Oral PCSK9 inhibitor lowers LDL-C by up to 60 percent

The oral PCSK9 inhibitor enlicitide lowers LDL-cholesterol (LDL-C) levels and other atherogenic lipids in high-risk patients with hypercholesterolaemia, as shown in the CORALreef Lipids study presented at AHA 2025.

By 24 weeks, patients treated with enlicitide experienced a 57.1 percent reduction in LDL- C relative to a 3 percent increase with placebo, reflecting an adjusted difference of 55.8 percent favouring enlicitide (p<0.001).

“Anecdotally, some patients prefer an oral therapy over an injectable, and I do have patients who will not start an injection and only want oral medication,” said the lead study investigator, Dr Ann Marie Navar from the University of Texas Southwestern Medical Center in Dallas, Texas, US. “Enlicitide can be prescribed easily, whereas it takes me a few minutes to actually explain to patients how to use an injectable—things like pulling it out from the fridge, where to inject, and what to look for. It’s much quicker to prescribe an oral agent.”

She said injectable PCSK9 inhibitors remain underutilised in primary care; about 40 percent of cardiologists surveyed said they had never prescribed them.

Navar mentioned, “Even though several patients might be willing to try an injectable, providers are not prescribing them.” She said offering oral therapy as an alternative could expand options and boost the number of patients receiving non-statin treatments.

Diverse population

The CORALreef Lipids study involved 2,912 patients (average age 62 years, 39% female) with a history of atherosclerotic cardiovascular disease (ASCVD) and LDL-C levels of at least 55 mg/dL, or those at high risk for ASCVD with LDL-C≥70 mg/dL. The participants’ racial composition was diverse, reflecting the study’s global reach. [AHA 2025, abstract 4391578]

Almost 60 percent of patients had previously experienced an ASCVD event, and 50 percent had type 2 diabetes. Overall, 97 percent were on a statin, with 54 percent on a high-intensity statin. A quarter were taking ezetimibe. The baseline LDL-C level was 96.1 mg/dL.

A post-hoc reanalysis of the data showed an even greater reduction of nearly 60 percent at 24 weeks. At one year, the mean LDL-C reduction between groups was 52.4 percent (p<0.001 for both).

Two-thirds of patients treated with enlicitide achieved an LDL-C reduction of >50 percent and reached the target level of <55 mg/dL after 24 weeks. In contrast, only 1.2 percent of the placebo group achieved this. Additionally, levels of non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) significantly declined with enlicitide, showing reductions of 53.7 percent, 49.6 percent, and 29 percent, respectively.

Safety and tolerability did not differ between enlicitide and placebo. However, Navar pointed out that 85 percent of patients chose to continue in the open-label extension study, which is a “reflection of the high degree of tolerability and enthusiasm from the participants for taking the medication.”

Large CVOT warranted

Discussant Dr Donald Lloyd-Jones from Boston University School of Medicine in Massachusetts, US, noted that although PCSK9 monoclonal antibodies have been available since 2015, their use remains limited. For instance, a recent study showed that fewer than 1 percent of patients with ASCVD use these medicines, which is even lower than those taking omega-3 supplements or niacin.

He said the data with enlicitide “looks quite promising.” Still, he also urged caution, noting that a large cardiovascular outcomes study is necessary to determine if the oral agent reduces hard clinical events.

The CORALreef Outcomes study, which is evaluating enlicitide in patients with or at high risk for ASCVD, has recently completed enrolment of over 14,500 individuals. However, results are not expected for several years.