The ACC.25 conference in Chicago spotlighted a new era of cardiovascular innovation, where precision medicine, patient-centric outcomes, and pathophysiological insight intersect. Across heart failure, structural interventions, and pulmonary hypertension, landmark trials are reconfiguring treatment strategies for complex, high-risk patients. The latest addition to this evolving landscape comes from the SUMMIT trial post-hoc analysis—further redefining the approach to obesity-related HFpEF and chronic kidney disease (CKD).
HFpEF, Obesity, and CKD: A Triad Responding to Tirzepatide
In a post-hoc analysis of the SUMMIT trial, investigators demonstrated that tirzepatide, a dual GIP/GLP-1 receptor agonist, consistently reduced major adverse heart failure events and improved health status in patients with HFpEF and obesity—regardless of CKD status. Notably, 60% of the HFpEF cohort had CKD, identifying them as an exceptionally high-risk group with worse baseline functional status and biomarker profiles.
While relative risk reduction was consistent across kidney function strata, absolute risk reduction was greater in those with CKD—an important clinical nuance that highlights the potential value of tirzepatide in patients burdened by the cardio-kidney-metabolic syndrome. Moreover, tirzepatide showed signs of improving renal function over 52 weeks, though interpretation was complicated by discordant changes between eGFR estimations using creatinine vs. cystatin C.
These discrepancies reinforce a critical point raised in the accompanying editorial: eGFR alone may be insufficient to guide therapy or risk stratification in patients with shifting muscle mass and adiposity, as often seen with GLP-1 receptor agonists. Direct GFR measurement may be necessary in future trials and possibly in clinical practice.
As Dr. Milton Packer emphasized, “This drug improves kidney function, obesity, and HFpEF outcomes. The interplay of these three conditions identifies a population that is exceptionally in need of treatments that work.”
FRESH-UP: Debunking Fluid Restriction in Stable HF
In parallel, the FRESH-UP study dismantled another long-standing dogma in heart failure management: routine fluid restriction. In 504 patients with stable HF, fluid restriction offered no benefit in health status, hospitalization, or mortality—but was linked to increased thirst distress. This randomized data supports immediate de-implementation of fluid restriction for stable HF patients.
ALIGN-AR: Dedicated Device for Aortic Regurgitation Shows Promise
The ALIGN-AR trial offered a milestone in structural cardiology by validating the Trilogy valve—the first transcatheter valve specifically designed for aortic regurgitation (AR). The trial met its prespecified noninferiority endpoint for 1-year survival (91.9%) and achieved high device success (96.4%) with low rates of residual regurgitation and valve embolization. Despite a relatively high pacemaker rate (~25%), Trilogy could soon become the standard-of-care for patients with AR previously limited to surgical intervention or off-label TAVR solutions.
ZENITH: Sotatercept Redefines PAH Treatment
In pulmonary arterial hypertension (PAH), the ZENITH trial showed that sotatercept, a novel activin signaling inhibitor, reduced the risk of clinical deterioration or death by 76%—prompting early trial termination due to overwhelming efficacy. This represents a potential breakthrough in targeting the vascular remodeling and proliferative biology of PAH, offering hope beyond traditional vasodilators.
Taken together, these studies reflect a growing appreciation for the interconnected nature of cardiovascular, renal, and metabolic systems. Whether it’s recognizing the need for personalized kidney function assessments in metabolic HFpEF, moving away from rigid fluid rules in stable HF, expanding device innovation in structural disease, or delivering disease-modifying therapies in PAH, the message is clear: precision, nuance, and integration must guide the future of cardiovascular care.
