Targeting Obesity and Diabetes to Treat Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes. Thus, pharmacological strategies to supplement nitric oxide and subsequent cyclic guanosine monophosphate (cGMP)—protein kinase G (PKG) signaling may have therapeutic promise. Other potential approaches include exercise and lifestyle modifications, as well as targeting endothelial cell mineralocorticoid receptors, non-coding RNAs, sodium glucose transporter 2 inhibitors, and enhancers of natriuretic peptide protective NO-independent cGMP-initiated and alternative signaling, such as LCZ696 and phosphodiesterase-9 inhibitors. Additionally, understanding the role of adipokines in HFpEF may lead to new treatments. Identifying novel drug targets based on the shared underlying microvascular disease process may improve the quality of life and lifespan of those afflicted with both HFpEF and obesity or diabetes, or even prevent its occurrence.

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

“…70,71 However, these deleterious effects may not be relevant to patients with type 2 diabetes, who are prone to the development of HFpEF rather than HFrEF. 17 accurately inform our understanding of their actions in patients with established HFrEF; the converse is also true. A similar cautionary note applies to our efforts to understand the effects of other antihyperglycaemic drugs, such as sodium-glucose co-transporter 2 (SGLT2) inhibitors.…”

“…Most of the patients who were enrolled in the large‐scale trials of statins had evidence of dyslipidaemia, obesity and type 2 diabetes, often with known vascular disease. These patients are at heightened risk of developing heart failure, but the most common phenotype in these individuals is heart failure with a preserved ejection fraction (HFpEF) . What action of statins is relevant to these patients?…”

Pharmacological Management of a Heart Failure Patient with Severe Obesity

“…Obesity is one of the commonest comorbidities in HF patients and is associated with increased mortality risk [5,6,7]. However, obese patients are often underrepresented in clinical trials and therefore evidence on their management remains scant.…”

“…It is widely accepted that obesity represents a common comorbidity in HF patients, with either preserved or reduced ejection fraction [5,6]. Notably, this factor is associated with increased mortality in HF patients, as well as with a number of other comorbidities [7].…”

Do sodium‐glucose co‐transporter‐2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis

“…Any hypothesis to explain the benefit of SGLT2 inhibitors for heart failure should consider their potential to ameliorate a specific phenotype of heart failure, namely, heart failure with a preserved ejection fraction (HFpEF). Although the trials with empagliflozin and canagliflozin did not characterize the phenotype of heart failure, obesity‐related HFpEF is the most frequent presentation of heart failure in type 2 diabetes . Obesity‐related HFpEF is characterized by sodium retention and plasma volume expansion; yet, the ventricles are only modestly enlarged because of an impairment in cardiac distensibility that is related to fibrosis .…”