Author + information
- Received October 22, 2018
- Revision received November 9, 2018
- Accepted November 13, 2018
- Published online February 4, 2019.
- Kelly McHugh, BAa,
- Adam D. DeVore, MD, MHSa,b,
- Jingjing Wu, MSb,
- Roland A. Matsouaka, PhDb,
- Gregg C. Fonarow, MDc,
- Paul A. Heidenreich, MDd,e,
- Clyde W. Yancy, MD, MScf,
- Jennifer B. Green, MDg,h,
- Natasha Altman, MDi and
- Adrian F. Hernandez, MD, MHSa,b,∗ (, )@texhern
- aDepartment of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
- bDepartment of Medicine, Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
- cDepartment of Medicine, Division of Cardiology, Ahmanson–UCLA Cardiomyopathy Center, Ronald Reagan–UCLA Medical Center, Los Angeles, California
- dVeterans Affairs Palo Alto Health Care System, Palo Alto, California
- eDepartment of Medicine, Division of Cardiology, Stanford University, Stanford, California
- fDepartment of Medicine, Division of Cardiology, Northwestern Feinberg School of Medicine, Chicago, Illinois
- gDepartment of Medicine, Division of Endocrinology, Duke University School of Medicine, Durham, North Carolina
- hDepartment of Medicine, Division of Endocrinology, Duke Clinical Research Institute, Durham, North Carolina
- iDepartment of Medicine, Division of Cardiology, University of Colorado-Denver, Aurora, Colorado
- ↵∗Address for correspondence:
Dr. Adrian F. Hernandez, 200 Trent Drive, Davison Building, Suite 120, P.O. Box 17969, Duke University School of Medicine, Durham, North Carolina 27710.
Heart failure with preserved ejection fraction (HFpEF) is now the most common form of HF, affecting over 3 million adults in the United States alone. HFpEF is a heterogenous syndrome. One important phenotype may be related to comorbid conditions, including diabetes mellitus (DM). DM has a prevalence of approximately 45% in HFpEF, but characteristics and outcomes of this population are poorly understood. In this review, the authors summarize data from several clinical trials of HFpEF therapeutics and provide original data from a large cohort using the Get With The Guidelines-HF registry, which together suggest that DM is associated with increased morbidity and long-term mortality in HFpEF. The authors then discuss several common pathological mechanisms in HFpEF and DM, including sodium retention, metabolic derangements, impaired skeletal muscle function, and potential therapeutic targets. As the understanding of comorbid HFpEF and DM improves, it is hoped clinicians will be better equipped to offer effective, patient-centered treatments.
Approximately 6.5 million Americans have heart failure (HF), and the prevalence is expected to rise by 46% by 2030 (1). Heart failure with preserved ejection fraction (HFpEF) is now the most common type of HF and is characterized by the HF syndrome and a normal or near-normal left ventricular ejection fraction (LVEF). At the same time, there is growing recognition that HFpEF may not be one disease entity. Instead, it is likely a heterogenous syndrome of multiple discrete phenotypes (2–4). One important phenotype may be related to underlying comorbid conditions. Understanding and targeting the pathological processes that contribute to these phenotypes may have greater benefit than targeting the final pathway of cardiac dysfunction alone.
Diabetes mellitus (DM) is a common comorbidity in HF and has a significant negative impact on prognosis. Approximately 30.3 million Americans have DM, 84.1 million have pre-diabetes, and the prevalence of DM is expected to rise by 54% by 2030 (5,6). Importantly, about 45% of patients with HFpEF have DM, and the prevalence of comorbid DM is increasing most significantly in those with new-onset HFpEF (7). DM has received increasing attention among the HF community both due to the negative prognostic effect of DM observed in HF with reduced ejection fraction (HFrEF), as well as results of clinical trials that have shown both beneficial and detrimental effects of antihyperglycemic medications on HF outcomes. However, data from clinical practice regarding characteristics and outcomes of patients with HFpEF and DM are limited. There is a need to understand the clinical characteristics and outcomes of patients with HFpEF and DM in order to guide therapeutic decision making, highlight potential phenotype-specific targets, and aid in the development of risk stratification tools. In this Review Topic of the Week, we provide an overview of the current paradigm of HFpEF. We summarize data from several clinical trials that examined the effect of DM in HFpEF and provide previously unpublished data from a large cohort of HFpEF patients with and without DM in the Get With The Guidelines (GWTG)-HF registry. Finally, we discuss several important potential pathophysiological mechanisms in patients with HFpEF and DM (Central Illustration) and possible therapeutic targets.
Heart Failure with Preserved Ejection Fraction
Data from registry and community-based studies demonstrate that patients with HFpEF are more often older, female, and more likely to have multiple comorbidities, including hypertension, diabetes, pulmonary disease, chronic kidney disease, and obesity (8,9). Outcomes in HFpEF are unfortunately poor and comparable to those of HFrEF, with 1-year mortality ranging between 10% and 30% (10). A study by Cheng et al. (9) using data from the GWTG-HF registry found no difference in 1-year mortality between HFrEF and HFpEF, and whereas HFrEF patients had higher rates of HF readmission, HFpEF patients had higher rates of all-cause readmission. Mortality due to noncardiovascular causes is higher in HFpEF than HFrEF, likely due to the increased comorbidity burden (9). Sudden death accounts for around 20% of total mortality in recent HFpEF studies and is predicted by male sex and insulin-treated DM (11). In addition, although the mortality rate for HFrEF has decreased in the past 15 years, it has stayed the same in HFpEF, likely due to the paucity of evidence-based treatments for HFpEF compared with HFrEF (1).
Over the past 2 decades, significant advancements have been made in the treatment of HFrEF, primarily through targeting neurohumoral activation. Although angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have shown mortality benefits in HFrEF, the same cannot be said in HFpEF, and no trial has achieved morbidity/mortality endpoints to date (4). There is an urgent need to develop novel treatment approaches for patients with HFpEF. Importantly, the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure and Preserved Left Ventricular Ejection Fraction) trial has now completed enrollment. A comparison of the baseline characteristics of the PARAGON-HF trial showed that whereas enrollees had a similar age and sex distribution compared with previous HFpEF trials, they had a higher prevalence of comorbidities, including DM and chronic kidney disease, when compared with other HFpEF trial enrollees (12).
Once thought to be a disease primarily of diastolic dysfunction, it is now recognized that there are multiple derangements in HFpEF, including, but not limited to, impaired diastolic and systolic reserve, atrial function, autonomic tone, and peripheral mechanisms such as endothelial and skeletal muscle function (4,13). Biomarker profiles of HFpEF also support a proinflammatory phenotype, as opposed to markers of cardiac stretch that predominate in HFrEF (14). However, given the diversity of functional and structural impairments in HFpEF, a variety of mechanistic pathways with differing effects likely contribute to the overall pathophysiology. The phenotypic heterogeneity of HFpEF is increasingly recognized, and a paradigm of HFpEF supporting comorbidity-driven inflammation leading to systemic and cardiac microvascular dysfunction has been proposed (3,14,15). Accordingly, there is a growing interest in the need for phenotypic-specific treatments. Because DM has a high prevalence in HFpEF and is known to affect multiple organ systems, the characteristics and outcomes of those with comorbid HFpEF and DM deserves further evaluation.
HFpEF and Comorbid DM
DM is associated with an increased risk of morbidity and mortality in patients with chronic HFrEF, and whereas clinical trial data suggest that the negative prognostic association with DM may be greater in HFpEF than in HFrEF, data from clinical practice regarding HFpEF and DM were previously limited (16,17).
Clinical Trial Data
Data from 4 large clinical trials of HFpEF patients have been used to evaluate the prognostic impact of DM. We focused on studies with definitive LVEF criteria, as well as those that described clinical features and outcomes of those with HFpEF and DM. Key findings are summarized in Table 1. Together, these data suggest DM is associated with worse morbidity and mortality in HFpEF.
The CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) trial followed 3,023 patients with LVEF >40% for a mean follow-up period of 37.7 months. Patients with DM had more signs and symptoms of volume overload, worse functional status, higher body mass index (BMI), and higher rates of hypertension, ischemic heart disease, and worse renal function compared with those without DM. DM was associated with a 2-fold increase in cardiovascular death or HF hospitalization, as well as an increase in all-cause mortality. The study also examined the effect of DM in patients with low LVEF (<40%), and found that the association of DM with cardiovascular mortality and HF readmissions was greater in HFpEF than those with low LVEF (17). Of note, at the time of the study, patients with LVEF between 40% and 49% were included in the HFpEF group. However, HF with LVEF 40% to 49% is now recognized as HF with mid-range ejection fraction, and recent studies show that patients with HF with mid-range ejection fraction may be more similar in characteristics to HFrEF than HFpEF (18).
The DIG (Digitalis Investigation Group) trial followed 987 patients with LVEF >45% for 37 months. Patients with DM had higher BMI and higher rates of congestion and peripheral edema, and were more likely to be younger, women, and to have a history of hypertension and ischemic heart disease. DM was associated with a 68% increased risk of HF hospitalization or HF death, as well as increased hazard of total mortality (19).
The I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial included 4,128 patients with LVEF ≥45% for 4.1 years. Patients with DM were younger, had higher BMI, more signs of volume overload, worse quality of life, and higher levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Detailed echocardiography data were obtained for 745 patients. Although the data were incomplete, patients with DM had larger end-systolic and end-diastolic dimensions, left ventricular mass, and left atrial area. There were no significant differences in left ventricular systolic function, but E/e′ ratios were higher in patients with DM. DM was associated with increased hazard of the composite outcome of cardiovascular death or HF hospitalization, as well as all-cause mortality (20).
The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial followed 216 patients with LVEF ≥50% for 6 months. Patients with DM were younger, more obese, male, and had higher proportion of hypertension, vascular disease, ischemic heart disease, obstructive lung disease, and renal disease. Biomarker analysis revealed patients with DM had similar levels of NT-proBNP compared with those without DM, but had higher levels of the vasoconstrictor, endothelin-1, inflammatory markers, c-reactive protein and uric acid, and profibrotic markers, galectin-3 and carboxy-terminal telopeptide of collagen type 1. Echocardiographic data showed that patients with DM had increased E/e′ ratios, but no differences in other measures of systolic or diastolic function. Patients with DM had increased left ventricular mass, but no differences in left ventricular volume or wall thickness. Exercise testing showed that patients with DM had lower peak Vo2, shorter 6-min walk distances, and higher rates of chronotropic incompetence. Patients with DM were more likely to be hospitalized for cardiac or renal causes at 6 months (21).
Clinical trial data suggest that DM in HFpEF is associated with multimorbidity, poor functional status and exercise capacity, increased markers of inflammation, fibrosis, and endothelial dysfunction, worse congestion, higher left ventricular filling pressures, and increased mortality and HF admissions. Although these data are valuable, clinical trials include a highly specific population, and the capacity for enrollment is relatively small compared with retrospective studies. For this reason, the authors conducted a retrospective analysis of a large cohort of patients with HFpEF with and without DM using the GWTG-HF registry to further characterize this population.
HFpEF With and Without DM: Findings from the GWTG-HF Registry
The GWTG-HF registry is a national, hospital-based, quality improvement initiative launched by the American Heart Association in 2005, which has been previously described (22,23). With over a decade of data from HF admissions, GWTG-HF is the largest contemporary registry of HF patients and has contributed to improvements in HF management across the country, making it a robust data source for our analysis. We conducted a retrospective cohort study of 232,656 patients with HFpEF (ejection fraction >50%) hospitalized for new or worsening HF in the GWTG-HF registry between 2006 and 2017, of which 62,402 patients were linked with Medicare claims for analysis of post-discharge outcomes (Online Figure 1). We compared baseline characteristics, in-hospital, and 30-day post-discharge outcomes in those with and without DM. Short-term outcomes of interest included in-hospital mortality, length of hospital stay (<4 or ≥4 days), and discharge destination (home vs. hospice, skilled nursing facility, etc.). Post-discharge outcomes included 30-day mortality, 30-day all-cause readmission, and 30-day HF readmission. (See the Online Appendix for the full Methods.)
Patients with HFpEF and DM were more likely to be younger, male, and nonwhite, and to have higher rates of the following comorbidities: hypertension, hyperlipidemia, chronic obstructive pulmonary disease/asthma, cerebrovascular accident/transient ischemic attack, peripheral vascular disease, ischemic history, prior heart failure, renal insufficiency, anemia, and depression. Patients with DM had higher systolic blood pressure, weight, and body mass index on admission and discharge, but lower B-type natriuretic peptide (BNP) levels compared with those without DM (Online Table 1).
Although patients with DM had a lower rate of in-hospital mortality compared with those without DM (2.1% vs. 2.8%), in adjusted analysis, DM was not independently associated with in-hospital mortality (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 0.99 to 1.11) (Table 2). DM was associated with significantly longer length of stay (OR: 1.27; 95% CI: 1.23 to 1.31) and significantly lower likelihood of discharge home (OR: 0.83; 95% CI: 0.81 to 0.86). Patients with DM had a lower 30-day mortality rate than those without DM (4.8% vs. 6.2%; p < 0.0001), but in adjusted analysis, DM was not independently associated with 30-day mortality (HR: 1.03; 95% CI: 0.95 to 1.11) (Table 3). DM was associated with a significantly increased likelihood of all-cause 30-day readmission (HR: 1.10; 95% CI: 1.05 to 1.15) and HF readmission (HR: 1.21; 95% CI: 1.12 to 1.31).
We also examined the association of BNP levels and in-hospital outcomes in those with and without DM. In adjusted analysis, increasing quartiles of BNP were associated with increasing risk of in-hospital mortality, longer length of stay, and lower likelihood of discharge home. However, a significant interaction between BNP and DM status was observed, such that the effect of elevated BNP on in-hospital mortality and length of stay was less in those with DM (Online Figure 2).
In this large retrospective study, we observed a significant increase in in-hospital and post-discharge morbidity associated with DM among HFpEF patients. These findings highlight a critical need for treatment and management strategies for HFpEF and DM, in order to improve quality of life and reduce resource utilization. Despite clinical trial data that showed an increase in mortality associated with DM, both in-hospital and 30-day mortality were not significantly affected by DM. The differential associations of DM with short-term morbidity and mortality may reflect 2 distinct mechanisms associated with DM in HFpEF. Faster-acting hemodynamic mechanisms may contribute to volume overload and manifest both in the hospital and shortly after discharge. Slower-acting remodeling mechanisms may drive increased mortality, but not yet become evident at 30 days. In the following text, we further discuss these and other possible pathophysiological mechanisms of comorbid HFpEF and DM.
Potential Mechanisms and Therapeutic Targets
Although definitive pathophysiological mechanisms of DM in HFpEF have yet to be elucidated, on the basis of the collective data from clinical trials and the GWTG-HF cohort, we propose several potential mechanisms and how we might target these processes to improve outcomes.
Sodium Retention and Volume Overload
Volume overload and congestion remain common reasons for HF hospitalizations. Patients with DM have increased neurohumoral activation and alterations in sodium handling, which may predispose to congestion, cardiorenal syndrome, and decreased diuretic responsiveness. Hyperglycemia in the setting of DM causes up-regulation of the sodium-glucose cotransporter-2 leading to increased proximal renal sodium absorption, volume expansion, and decreased responsiveness of diuretics (24). Evidence also supports a positive correlation between the metabolic syndrome and excess sympathetic and renin-angiotensin system activation (25).
In the CHARM, DIG, and I-PRESERVE trials, patients with DM had more signs of congestion. Although volume status was not directly analyzed in the GWTG-HF study, patients with HFpEF and DM had higher frequencies of mechanical ventilation and dialysis/ultrafiltration and worse renal function, which may suggest worse volume overload. Increased volume on admission and poor diuretic response may contribute to the longer length of stay observed in those with DM, and inadequate diuresis at discharge may explain the increase in HF readmissions at 30 days. Despite likely greater volume overload in those with DM, the association of BNP and NT-proBNP, markers of volume overload, and DM in patients with HFpEF has been inconsistent across studies. Differences in LVEF inclusion criteria may explain the heterogeneity of results, because natriuretic peptides have been shown to rise less in HFpEF than in HFrEF (15). The attenuation of the association with BNP and worse in-hospital outcomes in the GWTG-HF study may be because comorbidities or other clinical factors in patients with DM may affect length of stay to a greater degree than BNP.
Therapies targeting sympathetic and renin-angiotensin system activation have not shown mortality benefit in HFpEF. However, these therapies may have preferential benefits in those with DM, and studies in the subpopulation of patients with HFpEF and DM deserve further consideration. By contrast, recent outcomes trials of sodium-glucose cotransporter-2 inhibitors have shown promising effects on HF outcomes in those with HF and DM. In the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, empagliflozin was associated, not only with a reduction in major adverse cardiovascular endpoints, but also with a significant reduction in HF hospitalizations (26). By restoring sodium delivery to the distal tubule, sodium-glucose cotransporter-2 inhibitors promote diuresis and natriuresis, without sympathetic activation (27). Achieving natriuresis and alleviating volume overload may reduce morbidity in patients with HFpEF and DM. Studies investigating the effects of sodium-glucose cotransporter-2 inhibitors in the HFpEF population are ongoing (Table 4) (4).
Metabolic Derangements and Systemic Inflammation
Despite the proinflammatory nature of HFpEF, therapies targeting inflammation and subsequent endothelial dysfunction, such as statins, renin-angiotensin system inhibitors, and phosphodiesterase-5 inhibitors, have not been found to have long-term benefit in HFpEF (4). Targeting inflammation by a one-size-fits-all manner may not be adequate. Perhaps the pathological processes leading to inflammation and remodeling in DM need to be targeted more specifically. Insulin resistance in DM leads to increased free fatty acid utilization by cardiac myocytes, which may lead to mitochondrial dysfunction, production of toxic lipid intermediates, and increased reactive oxygen species (28). Increased adiposity both in the periphery and in epicardial tissue, more frequently seen in the DM population, also results in the release of proinflammatory cytokines. Hyperglycemia-induced advanced glycation end-products impair microvascular function and decrease nitric oxide availability (28). All of these processes may contribute to structural changes in cardiac myocytes, endothelial dysfunction, and multiorgan damage. Echocardiographic data in the RELAX and I-PRESERVE trials suggest that DM is associated with more severe diastolic dysfunction and left ventricular hypertrophy, and underlying metabolic and inflammatory changes likely account for this phenotype.
One strategy for targeting these derangements may be decreasing adiposity through caloric restriction. This would likely have beneficial effects on risk of ischemia, blood pressure, exercise capacity, responsiveness to insulin and overall inflammation. In addition, several novel antihyperglycemic drugs may have both glucose-lowering and anti-inflammatory and anti-remodeling effects that may improve vascular function and slow multiorgan damage in patients with DM and HFpEF. Glucagon-like peptide-1 receptor agonists are a class of antihyperglycemic agent that has been shown both in vivo and in humans to reduce atherosclerotic burden, inflammation, and endothelial dysfunction (29,30). Although clinical trials of glucagon-like peptide-1 receptor agonists have not shown improvement in HF outcomes, these agents have yet to be studied in the HFpEF population specifically. Sodium-glucose cotransporter-2 inhibitors have also been shown to decrease markers of inflammation, and it is hypothesized that sodium-glucose cotransporter-2 inhibitors may shift cardiac metabolism in favor of ketones, which could reduce oxygen consumption and free radical production (27). Finally, inhibition of neprilysin, an enzyme that breaks down natriuretic peptides, may restore levels of cGMP, leading to increased activation of protein kinase G, which has downstream effects at improving endothelial function and decreasing cardiomyocyte stiffness (2). The use of sacubitril/valsartan, an angiotensin neprilysin inhibitor, in HFpEF will be tested in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, the results of which are eagerly anticipated (2). Proinflammatory processes likely operate on a slower time frame in patients with HFpEF and DM, compared with hemodynamic mechanisms, and studies with long-term follow-up will be needed to assess improvement in mortality with these interventions.
Impairments in the Periphery
Impairments in the periphery, such as poor skeletal muscle function, impaired peripheral oxygen delivery, and chronotropic incompetence, likely contribute to decreased exercise capacity and poor functional status in those with DM and HFpEF. Decreased peak Vo2 and 6-min walk test were observed among those with DM in the RELAX study. Although poor exercise tolerance may relate to increased left ventricular filling pressure, studies have also shown that patients with HFpEF have alterations in skeletal muscle and reduced arterial–venous oxygen difference, the latter of which is due to reduced oxygen delivery or reduced oxygen uptake by skeletal muscle. Decreased vasodilatory deserve, endothelial dysfunction, and anemia may contribute to decreased oxygen delivery (21). Increased infiltration of adipose tissue in skeletal muscle, resulting in decreased capillary density and decreased peak Vo2, may also contribute to muscle weakness and poor exercise tolerance. HFpEF patients have also been shown to have decreased type 1 oxidative skeletal muscle fibers, and increased type 2 glycolytic fibers, leading to decreased oxygen utilization (2). These mechanisms are likely exacerbated in patients with DM, due to increased adiposity. Chronotropic incompetence also impairs the increase in cardiac output during exercise, and is likely due to autonomic neuropathy, a known complication of DM. Although neuropathy may be irreversible, through a graded exercise regimen, skeletal muscle may be regenerated and repaired, potentially improving exercise capacity and quality of life (2). In fact, peak Vo2 has been shown to increase in HFpEF following an exercise training program. This noninvasive treatment option may have benefits in the DM population.
It is well known that HFpEF patients have multiple comorbidities. Clinical trial data and data from the GWTG-HF registry clearly show increased comorbidity burden in the HFpEF population with DM. This is not surprising, because DM is known to increase risk for ischemia, vascular disease, stroke, renal dysfunction, etc. Increased comorbidity burden could explain longer length of stay due to more complicated in-patient treatment, as well as decreased likelihood of discharge home, and increased all-cause readmission observed in the GWTG-HF population. These data underscore the need for team-based, holistic care for patients with HFpEF and DM. Coordination between outpatient cardiologists, endocrinologists, nephrologists, and primary care physicians is necessary. Early follow-up should be arranged at discharge so as to prevent rehospitalizations in this high-risk population. Perhaps multidisciplinary clinics where patients can see multiple providers at 1 visit could improve coordination of care and decrease the burden of multiple physician visits for patients. Future studies categorizing the precise reasons for readmissions and noncardiovascular mortality in HFpEF patients with DM will improve our understanding of the health areas that require the most attention and allow for proper resource allocation.
HF is a global pandemic. Although the GWTG-HF registry and the aforementioned clinical trials were limited to patients in the United States, multiple registries of hospitalized HF patients outside of the United States, including those from Western Europe, Japan, and developing countries in Asia and Eastern Europe, exist (31). Regional variations in comorbidities and standards of living, as well as nutrition, exercise, and genetic predisposition, may lead to differences in characteristics and outcomes of patients with comorbid HFpEF and DM globally. For example, Asia is now the epicenter of the DM epidemic, and Asians develop DM at a lower BMI and younger age compared with the Western population (32). Differential metabolic phenotypes may lead to differences in the interplay between HFpEF and DM. In addition, whereas ischemia is the most common etiology of HF overall, in developing countries, hypertension, valvular abnormalities, and congenital heart disease may be common HF etiologies, possibly lessening the role of DM in the pathogenesis of HFpEF (31). Further research using global HF registries is needed to discern these potential differences.
HFpEF is no longer thought of as a single disease of diastolic dysfunction, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. The burden of comorbid DM in HFpEF is rising, and thus it is necessary to target this population therapeutically. Clinical trial data have shown that patients with DM and HFpEF have greater morbidity and long-term mortality than those without DM. Recent findings from the GWTG-HF registry show that in HFpEF, DM is associated with worse in-hospital and post-discharge morbidity, specifically longer length of stay, decreased likelihood of discharge home, and increased 30-day all-cause and HF readmissions. The short-term morbidity associated with DM may be mediated by sodium retention, neurohumoral activation, and volume overload, and sodium-glucose cotransporter-2 inhibitors may decrease volume overload and reduce readmissions in patients with HFpEF and DM. DM is a driver of systemic inflammation in HFpEF through multiple pathways, including fatty acid oxidation, decreased nitric oxide availability, and advanced glycation end-products, and targeting these derangements through the use of novel antihyperglycemic agents may slow long-term remodeling and improve mortality. A graded exercise regimen may improve peripheral derangements in skeletal muscle oxygen utilization and may improve exercise tolerance and quality of life. Finally, a coordinated effort between a multidisciplinary team of health care providers is necessary to address the multiple comorbidities of HFpEF patients with DM in order to decrease mortality and prevent readmission. Further research is needed to assess long-term outcomes and treatment effects of novel HF and DM therapies in patients with HFpEF and DM.
This work was supported by American Heart Association grant #16SFRN30180010 to Dr. Hernandez. The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF is sponsored, in part, by Amgen Cardiovascular and has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. Dr. DeVore has received research support from Akros Medical, the American Heart Association, Amgen, Bayer, Intra-Cellular Therapies, Luitpold Pharmaceuticals, the National Heart, Lung, and Blood Institute, Novartis, and the Patient-Centered Outcomes Research Institute; and has served as a consultant for Novartis. Dr. Wu is an employee of Cytel. Dr. Fonarow has received research support from the National Institutes of Health; and has served as a consultant for Amgen, Abbott, Janssen, Medtronic, Novartis, and St. Jude Medical. Dr. Yancy serves as chair of the American Heart Association GWTG-Heart Failure Subcommittee. Dr. Green has received research support from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, and Intarcia Therapeutics; and has served as a consultant for AstraZeneca, Merck Sharp & Dohme, Daiichi-Sankyo Company, Boehringer Ingelheim Pharmaceuticals, Sanofi/Regeneron, and Novo Nordisk. Dr. Altman has received research support from the American Heart Association. Dr. Hernandez has received research support from AstraZeneca, GlaxoSmithKline, Luitpold, Merck, and Novartis; and has served as a consultant to Bayer, Boston Scientific, Merck, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Abbreviations and Acronyms
- body mass index
- B-type natriuretic peptide
- confidence interval
- diabetes mellitus
- Get With The Guidelines
- heart failure
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- left ventricular ejection fraction
- N-terminal pro B-type natriuretic peptide
- odds ratio
- Received October 22, 2018.
- Revision received November 9, 2018.
- Accepted November 13, 2018.
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- Central Illustration
- Heart Failure with Preserved Ejection Fraction
- HFpEF and Comorbid DM
- Clinical Trial Data
- HFpEF With and Without DM: Findings from the GWTG-HF Registry
- Potential Mechanisms and Therapeutic Targets
- Sodium Retention and Volume Overload
- Metabolic Derangements and Systemic Inflammation
- Impairments in the Periphery
- Global Perspectives