The print publication of the ZENITH and SOUL trials – originally presented and published online during ACC.25 in Chicago – provides an additional platform for editorial commentary on their broader implication.

In the ZENITH trial, sotatercept, a first-in-class novel activin-signaling inhibitor, led to a 76% lower risk of a composite of death from any cause, lung transplantation or hospitalization for worsening pulmonary arterial hypertension (PAH) compared to placebo in high-risk adults with PAH.

The trial, which was stopped early based on the efficacy results following a prespecified interim analysis, "reshapes the treatment narrative for [PAH] by showing definitive therapeutic efficacy in a particularly vulnerable subgroup of patients on the basis of a hard clinical end point that included death," writes Bradley A. Maron, MD, in a New England Journal of Medicine (NEJM) editorial. In addition to adding a "measure of optimism" and a "steep upward bend in the arc of progress" when it comes to treating PAH, Maron says the trial results also introduce "the possibility that long-term clinical stability may be an achievable goal for this previously untreatable disorder.

In the SOUL trial, an oral formulation of semaglutide lowered the risk major adverse cardiovascular events by 14% in four years, with no change in safety profile compared to placebo in patients with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both.

In a related editorial in NEJM, Faiez Zannad, MD, PhD, highlights the way emerging science like SOUL is "now bridging cardiometabolic kidney (CKM) syndrome with metabolic dysfunction–associated steatotic liver disease in a cardiovascular–kidney–liver–metabolic entity, which may contribute to further breaking down of silos." According to Zannad, the next step is to address the design of integrative trials and "facilitate the generalizability of the findings." Additionally, ensuring greater representation among racial and ethnic groups at greater risk of the disease, as well as women and individuals with adverse social determinants of health should also be a goal.

Dive into all the coverage from ACC.25 Late-Breaking Clinical Trials (LBCT) and JACC Journal simultaneous publications on the ACC.25 Meeting Coverage page. Plus, watch all the LBCT sessions and more on ACC Anywhere, ACC's comprehensive video library.