Researchers have announced a promising new oral medication capable of slashing harmful cholesterol more powerfully than standard statins, a potential breakthrough for more than 86 million Americans if FDA-approved.
Decades of pioneering research at UT Southwestern have fundamentally transformed the scientific understanding of high LDL cholesterol, a major driver of heart attacks and strokes, shifting the focus beyond the liver’s receptors that catch and dispose of cholesterol particles.
Scientists have now identified a novel cholesterol-lowering mechanism that works independently of those receptors, challenging the long-held view that receptor activity is the only critical pathway for cholesterol clearance.
This offers a vital new strategy for patients with genetic forms of high cholesterol who have too few functional receptors. It is the world’s first effective oral pill that works by inhibiting the PCSK9 protein, a mechanism previously only available as an injection or infusion.
Normally, LDL receptors on the liver’s surface act like nets, catching ‘bad’ cholesterol from the blood and recycling back to catch more. The PCSK9 protein hijacks this process. It binds to the receptor and marks it for destruction, sending it to the cell’s disposal system to be permanently broken down. More PCSK9 means fewer receptors, crippling the liver’s ability to clear cholesterol and allowing LDL levels to soar.
Enlicitide works by binding directly to PCSK9 in the bloodstream, restraining it. This prevents PCSK9 from tagging receptors for destruction, allowing them to continue their recycling work and clear cholesterol efficiently.
After 24 weeks, participants taking the pill saw their LDL cholesterol levels plummet by more than 57 percent compared to a minimal three percent change in the placebo group. The drug also had a broader positive impact on the patients’ complete set of cholesterol and blood fat numbers to a greater degree than the placebo.
Patients who took the drug did not experience higher rates of common statin-associated side effects, such as muscle pain, liver enzyme changes or an increased risk of developing type 2 diabetes.
Heart disease affects about 128 million Americans. Specific conditions include over 16 million adults with coronary heart disease, 5.7 million with heart failure and 7 million with a history of stroke. Every year, about 805,000 people in the US have a heart attack (stock)
Dr Ann Marie Navar, a cardiologist at UT Southwestern Medical Center and leader of the study, said: ‘Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach LDL cholesterol goals.
‘An oral therapy this effective has the potential to dramatically improve our ability to prevent heart attacks and strokes on a population level.’
For heart health, total cholesterol should stay below 200 mg/dL.
The critical number is LDL cholesterol: below 100 mg/dL is good but for those at high cardiac risk, targets drop to 70 mg/dL or lower.
Danger begins when LDL exceeds 190 mg/dL, a level that substantially raises the immediate risk of heart attack and stroke.
Understanding these targets underscores why new, effective treatments are urgently needed.
The CORALreef Lipids trial, published in the New England Journal of Medicine, was a global study designed to test enlicitide’s effectiveness and safety.
It included more than 2,900 adult participants with either established heart disease or a high risk for it.
After 24 weeks, participants taking the pill saw their LDL cholesterol levels plummet by more than 57 percent compared to a minimal three percent change in the placebo group.
All of them were already taking standard cholesterol-lowering therapy, primarily statins, but still had elevated LDL levels, reflecting patients commonly seen in real-world practice.
Participants were randomly assigned to two groups: 1,935 people received a 20 mg daily dose of enlicitide while 969 took a placebo pill for 52 weeks. The study was double-blind, meaning neither the participants nor the researchers knew who received the drug or the placebo.
The primary goal was to measure the percent change in LDL cholesterol after 24 weeks, with additional measurements taken for other blood fats like non-HDL cholesterol and lipoprotein(a) over the full year.
In addition to lowering LDL cholesterol levels, all of the artery-clogging forms of cholesterol fell dramatically.
The actual number of harmful cholesterol-carrying particles in the blood dropped significantly. This is considered one of the most accurate measures of heart risk.
Lipoprotein(a), or Lp(a), a particularly stubborn, genetically influenced type of harmful cholesterol that is usually very hard to lower, also went down.
Dr Navar said: ‘Even the highest intensity statins are often not enough to get people to their cholesterol goals.
‘These reductions in LDL cholesterol are the most we have ever achieved with an oral drug by far since the development of statins.’
The drug slashed the total number of harmful cholesterol particles in the blood, a key measure of heart risk, and even reduced stubborn, genetic forms like lipoprotein(a) that are typically hard to treat
A separate clinical trial is already underway to study whether this decrease in LDL cholesterol translates into reductions in heart attacks and strokes.
The research team concluded: ‘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.
Heart disease affects about 128 million Americans. Specific conditions include over 16 million adults with coronary heart disease, 5.7 million with heart failure and 7 million with a history of stroke. Every year, about 805,000 people in the US have a heart attack.
