NEW ORLEANS — Like the injectable therapies that came before, an oral once-daily PCSK9 inhibitor appears to generate profound reductions in LDL cholesterol (LDL-C), new data show, a result that promises a simpler, more patient-friendly option to achieve treatment goals. Experts said the oral agent could prompt both patients and primary care physicians to embrace PCSK9 inhibitors, which are considered widely underused by people with stubbornly high cholesterol. 

The oral therapy, enlicitide, “has significant potential to help close gaps in lipid management,” said Ann Marie Navar, MD, PhD, a preventive cardiologist at the University of Texas Southwestern Medical Center in Dallas, who presented the results at the 2025 Scientific Sessions of the American Heart Association.

The approved monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, have been remarkably effective for profound reductions in LDL-C over those achieved with any previous lipid-lowering therapy, but they have been underused, according to Navar. Patient resistance to injectable therapies partly, but not completely, explains the underuse, she said.

PCPs Also Resistant 

“Physicians, particularly at the level of primary care, are frequently reluctant to move to the injectable drugs,” which take more time to prescribe because patients must be convinced they are needed and then educated about administration.

Enlicitide, which also blocks the enzyme PCSK9 from breaking down hepatocyte receptors responsible for removing LDL from circulation, was tested in a global placebo-controlled phase 3 trial called CORALREEF LIPIDS. 

The 2912 patients enrolled in the trial were required to have a history of a major adverse cardiovascular event (MACE), such as myocardial infarction (MI), and an LDL-C of 55 mm Hg or greater, or have characteristics, such as diabetes, placing them at high risk for MACE and an LDL-C of 70 mm Hg or greater.

Participants were randomly assigned to receive 20 mg of enlicitide or placebo once daily on top of optimized statin therapy (or other lipid-lowering therapies if they were intolerant to those drugs). The primary endpoint of the trial was change in LDL-C at week 24, and enlicitide dramatically outperformed placebo. 

Enlicitide was associated with an LDL-C reduction of 57.1% vs a 3% increase in the placebo arm at week 24, a highly statistically significant result (P < .001), Navar reported. An unexpected issue with the analysis of the data from five patients required a post-hoc reanalysis that did not meaningfully change the result, she added.

The change in LDL-C at week 52, a secondary endpoint, was a 50.4% reduction from baseline in the enlicitide arm and a 4% increase in the placebo arm (P < .001).

The mean reductions at week 24 for those in the enlicitide and placebo groups, respectively, for non-HDL-C (53.7% vs. 2.6%), apolipoprotein B (49.6% vs. 2.9%) and lipoprotein (a) (29.0% vs. 0%) were all highly significant (P < .001).

The proportions of patients at week 24 who met the treatment goal, defined as an LDL-C below 55 mg/dL with at least a 50% LDL-C reduction from baseline, were 67.5% in the enlicitide arm and 1.2% in the placebo arm, according to the researchers.

No Safety Signal

For enlicitide and placebo, respectively, the proportion of patients with at least one adverse event (64.3% vs 62.1%), a serious adverse event (9.9% vs 12%), or an adverse event leading to discontinuation of treatment (3.1% vs 4.1%) were comparable. When compared by organ systems, no notable differences emerged, Navar reported.

When comparing lipid lowering on once-daily enlicitide in CORALREEF LIPIDS to standard doses of evolocumab (140 mg injected every 2 weeks or 420 mg injected every 4 weeks) or alirocumab (75 mg injected every 2 weeks) as reported in published trials, the reductions in LDL-C, ApoB, and Lp(a) appeared remarkably similar. Differences for any of these values did not exceed 3%, with no pattern of greater or lesser benefit for one agent vs another across the three values, Navar reported.

When compared to published data with inclisiran, a small interfering RNA (siRNA) molecule that inhibits production of the PCSK9 enzyme, the data showed lipid lowering for LDL-C, non-HDL-C, ApoB, and Lp(a) to be about 10% greater for each subfraction with enlicitide and both of the injectable PCSK9 inhibitors.

Donald M. Lloyd-Jones, MD, ScM, section chief of preventive medicine and epidemiology at Boston University School of Medicine, and the invited discussant for the AHA meeting, called the study well-conducted and agreed enlicitide “looks like a very promising oral” substitute for reducing LDL-C as well as the other atherogenic lipid subfractions evaluated.

Despite the consistent proportionate reduction in MACE relative to LDL-C across all major lipid-lowering trials, Lloyd-Jones said a longer study powered for events would be reassuring to confirm efficacy and safety. 

Cost was an issue initially for the injectable PCSK9 inhibitors, Navar acknowledged. Payers typically required preapproval to cover these agents, but she said this barrier to prescribing is now less common. Even so, “we should not give a pass” to physicians hesitating to prescribe an expensive but otherwise effective therapy on the basis of cost alone, she said.

“Heart disease is also expensive,” observed Navar, pointing to the hospitalization, procedures, therapies, and other resources required to manage cardiovascular events, heart failure, and subsequent disability.

The CORALREEF Lipids trial received funding from Merck Sharp & Dohme. 

Navar reported a financial relationship Merck Sharp & Dohme, Amgen, Arrowhead, Bayer, Esperion, Janssen, Eli Lilly, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Roche, and Silence Therapeutics. Lloyd-Jones reported no relevant financial relationships.

Ted Bosworth is a medical writer in New York City.