The largest analysis to date on cholesterol-lowering treatments has found that people with blocked arteries or who are at very high risk of heart disease should be started immediately on a combination of a statin and ezetimibe, rather than waiting to see if statins alone are enough.
This approach could prevent hundreds of thousands of deaths each year from heart attacks, strokes, and related complications.
The study, published in Mayo Clinic Proceedings, analyzed data from 14 studies involving 108,353 patients who were either at very high risk of cardiovascular disease or had already experienced serious events like a heart attack or stroke.
It showed that starting ezetimibe together with a high-dose statin offered much greater protection than using high-dose statins alone.
What Did the Study Find?
Patients receiving both medications had:
- A 19% lower risk of death from any cause
- A 16% lower risk of death from heart-related causes
- An 18% lower risk of serious cardiovascular events (such as heart attacks)
- A 17% lower risk of stroke
In addition to reducing risks, the combination therapy also lowered “bad” LDL cholesterol by an extra 13 mg/dL, significantly improving the chance of reaching the recommended LDL-C goal of under 70 mg/dL—a key target in preventing further heart damage.
Even more striking were results from a network meta-analysis (a method that allows direct comparison between different treatments across studies). This showed:
- A 49% reduction in overall death
- A 39% reduction in major heart complications
- A 44% lower chance of patients stopping treatment, when using moderate-intensity statins combined with ezetimibe compared to high-intensity statins alone.
Traditionally, high-risk heart patients are given statins first. Doctors often wait at least two months before checking whether LDL-C has improved, only then considering ezetimibe if needed. But this study suggests that waiting could be dangerous, and that early combination therapy is far more effective.
“Adding ezetimibe immediately is a simple, safe, and cost-effective strategy that can prevent future heart problems and save lives,” said Professor Maciej Banach, the study’s lead author and a cardiologist at the John Paul II Catholic University of Lublin in Poland. He also serves as Adjunct Professor at Johns Hopkins University and leads the International Lipid Expert Panel.
Professor Peter Toth, another co-author from the University of Illinois and Johns Hopkins, emphasized that this isn’t about expensive new drugs. “This approach doesn’t require extra funding. It can actually reduce costs by preventing complications like heart failure, hospitalizations, and repeat heart attacks.”
How the Medications Work
- Statins lower LDL-C by reducing how much cholesterol the liver makes.
- Ezetimibe lowers LDL-C by blocking cholesterol absorption from food in the intestines.
Combined, they tackle cholesterol from two angles, making it much easier for patients to reach target cholesterol levels.
According to the American Heart Association and Global Burden of Disease data, high LDL-C caused about 4.5 million deaths worldwide in 2020, with the highest rates in Eastern Europe and Central Asia. Cardiovascular disease remains the leading cause of death globally, claiming about 20 million lives each year.
Based on previous modeling, Professor Banach estimates that adding ezetimibe from the start could prevent:
- 330,000 deaths annually in patients who’ve already had a heart attack
- Nearly 50,000 deaths per year in the United States alone
Strengths and Limitations
This analysis is powerful because of its large size—the biggest of its kind to date—and the inclusion of both randomized controlled trials and real-world studies. This gives a fuller picture of how these treatments work across different patient populations.
However, some limitations exist. Not all included studies were randomized, and a few were small or observational in nature, meaning they can’t prove cause and effect as strongly as clinical trials. Still, the results are consistent and compelling.
This study could help reshape global treatment guidelines for people with very high cholesterol or blocked arteries. Instead of waiting to see if statins alone work, doctors may need to adopt a more aggressive and immediate approach using combination therapy to give patients the best chance of survival.
As Professor Toth concluded, “These findings reinforce the saying: ‘the lower the better, for longer’—but also, ‘the earlier the better.’” Early, aggressive treatment saves lives—and it’s time for this to become the new standard.
If you care about heart health, please read studies that vitamin K helps cut heart disease risk by a third, and a year of exercise reversed worrisome heart failure.
For more health information, please see recent studies about supplements that could help prevent heart disease, stroke, and results showing this food ingredient may strongly increase heart disease death risk.
The research findings can be found in Mayo Clinic Proceedings.
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