28th July 2025, A/Prof Chee L Khoo
We are all aware of the four pillars of treatment in the guideline directed medical treatment (GDMT) of patients with heart failure with reduced ejection fraction (HFrEF) – SGLT2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI), beta blockers and mineralocorticoid receptor antagonist (MRA). When we come to heart failure with preserved ejection fraction (HRpEF), the pillar of treatment is rather lonely – SGLT2i only. We previously explored the beneficial effects on patients with HFpEF with the non-steroidal MRA, finerenone, in the FINEARTS-HF, semaglutide in the STEP-HFpEF and tirzepatide in the SUMMIT trials. We expect that these classes of agents will eventually make their way into the GDMT for HFpEF. Well, one of them just did.
The Definition
Patients with heart failure with preserved ejection fraction (HFpEF) have symptoms and signs of heart failure, with left ventricular ejection fraction (LVEF) ≥50%, not attributable to an underlying cause such as infiltrative cardiomyopathy, hypertrophic cardiomyopathy, valvular disease, pericardial disease, or high-output heart failure. The American Heart Association/American College of Cardiology/Heart Failure Society of America requires evidence of spontaneous increased LV filling pressures (e.g., elevated natriuretic peptide, non-invasive/invasive haemodynamic measurement) while European Society of Cardiology guidelines requires objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction or raised LV filling pressure, or raised natriuretic peptides.
Pathophysiology
The most common risk factors and comorbidities are hypertension, obesity, chronic kidney disease, diabetes mellitus, and coronary artery disease. Advanced age and female sex are also important risk factors. Sub-optimally controlled hypertension is suggested to be part of the biological pathway to developing HFpEF and implied that all patients with HFpEF have hypertension-induced ventricular hypertrophy and pathological myocardial fibrosis. However, less than 50% of patients with HFpEF meet criteria for ventricular hypertrophy and myocardial fibrosis was shown to be significantly but modestly greater in individuals with HFpEF (than controls (1-3).
The journey through excitements and disappointments
Previous management of heart failure revolves primarily around blood pressure control (with ACE inhibitors), diuretics and beta-blockers. We were all excited when PARADIGM-HF (2013) reported benefit from ARNI (i.e. Entresto) in patients with HFrEF (4). We thought that perhaps, it will be beneficial in patients with HFpEF. The world waited for PARAGON-HF to report similar benefits of ARNI in patients with HFpEF which did not report till 2019 (5).
In the meantime, TOPCAT (2014) reported amidst great expectations that spironolactone will be beneficial as we have seen in HFrEF (6). To great disappointment, unfortunately it failed to demonstrate benefit. When EMPA-REG reported in 2015, we were excited again. Empagliflozin was very beneficial in reducing hospitalisation for heart failure in patients with HFrEF. We are still unsure the mechanisms of the benefit of SLGT2 inhibitors in these patients (7). It wasn’t till 2021 and 2022 when DELIVER and EMPEROR-PRESERVED reported the benefits of dapagliflozin and empagliflozin in HFpEF (8,9).
The world was excited as this was the first class of agents that have been shown to be beneficial in HFpEF. We had some inkling that finerenone may be beneficial in patients with HFpEF when FIGARO-DKD (2021) reported improved cardiovascular outcomes in patients with T2D and CKD with microalbuminuria (10). Much of the improvements came from improvement in hospitalisation for heart failure.
In the meantime, a sub-analysis of TOPHAT trial reviewed regional differences in the results (11). All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone.
In the STEP-HFpEF trial (September 2023), 2.4mg semaglutide (i.e. Wegovy 2.4mg) led to larger reductions in heart failure–related symptoms and physical limitations (as measured with the KCCQ-CSS) and a greater degree of weight loss than placebo at 52 weeks. In addition, semaglutide increased the 6-minute walk distance and reduced CRP to a greater extent than placebo. Note that the primary outcomes were not hard cardiovascular outcomes.
FINEARTS-HF reported the following year (September 2024). In patients with HFpEF, finerenone significantly reduce the primary outcomes by 16% and significantly reduce total number of worsening heart failure by 18%. Only 50% of participants had diabetes. It was only a matter of time before finerenone would be recommended to be the second pillar in the fight against HFpEF. Indeed a fortnight ago, the US FDA has expanded the indications of finerenone to include patients with heart failure with a left ventricular ejection fraction (LVEF) of at least 40%. This is now the second pillar in the GDMT for HFpEF.
In the meantime, in November 2024, the SUMMIT trial reported tirzepatide 15mg led to 38% reduction in the primary composite end point was death from cardiovascular causes or a worsening heart-failure event over a median duration of 104 weeks. Now, compared with the STEP-HFpEF trial, these are hard cardiovascular outcomes.
Summary
We now have at least one class of agents which has been shown to reduce cardiovascular events in patients with HFpEF. That is the SGLT2i. The second is almost here. This is the non-steroidal MRA, finerenone. It will be sometime before it gets onto the PBS for HFpEF. In the meantime, we could use the other MRA, spironolactone as the sub-analysis of the TOPHAT trial suggest that it might be beneficial in HFpEF.
Further, if you have a patient with diabetes and CKD with severe microalbuminuria, they may qualify for finerenone with the CKD indication. If there is suspicion that there is heart failure, you could organise an NT-proBNP to confirm heart failure. The FIGARO-DKD and FINEARTS-HF trial suggests that finerenone might be very beneficial in these patients and they qualify under the PBS.
With the convincing data from the SUMMIT, the third agent for HFpEF is coming soon.
References:
1. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115(15):1982-1990
2. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131(6):550-559
3. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350(19):1953-1959
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6. Pitt B, Pfeffer MA, Assmann SF, et al. TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92.
7. Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.
8. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction [published online August 27, 2022]. N Engl J Med
9. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61.
10. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, Joseph A, Kolkhof P, Nowack C, Schloemer P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252–2263
11. Pfeffer MA, Claggett B, Assmann SF et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015 Jan 6;131(1):34-42
12. https://www.bayer.com/en/us/news-stories/fda-approves-kerendia Accessed 27th July 2025