Finerenone Proves Beneficial for Heart Failure with Preserved Ejection Fraction

Life is like riding a bicycle. To keep your balance, you must keep moving

Albert Einstein

We welcome the results of the FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) trial, which were recently presented at the 2024 Congress of the European Society of Cardiology (ESC), and simultaneously published in the New England Journal of Medicine.¹ In this double-blind, international trial, 6,001 patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) of at least 40% were randomly assigned to receive placebo or finerenone, in addition to usual therapy, with a starting dose of 20 mg once daily, and a maintenance dose of 40 mg once daily, unless there was evidence of renal dysfunction, in which case dosages were reduced to, respectively, 10 and 20 mg. Over a median follow-up of 32 months, finerenone reduced by 16% the primary endpoint of worsening HF events (unplanned hospitalization or urgent visit for HF) and death from cardiovascular causes, compared to placebo (rate ratio, 0.84; 95% confidence interval: 0.74 to 0.95; P=0.007). It should be noted that such benefit was driven mainly by a reduction in HF events, while there was no significant effect on cardiovascular death.

In the trial, finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. However, the number of hospitalizations due to hyperkalemia was low in both the finerenone and placebo groups and no episodes resulted in death. Results from the North American cohort of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial leveraging spironolactone, an older steroidal mineralocorticoid receptor antagonist (MRA), previously indicated that it was clinically beneficial.² Notably, finerenone is associated with a lower occurrence of hyperkalemia than spironolactone. Moreover, in FINEARTS-HF, hypokalemia was less common with finerenone than with placebo.

Finerenone is a novel third-generation nonsteroidal, selective MRA, which along with sodium-glucose co-transporter-2 (SGLT2) inhibitors, was recently recommended for prevention of HF in patients with diabetic chronic kidney disease (CKD).³ SGLT2 inhibitors had been recommended for the treatment of all forms of HF regardless of a reduction in LVEF and thus SGLT2 inhibitors and finerenone have been proven effective for treating HF with preserved ejection fraction (HFpEF).

As with SGLT2 inhibitors, the mechanism behind the beneficial actions of MRAs, finerenone in particular, remains enigmatic. Finerenone has diuretic and blood pressure lowering actions. But drugs that target those parameters have not shown consistently efficacy towards HFpEF. Rather, finerenone is likely acting by direct rapid non-genomic and slower genomic means on pathological remodeling effects of mineralocorticoids on the parenchyma of the kidney, vasculature, and heart.⁴ This drug may also protect against organ damage by attenuating inflammation and fibrosis,⁵ likely impacting on the inflammasome and autophagosome,⁶ and some of its benefit might arise also from actions on adipose tissue.⁷

During the same ESC Congress, important evidence on the use of a another new class of drug known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of HFpEF patients was presented and simultaneously published in The Lancet.⁸ Specifically, the evidence was from a pooled analysis of four randomized, placebo-controlled trials (SELECT [Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity], FLOW [Evaluate Renal Function with Semaglutide Once Weekly], STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF], and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity and HFpEF in Diabetes Mellitus]) comparing once-weekly subcutaneous semaglutide versus placebo in patients with obesity-related HFpEF, with or without type 2 diabetes mellitus (i.e. an individual-patient meta-analysis) Such work found that semaglutide reduced by 31% the incidence of the combined endpoint of cardiovascular death or HF events.

In conclusion, significant progress has been made in the treatment of HFpEF patients in recent years,⁹ especially considering that no specific medications were recommended for these patients in the relatively recent 2021 ESC Guidelines on Heart Failure.¹⁰ Since then, three different classes of drugs have been shown to be effective. Importantly, the combined effectiveness of SGLT2 inhibitors, GLP-1 RAs, and MRAs in treating HFpEF suggests that their combination, even in a polypill framework, possibly with the adjunct of angiotensin-neprilysin inhibitors (ARNI), may offer greater benefits than using these drugs individually (Figure 1).^11-12 This holds even truer given major developments in this field, such as the development of amycretin, single molecule that operates as a GLP-1 RA as well as amylin receptor agonist.¹³

Figure 1.

Pharmacologic treatments with established (in standard type) or probable (in italic type) benefit for patients with heart failure with preserved ejection fraction (HFpEF). ARNI=Angiotensin receptor-neprilysin inhibitor; GLP-1 RA=glucagon-like peptide-1 receptor agonist; MRA=mineralocorticoid receptor antagonist; SGLT2=Sodium glucose co-transporter-2.