New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2024

Abstract

Despite substantial advances in cardiovascular pharmacotherapy and devices in recent years, prevention and treatment of many cardiovascular diseases (CVDs) remain limited, thus reflecting the need for more effective and safer pharmacological strategies. In this review, we summarize the most relevant studies in cardiovascular pharmacotherapy in 2024, including the approval of first-in-class drugs for the treatment of resistant hypertension and pulmonary arterial hypertension, label expansions for bempedoic acid and semaglutide, and the results of major randomized clinical trials (RCTs) that have met the pre-specified primary endpoints, thereby filling some gaps in knowledge and opening new perspectives in the management of CVD, and those RCTs whose results did not confirm the proposed research hypotheses. We also include a section on drug safety, where we describe the newest data on adverse reactions and drug-drug interactions that may complicate treatment and/or reduce drug adherence with the consequent decrease in drug effectiveness. Finally, we present the most important ongoing phase 2 and phase 3 clinical trials assessing the efficacy and safety of cardiovascular drugs for the prevention and treatment of CVD.

Keywords: Cardiovascular drugs; Cardiovascular pharmacological strategies; Cardiovascular pharmacotherapy; Drug combinations; Drug interactions and safety; New cardiovascular drugs.

Graphical Abstract

Figure 1

Mechanism of action of first-in-class drugs. (A) In pulmonary arterial hypertension (PAH), endothelin-1 (ET-1) activates ET_A and ET_B receptors leading to endothelial dysfunction, vasoconstriction, vascular remodelling (hypertrophy, fibrosis, and proliferation), inflammation, sympathetic activation, and increased aldosterone synthesis. Aprocitentan, the active metabolite of macitentan, prevents the binding of ET-1 to both ET_A/ET_B receptors and inhibits ET-1-mediated signalling. (B) The fixed-dose combination of macitentan, a dual ET_A and ET_B receptor antagonist, and sildenafil, a phosphodiesterase-5 inhibitor (PDEI), simultaneously targeted the ET-1 and the nitric oxide (NO) pathways involved in the pathophysiology of PAH. NO produced in endothelial cells (ECs) enter the pulmonary vascular smooth muscle cells (PVSMCs) binds to soluble guanylate cyclase (sGC) increasing its catalytic activity, and the conversion of guanosine-5′-triphosphate (GTP) into guanosine 3′,5′-cyclic monophosphate (cGMP), which causes smooth muscle relaxation and antiproliferative effects. This signalling pathway is counterbalanced by sildenafil, which blocks the degradation of cGMP to 5′-guanosine monophosphate. The simultaneous blockade of the ET-1 and NO signalling with macitentan and sildenafil allows to reach better outcomes in patients with PAH as compared with each drug in monotherapy. (C) Sotatercept rebalances growth-promoting and growth-inhibiting signalling. In PAH there is a down-regulation of the bone morphogenetic protein (BMP) receptor type II (BMPR2)–Smad1/5/8 pathway in PVSMCs leading to an increased production of activin ligands and an up-regulation of the activin receptor type IIA (ActRIIA)–Smad2/3 pathway. Increased phosphorylated Smad (pSmad)2/3 activity promotes the expression of endogenous BMP antagonists, gremlin-1 and noggin, which further reduces BMP–Smad1/5/8 signalling. The result is a reduction in antiproliferative and an increase in proproliferative signalling pathways counteracting pulmonary vascular remodelling. Sotatercept acts to sequester excess of ActRIIA ligands, thereby reducing ActRIIA–Smad2/3 signalling to rebalance growth-promoting and growth-inhibiting signalling. ALK, activin receptor-like kinase; pSmad, phosphorylated Smad; Smad, small mothers against decapentaplegic protein.