ACC.25 Highlights: Groundbreaking Advances in Cardiovascular Medicine and Emerging Therapeutics

The American College of Cardiology’s 74^th Annual Scientific Session and Expo (ACC.25) convened from March 29 to March 31, 2025, in Chicago, Illinois, serving as a pivotal platform for the latest advancements in cardiovascular medicine. The conference attracted over 280 companies and organizations, showcasing innovations across pharmaceuticals, imaging, devices, health information technology, and services essential for high-quality patient care. 

Key Highlights from ACC.25

Major pharmaceutical companies such as Mineralys Therapeutics, AstraZeneca, Novo Nordisk, Eli Lilly, Alnylam Pharmaceuticals, SFJ Pharmaceuticals, SERB Pharmaceuticals, and others were among the prominent exhibitors. The conference addressed a spectrum of cardiovascular indications, including Atherosclerotic Cardiovascular Disease (ASCVD), Pulmonary Arterial Hypertension (PAH), hypercholesterolemia, heart failure, and dyslipidemia.

The conference also featured late-breaking clinical trials and interactive learning sessions, fostering collaboration and knowledge exchange among cardiovascular professionals. ACC.25 underscored the dynamic evolution of cardiovascular care, with industry leaders unveiling groundbreaking research and innovative solutions aimed at improving patient outcomes worldwide.

Eli Lilly at ACC.25

ALPACA Trial Highlights siRNA Potential in CVD

At the ACC.25 scientific sessions, Eli Lilly presented Phase II ALPACA trial results demonstrating that lepodisiran, an investigational siRNA therapy, significantly reduced lipoprotein(a) [Lp(a)]—a key genetic risk factor for cardiovascular disease. The study evaluated the efficacy and durability of lepodisiran at doses of 16 mg, 96 mg, and 400 mg, with reductions in Lp(a) levels sustained for up to 1.5 years.

Patients receiving 400 mg of lepodisiran experienced a 93.9% average reduction in Lp(a) over 60-180 days, with levels remaining 91% below baseline at 12 months and 74.2% below baseline at 18 months. The 96 mg and 16 mg doses led to 75.2% and 40.8% reductions, respectively. Additionally, apoB levels—a key cardiovascular biomarker—were lowered by up to 14.1%, further supporting lepodisiran’s potential as a durable therapy for high-risk patients.

The trial found no serious adverse events related to lepodisiran, and treatment-emergent adverse events were reported in 14% of patients at the highest dose, with no withdrawals due to side effects.

With approximately 20% of Americans having elevated Lp(a) levels, lepodisiran represents a major breakthrough in cardiovascular risk management. The ongoing Phase III ACCLAIM-Lp(a) trial aims to confirm its benefits in reducing cardiovascular events. If successful, lepodisiran could become the first targeted therapy for Lp(a)-driven cardiovascular disease, addressing a critical unmet need in cardiology.

Tirzepatide’s Impact on HFpEF

Eli Lilly presented post-hoc findings from the SUMMIT trial (NCT04847557) at the ACC.25, analyzing the impact of baseline estimated Glomerular Filtration Rate (eGFR) on heart failure outcomes with tirzepatide. The study included 731 patients with Heart Failure with preserved Ejection Fraction (HFpEF) and obesity (BMI ≥30 kg/m²), of whom 60% had Chronic Kidney Disease (CKD). 

Results showed that tirzepatide reduced the risk of major adverse heart failure events by 38% compared to placebo, regardless of baseline eGFR. Patients with CKD had a higher risk of worsening heart failure and poorer quality of life, yet tirzepatide demonstrated consistent benefits in both CKD and non-CKD groups. 

Renal function assessments indicated a discrepancy between creatinine-based and cystatin C-based eGFR measurements, with cystatin C yielding lower values. At 52 weeks, tirzepatide improved eGFR across all patients when measured by cystatin C and in CKD patients when measured by creatinine. These findings highlight tirzepatide’s potential to improve kidney function, HFpEF outcomes, and obesity-related risks, reinforcing the need for direct GFR measurements in clinical practice and trials, particularly in cardio-kidney-metabolic syndromes.

PROLONG-ANG3 Trial Findings

Eli Lilly presented Phase II findings from the PROLONG-ANG3 trial (NCT05256654) at ACC.25, demonstrating that solbinsiran, a GalNAc-conjugated siRNA targeting hepatic ANGPTL3, reduced apolipoprotein B (apoB) levels in patients with statin-treated mixed dyslipidemia. The study, conducted across 41 centers in seven countries, included 205 patients (median age 57 years, 54% women) randomized to solbinsiran at 100 mg, 400 mg, 800 mg, or placebo.  

At Day 180, the placebo-adjusted reduction in apoB was –3% for 100 mg, –14% for 400 mg, and –8% for 800 mg. The 400 mg dose also significantly reduced non-HDL-C by 25.5%, LDL-C by 16.8%, triglycerides by 50.3%, very-low-density lipoprotein cholesterol by 50.1%, high-density lipoprotein cholesterol by 16.4%, and hepatic fat fraction by 27.6%.  

Hepatic MRI showed fat reductions across all groups, though without dose-dependent effects. Solbinsiran was well-tolerated, with treatment-related adverse events occurring in 7–12% of solbinsiran patients vs. 9% in the placebo group.  

Investigators noted limitations, including a short follow-up period and a lack of patient diversity. Despite this, findings support further evaluation of solbinsiran as a potential therapy for mixed dyslipidemia.

AstraZeneca’s Oral PCSK9 Inhibitor Shows Success

AstraZeneca presented Phase II results from the PURSUIT trial (NCT06173570), demonstrating that AZD0780, a once-daily oral PCSK9 inhibitor, effectively reduced LDL-C in patients with hypercholesterolemia on moderate- or high-intensity statins. Conducted across 55 sites in North America, Europe, and Asia, the study randomized 428 patients (mean age 62 years) to receive AZD0780 at 1, 3, 10, or 30 mg or placebo for 12 weeks.  

Results showed a dose-dependent reduction in LDL-C, with placebo-corrected reductions of –35%, –38%, –45%, and –51% for the 1, 3, 10, and 30 mg doses, respectively. LDL-C reductions began within a week and stabilized by Week 2. The intensity of background statin therapy did not influence outcomes.  

AZD0780 was well tolerated, with adverse events comparable to placebo (38.2% vs. 32.6%). The most common adverse event was hypertension, and no deaths occurred. Investigators emphasized AZD0780’s potential as an alternative to injectable PCSK9 inhibitors, addressing accessibility and adherence challenges in LDL-C management.  

Sotatercept’s Novel Mechanism Offers New Hope for PAH Treatment 

Merck Sharp & Dohme presented results from the ZENITH study demonstrated that sotatercept, a novel activin-signaling inhibitor, significantly reduced the risk of a composite outcome—including death, lung transplantation, or hospitalization for worsening PAH—by 76% compared to placebo in high-risk PAH patients. The trial, which was halted early due to strong efficacy signals, randomized 172 patients with WHO functional class III or IV PAH to receive either standard care or add-on sotatercept.  

Over a median follow-up of 10.6 months in the treatment arm and 7.1 months in the placebo arm, 17.4% of sotatercept-treated patients vs. 54.7% in the placebo group met the primary endpoint (HR, 0.24; p < 0.001). Additionally, the sotatercept group showed lower rates of death (8.1% vs. 15.1%), lung transplantation (1.2% vs. 7.0%), and PAH-related hospitalization (9.3% vs. 50.0%). Adverse events, including epistaxis and telangiectasia, were more frequent in the treatment arm but were generally manageable, with fewer severe adverse events reported compared to placebo.  

These findings highlight sotatercept’s potential to transform PAH treatment by targeting the activin-signaling pathway to restore vascular homeostasis, marking a significant advancement in managing high-risk PAH.

Semaglutide in SOUL and STRIDE Trials: Cardiovascular and Functional Benefits Highlighted at ACC.25

Novo Nordisk presented compelling findings from the SOUL (NCT03914326) and STRIDE (NCT04560998) trials, underscoring the cardiometabolic and vascular benefits of semaglutide in patients with Type 2 Diabetes (T2D).

The SOUL trial, a large-scale, multinational Phase IIIb study, evaluated the cardiovascular efficacy of once-daily oral semaglutide in 9,650 patients with T2D, ASCVD, and/or CKD. Over a median follow-up of 49.5 months, semaglutide demonstrated a 14% reduction in Major Adverse Cardiovascular Events (MACE), including cardiovascular death, nonfatal myocardial infarction, and stroke (HR: 0.86; 95% CI: 0.77–0.96; p = 0.006). Notably, semaglutide’s cardioprotective benefits remained consistent across subgroups, regardless of concurrent use of Sodium-glucose Cotransporter-2 (SGLT2) inhibitors. Safety outcomes were comparable to placebo, with gastrointestinal disorders being the most frequently reported adverse events.

The STRIDE trial, conducted across 112 sites in North America, Asia, and Europe, assessed the impact of weekly SC semaglutide on walking capacity and quality of life in 792 patients with T2D and symptomatic Peripheral Artery Disease (PAD). Participants receiving semaglutide showed a significant 13% improvement in maximum walking distance after 52 weeks (estimated treatment ratio: 1.13; 95% CI: 1.06–1.21; p = 0.0004). Secondary outcomes, including pain-free walking distance and VascuQoL-6 scores, also favored semaglutide, highlighting its role in improving functional mobility. The safety profile remained favorable, with a low incidence of treatment-related adverse events and no treatment-related deaths.

The findings from these trials reinforce semaglutide’s role in reducing cardiovascular risk and enhancing mobility in high-risk T2D populations. With both injectable and oral formulations showing robust clinical benefits, semaglutide continues to expand its therapeutic potential beyond glycemic control, offering a promising approach for patients with PAD, ASCVD, and CKD.

Lorundrostat Lowers Blood Pressure in Resistant Hypertension

Mineralys Therapeutics presented results from the Advance-HTN trial, a Phase IIb study evaluating the efficacy and safety of lorundrostat, a novel aldosterone synthase inhibitor, in patients with uncontrolled and treatment-resistant hypertension. Conducted across 103 US sites, the trial randomized 285 participants who remained hypertensive despite taking two to five antihypertensive medications.

After 12 weeks, lorundrostat significantly reduced 24-h Systolic Blood Pressure (SBP) compared to placebo. Patients receiving lorundrostat 50 mg daily showed a placebo-adjusted SBP reduction of –7.9 mmHg (p = 0.001), while those on an escalated dose (50–100 mg) had a placebo-adjusted reduction of –6.5 mmHg (p = 0.006). At Week 4, a greater proportion of patients on lorundrostat achieved SBP <125 mmHg compared to placebo (41% vs. 18%, p<0.001).

Lorundrostat was generally well tolerated, though higher doses were associated with increased hyperkalemia (5–7%). The diverse study population, including 40% women and over 50% African Americans, suggests the broad applicability of lorundrostat across demographic groups. These findings support further Phase III trials to establish lorundrostat’s role in resistant hypertension management, particularly as a targeted aldosterone-lowering therapy.

Future Prospects for Ninerafaxstat in Cardiometabolic HFpEF

Imbria Pharmaceuticals presented positive clinical data from Part II of the Phase II IMPROVE-DiCE trial at ACC.25, highlighting the potential of ninerafaxstat in treating cardiometabolic heart failure with preserved ejection fraction (HFpEF). The study demonstrated that a 12-week treatment with ninerafaxstat significantly improved cardiac energetics, left ventricular reserve capacity, exercise tolerance, and patient-reported heart failure symptoms.  

Key findings included a statistically significant increase (p = 0.02) in the cardiac phosphocreatine to adenosine triphosphate (PCr/ATP) ratio, indicating improved cardiac energy reserves. Patients also showed enhanced left ventricular systolic reserve capacity during exercise (p = 0.03) and a meaningful increase in 6-minute walk distance (~14 m; p = 0.02). Additionally, individuals with greater symptom burden at baseline experienced a clinically significant improvement in heart failure-related health status, as measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS; ~8 points; p = 0.04).  

Given that HFpEF affects nearly half of all heart failure patients and is closely linked to metabolic disorders like T2D and obesity, these results support further development of ninerafaxstat. Imbria Pharmaceuticals sees potential for expanding its application to adjacent cardiovascular conditions, such as non-obstructive hypertrophic cardiomyopathy (nHCM).

Bentracimab Shows Rapid Ticagrelor Reversal in Phase III Trial

SFJ Pharmaceuticals and SERB Pharmaceuticals presented final results from the pivotal Phase III REVERSE-IT trial at ACC.25, demonstrating the efficacy of bentracimab in rapidly reversing the antiplatelet effects of ticagrelor in patients requiring urgent surgery or experiencing major bleeding. The trial met its primary endpoint, showing a significant restoration of platelet function within 5–10 minutes of bentracimab infusion (p < 0.0001), maintaining normal platelet function throughout the 16-hour infusion and beyond.  

The study also achieved its secondary endpoint, with 94.3% of eligible patients attaining effective hemostasis within 24 hours—100% in the urgent surgery group and 83.1% in the major bleeding group. Bentracimab demonstrated a favorable safety profile, with no serious adverse or allergic reactions reported and a thrombotic event rate of 4.0%, consistent with the baseline risk for these patients.  

Experts emphasized the critical need for a rapid ticagrelor reversal agent, as waiting 3–5 days for natural clearance is often impractical in emergencies. The rapid onset and short half-life of bentracimab allow for controlled normalization of platelet function while enabling clinicians to reinstate antiplatelet therapy as needed. Given its Breakthrough Therapy and Orphan Drug Designations, bentracimab represents a promising solution for managing ticagrelor-treated patients in critical scenarios.

Conclusion

The ACC.25 conference served as a powerful testament to the rapid pace of innovation and collaboration in cardiovascular medicine. From the debut of next-generation siRNA and oral PCSK9 therapies to landmark advances in heart failure, pulmonary hypertension, and dyslipidemia management, ACC.25 spotlighted a broad spectrum of transformative solutions with the potential to reshape clinical practice.

The promising results from pivotal trials—such as lepodisiran for Lp(a) reduction, sotatercept for PAH, and bentracimab for rapid antiplatelet reversal—highlight the industry’s commitment to tackling unmet needs with precision therapies. As these breakthroughs move through late-stage development and into real-world application, the future of cardiovascular care appears more personalized, accessible, and effective than ever before.