Can You Shrink Plaque?
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Today's Newsletter at a Glance:
- Can You Shrink Plaque?
- FLOWPROMOTE Trial
- My Hesitations: Cautiously Optimistic
- The Bottom Line
Can we shrink plaque in the coronary arteries (the arteries that supply the heart)?
I'm constantly bombarded with videos, emails, and ads claiming "this one food can clean out your arteries!" Sounds enticing, but these strong claims aren't backed by sound proof.
What does the evidence show? A handful of studies point to plaque regression.
An important point: in past regression studies (like GLAGOV) and the FLOWPROMOTE study we'll discuss today, we can't distinguish between plaque mass removal and remodeling.
In other words, is the plaque shrinking because it's being cleared out of the artery, or is the plaque remodeling into a smaller, flatter calcified pancake?
In today's newsletter, we'll examine a study recently published in JAMA Cardiology that may point to the first steps toward reversing plaque formation.
Let's dive in.
The FLOWPROMOTE Trial
FLOWPROMOTE was a randomized trial run at three hospitals in Denmark. It enrolled 104 people, with an average age of 64 and about 79% men.
Patients in the trial were recently diagnosed with stable coronary artery disease.
Inclusion criteria required a blockage of more than 50% on a coronary CT angiogram (CTA) and evidence that the blockage was limiting blood flow (an FFR-CT of 0.80 or lower).
Critically, none of them had ever been on a statin.
Participants were randomly assigned to one of two strategies for 18 months:
- Intensive: atorvastatin 40 mg daily
- More intensive: rosuvastatin 40 mg plus ezetimibe 10 mg daily
Note that there was no placebo group. Both arms received guideline-level therapy.
Each person had a coronary CTA at the start, at 9 months, and at 18 months.
Instead of examining a single artery segment, the researchers measured plaque across the entire coronary tree and divided it into total, noncalcified (soft), and calcified (hard) plaque volume.
One detail worth knowing: the trial’s primary endpoint was the change in blood flow through the narrowed artery. The plaque results I'm covering here were prespecified secondary endpoints.
The results: soft plaque shrank, and lower LDL meant more regression.
A few things to note:
- Soft plaque was the most responsive. It fell by about 28% in the combination group. That's the plaque type we worry about most, and it’s the one a coronary artery calcium (CAC) score can’t see, since CAC only detects calcified plaque.
- Almost everyone responded. 51 of 52 people on rosuvastatin plus ezetimibe had their soft plaque regress.
- Dose-response. Across both groups, the lower a patient’s LDL, the more their total and soft plaque regressed, in roughly a straight line.
- Calcified plaque increased, which isn't necessarily bad news. Statins are known to harden plaque through stabilization. Soft plaque shrinks while calcium increases. This can also mean a CAC score can rise on treatment.
"These findings suggest that coronary atherosclerosis is, at least in part, reversible with intensive lipid-lowering therapy in treatment-naive patients and supports targeting very low LDL-C levels to promote regression of coronary plaque burden." — The FLOWPROMOTE investigators, JAMA Cardiology
Atherosclerosis may not necessarily be a one-way street.
My Hesitations: Cautiously Optimistic
The results are exciting.
But I'd be doing a disservice if I didn't explain why it doesn't settle anything yet.
- It's small. 104 people, about 52 per group. That's fine for a proof-of-concept study, but small trials can overstate effects, and a few unusual patients can move the averages.
- No outcomes. The trial measured plaque on a scan. It did not count heart attacks, strokes, or deaths. Shrinking plaque is a surrogate marker. It's a logical one, but we've been misled previously by treatments that improved a number without improving outcomes.
- Plaque was a secondary endpoint. The trial was designed around blood flow, not plaque. Secondary results are hypothesis-generating, not definitive.
- A narrow population. These were mostly men in their 60s in Denmark who already had significant, flow-limiting blockages and had never taken a statin. Whether you'd see the same response in a 45-year-old with early soft plaque, or someone already on a statin for years, is an open question.
- CT plaque measurement is still maturing. Quantifying plaque volume from a CT scan has improved dramatically, but the precision is evolving. Differences of about 30 cubic millimeters are real in a trial.
The Bottom Line
The FLOWPROMOTE results are promising.
Here's the counterpoint I keep coming back to.
A scan measures size and density, not what's happening inside the plaque. When soft plaque "disappears" on CT, much of what we're likely seeing is stabilization, not cholesterol being physically removed from the artery.
• The scan can't distinguish removal from remodeling. CT sorts plaque by how dense it looks. If fatty material is replaced by fibrous tissue or calcium, it gets relabeled, it gets relabeled: soft plaque goes down, calcified plaque goes up. That's exactly the pattern FLOWPROMOTE showed. Even intravascular ultrasound, which images from inside the artery, struggles to tell what plaque is made of. In a substudy of the GLAGOV trial, it detected no difference in plaque composition.
• Statins change plaque in a predictable way. Statins tend to shift plaque toward a less fatty, more calcified makeup. Researchers call this "delipidation": the plaque drains of fat and becomes firmer and less likely to rupture. (PARADIGM; VH-IVUS meta-analysis)
• The proof that plaque can be cleared out comes from mice. Once ApoB is intensively lowered in the bloodstream, researchers have watched immune cells carry cholesterol out of plaque and switch from an inflammatory to a healing state. We don’t have direct proof of this in humans.
The bottom line is that lowering ApoB through lifestyle changes and, if needed, medications lowers your risk of heart attack or stroke. With current technology, we can't confirm whether plaque has been removed or remodeled through stabilization.
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Jeremy London, MD
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* Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user’s own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay seeking medical advice for any medical condition they may have and should consult their healthcare professionals for any such conditions.
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