SGLT2 Inhibitors for Heart Failure with Preserved Ejection Fraction

March 6, 2023

By Raymond Barry

Peer Reviewed

A 2020 report published by the American Heart Association (AHA) in conjunction with the National Institutes of Health (NIH) found that an estimated 6.2 million American adults had heart failure between 2013 and 2016, up from 5.7 million between 2009 and 2012.1 Approximately half of patients with heart failure exhibit a reduced ejection (HFrEF), while the other half display a preserved ejection fraction (HFpEF). Patients suffering from HFpEF are older compared to HFrEF, and the proportion of heart failure patients with HFpEF is expected to rise in the currently aging population.1 Thus, developing and establishing evidence-based medical therapies that reduce morbidity and mortality associated with HFpEF is imperative.

Heart failure is a clinical syndrome characterized by a constellation of signs and symptoms including exertional dyspnea, orthopnea, fatigue, pulmonary congestion, hepatomegaly, and lower extremity edema.2 The AHA and American College of Cardiology Foundation (ACCF) categorize patients based on left ventricular ejection fraction (LVEF).2 Patients with an LVEF less than or equal to 40% are designated as HFrEF, those with greater than or equal to 50% as HFpEF, and those with 41% to 49% are said to have a mildly reduced ejection fraction (HFmrEF). Whereas HFrEF is characterized by systolic dysfunction, HFpEF is predominately due to diastolic dysfunction, whereby decreased ventricular compliance leads to impaired ventricular filling and increased diastolic pressures. Consequently, although ejection fraction remains largely normal, stroke volume and overall cardiac output are reduced and unable to meet the metabolic demands of the body. This confluence of effects leads to the clinical manifestations of heart failure in HFpEF patients.

At the structural level, many patients with HFpEF exhibit left ventricular remodeling characterized by concentric myocardial hypertrophy.3 The exact molecular and pathophysiologic mechanisms that ultimately lead to these structural changes are unclear, and it appears that the syndrome of HFpEF may represent a heterogeneous mix of distinct processes. Consistent with this notion, several phenotypes associated with the development of HFpEF have been established, including aging, obesity, hypertension, and myocardial ischemia, and proper medical treatment may depend on the underlying cause.4 Current management recommendations for HFpEF include the use of diuretics for volume overload, maintenance of a systolic blood pressure less than 130 mmHg, and restoration of normal sinus rhythm in patients with atrial fibrillation.2

Unfortunately, identifying additional pharmacologic agents that improve outcomes in patients with HFpEF has proven difficult. Over the past decade, several clinical trials have attempted to identify such a therapy. These include the 2014 Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and the 2019 Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trials, which evaluated the response of patients with HFpEF to mineralocorticoid-receptor antagonists (MRAs) and angiotensin receptor-neprilysin inhibitors (ARNIs), respectively.5,6  The TOPCAT trial randomly assigned 3445 patients with HFpEF to receive spironolactone or placebo and found that spironolactone significantly reduced hospitalizations (hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). The PARAGON-HF trial followed 4822 patients with HFpEF randomly assigned to receive sacubitril-valsartan or valsartan alone and found that subjects treated with sacubitril-valsartan exhibited greater improvement in NYHA class (odds ratio, 1.45; 95% CI, 1.13 to 1.86), reduced decline in renal function (hazard ratio, 0.50; 95% CI, 0.33 to 0.77) and a nearly statistically significant decrease in hospitalizations (rate ratio, 0.85; 95% CI, 0.72 to 1.00). In light of this, the FDA expanded the indication for sacubitril-valsartan (brand name Entresto) to all heart failure patients regardless of ejection fraction.7 Overall, these studies provided promising evidence that MRAs and ARNIs may provide benefit to patients with HFpEF. However, the effects described in these studies were modest, and there was no difference in death from cardiovascular causes. To date, no drug has been definitively shown to reduce morbidity or mortality in HFpEF patients.

The shortcomings in identifying HFpEF treatments lie in sharp contrast to HFrEF, where much progress has been made, likely in part due to the greater abundance of research focused on HFrEF when compared to HFpEF. This is evident based on a query of the PubMed database, which yields 628 randomized controlled trials for HFrEF compared to 352 for HFpEF.8 Paradigms for medical treatment of HFrEF have been established based on the meta-analyses of several positive clinical trials, including PARADIGM-HF, EMPHASIS-HF, EMPEROR-Reduced, and DAPA-HF.9-13 This has led to the development of guideline-directed medical therapy (GDMT) by the AHA that emphasizes the use of four classes of medications that have been shown to provide a survival benefit in patients with HFrEF: 1) beta blockers, 2) ARNI/ACEI/ARBs, 3) mineralocorticoid-receptor antagonists, and 4) sodium–glucose cotransporter 2 (SGLT2) inhibitors.2

SGLT2 inhibitors have also garnered interest in the treatment of patients with HFpEF. SGLT2 inhibitors, such as empagliflozin, target sodium-glucose cotransporters located in the proximal convoluted tubule, reducing reabsorption and increasing excretion of glucose in the urine. They were initially developed for the treatment of diabetes and have been found to reduce all-cause mortality and slow the progression of renal disease in diabetic patients.14 Notably, SGLT2 inhibitors also decrease morbidity and mortality in patients with HFrEF, regardless of diabetes status, as demonstrated in the EMPEROR-Reduced and DAPA-HF trials.10,11 Clinical trials focused on diabetic patients with worsening heart failure have suggested benefits additionally to patients with HFpEF.15 These preliminary data ultimately led up to the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) Trial which sought to test directly whether the SGLT2 inhibitor empagliflozin reduces mortality in HFpEF patients, which would make it the first of its kind.

The EMPEROR-Preserved trial included 5988 patients with symptomatic heart failure (New York Heart Association Class II-IV) with an LVEF greater than 40%.16 Subjects were randomly assigned to receive empagliflozin (10 mg daily) or placebo and were followed over a median period of 26.2 months with a primary composite outcome of hospitalization for heart failure or cardiovascular death. Interestingly, the authors found that empagliflozin significantly reduced this combined risk in patients with HFpEF (hazard ratio, 0.79; 95% CI, 0.69 to 0.90; P<0.001). However, the majority of this effect was due to a reduction in hospitalizations (hazard ratio, 0.71; 95% CI, 0.60 to 0.83), as an analysis of cardiovascular death alone failed to achieve statistical significance (hazard ratio, 0.91; 95% CI, 0.76 to 1.09).

Importantly, the subjects from this study exhibited significant variability in LVEF: one third had an LVEF between 40% and 50%, one third between 50% and 60%, and one third greater than 60%. Subgroup analysis based on LVEF revealed that the patients with a lower LVEF benefitted the most from treatment. For example, patients with LVEF between 40% and 50% exhibited a significant reduction in the primary composite outcome (hazard ratio, 0.71; 95% CI, 0.57 to 0.88) whereas those with a normal LVEF greater than 60% did not (hazard ration, 0.87; 95% CI, 0.69 to 1.10). Arguably, patients with an LVEF between 40% and 50% may be more akin to patients with HFrEF than those with HFpEF, putting into question the potential benefit of empagliflozin in HFpEF patients.

Furthermore, a closer look at the exclusion criteria in the supplemental appendix from this study gives a better idea of the applicability of this therapy to a broader HFpEF patient population. The authors excluded subjects with recent history (< 90 days) of myocardial infarction, coronary artery bypass graft surgery, other major cardiovascular surgery, stroke, or transient ischemic attack. Additionally, patients with a recent episode of acute decompensated heart failure or those with severe valvular disease were excluded. This subpopulation represents a significant number of patients admitted to the hospital with HFpEF. The study also excluded patients listed for heart transplant or patients with implanted left ventricular assist devices or cardiac resynchronization therapy. Also excluded were patients with infiltrative cardiomyopathy (e.g. amyloidosis), muscular dystrophies, stress cardiomyopathy, accumulation diseases (e.g. hemochromatosis), pericardial constriction, or hypertrophic obstructive cardiomyopathy. Altogether, the exclusion of these populations, which represent a significant proportion of patients presenting with HFpEF, limits the broader applicability of the study’s findings.

And so the question remains, should all patients with HFpEF be on an SGLT2 inhibitor? For patients with other comorbid conditions, such as diabetes, empagliflozin is a preferred option. However, for HFpEF patients without comorbidities, especially those with a largely normal LVEF above 60%, there is insufficient evidence to suggest that SGLT2 inhibitors improve outcomes. Additionally, there is no evidence that SGLT2 inhibitors improve survival in patients with HFpEF. Further studies will be needed to determine whether a longer duration of treatment with SGLT2 inhibitors or the use of SGLT2 inhibitors in specific phenotypes of HFpEF patients provides a morbidity or mortality benefit.

Raymond Barry is a 4th-year medical student at NYU Grossman School of Medicine

Reviewed by Michael Tanner, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons: Bruce Blaus, [[File:Ventricular Assist Device (Power Pack).png|Ventricular_Assist_Device_(Power_Pack)]]


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