Efficacy and Safety of Enlicitide, an Oral PCSK9 Inhibitor for Lowering LDL Cholesterol in Adults with or at Risk for ASCVD: The Phase 3 CORALreef Lipids Trial

By Ann Marie Navar, M.D., Ph.D.

Associate Professor of Internal Medicine

A new oral medication may offer people with prior cardiovascular disease or those at high risk an effective alternative to injectable PCSK9 inhibitors for lowering LDL (“bad”) cholesterol, according to late-breaking clinical trial results we presented at #AHA25. Many patients with or at risk for ASCVD continue to fall short of guideline-recommended LDL targets. As a result, these patients remain at high residual risk for heart attacks and strokes.

PCSK9 inhibitors – currently available only as subcutaneous injections – lower cholesterol by blocking the PCSK9 protein, thereby increasing the number of LDL receptors available to clear LDL cholesterol from the bloodstream. Work from the Dallas Heart Study at UT Southwestern by Helen Hobbs, M.D., and Jonathan Cohen, Ph.D., was foundational to the discovery and development of this class of medications.

Enlicitide, an oral PCSK9 inhibitor, led to reductions in LDL and other cholesterol measures similar to injectable PCSK9 inhibitors. Enlicitide works through the same mechanism as monoclonal antibodies evolocumab and alirocumab that prevent the PCSK9 protein from binding to the LDL receptor in the bloodstream but is taken as a once-daily pill. Earlier short-term studies demonstrated its ability to reduce LDL, prompting the longer-term evaluation in the phase 3 CORALreef Lipids Trial.

The study enrolled 2,912 adults (mean age 63 years; 39% women) across 14 countries. All had elevated LDL-C despite stable lipid-lowering therapy; nearly all were on statins, and one-quarter were also taking ezetimibe. Participants were randomized 2:1 to enlicitide 20 mg daily or placebo.

After 24 weeks, enlicitide produced substantial lipid improvements compared with placebo: up to a 60% reduction in LDL cholesterol, and a 53% reduction in non-HDL cholesterol, 50% reduction in ApoB, and 28% reduction in lipoprotein(a). Safety profiles were similar between groups, with serious adverse events occurring in 10% of enlicitide users and 12% of placebo patients. Participants also discontinued enlicitide at a similar frequency as placebo. Seven in 10 enlicitide-treated participants achieved both a ≥ 50% LDL reduction and LDL < 70 mg/dL, and nearly two-thirds reached LDL < 55 mg/dL.

Many patients need more than statins and ezetimibe to get to LDL-C goals. Although prices have come down and insurance approval rates are now high, most primary care physicians and even a large proportion of cardiologists are still not routinely prescribing the injectable PCSK9 therapies. I hope that as an easy-to-prescribe oral therapy, enlicitide can ultimately help more patients get to guideline-recommended goals.

LDL-lowering effects with enlicitide were nearly identical to those seen with injectable antibodies alirocumab and evolocumab and numerically larger than those reported for the siRNA therapy inclisiran. The ongoing CORALreef trial outcomes will determine whether these LDL reductions translate into fewer major cardiovascular events.