This year’s AHA Scientific Sessions showcased breakthroughs in cholesterol management.
Three new PCSK9 inhibitor trials have found the medications can halve low-density lipoprotein cholesterol (LDL-C) in various populations, as well as providing a variety of other benefits.
The findings were presented at the 2025 American Heart Association’s Scientific Sessions earlier this month.
PCSK9 inhibitors became available within the last decade to combat high cholesterol levels that persisted despite lifestyle changes and maximum statin medication treatment.
Oral medication an effective alternative to injections
A new trial has found that enlicitide, an oral PCSK9 inhibitor, lowered LDL-C by 60% in the first 24 weeks of treatment, a reduction which was sustained at 52 weeks.
PCSK9 inhibitors are currently only available as injections.
Around seven in 10 participants achieved a minimum LDL-C reduction of 50% along with reaching a level below 1.8mmol/L, the Australian recommended goal for high-risk patients.
Two thirds who halved their LDL-C were able to reach a level of less than 1.4mmol/L.
Non-HDL cholesterol and ApoB were also halved at 24 weeks and Lp(a) was reduced by nearly 30%.
The phase 3 CORALreef Lipids trial included nearly 3000 adults with a previous heart attack or stroke or who were at intermediate or high risk of a heart attack or stroke within the next 10 years.
They were randomised 2:1 to receive 20 mg enlicitide once daily or placebo. The average age was 63 years and 40% were female.
The study ran across more than 150 healthcare centres in 14 countries between 2023 and 2025.
All participants had higher than recommended LDL-C levels that had not been controlled by moderate to high intensity lipid-lowering therapy that had been stable for at least 30 days prior.
At baseline, nearly all participants (97%) were taking statins and about one quarter were also using a cholesterol-absorption inhibitor such as ezetimibe.
Rates of serious side effects in the trial were similar between the two groups (10% in enlicitide vs. 12% in placebo), as was the proportion of participants who discontinued treatment (3% enlicitide vs.4% placebo).
“This oral medication is set to be another powerful addition to the treatments we currently have to lower LDL cholesterol and hopefully prevent cardiovascular events,” Associate Professor Ann Marie Navar, lead author and professor of cardiology the University of Texas Southwestern Medical Centre, told media.
“In addition to these dramatic improvements when compared with placebo, daily enlicitide resulted in almost identical changes in LDL, non-HDL and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab.”
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Enlicitide achieved numerically superior results than for the siRNA medication inclisiran, she said.
The CORALreef outcomes trial is ongoing, and researchers are next evaluating the impact on the prevalence of major cardiovascular events within the cohort.
Additional cardiovascular benefits on top of statins
In another trial, adding the PCSK9 inhibitor evolocumab to a high-intensity, cholesterol-lowering regimen reduced the risk of a first major cardiovascular event for adults with atherosclerotic cardiovascular disease (ASCVD) or diabetes.
The treatment group experienced a 27% composite reduction in cardiovascular death, heart attack or ischemic stroke compared to the placebo group.
They experienced a 36% reduction in heart attack alone.
Mortality rates were lower in the evolocumab group than in the placebo group: 2.8% vs 3.6% for cardiovascular death, and 7.9% vs. 9.7% for all-cause death.
Findings were consistent across subgroup analyses, such as for the one third of participants with high-risk diabetes without ASCVD.
The VESALIUS-CV trial included more than 12,000 adults with an average age of 66 years and an average follow up of 4.6 years.
They were randomised to receive a 140mg evolocumab injection of placebo injection every two weeks.
Participants had an LDL-C of at least 2.3mmol/L or met non-HDL cholesterol or apolipoprotein B criteria, had atherosclerosis (coronary, peripheral, or cerebrovascular) or high-risk diabetes and at least one additional cardiovascular risk factor.
Average LDL-C across all participants was 3.2mmol/L and 72% were already on a high-intensity lipid-lowering regimen.
The median LDL-C dropped to 1.2mmol/L across the cohort after 48 weeks of treatment – the evolocumab group reduced by more than half while the placebo group remained at their median of 2.8mmol/L.
The study was conducted at nearly 750 health care sites in 33 countries between 2019 and 2021.
People with a prior heart attack or stroke were excluded. Just over 40% were women and the majority (93%) were white.
At baseline, around two-thirds of participants had atherosclerosis and half had diabetes.
According to the AHA, ASCVD-related conditions remain the leading cause of morbidity and mortality globally.
“The results from the VESALIUS-CV trial represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor, or any non-statin for that matter, in patients without a previous heart attack or stroke who are already being treated with a high-intensity lipid-lowering regimen,” said Professor Erin Bohula, lead author and assistant professor of medicine at Harvard Medical School.
And after a heart transplant
Alirocumab, a PCSK9 inhibitor, combined with a statin also appeared to reduce LDL-C levels by more than 50% for patients following a heart transplant.
After one year of treatment, average LDL-C in the alirocumab group dropped from 1.9mmol/L at baseline to 0.8mmol/L.
Average LDL-C levels in the placebo group did not statistically change from the average 1.8mmol/L at enrolment.
The CAVIAR (Cardiac Allograft Vasculopathy Inhibition with AliRocumab) clinical trial included more than 100 adults initiating therapy within eight weeks of a heart transplant.
Participants were assigned to either 150mg alirocumab or a placebo, together with rosuvastatin.
The study found that the cholesterol-lowering impact of combining these therapies was beyond what was achieved with rosuvastatin alone.
Mean age was 58 years. Neither group experienced any significant side effects and the plaque progression in both groups was similar.
“Our study found treating patients who have had a heart transplant with a more aggressive cholesterol management regimen was safe and lowered their LDL-cholesterol levels significantly,” said Professor William Fearon, study author and professor of medicine and chief of interventional cardiology at Stanford University School of Medicine.
These studies are currently research abstracts only. The findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal.
All LDL values were originally released as mg/dL and were converted to mmol/L by the author.
