CORALreef Lipids Trial of Enlicitide an Oral PCSK-9 Inhibitor Demonstrates Substantial Efficacy
Could this mean an end to the much maligned statin class of drugs?
By Peter A. McCullough, MD, MPH
Statins have been bedrock in lipid lowering therapy for decades but have come with adverse effects that are subject to exaggeration and discontinuation. Many have asked is there a new class of drugs that will someday replace statins? This post signifies a breakthrough.
The CORALreef Lipids trial was a large, phase 3, multinational, randomized, double‑blind, placebo‑controlled study evaluating the efficacy and safety of enlicitide decanoate (Merck), a first‑in‑class oral proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor, for lowering low‑density lipoprotein cholesterol (LDL‑C). The trial addressed an important unmet need: despite strong evidence that intensive LDL‑C lowering reduces cardiovascular risk, many high‑risk patients fail to achieve guideline‑recommended LDL‑C targets, in part because currently available PCSK9 inhibitors require injection every two weeks and are commonly rejected for insurance coverage. An effective oral PCSK9 inhibitor could substantially improve uptake and long‑term adherence.
Trial Design and Population
CORALreef Lipids enrolled 2,909 adults across 168 sites in 14 countries. Participants either had a prior major atherosclerotic cardiovascular disease (ASCVD) event or were at intermediate to high risk for a first ASCVD event. Entry criteria required LDL‑C ≥55 mg/dL in those with established ASCVD or ≥70 mg/dL in those at elevated primary‑prevention risk.
Importantly, participants were required to be on stable background lipid‑lowering therapy before randomization. At baseline, 96.6% of participants were receiving a statin, and 95.4% were on moderate‑ or high‑intensity statin therapy, reflecting contemporary guideline‑directed care. Approximately 26% were also receiving ezetimibe or hybutimibe, highlighting that this was a population with residual hypercholesterolemia despite optimized standard therapy. Only a small minority were statin‑intolerant.
Participants were randomized in a 2:1 ratio to receive enlicitide 20 mg orally once daily or placebo for 52 weeks. Randomization was stratified by renal function, baseline statin use, and geographic region. The primary endpoint was the mean percent change in LDL‑C from baseline to week 24, with key secondary endpoints including LDL‑C change at week 52 and changes in non‑HDL cholesterol, apolipoprotein B (apoB), and lipoprotein(a).
