Year in Review: Top Prevention Stories of 2025

If an ounce of prevention is worth a pound of cure, research in the primary and secondary prevention space in 2025 added up to sizeable gains when it comes to tackling atherosclerotic cardiovascular disease (ASCVD).  

One of the biggest trials of 2025 was VESALIUS-CV, a large outcomes study that showed adding a PCSK9 inhibitor to statin therapy could reduce the risk of cardiovascular events in patients without a prior MI or stroke. The trial was unique in that it included high-risk patients without an event, but all had evidence of either coronary artery disease or type 2 diabetes.   

The study, which was presented at the American Heart Association Scientific Sessions and published simultaneously in the New England Journal of Medicine, showed that cutting LDL-cholesterol levels further with evolocumab (Repatha; Amgen) could reduce the absolute risk of death from coronary heart disease, MI, or stroke by 1.8% over a median follow-up of 4.6 years in this patient group.

For Eric Brandt, MD (University of Michigan Health, Ann Arbor), the large study was an important clinical trial in 2025, although the results didn’t exactly take him by surprise.

“We know that pretty much any therapy that lowers apolipoprotein B in individuals that are at risk will show benefit,” he told TCTMD. “The PCSK9 inhibitors have been around for a while now and they used to be very expensive, but over time these drugs will become much less expensive, so they will be a lot easier to prescribe and have them covered. I don’t think [VESALIUS-CV] is like a giant leap forward from the original FOURIER—it’s kind of a small step—but it pushes you into the primary prevention space a little bit more.”

Steven Nissen, MD (Cleveland Clinic, OH), also put VESALIUS-CV on his year-end list. “It’s not really a primary prevention study—these are people who had disease and so on—but nonetheless it extends the application of PCSK9 inhibitors to a broader group,” he told TCTMD.

Evolocumab is approved for use in adults with established ASCVD based on FOURIER, while alirocumab (Praluent; Regeneron/Sanofi) is approved for secondary prevention based on the ODYSSEY Outcomes study. In August, the US Food and Drug Administration approved evolocumab in high-risk adults without established disease to reduce the risk of major cardiovascular events.

In clinical practice as a lipidologist, Brandt said he and other physicians “feel pretty confident that lowering lipids, and maybe doing so earlier, will yield cumulative benefits.” His approach is to add lipid-lowering therapies sequentially to see how patients respond to each medication. For some patients with high LDL cholesterol, he’ll start with a statin and then move directly to a PCSK9 inhibitor, an approach that is now supported by the VESALIUS-CV study.

“I’ll jump to a PCSK9 sometimes because they might be far out from ezetimibe being sufficient to get them to the appropriate [LDL-cholesterol] threshold,” he said. “I think that because it’s gotten easier to prescribe the drug and get them approved, this is less of an issue, although sometimes we do have to jump through some hoops.”

Nissen, on the other hand, said that “most” patients should be able to lower LDL levels to the guideline-recommended target with a high-intensity statin and ezetimibe.

“As much as I do think PCSK9 inhibitors are very effective, if you can give somebody a statin and ezetimibe and get an LDL cholesterol below 55 mg/dL, it’s hard to make a case for a PCSK9 inhibitor,” he said. “I think at this point, given their cost—ezetimibe is essentially free—it should be used after you’ve tried the conventional inexpensive statin.”

Tackling Triglycerides

Another study that caught Brandt’s attention in 2025 was SOUL. Led by Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), the study tested oral semaglutide (Rybelsus; Novo Nordisk) in patients with type 2 diabetes plus established ASCVD, chronic kidney disease, or both. It showed the drug reduced major cardiovascular events when compared with placebo.

The oral formulation will be a welcome addition for physicians because these medications tend to be a little cheaper than injectables, said Brandt. For a drug that some patients already have difficulty accessing, any break on price would be appreciated. Other oral GLP-1s are currently in development, with investigators announcing positive results with orforglipron (Eli Lilly) earlier this year.   

In the expanding field of prevention, emerging treatments that address elevated triglycerides were also big news in 2025, said both Nissen and Brandt. These include small interfering RNA (siRNA) therapeutics targeting different genes involved in the regulation of triglyceride-rich lipoproteins and therapies such as olezarsen (Ionis Pharmaceuticals), an antisense oligonucleotide that targets APOC3 messenger RNA.  

Olezarsen is currently approved for the treatment of familial chylomicronemia syndrome (FCS), but recent studies have shown the drug is effective in a broader population of patients with moderate hypertriglyceridemia. The siRNA plozasiran (Redemplo; Arrowhead Pharmaceuticals) was recently approved in FCS patients, and there are plans to test it outside that population.

“If your triglycerides are more than 500 mg/dL, you’re at increased risk for pancreatitis,” said Nissen. “These drugs are obviously effective, and they will need to be studied in outcome trials to have a very broad application.”

CRISPR Gene Editing and Lp(a)

In addition to those trials, Nissen highlighted a phase I study, for which he was senior investigator, testing an investigational CRISPR-Cas9 gene-editing therapy that targets angiopoietin-like protein 3 (ANGPTL3) as one of his highlights of 2025. In that study, the onetime infusion safely cut LDL cholesterol and triglycerides in half in patients with various types of dyslipidemia refractory to treatment.

“It’s a one and done,” Nissen told TCTMD about the gene-based therapy.

For Brandt, one of the most anticipated clinical trials that didn’t come out in 2025 is Lp(a)HORIZON, the large randomized clinical trial testing the antisense oligonucleotide pelacarsen (Ionis Pharmaceuticals/Novartis). The therapy has been shown to lower lipoprotein(a), an independent predictor of ASCVD risk and calcific aortic stenosis. There’d been some talk Lp(a)HORIZON might be finished ahead of its projected 2026 completion, and the top-line results possibly announced, but that never came to pass, said Brandt.

“I was really hoping that we would’ve had that this calendar year, but we’re still waiting,” he said.

Nissen, who is the chair of Lp(a)HORIZON, said his team is hopeful the trial will be successful, but added that “there’s no guarantees in this world we live in.” He also noted that one of their other trials testing the siRNA lepodisiran (Eli Lilly) was positive—there was a 94% reduction in Lp(a) over 60 to 180 days—and that a fully enrolled, phase III cardiovascular outcomes study is now ongoing.