Decades of clinical trials have consistently demonstrated that lowering the low-density lipoprotein (LDL) cholesterol reduces cardiovascular events. Benefits are observed even at baseline LDL levels <70 mg/dL. Recent guidelines therefore recommend targeting LDL levels ≤55 mg/dL in individuals at the highest risk for atherosclerotic cardiovascular disease (CVD), yet more than half of patients fail to achieve these targets. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is one of the most effective non-statin strategies for lowering LDL cholesterol. Its clinical use is limited by the need for injectable formulations. Enlicitide decanoate is an oral macrocyclic PCSK9 inhibitor that has shown short-term LDL-lowering effects. A recent CORALreef Lipids clinical trial published in The New England Journal of Medicine aimed to evaluate the 52-week efficacy of enlicitide decanoate in individuals with established CVD or at risk for a first atherosclerotic cardiovascular event.
This clinical study was a multinational, Phase 3, randomized, double-blind, placebo-controlled trial conducted across 168 sites in 14 countries. Adults with prior atherosclerotic CVD and LDL cholesterol ≥55 mg/dL or those at intermediate to high risk for a first event with LDL of ≥70 mg/dL were eligible while on stable lipid-lowering treatment. A total of 2909 participants (mean age = 62.8±10.7 years, male = 60.7%, female = 39.3%) were included in this study. These individuals were randomized 2:1 to receive oral enlicitide 20 mg (treatment group; n = 1940) or placebo (n = 969) daily for 52 weeks. The primary endpoint was the percent change in LDL cholesterol at week 24. Secondary endpoints were average percentage change in LDL cholesterol at 52 weeks, changes in non-HDL lipid cholesterol and apolipoprotein B, as well as percentage change in lipoprotein(a) at 24 weeks. Efficacy of the drug was analyzed using an analysis of covariance (ANCOVA) with imputation, hierarchical testing, and multiplicity control.
At baseline, mean LDL levels were similar in both treatment and placebo groups (95.0±38.8 vs 98.3±39.2 mg/dL). At week 24, LDL level decreased to 38.7±35.6 mg/dL with enlicitide but remained unchanged with placebo (98.6±42.5 mg/dL). Enlicitide reduced LDL cholesterol level by 57.1% (95% confidence interval [CI]: −61.8 to −52.5) compared to 3% (95% CI: 0.9 to 5.1) increase with placebo, yielding a between-group difference of -55.8 percentage points (95% CI: −60.9 to −50.7) with p <0.001. There were significant reductions were also observed in lipoprotein(a) by -28.2% (95% CI: −30.3 to −26.0, p <0.001), non-HDL cholesterol by -53.4% ((95% CI: −55.5 to −51.2, p <0.001), and apolipoprotein B by -50.3% (95% CI: −52.1 to −48.5, p <0.001) between both groups. At week 24, over two-thirds of enlicitide-treated participants achieved LDL levels below 55 mg/dL with ≥50% reduction.
A post hoc reanalysis revealed that enlicitide showed greater LDL reductions compared to placebo at week 24 with -59.7 percentage points (95% CI: -62.3 to -57.1) and week 52 with -52.4 percentage points (95% CI: -55.1 to -49.7). Safety outcomes, including deaths (0.7% vs 0.7%), serious adverse events (9.9% vs 12%), adverse events (64.3% vs 62.1%), and discontinuations (3.1 vs 4.1), were similar between treatment and control groups. The most common adverse events were reported in ≥2.5% of participants in either group, including headache, diarrhea, bronchitis, hypertension, nasopharyngitis, diabetes mellitus, urinary tract infections, and upper respiratory tract infections.
Limitations of the trial included a relatively short follow-up period, trial-based efficacy, data imputation, and limited detection of rare adverse events.
In conclusion, this study highlights that oral enlicitide significantly reduces LDL cholesterol levels compared to placebo at 24 weeks in patients at high-risk or with established CVD, supporting its potential as an effective non-statin lipid-lowering therapy.
References: Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. N Engl J Med. 2026;394(6):529-539. doi:10.1056/NEJMoa2511002
