Enlicitide decanoate, an oral PCSK9 inhibitor, significantly reduced LDL-C levels in patients with a history of or at risk for a first atherosclerotic cardiovascular disease (ASCVD) event, according to results of the CORALreef Lipids trial published Feb. 4 in the NEJM.

In the phase 3 trial, Ann Marie Navar, MD, FACC, et al., randomized 2,909 participants across 168 sites in 14 countries (mean age 63 years; 40% women) 2:1 to either daily 20 mg enlicitide (n=1,935) or placebo (n=969) for 52 weeks.

Participants had a history of a major ASCVD event and an LDL-C level ≥55 mg/dL (58%) or were at risk for a first ASCVD event and had an LDL-C level ≥70 mg/dL (42%). Mean baseline LDL-C was 96.1 mg/dL and 97% of participants were on statins.

Results at 24 weeks revealed a greater reduction in LDL-C with enlicitide than placebo (–57.1% vs. 3.0%), with an adjusted between-group difference of –55.8 percentage points (p<0.001).

Key secondary outcomes also showed greater benefit with enlicitide than placebo, with large between-group differences for mean percent change at 52 weeks for LDL-C (–47.6), and at 24 weeks for non-HDL-C (–53.4) and apolipoprotein B (–50.3) as well as a percent change in lipoprotein(a) (–28.2) (p<0.001 for all).

Notably, of patients treated with enlicitide, 70.3% achieved a reduction in LDL-C to <70 mg/dL and a ≥50% reduction from baseline and 67.5% achieved a reduction to <55 mg/dL and a ≥50% reduction from baseline, compared to 1.5% and 1.2% in the placebo group, respectively.

Looking at safety, the rate of adverse events (AEs) was similar with enlicitide and placebo (64% vs. 62%), respectively, as well as for discontinuation of trial regimen due to AEs (3% vs. 4%), serious AEs (10% vs. 12%), new-onset or worsening diabetes (6% vs. 6%) or mortality (0.7% vs. 0.7%).

"Observational data and simulation studies have shown that approximately 40% of adults with [ASCVD] will need additional [LDL-C]-lowering therapies beyond statins and ezetimibe to bring [LDL-C] levels to the target range of less than 55 mg per deciliter," write the trial authors. "Enlicitide has the potential to help reach lipid goals in patients with a history of cardiovascular events and those at risk for cardiovascular events and ultimately to help address the ongoing cardiovascular disease epidemic."

In an accompanying editorial comment, William E. Boden, MD, FACC, calls the results "impressive" and "compelling evidence that enlicitide provides incremental benefit." He notes that "a simpler formulation of PCSK9 inhibitors that would enable eligible patients to take drugs from this class of medication orally would represent an important step forward to facilitate greater medication adherence and more effective long-term [LDL-C] lowering for at-risk patients."