Reversing Artery Plaque: 8 Supplements Ranked by the Evidence | with Simon Hill, MSc

0:03Can supplements actually reverse plaque or atherosclerosis that's already built up in your arteries? Not just slow it down, but genuinely reverse it. In 2024, I found out myself that I had mild plaque in my left anterior descending artery. And so naturally, I wanted to know if I could shrink this with any particular supplements. If that question has ever crossed your mind, you're going to get a lot out of this episode. Over the years, I've interviewed some of the top cardiologists and lipidologists in the world. And one question keeps coming up from this community. Outside of pharmaceuticals, are any supplements actually effective, truly effective at reversing plaque?

0:49That's exactly what I'm going to answer today, following a deep dive into the human trial evidence. And the answer, well, that might surprise you. This is part two of a three-part series on reversing atherosclerosis. Part one, we covered diet. Today, I'm going to go through eight supplements, including some you've definitely heard of, and at least one that I think will surprise you. Part three, we'll cover the pharmaceutical side of things. Statins, PCSK9 inhibitors, benpedeic acid, and more, including some emerging medicines that could potentially eradicate cardiovascular disease. As always, studies are in the show notes.

1:32Let's go. Starting with the strongest evidence we have in this episode, and that is on omega-3 fatty acids. EPA and DHA are long-chain omega-3 fatty acids that our body cannot make, and they're found in fatty fish and supplements. benefits. EPA tends to drive the cardiovascular and anti-inflammatory benefits and DHA is thought to be more important for brain health. We're going to look at three randomized controlled studies that were studying a specialized form of EPA and then one that used a standard combined fish oil supplement. Evaporate published in 2020 tested whether high dose icosapent ethyl, which is a purified prescription strength form of EPA, could reverse atherosclerotic plaque in people who were already taking statins.

2:2480 participants with coronary atherosclerosis and elevated triglycerides were enrolled into this study. Again, they were all already on statins and still had plaque buildup and their triglyceride levels were above normal. They were randomly assigned to either 4 grams per day of icosapent ethyl, the brand name for that is Vucepa, or a placebo, while continuing their existing statin therapy throughout the 18-month study. So the difference between the two groups was whether they had a placebo or this potent, strong form of EPA. The researchers used CCTA, which stands for Coronary Computed Tomographic angiography to measure different types of plaque.

3:10Because not all plaque is created equal, they broke it down into categories. Non-calcified plaque, fibro fatty plaque, fibrous plaque, and calcified plaque. After 18 months, the results were quite striking. In the placebo group, total plaque volume increased by 11 % compared to baseline. In the icosapen ethyl group, total plaque volume actually decreased by 9%. That's a regression, a shrinking of plaque, not just a slowdown. But there's more. The standout finding here was with the most dangerous type of plaque, known as low attenuation plaque. This is the lipid-rich, unstable plaque that is most likely to rupture and cause a heart attack.

3:58The icosapen ethyl group saw a 17 % reduction in this vulnerable plaque after just 18 months. Again, remember, during this 18-month follow-up, both groups were taking statins. What makes this compelling is that the benefits occurred independently of LDL changes. The participant's LDL was already well-controlled by the statins. This tells us EPA has plaque stabilizing and regression effects that go beyond cholesterol lowering. The reason EPA ethyl ester works directly on plaque, not just in the circulation. So what's going on here? What's the proposed mechanism? Well, the reason EPA ethyl ester is thought to work directly on plaque, not just in circulation, comes down to what happens at the arterial wall.

4:46A 2010 randomized controlled trial by Kerwood and colleagues gave patients 4 grams per day of EPA ethyl esters for just 21 days before doing carotid surgery. When the plaque was analyzed post-surgery, EPA had already incorporated itself into the plaque tissue in just 21 days, and plaques with higher EPA content showed fewer foam cells, less inflammation, and reduced levels of the enzymes that degrade the fibrous cap. EPA gets into the plaque and changes its biology directly, which helps explain the imaging results we just went through. so evaporate tells us even on statins adding high dose purified epa can reverse plaque especially the most dangerous kinds now one limitation is that the study didn't track whether these plaque improvements translated into fewer cardiovascular events it was purely an imaging study before we get into the events data there's one more imaging trial worth knowing and that is cherry the cherry Every study published 3 years before Evaporate asked a similar question.

5:56Does adding EPA to high dose statin therapy reinforce plaque regression and stabilization? 193 coronary patients with existing heart disease were randomized to either a statin alone or a statin plus 1800 mg per day of highly purified EPA and followed these people for 6-8 months. That dose is about half the dose used in Evaporate. In this study, plaque was measured using intravascular ultrasound. The combination of EPA plus statin significantly reduced coronary plaque volume compared to the statin alone. Total plaque volume fell by around 18 % in the EPA group, dropping from 74.5 to 61.4 cubic millimeters, while the statin-only group showed no significant change.

6:48Perhaps more striking, 48 % of patients in the EPA group showed meaningful plaque regression, compared to just 25 % in the statin-only group. Plaque stabilization was also reinforced in stable angina patients specifically. The findings from CHERRY corroborate those from EVAPORATE. Two different EPA formulations, two different imaging techniques, the same directional result. Both Evaporate and Cherry looked at high doses of purified forms of EPA. But what about DHA, the other long-chain omega-3 fat that's found in fish, fish oil, and algae oil? In 2022, Shepard et al. conducted a meta-analysis pulling data from 10 randomized controlled trials, covering 860 patients on statins, and asked a simple but important question.

7:42Does pure EPA reduce coronary plaque on imaging? and does EPA combined with DHA do the same? The authors concluded that the imaging evidence supports pure EPA but not EPA-DHA combinations as an adjunct to statins and they proposed a biological reason. EPA and DHA compete for the same spots in cell membrane lipid layers So DHA may actually blunt or dilute EPA's beneficial effects on plaque. A separate analysis from the same group found that it was serum EPA levels, not DHA, that correlated with reductions in coronary lipid plaque volume across studies. This is very important context for anything you've heard about fish oil supplements and heart health.

8:32Standard fish oil supplements contain both EPA and DHA. The imaging data and the clinical events data from ReduceIt both point specifically to pure EPA for patients with existing cardiovascular disease that have high triglycerides and are on statins. Now I know you're wondering, does this translate to fewer cardiac events? The first study I want to discuss here is JEALUS, a large Japanese outcomes trial published in The Lancet in 2007 that is often missed in these conversations. Jellis enrolled over 18 ,000 hypercholesterolemic patients and randomized them to statin therapy plus 1 ,800 mg per day of highly purified EPA or statin therapy alone, with no placebo in the control group.

9:21After a mean follow-up of 4.6 years, the EPA group had a 19 % relative reduction in major coronary events. Crucially, LDL fell by the same amount in both groups, yet the EPA group had meaningfully fewer events, pointing to mechanisms beyond cholesterol lowering, including anti-inflammatory, anti-thrombotic, and plaque stabilizing effects. Jealous didn't use a placebo, which is a limitation, but it is the largest pure EPA outcomes trial prior to the high-profile REDUCE-IT trial. So at this point we have two imaging trials and one large outcomes trial all pointing in the same direction. Pure EPA can promote plaque regression and lower clinical events.

10:09Fast forward a few years and we have REDUCE-IT. REDUCE-IT asked the question directly this time with a control and a placebo. This trial didn't measure plaque. It measured actual cardiovascular events, cardiovascular death, heart attacks, stroke, revascularization, and unstable angina. Over 8 ,000 high-risk participants who were already on statins with elevated triglycerides were randomized to either 4 grams per day of pure EPA, the same icosapen ethyl from Evaporate that we spoke about earlier, or a placebo. These were people with either established cardiovascular disease or diabetes plus additional risk factors.

10:52After a median follow-up of 4.9 years, the EPA group had a 25 % relative risk reduction in major cardiovascular events, 17.2 % versus 22 % in the placebo group. And cardiovascular deaths fell from 5.2 % to 4.3%, a 20 % relative reduction. Now it's worth flagging an ongoing debate. Reducit used a mineral oil as its placebo, and some researchers argue mineral oil, raised LDL, and inflammatory markers in the control group potentially inflating EPA's apparent benefit. The trial that sits at the center of that debate is STRENGTH, a 13 ,000 patient RCT that tested a combination of EPA and DHA at the same 4 gram daily dose against a corn oil placebo in a similarly high risk statin treated population.

11:47STRENGTH showed no benefit whatsoever, an almost identical event rate in both groups and was stopped early for futility. Critically, unlike mineral oil, corn oil had no effect on LDL or inflammatory markers, which is why strengths investigators led by Steve Nissen at the Cleveland Clinic have argued that reduced its apparent benefit was inflated by the mineral oil placebo, rather than reflecting a true effect of EPA. if you've been listening to me or some of my guests talk about the gut microbiome you'll know that it thrives on very specific types of fiber and polyphenols and resistant starch many of which the average person falls short on despite the very best of intentions that's why dr will bolsewitz and i founded 38 terra a gut health company where science meets supplementation an independently conducted 15-day M.

12:42Scheim study found that our first product, Daily Microbiome Nutrition, or DMN for short, significantly increased short-chain fatty acid production and encouraged the growth of beneficial microbes linked to better gut and metabolic health. It's a simple daily scoop that you can add to water or your smoothie, no sugar, no fillers, just clinically backed ingredients that make your gut bugs happy. So if you want to support your microbiome in a meaningful, science-backed way, check out 38terra.com and use the code THEPROOF to save 20 % off your first order. Now the counter-argument, and there is one, which makes the most sense to me, is that strength used EPA plus DHA rather than pure EPA.

13:30And the Shepard et al. meta-analysis that we discussed before suggests that DHA may blunt EPA's plaque effects. But there's a second related point that nutrition scientist PhD Alan Flanagan has made compellingly. It's not just about EPA versus EPA plus DHA. It's also about the form. Strength used EPA and DHA in free fatty acid form, whereas ReduceIt and Jealous and the imaging trials all used EPA in the ethyl ester form. There is a body of evidence showing that EPA ethyl ester is rapidly incorporated into arterial plaque in as little as 21 days, where it exerts direct effects on plaque biology.

14:13It's plausible that the free fatty acid form used in strength was preferentially taken up and oxidized in the liver before it could reach the arterial wall. If that's true, strength may have been testing a fundamentally different molecule with different absorption and metabolism. So the honest answer is we can't fully disentangle these explanations just yet. What we can say is that this debate is real, involves credible scientists on both sides, and it's why I'd encourage you to not think of EPA as a settled story. There's more to learn here, hopefully in the coming years. One more trial worth briefly flagging, Respect EPA, a 2024 Japanese randomized controlled trial of a little more than 2 ,000 patients with stable coronary artery disease on statins who were randomized to 1 ,800 mg of icosapent ethyl or a control.

15:07The patients were selected by low EPA to arachidonic acid ratio, a marker of inflammation, rather than by triglyceride levels. The primary endpoint just missed significance, but the effect size for the secondary coronary composite, which included fatal and non-fatal heart attacks was significant with those randomized to EPA experiencing a 27 % reduction in risk. The trial was open label and underpowered so it can't stand alone but it's directionally consistent with Jealous and Reduce-It and now gives us data across three different countries and suggests EPA's benefits may extend beyond patients with elevated triglycerides and to anyone with low baseline EPA levels.

15:56Reduce it and evaporate enrolled high-risk patients. What about people who don't have established cardiovascular disease? Does EPA and or DHA omega-3s lower their risk of having a future cardiac event? The vital trial asked exactly that. Nearly 25 ,000 healthy U.S. adults were randomized to either 1 gram per day of combined EPA and DHA, 460 mg of EPA and 380 mg of DHA or placebo and followed for 5 years. Notice the dose is much lower than Reduce-It and it's a combination supplement rather than a pure form EPA. Overall there was no significant reduction in major cardiovascular events. This is a consistent finding across omega-3 trials in general populations.

16:42But there is one subgroup finding that's worth flagging. Among participants who ate less than 1.5 servings of fish per week, the supplement was associated with a 19 % reduction in major cardiovascular events and a 40 % reduction in heart attack risk, a pattern consistent with the idea that supplementation fills a gap when dietary intake is low. I want to be upfront with you here. This is a subgroup analysis from a trial that missed its primary endpoint, so consider this exploratory rather than definitive. But the pattern is biologically plausible. If you're already eating fish regularly, you're getting omega-3s from your diet and supplementation therefore may not be of much value.

17:29If your intake is low, it might fill a real gap. So if you don't eat fish regularly, less than about 2-3 servings per week, a 1g daily omega 3 supplement may be worth considering, though we should treat that finding as suggestive rather than confirmed. I myself take a little over 1g of DHA and EPA daily from algae oil. Now there's one more point I want to make here on omega 3s. The case for EPA has only continued to build. At the 2026 American College of Cardiology meeting, a new analysis of ReduceIt showed the benefit held up even in the highest risk patients. And early data presented there suggested that EPA may inhibit the oxidation of LP little a, a particularly atherogenic particle.

18:18Now, if that holds up, this could be relevant for people with elevated LP little a, especially in the interim while we wait on outcome data from the drugs that are in development to lower LP a levels. Next up, we are going to chat about aged garlic extract. Aged garlic extract or AGE, this is not the garlic powder that you cook with at home. It's a very concentrated form fermented for up to 20 months to increase beneficial compounds. And the aging process also reduces the harsh compounds that are responsible for garlic's odor. Now, the research here is earlier stage than omega-3s which we've just been through there are no large outcome trials yet but the imaging studies are interesting and the first that i want to discuss is the matsumoto trial this was published in 2016 it's a randomized controlled trial they gave participants with metabolic syndrome either 2400 milligrams per day of aged garlic extract or a placebo for about one year and they measured plaque along the way with cardiac CT angiography.

19:24Total plaque volume didn't change significantly between groups but something more subtle was happening beneath the surface. The aged garlic extract group saw a significant decrease in low attenuation plaque. Now remember that is the dangerous lipid rich vulnerable type of plaque that I mentioned earlier. This plaque fell by 1.5 % in the AGE group while actually increasing by 0.2 % in the placebo and that difference, importantly, was statistically significant. There were no adverse events reported throughout this study. The authors called for further research on whether reducing that vulnerable plaque translates into fewer cardiovascular events, which is the correct next question and is in fact still to this day an open question a 2020 replication study by shake and colleagues found the same low attenuation plaque signal in a different high risk population this time patients with diabetes using the same dose and imaging approach aged garlic extract again produced a statistically significant reduction in that low attenuation plaque compared to placebo with no change in total plaque volume, suggesting the effect generalizes beyond people with metabolic syndrome.

20:43Though it's worth noting that both of these studies came from the same UCLA research group, independent replication from other labs throughout the world, throughout the United States would strengthen the case here considerably. And in 2020, in fact, we got the Walsinka study, which was the independent replication of this study that we were waiting for, this time from a European group. This study focused on people at high risk of cardiovascular disease. Just over 100 subjects received either 2 ,400 mg per day of aged garlic extract or placebo for 12 months. Unlike the Matsumoto and Shake studies, Walsinka used a standard calcium CT scan rather than full CT angiography.

21:33So it couldn't measure soft or non-calcified plaque composition. What it could measure was calcification progression and here aged garlic extract performed well. The logistic regression in this analysis showed an odds ratio of about 2.95 meaning that those taking the supplement were nearly three times as likely to show slower calcification build-up compared to placebo. So not true regression or shrinking a plaque, but slowing progression, which still could be meaningful. The benefits went beyond calcification. The AGE group saw a systolic blood pressure reduction of about 8 mmHg, which is clinically meaningful, roughly in the range of what some antihypertensive medications achieve.

22:20They also saw improvements in the inflammatory marker IL-6 and better fasting glucose, no side effects were reported in either group. The fact that we're seeing blood pressure, inflammation, and blood sugar all improve suggests that this isn't a one-trick pony or a one-trick supplement. It appears to be working through multiple pathways simultaneously. So where does that leave aged garlic extract today in 2026? Aged garlic extract shows promise for stabilizing lipid-rich plaques and slowing calcification, even when total plaque volume doesn't shift. The soft plaque signal comes specifically from the Matsumoto and Shake studies that used the CT angiography, and the Walenska study adds independent evidence on calcification and systemic risk factors but couldn't assess plaque composition.

23:15And the honest truth as to whether this results in less risk of events we don't know we don't yet have large trials showing that it prevents heart attacks or strokes that evidence exists for statins and for high dose epa not for aged garlic extract based on the lack of heart outcome data from clinical trials under the guidance of a physician it may be a reasonable complementary addition for high risk individuals already on optimal medical therapy, but never a replacement for established treatments that we know lower cardiovascular events. That would be a risk I wouldn't want to personally take and therefore would not recommend for you.

23:56On a personal note, as part of my own approach to reversing atherosclerosis, I am planning to add 2 ,400 milligrams of aged garlic extract per day to my own supplement stack and i will be transparent about what i'm personally planning to do at the end of this episode in addition to other episodes that are coming out shortly okay now let's shift to vitamin k2 aged garlic extract is largely about plaque composition specifically that dangerous soft plaque vitamin k2 takes a completely different angle targeting calcification instead And this comes with an interesting paradox that I want to walk you through.

24:38Vitamin K2 acts as a calcium traffic controller, directing calcium towards bones and away from arterial walls, where it contributes to plaque calcification. But here's the thing. Calcification isn't always harmful. There's a credible school of thought that calcium can actually stabilize soft, vulnerable plaques, making them less likely to rupture. So vitamin K2's effect on calcification may not automatically mean an improvement in plaque stability and a reduction in events. It's an assumption that needs to be tested. A randomized controlled trial of over 300 men tested a daily supplement of 720 micrograms of vitamin K2, specifically in the MK7 form, which has a longer half-life and is the most studied form of vitamin K2 for vascular calcification plus 1000 IUs of vitamin D3 versus placebo for 24 months.

25:38Now you might be thinking why include vitamin D? Both K2 and D work together to stimulate matrix GLA protein which is considered the strongest inhibitor of calcification within the artery wall. Overall coronary artery calcification scores still increased in both groups after two years so So this isn't a reversal story. But when researchers looked at participants who started with high calcification scores, scores of 400 units or higher, the supplement group showed meaningfully slower progression compared to placebo. To give that number some context, a coronary artery calcium score under 100 is generally considered low risk.

26:21and annual progression of 25 to 50 units is typical in untreated patients. Slowing that trajectory in people who already have high scores is considered clinically relevant. And slowing down that trajectory in people who already have high scores is considered clinically relevant. These findings contributed to another randomized controlled trial that's currently underway called the DANCODE study out of Denmark, specifically designed for participants with high baseline coronary artery calcium scores, looking at both calcification progression and cardiovascular events. Until then, all we can go off are the randomized controlled trials looking at vitamin K2 supplementation, tracking atherosclerosis.

27:08Importantly, that study of over 300 men that I mentioned is not an outlier. A meta-analysis of 14 trials and over 1 ,500 participants found vitamin K supplementation slowed calcification progression by around 17 units on average. And that was consistent across vitamin K1 and K2 forms. One important safety note here, if you're taking warfarin, a blood thinner that works by blocking vitamin K, do not take vitamin K2 without talking to your physician first, as it could interfere with your anticoagulation. Vitamin K2 tells a more nuanced story than EPA. It slows calcification in people who already have high coronary artery calcium scores, but there's no evidence it reverses existing calcified plaque.

27:57Once calcium is deposited into artery walls, it's much harder to remove than it is to prevent new deposition. And as of today, as we sit here in 2026, we have no clinical trials yet telling us if vitamin K2 supplementation affects cardiovascular disease event risk. And as I said earlier, I'm not convinced that in all circumstances, less calcification means fewer events, as we know that calcification can result in plaque stability. Could K2 supplementation actually increase the risk of plaque rupturing and causing a heart attack or stroke maybe maybe not that's why the dan code study which is looking at plaque composition and cvd events is so important right now i think it's fair to say there is a fair bit of uncertainty when it comes to vitamin k2 atherosclerosis and cardiovascular events moving on to niacin niacin is where this episode gets really instructive because it's a perfect example of why improving a biomarker doesn't always mean improving outcomes niacin is a b vitamin that in high doses raises hdl cholesterol you may have heard of hdl cholesterol as the quote-unquote good cholesterol which we typically want more of and also niacin lowers triglycerides for years this made it an appealing add-on to statin therapy since statins primarily work through low density lipoprotein or LDL.

29:30The logic seemed sound. Statins lower the bad cholesterol and niacin raises the good cholesterol. And if you combine them, you should get better cardiovascular protection. Two niacin studies are worth knowing about here. The NIA-PLARC MRI study used MRI to measure carotid artery wall volume and the AIM-HI trial combined imaging with clinical outcomes. Both compared niacin plus statin to statin alone. The imaging results were null. After 18 months, adding niacin to statin therapy did not significantly enhance plaque regression and no additional benefit on carotid artery wall volume. The biochemical changes were exactly what you'd expect.

30:17Niacin plus statin raised HDL by 17 % versus statins alone, while the statin-only group saw a slight decrease. So niacin was doing its job mechanistically. It just didn't translate into better plaque outcomes. The AIMHI study asked the harder and more important question, can niacin prevent actual cardiovascular events? Despite the improvements in HDL and triglycerides, there was no additional reduction in heart attacks, strokes, or cardiovascular deaths when niacin was added to statins. Notably, AIMHI was actually stopped early due to fertility, meaning the data monitoring committee determined that there was no plausible chance of showing benefit, even if the trial continued.

31:04That's a strong signal, not just a null result. The niacin story, the science that I've walked you through, is a reminder of the biomarker trap. HDL levels correlate with lower cardiovascular risk in observational studies, that is true. But that doesn't mean raising HDL through medication or supplementation improves outcomes. The niacin trials, alongside failed trials of other HDL-raising drugs like CETP inhibitors and genetic Mendelian randomisation studies, have raised serious questions about whether HDL is a causal driver of protection or just a marker that tracks with other things. The relationship is much more complex than the simple good cholesterol equals good outcomes framing.

31:53Every single major human trial has failed to show clinical benefit when niacin is added to statin therapy. Now, it is worth noting here an important piece of context, otherwise I might get some pushback. Before statins existed, niacin did show cardiovascular benefit. That is true. the coronary drug project found a 14 % reduction in death from coronary heart disease or myocardial infarction with 3 ,000 mg per day of immediate release niacin as a standalone therapy. The failure is specifically about adding niacin on top of already effective statin therapy, where there's simply less room to benefit.

32:35Aim High and the much larger HPS2 Thrive trial, 25 ,000 patients both confirmed this. HPS2 Thrive also showed increased serious adverse effects including new onset diabetes and gastrointestinal disorders making the risk benefit case even harder to justify. Given statins often combined with other agents in high risk patients are first-line therapy today. Niacin offers no meaningful benefit for people with moderate or high cardiovascular disease that are currently undergoing treatment. However, if for whatever reason someone isn't on a statin, isn't lowering their lipids with medicine, there may be benefit.

33:22And as a reminder, the Coronary Drug Project used 3 ,000 mg per day of immediate release niacin. That's not a casual supplement dose. The side effect profile here is significant and anyone considering it really should do so under medical supervision. The take-home notes here, the lesson from niacin, raising HDL impressively and lowering triglycerides still added nothing meaningful to statin therapy in terms of plaque or cardiovascular events. Once LDL is already well controlled, optimized there's little room left for niacin to add benefit and the side effect burden remains we're four supplements in one with strong evidence epa two with interesting but early imaging signals aged garlic extract and vitamin k2 and one that taught us not to trust biomarkers alone niacin now four more to get through the niacin story is a cautionary tale about biomarkers CoQ10, the next supplement we're covering, is a different kind of story.

34:27It's not about biomarkers that look good but fail to deliver. It's about a supplement with real mechanistic rationale, some supportive data, but a notable absence of the imaging evidence that we would need to say that it actually moves plaque. So what does the evidence actually show for CoQ10? CoQ10 or coenzyme Q10 is an antioxidant that is central to mitochondrial energy production. It helps our cells powerhouses function efficiently. Levels of CoQ10 decline with age and certain medications including statins can reduce them further since statins inhibit a metabolic pathway shared by both cholesterol and CoQ10 synthesis.

35:11In preclinical studies and small human trials, CoQ10 has been shown to support endothelial cell function, the cells that line the arterial wall, reduce markers of oxidative stress, and it may enhance cholesterol efflux from arterial wall cells. These are all mechanisms that are relevant to atherosclerosis. But these findings come largely from cell studies, animal models, and small randomized controlled trials. So how much they translate to meaningful plaque reduction in humans remains an open question. And when it comes to direct plaque imaging evidence, there are no clinical trials demonstrating that CoQ10 alone reduces plaque volume.

35:54The most relevant plaque data comes from a small study combining CoQ10 with aged garlic extract. In this study, 65 participants were given either 1 ,200 mg of aged garlic extract plus 120 mg of CoQ10 or placebo. It's worth noting that this comes from the same research group behind much of the aged garlic extract literature that we went through earlier in this episode. The combination group showed significantly less progression of coronary artery calcification and reductions in inflammatory markers like CRP. But this raises the obvious question, I bet you're thinking this right now. Was it the aged garlic extract, the CoQ10, or their combination?

36:42Well, we can't tell from this study. When it comes to CoQ10 and cardiovascular events, the picture is similarly limited. There is one small older randomized controlled trial, Sing et al., that gave 120 mg per day of CoQ10 to patients who had recently had a heart attack. After one year, total cardiac events were significantly lower in the CoQ10 group compared to controls, around 25 % versus 45%. Now that sounds impressive, but this was a very small trial compared against B vitamins rather than a true placebo and conducted before modern standard of care. It is an interesting signal, but by no means is a settled finding.

37:26There is also the Q-SYMBIO trial showing CoQ10 may reduce mortality and major cardiac events in patients with moderate to severe heart failure. But again, that's a specific population with a different underlying condition to the one that we're focused on in this series on atherosclerosis. Where CoQ10 does have more consistent trial support is in managing statin-associated symptoms. A 2024 systematic review and meta-analysis of seven randomized controlled trials found that CoQ10 supplementation may help reduce muscle pain that some people experience on statins. So if you're on a statin and struggling with that side effect, it's worth discussing CoQ10 with your physician.

38:14That's probably the most evidence-supported use case right now. These trials have used doses ranging from 100 to 200 mg per day, though the evidence on optimal dosing remains unclear. And it's worth noting, the overall evidence for CoQ10 and statin muscle symptoms, it is mixed, with some meta-analyses showing benefit and others not. Overall, CoQ10 has a plausible mechanistic rationale and some cardiovascular support effects observed in smaller studies, better endothelial function, less oxidative stress, improved cellular energy production. And these could theoretically contribute to better arterial health over time.

38:57But the direct plaque imaging evidence doesn't exist and the events data in atherosclerosis populations is absent. So don't take CoQ10 expecting plaque regression or a reduction in cardiovascular events. Neither claim is supported by current trial data. However, if you're on a statin and experiencing muscle symptoms, it may be worth a conversation with your doctor. Next on our list today is berberine. Berberine is the most mechanistically distinct supplement that we're going to talk about today and the one that I find most intellectually interesting. even though I will say the clinical evidence is thin.

39:38It works through a pathway that we haven't touched on yet, your gut. Berberine is extracted from plants like goldenseal and barberry and has been used in traditional medicine for centuries. It's gained modern attention primarily for its glucose-lowering effects, sometimes informally called nature's metformin due to overlapping mechanisms with the diabetes drug, though that comparison does have its limits. Mechanistic studies suggest that berberine reinforces the integrity of blood vessel cells and down-regulates inflammatory pathways, effects that support plaque stabilization. The most direct human evidence that we have comes from a small pilot study of 21 patients with arteriosclerosis.

40:25Using ultrasound to measure plaque scores across 12 positions in the carotid artery. They found a 3.2 % reduction in plaque score after 4 months of berberine supplementation. Super interesting, but with only 21 participants and no control group, this is preliminary signal finding research, not evidence to act on confidently. Much larger, well-controlled trials are needed before that. Berberine may also affect TMAO, a gut-derived compound that is produced when gut bacteria process red meat, eggs, and certain fish. Higher TMAO levels have been associated with increased cardiovascular risk, particularly from Stanley Hazen's group at Cleveland Clinic.

41:09Though whether TMAO causally drives that risk or simply tracks with dietary patterns is still actively debated. Either way, berberine may work, at least in part, by modulating the gut microbiome in ways that affect TMAO production, a cardiovascular pathway that has nothing to do with lipids. Worth noting here that berberine is not without risk. It has meaningful interactions with several medications, including metformin, cyclosporine, and anticoagulants. It can also lower blood glucose, which matters if you're already on glucose-lowering therapy. So as is the case with all of these, please check with your doctor before adding it to your supplement stack.

41:53To summarize, berberine shows potential for plaque stabilization and modest regression through anti-inflammatory, metabolic and gut microbiome modifying pathways. But the human evidence is thin and no studies show that it reduces heart attacks or strokes. It's a supplement worth watching, but clinical recommendations have to wait for outcome data. Moving on to natto kinase. Natto kinase is the one supplement in this episode where two studies point in almost opposite directions, and the reason why matters. Natto kinase is an enzyme derived from natto, a traditional Japanese fermented soybean food that's been consumed in Asia for over a thousand years.

42:39This enzyme is thought to have antithrombotic and fibrinolytic properties, meaning that and it may help break down blood clots and prevent their formation. Nato consumption has also been associated with lower cardiovascular mortality in Japanese populations, though that's observational data and Japan has many other dietary and lifestyle factors that could explain this result. The cardiovascular mechanism here is different from the other supplements that we've discussed. Rather than primarily targeting inflammation or plaque composition, natokinase is thought to work mainly through blood coagulation pathways, reducing clot formation, and improving blood flow.

43:19A large Chinese clinical study followed more than 1 ,000 participants with hyperlipidemia and early carotid plaque over 12 months. At a high dose of 10 ,800 fibrinolytic units or FUs per day, natokinase produced significant reductions in carotid intima media thickness and carotid plaque size, with plaque area reduced by up to 36 % on average. Lipid profiles also improved somewhat. In fact, David Sinclair recently spoke about this study. Here's that clip. The long-term benefit was there was a study with 1 ,086 people, a Chinese study, but it was very well-powered, and they showed that up to 95 % of plaque got removed in one year.

44:03Wow. Just by taking, but you need at least 12 units a day. They're called FU units, but not FU, but five fibrillitic units. So I've been doing that and it's been so far great. I measure my carotid with ultrasound and there's no plaque buildup there at all. So it's hard to reduce that, but I do take it as prevention. Let me see where I am on natokinase. Natokinase is an enzyme that digests fibrin, which is part of - I'm on 100 milligrams. Part of your block. I'm on 100 milligrams of natokinase. I don't know how many units that translates to. Yeah. I would say if you don't want to take a lot of pills, at least 6 ,000 units would be a good start and then work out from there.

44:46But of course, do this with the knowledge of your physician. Sounds exciting, right? However, Dr. Sinclair left a few important pieces of context out. So before you run out to buy natokinase, this study has some important limitations that you should know about. Firstly, a factual correction. Dr. Sinclair said 95 % of plaque was reduced. That's a little inaccurate. In fact, it's inaccurate. The improvement rate refers to the percentage of people who had plaque reduction, not the degree of plaque reduction. Carotid plaque reduced by 36 % on average, not 95%. I'm sure that this was an honest oversight, but I did want to clear it up nonetheless.

45:30Second and most importantly, this was a retrospective observational design. This was not a blinded randomized controlled trial. What do I mean by that? Patients were not randomly assigned to natokinase versus a placebo. The researchers looked back at outcomes in people who had already been taking it, which means we can't rule out confounding. People who choose to take natokinase may differ in other ways from those who don't. The study also didn't control for other lifestyle changes during that period. Diet, exercise, alcohol, other supplements, etc. So we can't rule out that some or all of the improvements came from other health behaviors.

46:14Fortunately, we do have a legitimate randomized controlled trial that's looked at natokinase and atherosclerotic plaque. the natokinase atherothrombotic prevention study, the NAPS trial. This was a double-blind placebo-controlled trial from the University of Southern California. In this study, they randomized 265 healthy adults without cardiovascular disease to either natokinase or placebo for a median of three years. Carotid IMT was measured by ultrasound every six months. The result? No significant difference between natokinase and placebo in the rate of carotid atherosclerosis progression. No effect on blood pressure.

46:58No effect on any of the lab markers measured. Inflammatory markers, blood coagulation factors, metabolic markers, nothing moved. This is a well-designed trial from a credible research group with rigorous ultrasound protocols and centralized reading. The null finding here carries real weight. There are a few possible explanations for why these studies disagree. The most important one is DOS. The two studies used very different amounts, something that I'll come back to in a moment. The populations were also very different. The Chinese study enrolled people with existing hyperlipidemia and plaque, while NAPS enrolled generally healthy, low-risk individuals.

47:41NADOKINase may only have meaningful effects in people with more advanced disease. These are legitimate scientific questions, but there are also questions that remain unanswered. We don't yet have a high-dose, well-designed randomized controlled trial in a higher risk population. Until that exists, we're left in an uncertain position. Natokinase is a supplement where the headline number from the large observational study looks very impressive, but the only rigorous randomized controlled trial was completely null. There are no cardiovascular events trials, the dose question remains unresolved and the mechanism, while plausible, works through blood coagulation rather than the anti-inflammatory pathways that drive the most promising results in this episode.

48:30The Chinese observational data is hypothesis generating at best. What's needed is a well-designed high-dose randomized controlled trial in a higher risk population and that trial hasn't been done yet. One thing worth adding here before we move on from a 2023 systematic review and meta-analysis of randomized controlled trials. Across the controlled trials, natokinase showed a reasonably consistent effect on blood pressure, reducing systolic by about 3.5 millimeters of mercury and diastolic by about 2.3 millimeters of mercury. That is a real replicated finding. Now, what dose is required to get those blood pressure benefits?

49:11This is complicated and worth being transparent about. The blood pressure benefit was seen at around 2 ,000 FUs per day, a dose that was used across multiple randomized controlled trials and generally considered the standard supplementation dose. Whereas the plaque data from the Chinese observational study, which again was not a randomized controlled trial use 10 ,800 FUs per day, which is more than five times higher. So if you're considering natokinase for blood pressure, then 2 ,000 FUs per day has some controlled trial backing. If you're hoping for plaque effects, the dose that was associated with improvements was 10 ,800 FUs, but I can't in good conscience recommend that dose for plaque based on a single observational study.

50:02Either way, given natokinase's blood thinning properties and its interactions with anticoagulants and antiplatelet drugs, this is not a supplement to take without talking to your physician first, especially if you're on existing cardiac medications. Alright, we're nearly there. Last one, pomegranate extract. The animal data here is striking, but the human evidence hasn't caught up yet. Pomegranate extract is rich in polyphenols, plant compounds with potent antioxidant and anti-inflammatory properties that give pomegranates their deep red color. The cardiovascular appeal comes from its ability to reduce oxidative stress and inflammation, two key drivers of atherosclerosis.

50:47In animal models, pomegranate extract reduced plaque size by about 17%, improved plaque stability markers, reduced necrosis, and lowered inflammatory markers. Compelling results, but as we've seen throughout this episode, and as you've learned, no doubt, in other episodes of The Proof, animal models don't always translate to humans. The main positive human imaging study on pomegranate extract is small, just 19 people, 10 in the pomegranate group, and 9 controls, all with severe carotid artery stenosis, which means narrowing. Over one year, the pomegranate juice group saw up to a 30 % reduction in carotid intima media thickness, while the control group saw a 9 % increase.

51:34That magnitude is striking, but 19 people with severe pre-existing stenosis is a very specific and small population, and the result needs independent replication before drawing firm conclusions. The same study found LDL oxidation, a key step in plaque formation, reduced by 90 % and antioxidant enzyme activity increased by 83%. These biochemical changes support the antioxidant and anti-inflammatory mechanism. However, a much larger and better powered trial tells a more sobering story. The Davidson trial, a randomized double-blind study of 289 subjects at moderate cardiovascular risk without significant stenosis, without significant narrowing, had participants drink 240 mls of pomegranate juice per day for up to 18 months.

52:30That's a lot of pomegranate juice. This study found no significant difference in CIMT progression between the pomegranate and control groups. There were hints of benefit in exploratory subgroup analyses for people with higher oxidative stress and worse lipid profiles, but those are hypothesis-generating observations, not confirmatory findings. Taken together, the human CIMT data is mixed at best. The one positive study included 19 people with severe advanced disease. The larger, better-designed trial in a broader, moderate-risk population found nothing. Beyond plaque, pomegranate does have blood pressure data worth noting.

53:12a meta-analysis of 22 randomized controlled trials found it significantly lowered systolic blood pressure by about 8 mmHg and diastolic by about 3 mmHg, with the greatest effects in people who started with higher baseline blood pressure. Of everything we have on pomegranate, the blood pressure benefit is probably the most robustly supported cardiovascular effect. The meta-analysis provides more confidence than any single small imaging study. The mechanistic rationale for pomegranate extract is strong and the animal data is impressive. But the human evidence is mixed. The one positive imaging study was tiny and enrolled people with severe advanced disease and the larger independent trial in moderate risk individuals found no effect.

54:01As we sit here today we're still missing the large independent imaging studies that would let us draw firm conclusions and there are no cardiovascular event trials at all. No data on whether pomegranate reduces heart attacks or strokes in humans. The blood pressure data is by far the most reliable signal that we currently have. So can supplements reverse atherosclerosis? Here's the honest summary of everything we've been through. High-dose EPA, specifically icosapen ethyl, has the strongest case of anything we've covered. Multiple imaging trials showing plaque regression and large outcome trials showing fewer heart attacks and cardiovascular deaths in high-risk patients.

54:44Aged garlic extract and vitamin K2 have early but genuinely interesting imaging signals. CoQ10, berberine, natokinase, pomegranate. These have plausible mechanisms and some supportive data, but not the type of imaging or outcome evidence that you'd want before putting much weight on them. And niacin, well, niacin is a gentle reminder that just because you improve a biomarker, it doesn't mean you've improved the health of your arteries or your risk of having a heart attack or stroke. The big picture, supplements are potential additions to never replacements for proven therapies. If you are at elevated risk, know your numbers, get a coronary artery calcium score if appropriate, talk to your physician, and build a comprehensive approach around the interventions with the strongest evidence.

55:39That means statins, PCSK9 inhibitors, or ezetimibe were indicated. And that often means lipid-lowering therapy. Statins, PCSK9 inhibitors, ezetimibe, and or bempedoic acid were indicated. And if you're already on optimal lip lowering therapy but still have elevated triglycerides, typically 150 mg per deciliter or above, and have either established cardiovascular disease or diabetes with additional risk factors, that's the profile most closely matched to reduce it. talk to your doctor about whether you are a good candidate for prescription EPA, a cosapen ethyl. And remember, a standard over-the-counter fish oil or algae oil is not a substitute for this pure form of EPA.

56:27On a personal note, you may recall from a previous video, my own CT angiogram showed minimal calcification, but there was some soft non-calcified plaque a very very small amount in my left anterior descending artery or LAD. I'm doing a 12 month follow-up scan to establish whether that plaque is regressing, is it stable or progressing and then I'm starting lipid lowering therapy regardless of the result and I'll be walking through that in a future video with aged garlic extract alongside it given the reduction in low attenuation soft plaque that has been shown in trials. I'll track and share that journey in future episodes.

57:10Of course, as a reminder, I'm definitely not suggesting you go out and follow exactly what I follow. Work with your physician and make decisions that are right for your individual presentation and health history. Part three of this series, which is coming up soon, is the pharmaceutical episode statins pcs canine inhibitors bempedoic acid ezetimibe and others and more specifically what the imaging data shows about how those drugs affect plaque in the artery wall so if you're interested in that hit subscribe on youtube or follow on spotify or apple so you don't miss it and if this episode changed how you think about supplements for heart health please share it with your family and or friends as always thanks for hanging out with me stay well and i'll catch you in the next one there you have it friends i hope you enjoyed this episode if you did and want to stay up to date with future episodes be sure to hit that subscribe button on youtube and follow on apple or spotify finally thank you for showing up and the effort that you're making to take control of your health i look forward to hanging out with you again in the next episode Thank you.