is currently unclear whether this is true in chronic HF as well and how these results should be interpreted. These adverse effects could be specific for treatment with exogenous EPO, but it has also been suggested that the Hb level is just a marker of disease severity instead of a treatment target. Alternatively, the positive effects of ESA might be obscured by the negative. The ancillary properties of ESA (e.g. stimulating angiogenesis and anti-apoptosis) might have been obscured by the adverse rheological effects, leading to an increased risk of thromboembolic events and strokes. To assess different pathways, new strategies for the treatment of anemia are currently being explored, including EPO receptor targeting drugs (mimetic peptides, fusion proteins, receptor antibodies, and gene therapy), activin traps (members of the transforming growth factor-β superfamily, which are involved in the regulation of erythropoiesis) and, the most promising so far, hypoxia-inducible factor (HIF) stabilizers [71]. All of these, except for the epoetin fusion proteins, have been assessed in phase II trials and were shown to have Hb-increasing effects. Sotatercept, the best-studied activin trap, additionally inhibits hepcidin expression, which makes it interesting for the treatment of ID anemia and anemia of chronic inflammation [71,72]. The EPO mimetic peptides were considered a promising class until one of the compounds, peginesatide, showed increased rates of death, unstable angina and arrhythmia in patients with chronic kidney disease and life-threatening hypersensitivity reactions in patients with EPO-related pure red cell aplasia, resulting in its worldwide recall [73,74]. HIF-stabilizing drugs upregulate multiple pathways normally induced by hypoxia, among which EPO [75]. HIF stabilizers have the advantage of inducing more stable EPO levels compared to the level achieved with ESA administration. In addition, HIF stabilizers can be administered orally and have been reported to improve iron metabolism [76]. Several phase-2 and -3 studies are currently being performed with the following compounds: FG-4592 (Roxadustat; FibroGen), GSK1278863 (GlaxoSmithKline), AKB-6548 (Akebia Therapeutics) and BAY89-3934 (Molidustat, Bayer Pharma) [71]. The first three compounds already proved to increase Hb levels in phase-2 studies. BAY86-3934 showed an increase in reticulocyte count after a single oral dose in healthy men. Care should be taken, however, because HIF stabilizers activate several hundreds of genes, and thus a broad spectrum of biological pathways (e.g. fatty acid and glucose metabolism, angiogenesis), which might lead to an increased risk of adverse and off-target effects (e.g. tumor growth promotion).

5. Hematinic deficiencies

5.1. ID

The essential trace element iron is obligatory for various physiological pathways, among others erythropoiesis, oxygen transport and storage, mitochondrial functioning, and skeletal and cardiac muscle metabolism. ID is highly prevalent in patients with chronic HF; up to half of all HF patients have ID, based on the criteria used in large trials assessing intravenous iron therapy in HF patients (serum ferritin <100 μg/L, or serum ferritin 100–300 μg/L with transferrin saturation <20%) [58,77–80]. ID in chronic HF is a strong and independent predictor of health-related quality of life [81,82], exercise capacity [77,83] New York Heart Association (NYHA) functional class, and mortality, even in non-anemic subjects [58,77].

Two randomized clinical trials assessed the effect of intravenous ferric carboxymaltose in iron-deficient HF patients with respect to clinical and prognostic endpoints. The Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) trial aimed to demonstrate whether intravenous iron administration would lead to symptom improvement (in terms of the self-reported Patient Global Assessment and NYHA functional class) in iron-deficient HFrEF patients, with or without anemia. In this randomized, double-blind, placebo-controlled trial, 459 patients were assigned to receive either intravenous iron (ferric carboxymaltose) or placebo (saline) [80]. Patients assigned to intravenous iron received 200-mg ferric carboxymaltose weekly until normalization of iron status (correction phase), and subsequently 200 mg every 4 weeks (maintenance phase). The intravenous iron group showed improvement in symptoms, NYHA functional class, and quality of life, independent of baseline Hb levels. Adverse events were comparable between randomization arms. The CONFIRM-HF trial elaborated the role of intravenous iron in chronic HF patients [79]. Subjects randomly received either ferric carboxymaltose or saline. At baseline and 6 weeks, subjects assigned to intravenous iron received 500–2000 mg ferric carboxymaltose based on their body weight and Hb level, and subsequently 500 mg every 12 weeks until end of study (i.e. 52 weeks) if ID was still present. Six-minute walking distance increased significantly compared to placebo (P = 0.002). A significant reduction in HF hospitalization was observed in the treatment group (HR, 0.39; 95% CI, 0.19–0.82; P = 0.009), although it must be noted that this study was not powered for this endpoint. In the abovementioned trials, only HFrEF patients were studied; it is currently unclear whether similar beneficial effects could be achieved in HFpEF patients.

Apart from intravenous iron administration, oral iron supplementation might also constitute a pharmacotherapeutical target. However, several researchers have hypothesized that oral iron supplementation might be less effective compared to intravenous iron, for example due to bowel edema and hypoperfusion, drug interactions, therapy compliance issues, and significant side effects [84]. The most important downside of oral iron therapy might be the inability of oral iron to overcome the reticuloendothelial system, where iron can be trapped into macrophages, especially in chronic inflammatory conditions when the iron exporter ferroportin is degraded by hepcidin [85].

The IRON-HF study, a randomized, double-blind, placebo-controlled clinical trial, is the only trial, which compared oral versus intravenous iron therapy [86,87]. In this study, comprising only 23 anemic HFrEF patients with ID, patients randomly received either iron sucrose 200 mg (weekly for 5 weeks), oral ferrous sulfate 200 mg (thrice daily for 8 weeks), or placebo. Although underpowered for the primary endpoint due to early study termination (slow recruitment), the authors demonstrated a non-significant difference in increase in VO₂ max of 4.36 mL/kg/min between the intravenous and oral iron group, which was independent of the increase in Hb. Both VO₂ max levels and Hb levels increased in the control group (although not significant). Serum ferritin and transferrin saturation increased in both treatment groups, the latter more pronounced in the intravenous group. No significant side effects were reported.

Finally, one study comprising 105 iron-deficient HFrEF patients retrospectively aimed to assess whether oral iron supplements were able to improve iron status [88]. All patients received oral iron supplementation (median [+interquartile range] daily dose 130 [65–15] mg) as ferrous sulfate (82%), iron polysaccharide (11%), or ferrous gluconate (7%). Iron status was assessed at least twice (before and after oral iron treatment). After a median 164 days of oral iron therapy, a significant increase in transferrin saturation (TSAT, from median 9.9–20.8%, P < 0.0001) was observed, which resembled the change in TSAT measured in the FAIR-HF trial (i.e. median from 17.9% to 29% over 180 days) [80,88]. To a lesser extent, although significant, ferritin levels increased as well (median from 40 to 72 µg/L, P < 0.0001), however this was not comparable to the amount of change in ferritin levels in the FAIR-HF trial (median level from 53 to 312 µg/L). The authors suggest that oral iron therapy might constitute a therapeutic target, as it might be able to replete iron stores. This hypothesis will be explored more thoroughly in randomized clinical trials: the IRONOUT study. This is an ongoing phase-3, randomized, double-blinded placebo-controlled trial investigating the effect of oral iron polysaccharide on exercise tolerance measured by change in VO₂ max after 16 weeks in 220 patients with stable, symptomatic HFrEF and ID with or without anemia (Clinicaltrials.gov identifier: NCT02188784). Subjects will receive either polysaccharide iron complex (150 mg), or oral placebo, twice daily for 16 weeks. In patients with chronic kidney disease, intravenous iron has been shown to be superior to oral iron therapy with respect to ferritin and Hb response, and treatment-related adverse event rate (gastrointestinal disorders) [89,90]. However, whether this translates into an improved outcome is currently unknown.

5.2. Vitamin B₁₂ and folate deficiency

Studies addressing other hematinic deficiencies (vitamin B₁₂ and folate deficiency) in chronic HF are scarce. Both vitamin B₁₂ and folic acid are important for erythropoiesis, and deficiencies may lead to (megaloblastic) anemia. In general, low dietary intake of vitamin B₁₂ and folate are associated with higher levels of homocysteine [91,92]. Several studies have demonstrated that hyperhomocysteinemia is an independent risk factor for cardiovascular disease, including chronic HF [93,94].

In the past decade, two studies have focused on the role of vitamin B₁₂ and folate deficiency in chronic HF patients. The first study from Witte et al. showed a relatively low prevalence of hematinic deficiencies in a cohort of 296 HF patients with both preserved and reduced left ventricular ejection fraction (vitamin B₁₂ deficiency [normal range: 180–1130 ng/L] 6% and folate deficiency [normal range red cell folate: 147–650 µg/L] 8%) [95]. Another study confirmed that these deficiencies are relatively rare (vitamin B₁₂ deficiency [i.e. serum level <200 pg/mL] 5% and folate deficiency [i.e. serum level <4.0 ng/mL] 4%) [96]. An independent association between lower folate levels and an impaired health-related quality of life was observed in this cohort. No association was found between vitamin B₁₂ and folate levels and mortality. Whether treatment of these deficiencies by means of a micronutrient-enriched diet or vitamin supplementation has any beneficial effects with respect to clinical status, quality of life, or mortality is currently unclear. A recent, revised Cochrane review comprising 12 randomized clinical trials found no evidence that homocysteine-lowering therapy with vitamin B-complex was associated with a decrease in the number of cardiovascular events in patients with and without established cardiovascular disease [97].

6. Hyperkalemia

High levels of potassium (serum levels >5.0 mmol/L) are independently associated with cardiac arrhythmia and impaired outcome [98–100]. High potassium levels can be a major limiting factor in the pharmacological treatment of chronic HF, as it impairs optimal uptitration of RAAS inhibitors. A recent observational study focusing on RAAS-inhibitor use in more than 200,000 patients showed that nearly half of all patients on maximum RAAS-inhibitor dose were down-titrated after an episode of moderate-to-severe hyperkalemia [101]. Adequate doses of these drugs are obligatory to improve prognosis in chronic HF patients [1,28]. A major downside of RAAS-inhibitors inherent to their pharmacological properties is the ability to induce hyperkalemia, thus inhibiting their optimal use. Not even one-third of all eligible HF patients receive RAAS-inhibitors at target dose [101–103]. HF patients with coexisting DM and/or renal insufficiency are even more prone to develop hyperkalemia [104]. Although speculative, lowering of serum potassium levels might possibly imply that more HF patients can be treated at target dose of RAAS-inhibitors, especially in HF patients with DM or renal failure. Current treatment modalities for acute hyperkalemia include administration of aerosolized beta-2-agonists, intravenous insulin or calcium salts, and hemodialysis [105]. For chronic hyperkalemia, subjects might be treated using dietary potassium restriction (which is difficult to maintain), and diuretics. Hyperkalemia can be treated more specifically using sodium polystyrene sulfonate, which is discussed in the next paragraph. Only very recently, several promising potassium-binding agents have become available. Common characteristics of these agents include oral administration, their gastrointestinal site of action, no systemic absorption or metabolism, and fecal potassium excretion.

6.1. Treatment

6.1.1. Sodium polystyrene sulfonate (SPS)

SPS is an organic ion-exchange resin, which binds cations, among others potassium, in the gastrointestinal lumen. This substance was approved for the treatment of hyperkalemia by the US Food and Drug Administration (FDA) in 1958. To improve gastrointestinal passage to the colon and reduce SPS-induced constipation, SPS is frequently prescribed in sorbitol. The efficacy of SPS has never been formally evaluated in randomized, placebo-controlled trials; only one retrospective study assessed the effect of SPS in different doses on potassium levels in 122 hyperkalemic subjects, demonstrating that a single dose of SPS was able to decrease potassium levels to normal in nearly all subjects [106]. Safety concerns have been raised however, because SPS in sorbitol is associated with an increased risk of colonic necrosis [107]. Moreover, being a sodium–potassium exchanger, (chronic) SPS use might predispose to hypernatremia, which may have detrimental hemodynamic effects in chronic HF patients.

6.1.2. Sodium zirconium cyclosilicate (ZS-9)

Sodium zirconium cyclosilicate (ZS-9) and its role in the management of hyperkalemia have been discussed very recently by Rafique et al. [108]. In short, ZS-9 is an orally administered and sorbitol-free potassium trap, which binds potassium (in exchange for sodium) in a highly selective way in the gastrointestinal tract (mainly duodenum) [109]. Three randomized, placebo-controlled phase-2 and -3 trials focused on the effectivity and safety of ZS-9 in a broad range of hyperkalemic subjects [110–112]. All trials demonstrated a significant potassium level reduction in the ZS-9 groups compared to placebo, both in the initiation and maintenance phase. ZS-9 was in general well tolerated; diarrhea was the most common side effect. Serious adverse events were not observed. A substudy of one of these randomized trials (i.e. The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance [HARMONIZE] trial) focused on the efficacy of ZS-9 for the treatment of hyperkalemia in 94 HF patients [113]. Patients with hyperkalemia received open-label ZS-9 10 g for 48 h. After 48 h of ZS-9 therapy, mean serum potassium levels significantly decreased from 5.6 mmol/L (95% CI, 5.5–5.7) at baseline to 4.4 mmol/L (4.3–4.5). Subjects who were normokalemic after 48 h of treatment were randomized to ZS-9 (5, 10, or 15 g once daily) or placebo for 28 days. RAAS-inhibitor (used in 69% of all patients) doses were kept constant post-randomization. Compared to placebo, subjects receiving ZS-9 maintained lower potassium levels (mean for placebo, 5.2 mmol/L; means for ZS-9 doses, 4.7, 4.5, and 4.4 mmol/L, respectively; P < 0.01) and remained more frequently normokalemic (40% for placebo; 83%, 89%, and 92% for ZS-9 doses, respectively; P < 0.01). No clinically significant hypokalemia or treatment-related serious adverse events were observed. During the maintenance phase, edema occurred in 13% of all patients treated with ZS-9, compared to 4% in the placebo group. This might be due to the sodium exchange of ZS-9, possibly promoting fluid retention.

Until now, only short-term follow-up data is available for ZS-9. Future studies should definitely focus on the long-term effect of ZS-9 on hyperkalemia and related events in chronic HF patients receiving RAAS-inhibitors. In addition, more research is needed to assess whether lowering potassium levels will increase the use of RAAS-inhibitors and subsequently improve outcome [108].

6.1.3. VELTASSA^TM (patiromer) for oral suspension

Patiromer (VELTASSA™ [patiromer] for oral suspension; Relypsa Inc., Redwood City, CA) is the second novel potassium binder, which consists of non-absorbed polymeric beads, primarily binding potassium (in exchange for calcium) in the distal colon. Patiromer is FDA approved as (chronic) treatment modality for hyperkalemia and is now clinically available [114]. Three randomized clinical trials focused on the efficacy and safety of patiromer in treating hyperkalemia [115–117]. Main findings of these studies include significant lowering of potassium levels (both short term and longer term) and low prevalence of hypokalemia and other adverse events. The most common side effect was constipation. These three trials were discussed in more detail in a very recent clinical review by Montaperto et al. [118]. Of these trials, the PEARL-HF trial is of significant importance, as this study elaborated the role of patiromer in chronic HF patients [115]. This study included 105 chronic HF patients with an indication for spironolactone, a potassium level of 4.3–5.1 mmol/L, and either renal dysfunction (i.e. estimated glomerular filtration rate <60 mL/min/1.73 m²) or discontinuation of RAAS-inhibitors due to hyperkalemia. Eligible subjects were randomly assigned to either patiromer (15 mg twice daily) or placebo. All subjects received 25 mg spironolactone daily, which was uptitrated to 50 mg daily after 2 weeks when potassium levels were <5.1 mmol/L. The primary study endpoint was the mean change in potassium levels from baseline to end of study (28 days). Baseline potassium levels were comparable in both groups (4.69 mmol/L for patiromer and 4.65 mmol/L for placebo). The patiromer groups showed significantly lower potassium levels (between group difference, −0.45 mmol/L; P < 0.001) and a higher proportion of subjects in the patiromer groups was uptitrated to 50 mg spironolactone daily (91% in patiromer vs. 74% in placebo; P = 0.019). Patiromer was well tolerated in general; adverse events were mild to moderate and mostly included gastrointestinal disorders. No therapy-related serious adverse events were observed. The incidence of hypokalemia was numerically higher in the patiromer group (6% vs. 0%; P = 0.094) and calcium levels were similar in both groups. Comparable results were observed in the OPAL-HK trial [116]. The OPAL-HK trial focused on the safety and efficacy of patiromer in 237 CKD patients with hyperkalemia and receiving RAAS inhibitors. After the initial treatment phase with patiromer (4.2 or 8.4 g twice daily for 4 weeks), mean potassium levels (±SE) dropped with 1.01 ± 0.03 mmol/L (95% CI, 0.95–1.07; P < 0.001). Forty-five percent (n = 107) of all patients were subsequently randomized to either patiromer or placebo for 8 weeks. Only normokalemic patients were eligible for the randomized withdrawal phase. In the placebo group, recurrence of hyperkalemia (potassium level ≥5.5 mmol/L) was observed in 60% of all patients compared to 15% in the patiromer group. The most common side effect was constipation (11%); no serious adverse events related to patiromer were observed. Three percent of all patients had an episode of hypokalemia. A recent pre-specified substudy of HF patients in the OPAL-HK study further elaborated the effects of patiromer specifically in HF patients. This substudy consisted of 102 mostly mild HF patients with a mean potassium level of 5.6 ± 0.6 mmol/L. During the initiation phase, mean potassium levels change (±SE) was −1.06 ± 0.05 mmol/L (95% CI, −1.16 to −0.95; P < 0.001). Forty-nine patients were eligible for the randomized withdrawal phase (i.e. normokalemic and still receiving patiromer and RAAS-inhibiting therapy). In this phase, recurrent hyperkalemia was observed in 8% of the patients assigned to patiromer compared to 52% in patients on placebo [119]. Taking the PEARL-HF trial and OPAL-HF substudy into account, patiromer seems an effective and safe drug to decrease episodes of hyperkalemia in HF patients. Moreover, short-term RAAS-inhibitor uptitration might be improved when using patiromer. Whether this also implies stable and long-term uptitration of RAAS-inhibitors in HF patients still needs to be elucidated.

7. Conclusion

HF is increasingly considered a multimorbid syndrome, including neurohormonal activation, metabolic derangements, and chronic low-grade inflammation. These systemic derangements might lead to the development and progression of several cardiac and non-cardiac comorbidities, even more in patients with HFpEF compared to HFrEF. Therefore, we believe that more trials evaluating treatment possibilities of comorbidities are needed especially in HFpEF patients. An overview of high-impact comorbidities and possible pharmacotherapeutic approaches is provided in Table 1.

Table 1. Overview of high-impact comorbidities and pharmacotherapeutic approaches in chronic HF.

Comorbidity	Prevalence (%)	Clinical and prognostic consequences	Pharmacotherapeutic approach	Treatment effect	References
Diabetes mellitus	40–45		DDP-4 inhibitors	Mortality?	[9,10,12,24–27,31–38,40,44]
				HF hospitalization?
			Thiazolidinediones	↑ HF events (hospitalization/death)
			SGLT2 inhibitors	↓ HF hospitalization (empagliflozin)
			Insulin	Mortality?
				HF hospitalization?
			GLP-1 receptor agonists	○ Mortality (lixisenatide)
				○ HF hospitalization (lixisenatide)
				↓ Cardiovascular risk (semaglutide)
Anemia	25–40	↓ Functional capacity	Erythropoiesis-stimulating agents (e.g. darbepoetin-α)	↑ Hemoglobin	[50,51,65,66]
		↓ Health-related QoL		↑ Thromboembolic adverse events
		↑ Hospitalization		○ Mortality
		↑ Mortality		○ Hospitalization
Hematinic deficiencies
Iron deficiency	~50	↑ NYHA class	Intravenous iron	↓ NYHA functional class	[58,77–81,83,86–88] NCT02188784
		↑ NT-pro-BNP levels		↑ Health-related QoL
		↓ Health-related Qol		↓ Rehospitalization
		↑ Mortality
			Oral iron	↑ VO2 max
				↑ TSAT
				↑ Ferritin
Vitamin B12 deficiency	5–6	–	–	–	[95,96]
Folate deficiency	4–8	↓ Health-related QoL	–	–	[95,96]
Hyperkalemia	36	↓ Uptitration RAAS-inhibitors	Sodium polystyrene sulfonate (SPS)	↓ K^+	[98–100,106,107,110–113,115–117,120–122]
				↑ Adverse events (colonic necrosis)
		Arrhythmias	Sodium zirconium cyclosilicate (ZS-9)	↓ K^+
				○ Adverse events
			Patiromer sorbitex calcium	↓K^+
				○ Adverse events
				↑ Tolerability spironolactone

↑ increase; ↓ decrease; ○ no change.

DDP-4: dipeptidyl peptidase-4 inhibitor; HF: heart failure; SGLT2: sodium-glucose contransporter 2; QoL: quality of life; NYHA: New York Heart Association; NT-pro-BNP: N-terminal prohormone brain natriuretic peptide; VO₂: oxygen uptake; TSAT: transferrin saturation; RAAS: renin–angiotensin–aldosterone system; K⁺: potassium.

8. Expert opinion

8.1. DM

There are conflicting data regarding the safety profile of glucose-lowering therapy in chronic HF patients. This is especially true for insulin therapy and DDP-4 inhibitors. Current data suggests that metformin is widely used and is safe to use in HF patients. Thiazolidinediones have been shown to increase the risk of HF-related hospitalization and mortality and must be avoided in HF. Although some DDP-4 inhibitors and GLP-1 receptor agonists might be safe to use, there are currently hardly any long-term studies focusing on adequately adjudicated HF-related endpoints. A recent trial assessing empagliflozin (SGLT2 inhibitor) showed a 35% reduction of HF hospitalization risk in the empagliflozin group. Empagliflozin is currently the only glucose-lowering drug with beneficial effects on cardiovascular mortality, and consequently may play a role in the treatment of DM in chronic HF patients. However, data on the mechanism behind these beneficial effects on HF hospitalization are lacking, and it is currently unclear whether the drug has an effect on new onset HFrEF, HFpEF or both. Furthermore, when prescribing empagliflozin, the increased risk of urogenital infections should be taken into consideration, especially in the old and frail population. Trials on other SGLT2 inhibitors are currently ongoing and will provide more data on the safety profile of this drug group.

8.2. Anemia

Randomized clinical trials demonstrated no effect of ESA therapy on mortality and HF rehospitalizations in chronic HF patients. Moreover, treatment with ESA seems to be associated with an increased risk of venous thromboembolisms and stroke. Treatment of anemia with ESA is, therefore, not recommended in patients with chronic HF and anemia, although severe renal anemia might warrant ESA therapy to prevent erythrocyte transfusion. To overcome the adverse effects of ESA, intervening at EPO-regulating pathways (increasing endogenous EPO levels instead of administering exogenous EPO) could be an interesting option. In this light, HIF stabilizers might be an attractive new therapeutic modality, upregulating several hypoxia-driven pathways. The safety and efficacy of several HIF stabilizers are currently being assessed in phase-2 and -3 studies, mainly in patients with chronic kidney disease. For now, the underlying cause of anemia should be established and treated accordingly (e.g. ID).

8.3. ID

Intravenous iron therapy has the ability to reduce symptoms, improve health-related quality of life and exercise tolerance. The role of intravenous iron therapy in the risk reduction of HF rehospitalization and mortality still needs to be elucidated, as well as the effects of intravenous iron in HFpEF patients. Although intravenous iron hypothetically might be superior compared to oral iron treatment, this hypothesis has never been tested formally in a randomized clinical trial in chronic HF patients. More insight in the pathophysiological mechanisms of ID and the mechanism of action of intravenous and oral iron supplements is needed.

8.4. Hyperkalemia

SPS should be used very cautiously for treatment of hyperkalemia, as its sideeffects can be significant. Compared to SPS, novel potassium-binding substances seem more promising. ZS-9 has been shown to reduce potassium levels and maintain normokalemia during 28 days of follow-up with no serious adverse events. Long-term efficacy and safety is currently unknown, as well as the effect of ZS-9 on uptitration of RAAS-inhibitors and whether ZS-9 therapy may allow greater tolerability of RAAS-inhibitor therapy in chronic HF patients. Patiromer has the ability to reduce potassium level and allows treating HF patients with higher spironolactone doses compared to placebo. In contrast to ZS-9, the long-term (1-year) safety and efficacy of patiromer have been demonstrated in patients with type 2 diabetes. It should, however, be taken into account that patiromer also binds several drugs, aside from solely binding to potassium. This might have substantial influence on the dosage regimens of other drugs, as these drugs have to be administered at least 6 hours before or after patiromer. Sideeffects of both ZS-9 and patiromer are generally mild and include gastrointestinal disorders. It is however worth noting that ZS-9 has been associated with episodes of edema. Such an association has not been reported for patiromer. Although the novel potassium-binding agents seem to be effective and safe for short-term use in chronic HF patients, it is conceivable that potassium-binding agents need to be used chronically in this patient group with high risk of hyperkalemia. Therefore, long-term, randomized, placebo-controlled trials are needed to establish the effectivity of these agents in chronic HF patients receiving RAAS-inhibitors, especially in patients with more severe HF, as current studies mainly included patients with mild HF.

Article highlights

• Heart failure is frequently accompanied by cardiac and non-cardiac comorbidities, which impair prognosis.

• Metformin is widely used in heart failure and is considered safe. Empagliflozin (SGLT2 inhibitor) is currently the only glucose-lowering drug with beneficial effects on cardiovascular mortality.

• In general, treatment of anemia with erythropoiesis-stimulating agents should be avoided in heart failure; new drugs targeting on EPO-regulating pathways are being studied.

• Intravenous iron therapy has beneficial effects on clinical status of heart failure patients with iron deficiency, but the effect on morbidity and mortality are largely unknown. Whether oral iron therapy also has beneficial effects is currently unknown.

• Novel potassium binders significantly lower potassium levels; however their long-term efficacy, safety and effect on RAAS-inhibitor uptitration are currently unclear.

This box summarizes key points contained in the article.

Declaration of interest

P van der Meer has received consultancy and research fees from Vifor Pharma and ZS Pharma. A.A Voors has received consultancy and research fees from Vifor Pharma and ZS Pharma. D.J. van Veldhuisen has received board membership fees/travel expenses from BioControl, Cardiorentis, Johnson & Johnson, Novartis and Vifor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.