Oral PCSK9 Inhibitor Enlicitide Cuts LDL Cholesterol: CORALreef Lipids

NEW ORLEANS, LA—Use of enlicitide 20 mg, an oral PCSK9 inhibitor, significantly cut levels of LDL cholesterol and other atherogenic lipids in a large cohort of high-risk patients, results from the CORALreef Lipids study show.

By 24 weeks, treatment with enlicitide resulted in a 57.1% reduction in LDL cholesterol compared with a 3.0% increase in the placebo group, resulting in an adjusted between-group difference of 55.8% favoring enlicitide (P < 0.001), investigators reported this week at the American Heart Association 2025 Scientific Sessions.

The researchers say it’s early days for the oral PCSK9 inhibitor, but that they are excited about the prospect of the drug’s availability.

“Anecdotally, there are a number of patients who would prefer an oral to an injectable therapy, and I do have patients who will not initiate an injection and only want to take an oral medication,” lead investigator Ann Marie Navar, MD (UT Southwestern Medical Center, Dallas, TX), told TCTMD. “The other thing that I’m excited about though, as it relates to an oral therapy, is the ability to prescribe it easily. It takes me a few minutes in clinic to actually explain to somebody how to use an injectable—pull it out of the fridge, where to inject, and what to look for. It’s a lot quicker to prescribe an oral agent.”

The injectable PCSK9 inhibitors also remain underutilized by primary care physicians in clinical practice, said Navar. Moreover, roughly 40% of cardiologists surveyed said they’d never prescribed the drugs.

“Even though there may be a number of patients who are willing to take an injectable, providers are not prescribing them,” said Navar. “I think having more options, including an oral therapy, is going to open the aperture and increase the number of people prescribing nonstatins.”

Nearly 3,000 Patients

The CORALreef Lipids study included 2,912 patients (mean age 62.8 years; 39% female) with a history of atherosclerotic cardiovascular disease (ASCVD) and LDL cholesterol ≥ 55 mg/dL or those at high risk for ASCVD and LDL cholesterol ≥ 70 mg/dL. The racial makeup of participants was diverse, reflecting the study’s global nature, said Navar.

Nearly 60% of patients had a prior ASCVD event and half had type 2 diabetes. In all, 97% of patients were taking a statin, including 54% who were on a high-intensity statin, and one-quarter were taking ezetimibe. The baseline LDL-cholesterol level was 96.1 mg/dL.

In addition to the primary outcome, investigators performed a prespecified reanalysis to account for erroneously low on-treatment LDL levels using the beta-quantification method. In this analysis, treatment with enlicitide reduced LDL cholesterol by 59.7% after adjusting for the change with placebo. At 1 year, the mean between-group reduction in LDL cholesterol was 52.4% (P < 0.001 for both).

Two-thirds of enlicitide-treated patients had a more than 50% reduction in LDL cholesterol and achieved the recommended target of less than 55 mg/dL at 24 weeks, compared with just 1.2% in the placebo arm. Non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) were all significantly reduced with enlicitide at 24 weeks (53.7%, 49.6%, and 29.0% reductions, respectively).

The reductions in LDL cholesterol, non-HDL cholesterol, apoB, and Lp(a) at 24 weeks were nearly equivalent to reductions with alirocumab (Praluent; Regeneron/Sanofi) and evolocumab (Repatha; Amgen), the two approved injectable PCSK9 inhibitors.

“This perhaps shouldn’t be surprising given the similar mechanism of action,” said Navar.

Safety and tolerability did not differ between the oral PCSK9 inhibitor and placebo. Navar noted that 85% of patients opted to continue in the open-label extension study, which is a “reflection of the high degree of tolerability and excitement from the participant side for taking the medication.”

Some Unknowns Still

Donald Lloyd-Jones, MD (Boston University School of Medicine, MA), the discussant following the presentation, said that while PCSK9 monoclonal antibodies have been commercially available since 2015, uptake and utilization remain low. For example, one recent analysis found that less than 1% of patients with ASCVD were taking the medications, which was less than the percentage of patients taking omega-3 supplements or niacin.

The data with enlicitide “looks quite promising,” said Lloyd-Jones, but he also urged caution, noting that a large cardiovascular outcomes study will be needed 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 enrollment with more than 14,500 subjects, although results aren’t expected for several years.

There are also additional unknowns, including whether the drug will be approved by regulators, said Lloyd-Jones. Cost will be a factor, too. When the injectable monoclonal antibodies were approved a decade ago, there was widespread criticism for their high price tag, which led insurers to balk at covering them.

That problem is largely resolved as the price for evolocumab and alirocumab has come down. Today, Navar said, some insurers no longer require preauthorization. She added that trialists and physicians are not involved in setting the price of enlicitide but emphasized that the cost of heart disease is high, too.