Heart failure (HF) is a leading cause of disability worldwide and has a major impact on the global economy and healthcare systems. It is estimated that around 64 million people worldwide live with HF and about half will die within 5 years of disease diagnosis. HF is a major cause of hospitalizations in patients aged 65 and above. The severity of the disease warrants the development of innovative solutions to address the current treatment gap.
Based on left ventricular ejection fraction, HF is classified as HF with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF). Sodium-glucose transport protein 2 (SGLT-2) inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and renin-angiotensin system inhibitors are the four main therapeutic classes included in guideline-directed medical therapy for HFrEF. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and angiotensin receptor-neprilysin inhibitors (ARNIs) are recommended as first-line agents in HFrEF. SGLT-2 inhibitors, mineralocorticoid receptor antagonists, and ARNIs are recommended (class 2) for HFpEF.
The Paradigm of Heart Failure Therapy has Evolved Considerably Over the Past Decades
Therapeutic approaches in the 1970s focused on the empirical management of HF involving the relief of symptoms such as edema and dyspnea. The effect of hemodynamics on HF progression was unknown at that time. The Vasodilator in Heart Failure Trial (V-HeFT) was the first study to demonstrate the role of hemodynamics in HF progression. The study, published in 1986, showed that vasodilators such as hydralazine and isosorbide dinitrate can reduce mortality outcomes in patients with chronic HF. However, these effects on mortality were not observed with other vasodilators such as prazosin, prompting that additional mechanisms are involved in HF progression.
The Studies of Left Ventricular Dysfunction (SOLVD) biomarker study and other similar studies shifted the focus of HF therapy from hemodynamic to neurohormonal modulation. The SOLVD biomarker study found that neurohumoral activation precedes the development of HF symptoms. In 1987, the COoperative North Scandinavian ENalapril SUrvival (CONSENSUS) study found a beneficial effect on mortality with angiotensin-converting enzyme (ACE) inhibitor enalapril.
Further research in HF found the beneficial effects of beta-blockers in decreasing morbidity and mortality. More recent developments in the treatment landscape involve the use of ARNI and SGLT-2 inhibitors.
Current Market Leaders
Entresto (Sacubitril and Valsartan) - Novartis
A combination of sacubitril and valsartan, Novartis' blockbuster Entresto was first approved by the US Food and Drug Administration (FDA) to treat HFrEF in July 2015. It is also approved to treat symptomatic HF with systemic left ventricular systolic dysfunction in pediatric patients. In February 2021, Entresto was FDA-approved to treat patients with HFpEF, a form of HF that has very limited treatment options. Entresto, a major growth driver for Novartis, made $4.64bn in sales in 2022. However, the blockbuster drug is set to face generic competition in the coming years with several of its patents expiring in the next few years.
Jardiance (Empagliflozin) - Boehringer Ingelheim/Eli Lilly
Jardiance (empagliflozin) is an SGLT-2 inhibitor that was initially approved for type 2 diabetes. In 2021, Jardiance was FDA-approved to reduce the risk of cardiovascular death plus hospitalisation for HF in adults with HFrEF. In 2022, the FDA approved Jardiance to treat adults with HFpEF. As per Boehringer Ingelheim, Jardiance generated 5.8 billion euros ($6.1 billion) of sales in 2022. Apart from type 2 diabetes and HF, Jardiance is also approved for chronic kidney disease.
Verquvo (Vericiguat) - Bayer / Merck Sharp & Dohme’s
Verquvo (vericiguat), from Merck and Bayer, won FDA approval in January 2021 for HFrEF patients. The drug is proven to significantly reduce the risk of cardiovascular death or hospitalization due to HFrEF in patients who have had a recent worsening HF event. Vericiguat is a soluble guanylate cyclase (sGC)-stimulator that restores...
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