Abdulla A. Damluji Summarizes CORAL Reef Trial

Abdulla A. Damluji, Director of the Cardiovascular Center on Aging at Cleveland Clinic, shared on LinkedIn:

”CORAL reef trial – NEJM Group

Here is the summary

Lowering low density lipoprotein cholesterol remains one of the most reliable strategies for reducing the risk of myocardial infarction, ischemic stroke, and cardiovascular death. Contemporary recommendations advise very low targets for patients at highest risk.

Yet many individuals who receive statins, and often additional lipid lowering agents, continue to have levels above those thresholds.

Therapies that inhibit proprotein convertase subtilisin kexin type 9 have transformed care, but their uptake in routine practice has been limited in part because available options require injection.

A phase three trial published in the New England Journal of Medicine evaluated a potential solution.

CORALreef Lipids tested enlicitide decanoate, a once daily oral macrocyclic peptide designed to block the interaction between proprotein convertase subtilisin kexin type 9 and the low density lipoprotein receptor.

The central question was straightforward.

Can an oral agent deliver reductions in atherogenic lipoproteins comparable to those seen with injectable therapies while maintaining acceptable safety?

Trial Design

Investigators enrolled adults with a history of major atherosclerotic cardiovascular disease or with clinical characteristics that conferred high predicted risk for a first event.

Entry required low density lipoprotein cholesterol at or above contemporary thresholds despite background therapy.

Participants continued usual lipid management, which in nearly all cases included moderate or high intensity statins.

A total of 2909 participants underwent randomization at 168 sites across fourteen countries.

Patients received enlicitide at a dose of twenty milligrams once daily or placebo in a two to one ratio.

Treatment continued for fifty two weeks.

The primary end point was the percent change in low density lipoprotein cholesterol at twenty four weeks.

Population

The mean age was approximately sixty three years. Women comprised about forty percent of the cohort.

More than half of the participants had already sustained a major cardiovascular event.

Baseline low density lipoprotein cholesterol averaged roughly ninety six milligrams per deciliter, underscoring persistent risk despite widespread use of established therapies.

Lipid Effects

The magnitude of reduction in low density lipoprotein cholesterol was large. At twenty four weeks, participants assigned to enlicitide experienced a mean decrease of 57.1 percent from baseline.

In contrast, those assigned to placebo had a small increase of about three percent. The adjusted difference between groups was 55.8 percentage points, with strong statistical support.

Importantly, the effect persisted. At fifty two weeks, the separation between groups remained 47.6 percentage points.

Other atherogenic measures moved in parallel. Non high density lipoprotein cholesterol fell by 53.4 percentage points relative to placebo, and apolipoprotein B declined by 50.3 percentage points. Lipoprotein a levels were also lower, with a median reduction of 28.2 percentage points.

Goal attainment reflected these shifts.

Approximately seventy percent of treated participants achieved a low density lipoprotein cholesterol level below seventy milligrams per deciliter along with at least a fifty percent reduction.

Two thirds reached values below fifty five milligrams per deciliter with that same proportional decline.

Safety and Adherence

Adherence exceeded ninety seven percent and was similar in both groups. The frequency of adverse events, serious adverse events, discontinuations, and deaths did not appear different between enlicitide and placebo.

Investigators monitored new or worsening diabetes and liver injury, and rates were comparable.

Context Within Current Therapy

The reductions observed in this trial approach those reported with monoclonal antibody therapies directed at the same pathway.

For many clinicians, the key distinction lies in route of administration.

A once daily pill may fit more naturally into chronic preventive care, particularly for patients who hesitate to initiate injectable treatment or who face logistical barriers.

The trial did not evaluate cardiovascular outcomes. An event driven study is underway and will determine how these lipid changes translate into clinical benefit.

Key implications helpful to clinical practice

1. An oral inhibitor of proprotein convertase subtilisin kexin type 9 can reduce low density lipoprotein cholesterol by roughly one half in patients already treated with statins.
2. The effect remains durable for at least one year.
3. Large proportions of patients can achieve targets below fifty five milligrams per deciliter.
4. Reductions extend beyond low density lipoprotein cholesterol to non high density lipoprotein cholesterol, apolipoprotein B, and lipoprotein a.
5. Safety signals in this trial resembled placebo.
6. Oral administration may lower barriers to treatment initiation and long term persistence.
7. Definitive evidence regarding prevention of myocardial infarction and stroke awaits completion of the outcomes trial.”

Title: A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide

Authors: Ann Marie Navar, Elina Mikhailova, Alberico L. Catapano, Puja Banka, Dirk J. Blom, Alberto Cadena, Susan Kourpanidis, Norman E. Lepor, Kazuhisa Tsukamoto, Geraldine Mendizabal, Julio Nunez, Wenjuan Zhang, Pengfei Zhu, Min Zhuo, Christie M. Ballantyne

Read the Full Article on NEJM

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