Finerenone and semaglutide: Role in heart failure with reduced ejection fraction

Abstract

Obesity and type 2 diabetes mellitus commonly coexist with heart failure (HF) and may contribute to the pathogenesis of HF with preserved ejection fraction. With progression in management therapies for HF with preserved ejection fraction, the mechanism behind beneficial actions of finerenone and semaglutide remains enigmatic. For decades, the cardiorenal protective effects of aldosterone blockage in patients with chronic kidney disease have been of significant interest. But due to multiple side effects, these trials were likely to stop.

Key Words: Mineralocorticoid receptor antagonist; Finerenone; Semaglutide; Polypill framework; Antifibrotic; Glucagon-like peptide 1; Heart failure

Core Tip: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, acts by reducing pathologic remodeling effects on the heart and kidney while semaglutide improves glycemic control and improves lipid metabolism thereby regulating cardioprotective functions. The combination of finerenone and semaglutide reduces albuminuria and inhibits proinflammatory gene expression, preventing organ damage by mitigating fibrosis and inflammation and reducing obesity-related cardiac remodeling. It has also shown beneficial effects on heart failure with preserved ejection fraction by reducing preload and afterload, thereby improving left ventricular function.

TO THE EDITOR

Finerenone is a selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), structurally derived from a naphthalene backbone and engineered using a dihydropyridine framework. It exhibits high binding affinity and exceptional selectivity for the mineralocorticoid receptor (MR) over other steroid hormone receptors, effectively eliminating anti-androgenic and progestogenic effects. Finerenone has a relatively short plasma half-life of approximately 2-3 hours. Upon binding to the MR ligand-binding domain, it induces a specific conformational rearrangement, particularly the projection of Helix 12, leading to an unstable receptor-ligand complex and inhibition of transcriptional coregulator recruitment[1]. This mechanism underlies its capacity to attenuate the deleterious genomic and non-genomic actions of mineralocorticoids on both renal and cardiac tissues[2].

Semaglutide, a glucagon-like peptide-1 receptor agonist composed of a 31-amino acid sequence, functions by promoting weight loss and improving glycemic control. It modulates glucose-dependent insulin and glucagon secretion, delays gastric emptying, promotes early satiety, and enhances lipid metabolism and energy expenditure[3]. Semaglutide significantly mitigates major cardiovascular complications in individuals with type 2 diabetes mellitus (T2DM) and obesity.

RECENT ADVANCES IN THE TREATMENT OF HEART FAILURE

Recent advances in the treatment of heart failure (HF) have led to revised clinical guidelines endorsing the use of finerenone and semaglutide for the prevention of HF and chronic kidney disease (CKD) in patients with diabetes. This therapeutic combination offers multiple advantages over conventional pharmacotherapies, including the reduction of fibrosis and inflammation, thereby improving end-organ outcomes[4]. Notably, studies have shown that finerenone exhibits superior antifibrotic, antiproliferative, and anti-inflammatory effects compared to equinatriuretic doses of eplerenone, particularly in the regression of cardiac and renal remodeling[5]. In preclinical models of cardiac fibrosis, finerenone has demonstrated significant benefits by reversing left ventricular hypertrophy, reducing albuminuria, and downregulating biomarkers of inflammation and fibrosis[6].

In clinical trials, finerenone significantly improved cardiovascular outcomes and decreased albuminuria in patients with T2DM and CKD with moderately elevated albuminuria, likely through the downregulation of renal proinflammatory gene expression[7]. Similarly, semaglutide has shown efficacy in reducing obesity-related cardiac remodeling and improving cardiac structure and function in patients with HF with preserved ejection fraction (HFpEF) associated with obesity. These benefits may result from reductions in both preload and afterload, decreased left ventricular wall stress, and facilitation of beneficial cardiac remodeling[8].

Obesity and T2DM frequently coexist with HF and are key contributors to the pathophysiology of HFpEF. Although the precise mechanisms underlying the cardioprotective effects of finerenone and semaglutide remain under investigation, the historical challenge of balancing aldosterone blockade with side effect profiles has limited the clinical utility of earlier MRAs[9]. Finerenone and semaglutide, however, have demonstrated robust therapeutic effects with improved tolerability and safety.

Emerging evidence suggests that a polypill strategy - combining sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and MRAs, possibly in conjunction with angiotensin receptor-neprilysin inhibitors - may offer synergistic benefits in treating HFpEF and CKD, surpassing the efficacy of monotherapy[10]. This approach appears particularly promising for patients with concomitant HF and CKD and warrants further exploration through high-quality clinical trials to validate safety, efficacy, and long-term outcomes.

CONCLUSION

The combined use of finerenone and semaglutide has shown promising effects by reducing HF risks in patients with CKD and obesity.