New Treatments for Coronary Artery Disease
In a previous blog, I discussed the Coronary Artery CT Angiogram and why you should have one done. Many people who do this test discover they have plaque in their coronary arteries and wonder what to do about it.
The conventional treatment for known plaques in the coronary arteries is LDL-cholesterol focused. Essentially this means statin drugs and drugs such as Repatha or Nexlitol or which all lower LDL cholesterol synthesis in the liver, and they may be combined with other drugs which reduce cholesterol absorption from the gut, such as ezetimibe. Aspirin and other anticoagulants such as rivaroxaban, may be added for the anticoagulant effect. Unfortunately, none of these measures has been shown to significantly reverse plaque; at best they can stabilize plaque and slow its progression, and they do have some benefit in reducing the risk of heart attack, stroke, and death from atherosclerosis but unfortunately people continue to have heart attacks and strokes while on these standard drugs. In addition, many patients complain of side effects from the LDL-lowering drugs, particularly the statins. Many patients therefore want to know if there are other effective treatments to slow or even reverse coronary artery plaque, which can be added to the standard therapies or perhaps used instead of them. The answer is a qualified yes. There are many newer treatments (or repurposed older drugs) and supplements that have been shown to be effective at reducing the risk of heart attack or death from atherosclerosis and, in some cases, studies have shown plaque reversal.
When evaluating potential additions to or alternatives to statins, or LDL-targeting drugs, it is important to compare their relative benefits. The best measure of this is the NNT or number needed to treat to prevent 1 death or adverse outcome. In general, for a drug to be considered a worthwhile drug, it should have an NNT less than 50. In other words, we should be able to prevent at least one serious adverse outcome for every 50 people we treat with a drug. The NNT can vary based on how likely the adverse effect is in a given patient population. We would expect a lower NNT in patients with a prior heart attack (therefore they have severe atherosclerosis) vs people who are otherwise healthy but just have higher than optimal LDL on a blood test. For statins, in patients who have not yet had a heart attack, the NNT is 100-400 people per 2016 published data. PMID: 31015226 For secondary prevention, ie preventing a second heart attack in those who already had one, the NNT is about 20. Link. That means to prevent 1 person with a recent heart attack from having a second one, we would need to treat about 20 similar patients to prevent one heart attack or death; to prevent one person with high LDL cholesterol but no heart attack yet, from dying of a heart attack, stroke, or from needing coronary artery revascularization, you would need to treat between 100 and 400 people, exposing them to all the potential side effects. Repatha has an NNT of about 30, meaning that of 30 patients with proven coronary plaque, we can prevent one of them by treating all patients with Repatha; in terms of percentage, it reduces the risk of a heart attack by about 30% in high-risk patients. Similar numbers to statins. PMID36531722.
NNT helps us understand how “good” a drug is for a given purpose. We wouldn’t want to take an antibiotic that you have to treat 400 people with urinary burning to stop one case of urinary infection; the same applies to all other drugs. We want an NNT as low as possible.
Here is the latest information on many drugs and supplements that are potentially helpful to treat atherosclerosis and their NNT when available:
- Colchicine (Lodoco). NNT 36. Clinical studies show a 30% reduction in death after a heart attack in patients who took 0.5mg colchicine daily vs. placebo. PMID: 31733140 Colchicine also worked to prevent death or heart attack in patients who had plaque but had no history of heart attack. The risk reduction was also about 30% vs placebo. PMID: 34446156. Mechanism of action is anti-inflammatory, reducing activity of macrophages in plaque. Minimal side effects, such as diarrhea in some patients, some potential drug interactions, and avoid in patients with serious kidney or liver disease. Can be combined with statins. PMID: 37558377
- Semaglutide (Wegovy, Ozempic): NNT 47. In addition to causing weight loss, once per week injections of this medication reduced risk of serious coronary event (heart attack, stroke) by 30% vs placebo in high risk patients with type 2 diabetes over a 2 year period. PMID: 36514266. It works by improving insulin resistance and by causing weight loss by reducing consumed calories, leading to better metabolic health, reflected in lower triglycerides and LDL and higher HDL, etc. Minimal side effects, mainly gastrointestinal issues, as is expected with this class of drugs. PMID: 27633186
- Bempedoic Acid, (Nexletol). NNT 43. Over 4 years, patients treated with this non-statin, LDL-lowering drug had a 20% lower risk of major adverse cardiovascular event (death, heart attack, stroke, need for revascularization). This is comparable to statins if used in high risk patients. No adverse effects, but some increase in uric acid levels and gout attacks. PMID: 36876740
- Ramipril. NNT about 60-100 (stroke vs heart attack or death). This is a type of drug called an ACE-inhibitor, commonly prescribed for hypertension but also reduces risk of adverse cardiovascular events. Data shows a significant, but not as great reduction in cardiovascular complications vs the above drugs. It has been shown to improve endothelial function, a problem underlying the entire origin of plaque in arteries. I recommend it in low dose of 1.25-2.5mg per day in high risk patients. Minimal side effects at this dose, possibly some dizziness or decreased blood pressure. PMID: 12076194
- Metformin. NNT 14. This is a powerful drug in terms of benefit from preventing adverse cardiovascular outcomes. Over a 10-year period, among type-2 diabetics, the risk of death, diabetes-related death, heart attack, or stroke were reduced by about 40%. Minimal side effects, typically some diarrhea. It also reduces weight, risk of death from cancer, and may have anti-ageing effects. It improved cholesterol, LDL, triglycerides as well, likely due to improved metabolic health. It works by reversing insulin resistance at the level of the mitochondria, leading to less inflammation, improved endothelial function. PMID: 3605276
- Fish Oil (Vascepa). NNT 17. A purified version of fish oil at 4grams per day (plus statin drug) showed regression of soft, fatty plaque vs control patients taking only a statin drug, who had plaque enlargement, documented by angiogram. PMID: 32860032 Studies of taking standard fish oil capsules have not shown plaque regression, although fish oil does have an anticlotting effect, similar to aspirin, which could be of benefit in reducing the risk of a heart attack. Vascepa+statin also reduced all cause adverse cardiac events by 25% at 5 years vs. patients taking a statin only.
- Rivaroxiban. This is an anticoagulant, which has been studied in combination with aspirin for the prevention of heart attack, death from heart attack, and stroke. It demonstrated a strong reduction in death rates in both diabetics and non-diabetics. The reduction in the death from heart attack or stroke was about 25% over a 3 year period for both groups. NNT=10 to 100 depending on how high risk the patient. PMID 32223318. PMID 31163978. The reason this works is the root cause event leading to plaque or a cardiovascular death is the formation of a blood clot at the damaged artery wall. Anticoagulants prevent the rapid growth of the plaque, preventing the blood vessel from becoming blocked. They also reduced or prevent the plaque from enlarging since plaques grow by incorporating cholesterol-rich red blood cells as the clot forms.
- Cyclodextrins (Cholrem). NNT unknown as no published clinical trials. PMID: 34829992 This is an experimental, although commercially available medication, already approved by the FDA for human use, which has been shown to induce plaque regression in animal models. No clinical trials in humans have been published thus far. It is used “off label.” It is administered either intravenously or by enema(Cholrem). Intravenous use has been associated with hearing loss, although newer formulations do not appear to carry this risk. PMID: 31843641. It activates macrophages to remove plaque and it then carries the released cholesterol out of the body through the urine. Basically it enhances the natural plaque removal process of the body. There are published cases of plaque regression in humans documented by angiogram. Link
- Plaquex is an intravenous solution of Phosphatidyl Choline which, like Cholrem, appears to activate enzymes that mobilize plaque from arteries. Case reports are available showing reduction of plaque in the carotid arteries by ultrasound after treatment with Plaquex. Unfortunately, we do not have imaging studies of the coronary arteries to demonstrate reduction in plaque, but patients do report relief of angina after treatment, suggesting that it works. Much of the data concerning plaquex has focused on improvement in lipids, which we now know is not the whole story. Modern studies look at the reduction of risk of death or adverse cardiac outcome, not just lipid levels. Since Plaquex is not a patented drug, there is little money to do these trials that look at clinical outcomes. However, it is offered as a treatment by many clinics and is likely beneficial. No toxicity reported. Link
- Tadalafil is FDA approved for ED and pulmonary hypertension. It can be prescribed “off-label” to improve cardiovascular function in general. PMID: 15661417. Tadalafil works by increasing levels of nitrous oxide and improves endothelial function. This should improve coronary artery function as well as treat ED. Tadalafil has been shown to reduce atherosclerosis in animal models. PMID: 26526520
- Rapamycin is FDA approved (as sirolimus) for prevention of organ rejection and it is also used as everolimus in coronary artery stents to prevent atherosclerotic blockage of the stent. It has been shown to extend lifespan in many animal trials and is prescribed “off label” for uses such as anti-aging, usually in a once per week dose. It inhibits an enzyme called mTOR, which is apparently a prerequisite to develop atherosclerosis and thus could possibly be used to treat atherosclerosis. There are no human trials for this use to date, but the basic research seems to suggest it could be effective at inhibiting atherosclerosis. mTor activation is a precursor to forming fatty plaque and foam cells as well as smooth muscle proliferation leading to plaque. Inhibiting mTOR would seem to be a logical way to slow or reverse this process. PMID: 30259816
- EDTA Chelation. A recent clinical trial (TACT) PMID: 23532240 showed a slight reduction (about 5%) in the adverse effect rate of patients with previous heart attack who were treated with 40 IV EDTA chelation infusions (also containing vitamin C and vitamins) over 30 weeks. The subgroup of patients with diabetes showed a greater benefit. The mechanism is not understood; possibly it improved endothelial function by removing heavy metals or via improved nutritional status from the IV vitamins and high dose vitamin C, an antioxidant.
- Nattokinase: There are mixed results for this supplement, which may be due to dosing. At high doses, over 10,000 units/day, it appears to inhibit and even regress atherosclerosis, documented by carotid artery ultrasound, whereas no benefit was seen at lower doses. PMID: 36072877 PMID: 28763875 PMID: 30013308
- Berberine. This is a commonly used herbal product with metformin-like effects in improving insulin sensitivity. It also appears to lower the TMAO levels which are linked to plaque formation. It does so by improving the quality of the microbiome through its antimicrobial effects, thereby reducing TMAO production derived from gut bacteria. Patients taking berberine 500mg twice daily for 4 months showed a reduction in plaque vs patients taking statins and aspirin. PMID: 35794102
- Garlic Extract. This has been shown to reduce coronary artery calcification and lower inflammatory markers in the blood, presumably correlating with a lower risk for atherosclerosis. PMID: 32349742 Garlic extract has also been shown to improve small vessel circulation. PMID: 31518044 Garlic has been shown to inhibit plaque progression vs placebo measured with carotid ultrasound. PMID: 25573347
And finally, Diet and lifestyle. NNT=1(Theoretically). In other words, everyone who eats a healthy diet and lives a healthy lifestyle with plenty of sleep, and lives a low stress life should not suffer an adverse outcome from coronary artery disease. In more primitive parts of the world, "the Blue Zones", not exposed to the western diet and lifestyle, atherosclerotic disease is virtually unknown. When these peoples’ children migrate to the US, their rates of atherosclerosis rapidly catch up to the natives. Clearly diet and lifestyle matter more than anything else. Adopting a healthy diet and lifestyle can cause regression of plaque, PMID 9863851, although there is some disagreement over what exactly the healthy diet should consist of. Guidelines seem to change. My take is that for purposes of plaque prevention and regression, we should adopt a “Paleo-Mediterranean” diet, eating lean proteins from meat, fish, poultry, legumes and plenty of phytonutrient-containing plants, nuts, seeds, berries, and extra-virgin olive oil of high polyphenol content. Avoid grains, sugars and all processed foods, chemicals, preservatives, microplastics, heavy metals, avoid alcohol, don’t smoke, get regular exercise (6 hrs per week in zone 2), sleep enough to get 6 hours of REM/deep sleeper night, avoid stress, practice mindfulness/meditate/relaxation.
