Podcast: Are Statins Worth It? (Part 2)

Trying to stay healthy can seem  like a full-time job sometimes.   Especially with all the conflicting  information that’s out there.   But, I’m here to make that job a little easier.   Welcome to the Nutrition Facts podcast, I’m your host Dr. Michael Greger. Today we have Part 2 of our series on statins.   And we start with a look at what happens  when statin-“intolerant” patients  are challenged blindly, to discover how many  are really suffering muscle side effects? In my last video, I tried to quantify the benefits of starting cholesterol-lowering statin drugs, but that’s only half the equation. The number one reason people may refuse to take statins or stop taking them is a concern about side effects. Statins are considered mandatory for secondary prevention, for those with known cardiovascular disease to prevent a second heart attack or stroke, but primary prevention, trying to prevent our first event, is more of a gray area. A hundred adults between the ages of 50 and 75 without known cardiovascular disease would have to be treated with a statin for 2. 5 years to prevent one major adverse cardiovascular event, like a stroke or a heart attack. That’s the upside. The downside, if you treated 10,000 such people for a year, the statins would be expected to cause fifteen cases of muscle symptoms, eight cases of liver dysfunction, twelve cases of kidney dysfunction, and 14 more eye conditions, while at the same time preventing 19 heart attacks, nine strokes, and eight cardiovascular deaths. So, approximately the same risk of having a major side effect or a major benefit, but a benefit like preventing a heart attack or death is more important than avoiding a case of blurred vision; so, these reviewers suggest cardiovascular benefits of statins outweigh adverse effects in primary prevention. But wait. There were only 15 cases of muscle symptoms out of 10,000 people treated? That is based on the clinical trials that found approximately one in a thousand users over a ten-year period develops serious muscle disease. Cases of muscle weakness or muscle breakdown are hard to miss, whereas the incidence of statin-induced muscle aches and pains is far more contentious. Such randomized controlled trials may seriously underestimate adverse effects like muscle pain, since industry-sponsored trials include these run-in periods before the study even starts to exclude people who can’t tolerate the drugs; so, no wonder they see such low rates in the actual trials where all those folks who suffered never made it into the trials in the first place. Furthermore, the majority of clinical trials don’t systematically ask if people are experiencing side effects, since the trials are often run by the company that makes them; so, there’s an incentive to "don’t ask, don’t tell. " Observational studies out in the real world, on the other hand, don’t find muscle symptoms in one in a thousand, but rather one in ten or even one in five, that’s one or two hundred times higher rates than seen in the trials. Some have attributed this difference between observational and experimental studies to the nocebo effect, where patients experience side effects they are expecting, but it’s really all in their head. Or it could be because nearly all trials never actually asked, and even when they did ask, industry-sponsored trials are known to underreport, known to sweep adverse effects under the rug. Finally, statin trials have often excluded patients with a history of muscle problems, who may be in the population most at risk. How do we get to the bottom of this? Well, if you rechallenge patients who claim to be statin intolerant with the real thing or a placebo, you can see what proportion have muscle aches that are actually caused by the drugs, and when you do that, between 1/3 and 1/2 of patients consistently report muscle pain on statins but not placebo. So, yes, a lot of people who think statins are causing their muscle pains are actually mistaken, but, at the same time, a lot of people really are suffering because of these drugs. The European Atherosclerosis Society estimates the overall risk of developing statin-related muscle symptoms to be anywhere from 1 in 14 who go on statins to nearly one in three. Most trials also don’t systematically ask about other potential adverse effects like fatigue, even though fatigue is among the most commonly reported problems by patients on statins. In a non-industry-funded trial on the effects of statins versus placebos, on energy and fatigue with exertion, effectively 4 out of 10 treated women cited worsening in either energy levels or exertional fatigue. What about effects on the brain? In 2012, the U. S. Food and Drug Administration

issued a new warning for the labeling of statin drugs regarding potential adverse effects on cognition, including memory loss and confusion. That was based on early studies like these, but, thankfully, more recent evidence does not strongly support a link between statins and cognitive impairment. By 2015, putting all the relevant studies together, a systematic review concluded that statin therapy did not appear to be associated with cognitive impairment, but again, that’s from clinical trials. What about statin use and dementia risk? Dozens of studies, involving a total of more than seven million patients, found that statin use was linked to lower risks of dementias, like Alzheimer’s disease. This could be because of the role cholesterol plays in the development of Alzheimer’s, as I’ve explored before, but it also could be due to things like "healthy user bias," where people who diligently take statins may also engage in other health-promoting behaviors, and it’s those behaviors that reduce the risk rather than the drugs themselves. In the Alzheimer’s video, I profiled Dr. Dean Ornish’s landmark 2024 study showing that a whole food plant-based diet and other healthy lifestyle behaviors could apparently reverse the progression of early-stage Alzheimer’s disease similar to his previous work showing that a similar plant-based diet and lifestyle could reverse the progression of heart disease, but it doesn’t have to be all or nothing. In the Lyon Diet Heart Study, heart attack survivors were randomized to advice to eat a more Mediterranean-style diet rich in plant-based omega-3s or to just continue to eat whatever their doctors told them to eat. And the dietary advice group ate more bread, more fruit, less ham and sausage and other meat, less butter and cream, and though they didn’t significantly change their fish consumption, they did eat more of a provided butter-less spread enriched with plant-based omega-3s, like the kind found in flaxseeds and walnuts. And check out those survival curves. Over the next five years, only about 5% of the people in the diet group suffered a fatal or nonfatal heart attack, compared to more than 20% of the control group. Health professionals, the pharmaceutical industries, and research funding and regulatory agencies are almost totally focused on lowering cholesterol levels using drugs, so it’s heartening to see a well-conducted study find that relatively simple dietary changes achieved greater reductions in the risk of all-cause mortality and heart disease mortality in a secondary prevention trial than any of the drug studies to date. Diet beat out drugs when it came to death. Despite the striking findings, we’re talking 70% reduction in the risk of premature death from just eating more plant foods and less meat and dairy. Few cardiologists may even be aware of the study, even though it was published in one of the most prestigious medical journals in the world. Finally today which is the  safest and most effective statin? No fewer than 13 Nobel Prizes have been awarded to scientists researching cholesterol, culminating in a constellation of new cholesterol-lowering modalities. Let me simplify. Our liver can make cholesterol from scratch through a long series of reactions, I’ve shown just two here, which can then be packaged and end up as LDL in our bloodstream to deliver cholesterol throughout the body. Now, we don’t want to have too much, as it can lodge in our artery walls, become oxidized, and trigger inflammation that can lead to atherosclerotic plaque and kill us. So, our liver also has LDL receptors that pull LDL out of the blood and dispose of the cholesterol through our bile by dumping it into our digestive tract, presuming our intestines will be packed with dietary fiber that will trap it and ultimately flush it away. But if the cholesterol doesn’t get trapped, it can be reabsorbed and get repackaged as LDL and re-enter our bloodstream. The same if we eat a bunch of cholesterol. But the most important dietary determinant of cholesterol is saturated fat. That reduces the number of LDL receptors; so, more LDL stays in our blood. Okay, stick with me. There’s also a protein called PCSK9 made in our liver that helps break down LDL receptors. I did a video about longevity syndromes, where people who have a faulty PCSK9 gene luckily leading to more LDL receptors and a 90% drop in heart disease risk. We can also boost our number of LDL receptors to pull more LDL out of our blood by cutting down on saturated fat intake, but where do drugs come in? We could also block the absorption and re-absorption

of cholesterol with a drug called ezetimibe. Or, we can block the production of PCSK9, or the activity of PCSK9, so that we can maintain our LDL receptors to pull more LDL out of our blood. These PCSK9 inhibitors cost about $6,000 a year. Inclisiran is more like $10,000 for the first year. And a combo of bempedoic acid and ezetimibe is about $5,000 a year, whereas statins are typically free with insurance, and even out of pocket could just be like 50 bucks a year, especially since you can take the two long-acting ones, atorvastatin and rosuvastatin, every other day and cut the cost in half. You can see why statins are the first-line treatment and have been for nearly 40 years. We actually just lost Dr. Endo, who discovered the first statin. Microbes are constantly at war with each other. We look to fungus like penicillin for compounds that kill bacteria, and we look to bacteria to find antifungal drugs. Since some microbes rely on cholesterol-like sterols, he was hoping to find some other microbe that produced an anti-sterol production compound, and after years looking at approximately 6,000 different microbes, in 1972, he came across this one, a blue-green mold that produced something that worked. If he had given up after 5,000 attempts, then millions more people may have died prematurely in the ensuing decades. If you are going to start a statin, which one’s best? There are seven on the market, lowering LDL levels from about 20% to 60% based on brand and dose. In terms of comparative effectiveness and safety for primary prevention, atorvastatin and rosuvastatin were most effective in reducing cardiovascular disease events, while atorvastatin appeared to have the best safety profile. No wonder atorvastatin became the best-selling drug of all time, raking in more than a hundred billion dollars as Lipitor before it went off patent in 2011. Visit nutritionfacts. org/audio to  see all of the podcast episodes  with descriptions that include  links to their associated videos.   Sources cited and other details  are available on each video's page.   Information about my books How Not to Die, How Not to Diet,   and How Not to Age, and the upcoming How Not   to Hurt, and my primers on Ozempic: Ultrarocessed Foods,   and Natural Approaches to Cholesterol Lowering can be found at nutritionfacts. org/books.   All proceeds from book sales go to charity. And sign up for our free newsletter at   nutritionfacts. org/subscribe to stay updated on the   latest bite-sized videos and articles. NutritionFacts. org is a science-based non-profit,   and everything on the website is free. There are no ads,   no corporate sponsorships, no kickbacks. Strictly non-commercial, not selling anything.   Just put up as a public service, as a labor  of love as a tribute to my grandmother  whose own life was saved with  evidence-based nutrition.