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Tag: Statins

  • How Low Can LDL Cholesterol Go on PCSK9 Inhibitors? | NutritionFacts.org

    People with genetic mutations that leave them with an LDL cholesterol of 30 mg/dL live exceptionally long lives. Can we duplicate that effect with drugs?

    Data extrapolated from large cholesterol-lowering trials using statin drugs suggest that the incidence of cardiovascular events like heart attacks would approach zero if LDL cholesterol could be forced down below 60 mg/dL for first-time prevention and around 30 mg/dL for those trying to prevent another one. But is lower actually better? And is it even safe to have LDL cholesterol levels that low?

    We didn’t know until PCSK9 inhibitors were invented. Are PCSK9 Inhibitors for LDL Cholesterol Safe and Effective? I explore that issue in my video of the same name. PCSK9 is a gene that mutated to give people such low LDL cholesterol, and that’s how Big Pharma thought of trying to cripple PCSK9 with drugs. After a heart attack, intensive lowering of an individual’s LDL cholesterol beyond a target of 70 mg/dL does seem to work better than more moderate lowering. There were fewer cardiovascular deaths, heart attacks, or strokes at an LDL less than 30 mg/dL compared with 70 mg/dL or higher, and even compared to less than 70 mg/dL. There is a consistent risk reduction even when starting as low as an average of 63 mg/dL, and pushing LDL down to 21 mg/dL, remarkably, showed “no observed offsetting” of adverse side effects.

    Maybe that shouldn’t be so surprising, since that’s about the level at which we start life. And there’s another type of genetic mutation that leaves people with LDL levels of about 30 mg/dL their whole lives, and they are known to have an exceptionally long life expectancy. So, where did we get this idea that cholesterol could fall too low?

    The common claim that lowering cholesterol can be dangerous due to depletion of cell cholesterol is unsupported by evidence and does not consider the exquisite balancing mechanisms our body uses. After all, that’s how we evolved. Until recently, most of us used to have LDL levels around 50 mg/dL, so that’s pretty normal for the human species. The absence of evidence that low or lowered cholesterol levels are somehow bad for us contrasts with the overwhelming evidence that cholesterol reduction decreases risk for coronary artery disease, our number one killer.

    What about hormone production, though? Since the body needs cholesterol for the synthesis of steroid hormones—like adrenal hormones and sex hormones—there’s a concern that there wouldn’t be enough. You don’t know, though, until you put it to the test. For decades, we’ve known that women on cholesterol-lowering drugs don’t have a problem with estrogen production and that lowering cholesterol doesn’t affect adrenal gland function. As well, it doesn’t impair testicular function in terms of causing testosterone levels to fall below normal. If anything, statin drugs can improve erectile function in men, which is what you’d expect from lowering cholesterol. But you’ll notice these studies only looked at lowering LDL to 70 mg/dL or below. What about really low LDL?

    On PCSK9 inhibitors, you can get most people under an LDL of 40 mg/dL and some under 15 mg/dL! And there is no evidence that adrenal, ovarian, or testicular hormone production is impaired, even in patients with LDL levels below 15 mg/dL. The risk of heart attacks falls in a straight line as LDL gets lower and lower, even below 10 mg/dL, for example, without apparent safety concerns, but that’s over the duration of exposure to these drugs. The longest follow-up to date of those whose LDL, by way of using multiple medications, was kept less than 30 mg/dL is six years.

    Now, we can take comfort in the fact that those with extreme PCSK9 mutations, leading to a lifelong reduction in levels of LDL to under 20 mg/dL their whole lives, remain healthy and have healthy kids. Cholesterol-affecting mutations are what cause the so-called “longevity syndromes,” but that doesn’t necessarily mean the drugs are safe. The bottom line is we should try to get our LDL cholesterol down as low as we can, but much longer follow-up data are necessary anytime a new class of drugs is introduced. So far, so good, but we’ve only been following the data for about 10 years. For example, we didn’t know statins increased diabetes risk until decades after they were approved and millions had been exposed. Also worth noting: PCSK9 inhibitors cost about $14,000 a year.

    Doctor’s Note

    How can we decrease cholesterol with diet? See Trans Fat, Saturated Fat, and Cholesterol: Tolerable Upper Intake of Zero.

    For more on statin drugs, see the related posts below. 

    Michael Greger M.D. FACLM

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  • Ideal vs. Normal Cholesterol Levels  | NutritionFacts.org

    Having a “normal” cholesterol level in a society where it’s normal to die from a heart attack isn’t necessarily a good thing.

    “Consistent evidence” from a variety of sources “unequivocally establishes” that so-called bad LDL cholesterol causes atherosclerotic cardiovascular disease—strokes and heart attacks, our leading cause of death. This evidence base includes hundreds of studies involving millions of people. “Cholesterol is the cause of atherosclerosis,” the hardening of the arteries, and “the message is loud and clear.” “It’s the Cholesterol, Stupid!” noted the editor of the American Journal of Cardiology, William Clifford Roberts, whose CV is more than 100 pages long as he has published about 1,700 articles in peer-reviewed medical literature. Yes, there are at least ten traditional risk factors for atherosclerosis, as seen below and at 1:11 in my video How Low Should You Go for Ideal LDL Cholesterol?, but, as Dr. Roberts noted, only one is required for the progression of the disease: elevated cholesterol.

    Your doctor may have just told you that your cholesterol is normal, so you’re relieved. Thank goodness! But, having a “normal” cholesterol level in a society where it’s normal to have a fatal heart attack isn’t necessarily good. With heart disease, the number one killer of men and women, we definitely don’t want to have normal cholesterol levels; we want to have optimal levels—and not optimal by current laboratory standards, but optimal for human health.

    Normal LDL cholesterol levels are associated with the hidden buildup of atherosclerotic plaques in our arteries, even in those who have so-called “optimal risk factors by current standards”: blood pressure under 120/80, normal blood sugars, and total cholesterol under 200 mg/dL. If you went to your doctor with those kinds of numbers, you’d likely get a gold star and a lollipop. But, if your doctor used ultrasound and CT scans to actually peek inside your body, atherosclerotic plaques would be detected in about 38% of individuals with those kinds of “optimal” numbers.

    Maybe we should define an LDL cholesterol level as optimal only when it no longer causes disease. What a concept! When more than a thousand men and women in their 40s were scanned, having an LDL level under 130 mg/dL left them with atherosclerosis throughout their body, and that’s a cholesterol level at which most lab tests would consider normal.

    In fact, atherosclerotic plaques were not found with LDL levels down around 50 or 60, which just so happens to be the levels most people had “before the introduction of western lifestyles.” Indeed, before we started eating a typical American diet, “the majority of the adult population of the world had LDLs of around 50 mg per deciliter (mg/dL)”—so that’s the true normal. “Present average values…should not be regarded as ‘normal.’” We don’t want to have a normal cholesterol based on a sick society; we want a cholesterol that is normal for the human species, which may be down around 30 to 70 mg/dL or 0.8 to 1.8 mmol/L.

    “Although an LDL level of 50 to 70 mg/dl seems excessively low by modern American standards, it is precisely the normal range for individuals living the lifestyle and eating the diet for which we are genetically adapted.” Over millions of years, “through the evolution of the ancestors of man,” we’ve consumed a diet centered around whole plant foods. No wonder we have a killer epidemic of atherosclerosis, given the LDL level “we were ‘genetically designed for’ is less than half of what is presently considered ‘normal.’”

    In medicine, “there is an inappropriate tendency to accept small changes in reversible risk factors,” but “the goal is not to decrease risk but to prevent atherosclerotic plaques!” So, how low should you go? “In light of the latest evidence from trials exploring the benefits and risks of profound LDLc lowering, the answer to the question ‘How low do you go?’ is, arguably, a straightforward ‘As low as you can!’” “‘Lower’ may indeed be better,” but if you’re going to do it with drugs, then you have to balance that with the risk of the drug’s side effects.

    Why don’t we just drug everyone with statins, by putting them in the water supply, for instance? Although it would be great if everyone’s cholesterol were lower, there are the countervailing risks of the drugs. So, doctors aim to use statin drugs at the highest dose possible, achieving the largest LDL cholesterol reduction possible without increasing risk of the muscle damage the drugs may cause. But when you’re using lifestyle changes to bring down your cholesterol, all you get are the benefits.

    Can we get our LDL low enough with diet alone? Ask some of the country’s top cholesterol experts what they shoot for, “and the odds are good that many will say 70 or so.” So, yes, we should try to avoid the saturated fats and trans fats found in junk foods and meat, and the dietary cholesterol found mostly in eggs, but “it is unlikely anyone can achieve an LDL cholesterol level of 70 mg/dL with a low-fat, low-cholesterol diet alone.” Really? Many doctors have this mistaken impression. An LDL of 70 isn’t only possible on a healthy enough diet, but it may be normal. Those eating strictly plant-based diets can average an LDL that low, as you can see here and at 5:28 in my video.

    No wonder plant-based diets are the only dietary patterns ever proven to reverse coronary heart disease in a majority of patients. And their side effects? You get to feel better, too! Several randomized clinical trials have demonstrated that more plant-based dietary patterns significantly improve psychological well-being and quality of life, with improvements in depression, anxiety, emotional well-being, physical well-being, and general health.

    For more on cholesterol, see the related posts below.

    Michael Greger M.D. FACLM

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  • A Longer Life on Statins?  | NutritionFacts.org

    What are the pros and cons of relative risk, absolute risk, number needed to treat, and average postponement of death when taking cholesterol-lowering statin drugs?

    In response to the charge that describing the benefits of statin drugs only in terms of relative risk reduction is a “statistical deception” created to give the appearance that statins are more effective than they really are, it was pointed out that describing things in terms of absolute risk reduction or number needed to treat can depend on the duration of the study.

    For example, let’s say a disease has a 2% chance of killing you every year, but some drug cuts that risk by 50%. That sounds amazing, until you realize that, at the end of a year, your risk will only have fallen from 2% to 1%, so the absolute reduction of risk is only 1%. If a hundred people were treated with the drug, instead of two people dying, one person would die, so a hundred people would have to be treated to save one life, as shown below and at 1:01 in my video How Much Longer Do You Live on Statins?.

    But there’s about a 99% chance that taking the drug all year would have no effect either way. So, to say the drug cuts the risk of dying by 50% seems like an overstatement. But think about it: Benefits accrue over time. If there’s a 2% chance of dying every year, year after year, after a few decades, the majority of those who refused the drug would be dead, whereas the majority who took the drug would be alive. So, yes, perhaps during the first year on the drug, there was only about a 1% chance it would be life-saving, but, eventually, you could end up with a decent chance the drug would save your life after all.

    “This is actually the very reason why the usage of relative risk makes sense…” Absolute risk changes depending on the time frame being discussed, but with relative risk, you know that whatever risk you have, you can cut it in half by taking the drug. On average, statins only cut the risk of a cardiovascular “event” by 25%, but since cardiovascular disease is the number one killer of men and women, if you’re unwilling to change your diet, that’s a powerful argument in favor of taking these kinds of drugs. You can see the same kind of dependency on trial duration, looking at the “postponement of death” by taking a statin. How much longer might you live if you take statins?

    The average postponement of death has some advantages over other statistics because it may offer “a better intuitive understanding among lay persons,” whereas a stat like a number needed to treat has more of a win-or-lose “lottery-like” quality. So, when a statin drug prevents, say, one heart attack out of a hundred people treated over five years, it’s not as though the other 99 completely lost out. Their cholesterol also dropped, and their heart disease progression presumably slowed down, too, just not enough to catch a heart attack within that narrow time frame.

    So, what’s the effect of statins on average survival? According to an early estimate, if you put all the randomized trials together, the average postponement of death was calculated at maybe three or four days. Three or four days? Who would take a drug every day for years just to live a few more days? Well, let’s try to put that into context. Three or four days is comparable to the gains in life expectancy from other medical interventions. For example, it’s nearly identical to what you’d get from “highly effective childhood vaccines.” Because vaccines have been so effective in wiping out infectious diseases, these days, they only add an average of three extra days to a child’s life. But, of course, “those whose deaths are averted gain virtually their whole lifetimes.” That’s why we vaccinate. It just seems like such a small average benefit because it gets distributed over the many millions of kids who get the vaccine. Is that the same with statins?

    An updated estimate was published in 2019, which explained that the prior estimate of three or four days was plagued by “important weaknesses,” and the actual average postponement of death was actually ten days. Headline writers went giddy from these data, but what they didn’t understand was that this was only for the duration of the trial. So, if your life expectancy is only five years, then, yes, statins may increase your lifespan by only ten days, but statins are meant to be taken a lot longer than five years. What you want to know is how much longer you might get to live if you stick with the drugs your whole life.

    In that case, it isn’t an extra ten days, but living up to ten extra years. Taking statins can enable you to live years longer. That’s because, for every millimole per liter you lower your bad LDL cholesterol, you may live three years longer and maybe even six more years, depending on which study you’re reading. A millimole in U.S. units is 39 points. Drop your LDL cholesterol by about 39 points, and you could live years longer. Exercise your whole life, and you may only increase your lifespan by six months, and stopping smoking may net you nine months. But if you drop your LDL cholesterol by about 39 points, you could live years longer. You can accomplish that by taking drugs, or you can achieve that within just two weeks of eating a diet packed with fruits, vegetables, and nuts, as seen here and at 5:30 in my video. 

    Want to know what’s better than drugs? “Something important and fundamental has been lost in the controversy around this broad expansion of statin therapy.…It is imperative that physicians (and drug labels) inform patients that not only their lipid [cholesterol] levels but also their cardiovascular risk can be reduced substantially by adoption of a plant-based dietary pattern, and without drugs. Dietary modifications for cardiovascular risk reduction, including plant-based diets, have been shown to improve not only lipid status, but also obesity, hypertension, systemic inflammation, insulin sensitivity, oxidative stress, endothelial function, thrombosis, and cardiovascular event risk…The importance of this [plant-based] approach is magnified when one considers that, in contrast to statins, the ‘side effects’ of plant-based diets—weight loss, more energy, and improved quality of life—are beneficial.” 

    Michael Greger M.D. FACLM

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  • The Real Benefits of Statins and Their Side Effects  | NutritionFacts.org

    A Mayo Clinic visualization tool can help you decide if cholesterol-lowering statin drugs are right for you.

    “Physicians have a duty to inform their patients about the risks and benefits of the interventions available to them. However, physicians rarely communicate with methods that convey absolute information, such as numbers needed to treat, numbers needed to harm, or prolongation of life, despite patients wanting this information.” That is, for example, how many people are actually helped by a particular drug, how many are actually hurt by it, or how much longer the drug will enable you to live, respectively.

    If doctors inform patients only about the relative risk reduction—for example, telling them a pill will cut their risk of heart attacks by 34 percent—nine out of ten agree to take it. However, give them the same information framed as absolute risk reduction—“1.4% fewer patients had heart attacks”—then those agreeing to take the drug drops to only four out of ten. And, if they use the number needed to treat, only three in ten patients would agree to take the pill. So, if you’re a doctor and you really want your patient to take the drug, which statistic are you going to use?

    The use of relative risk stats to inflate the benefits and absolute risk stats to downplay any side effects has been referred to as “statistical deception.” To see how one might spin a study to accomplish this, let’s look at an example. As you can see below and at 1:49 in my video, The True Benefits vs. Side Effects of Statins, there is a significantly lower risk of the incidence of heart attack over five years in study participants randomized to a placebo compared to those getting the drug. If you wanted statins to sound good, you’d use the relative risk reduction (24 percent lower risk). If you wanted statins to sound bad, you’d use the absolute risk reduction (3 percent fewer heart attacks).

    Then you could flip it for side effects. For example, the researchers found that 0.3 percent (1 out of 290 women in the placebo group) got breast cancer over five years, compared to 4.1 percent (12 out of 286) in the statin group. So, a pro-statin spin might be a 24 percent drop in heart attack risk and only 3.8 percent more breast cancers, whereas an anti-statin spin might be only 3 percent fewer heart attacks compared to a 1,267 percent higher risk of breast cancer. Both portrayals are technically true, but you can see how easily you could manipulate people if you picked and chose how you were presenting the risks and benefits. So, ideally, you’d use both the relative risk reduction stat and the absolute risk reduction stat.

    In terms of benefits, when you compile many statin trials, it looks like the relative risk reduction is 25 percent. So, if your ten-year risk of a heart attack or stroke is 5 percent, then taking a statin could lower that from 5 percent to 3.75 percent, for an absolute risk reduction of 1.25 percent, or a number needed to treat of 80, meaning there’s about a 1 in 80 chance that you’d avoid a heart attack or stroke by taking the drug for the next ten years. As you can see, as your baseline risk gets higher and higher, even though you have that same 25 percent risk reduction, your absolute risk reduction gets bigger and bigger. And, with a 20 percent baseline risk, that means you have a 1 in 20 chance of avoiding a heart attack or stroke over the subsequent decade if you take the drug, as seen below and at 3:31 in my video.

    So, those are the benefits. In terms of risk, that breast cancer finding appears to be a fluke. Put together all the studies, and “there was no association between use of statins and the risk of cancer.” In terms of muscle problems, estimates of risk range from approximately 1 in 1,000 to closer to 1 in 50.

    If all those numbers just blur together, the Mayo Clinic developed a great visualization tool, seen below and at 4:39 in my video.

    For those at average risk, 10 people out of 100 who do not take a statin may have a heart attack over the next ten years. If, however, all 100 people took a statin every day for those ten years, 8 would still have a heart attack, but 2 would be spared, so there’s about a 1 in 50 chance that taking the drug would help avert a heart attack over the next decade. What are the downsides? The cost and inconvenience of taking a pill every day, which can cause some gastrointestinal side effects, muscle aching, and stiffness in about 5 percent, reversible liver inflammation in 2 percent, and more serious damage in perhaps 1 in 20,000 patients.

    Note that the two happy faces in the bottom left row of the YES STATIN chart represent heart attacks averted, not lives saved. The chance that a few years of statins will actually save your life if you have no known heart disease is about 1 in 250.

    If you want a more personalized approach, the Mayo Clinic has an interactive tool that lets you calculate your ten-year risk. You can get there directly by going to bit.ly/statindecision.

    Michael Greger M.D. FACLM

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  • Are We Being Misled About the Benefits and Risks of Statins?  | NutritionFacts.org

    What is the dirty little secret of drugs for lifestyle diseases?

    Drug companies go out of their way—in direct-to-consumer ads, for example—to “present pharmaceutical drugs as a preferred solution to cholesterol management while downplaying lifestyle change.” You see this echoed in the medical literature, as in this editorial in the Journal of the American Medical Association: “Despite decades of exhortation for improvement, the high prevalence of poor lifestyle behaviors leading to elevated cardiovascular disease risk factors persists, with myocardial infarction [heart attack] and stroke remaining the leading causes of death in the United States. Clearly, many more adults could benefit from…statins for primary prevention.” Do we really need to put more people on drugs? A reply was published in the British Medical Journal: “Once again, doctors are implored to ‘get real’—stop hoping that efforts to help their patients and communities adopt healthy lifestyle habits will succeed, and start prescribing more statins. This is a self-fulfilling prophecy. Note that the author of these comments [the pro-statin editorial] disclosed receipt of funding from 11 drug companies, at least four of which produce or are developing new classes of cholesterol-lowering agents,” which make billions of dollars a year in annual sales.

    Every time the cholesterol guidelines expand the number of people eligible for statins, they’re decried as a “big kiss to big pharma.” This is understandable, since the majority of guideline panel members “had industry ties,” financial conflicts of interest. But these days, all the major statins are off-patent, so there are inexpensive generic versions. For example, the safest, most effective statin is generic Lipitor, sold as atorvastatin for as little as a few dollars a month. So, nowadays, the cholesterol guidelines are not necessarily “part of an industry plot.”

    “The US way of life is the problem, not the guidelines…” The reason so many people are candidates for cholesterol- and blood-pressure-lowering medications is that so many people are taking such terrible care of themselves. The bottom line is that “individuals must take more responsibility for their own health behaviors.” What if you are unwilling or unable to improve your diet and make lifestyle changes to bring down that risk? If your ten-year risk of having a heart attack is 7.5 percent or more and going to stay that way, then the benefits of taking a statin drug likely outweigh the risk. That’s really for you to decide, though. It’s your body, your choice.

    “Whether or not the overall benefit-harm balance justifies the use of a medication for an individual patient cannot be determined by a guidelines committee, a health care system, or even the attending physician. Instead, it is the individual patient who has a fundamental right to decide whether or not taking a drug is worthwhile.” This was recognized by some of medicine’s “historical luminaries such as Hippocrates,” but “only in recent decades has the medical profession begun to shift from a paternalistic ‘doctor knows best’ stance towards one explicitly endorsing patient-centered, evidence-based, shared decision-making.” One of the problems with communicating statin evidence to support this shared decision-making is that most doctors “have a poor understanding of concepts of risk and probability and…increasing exposure to statistics in undergraduate and postgraduate education hasn’t made much difference.” But that understanding is critical for preventive medicine. When doctors offer a cholesterol-lowering drug, “they’re doing something quite different from treating a patient who has sought help because she is sick. They’re not so much doctors as life insurance salespeople, peddling deferred benefits in exchange for a small (but certainly not negligible) ongoing inconvenience and cost. In this new kind of medicine, not understanding risk is the equivalent of not knowing about the circulation of the blood or basic anatomy. So, let’s dive in and see exactly what’s at stake.

    Below and at 3:55 in my video Are Doctors Misleading Patients About Statin Risks and Benefits? is an ad for Lipitor. When drug companies say a statin reduces the risk of a heart attack by 36 percent, that’s the relative risk.

    If you follow the asterisk I’ve circled after the “36%” in the ad, you can see how they came up with that. I’ve included it here and at 3:56 in my video. In a large clinical study, 3 percent of patients not taking the statin had a heart attack within a certain amount of time, compared to 2 percent of patients who did take the drug. So, the drug dropped heart attack risk from 3 percent to 2 percent; that’s about a one-third drop, hence the 36 percent reduced relative risk statistic. But another way to look at going from 3 percent to 2 percent is that the absolute risk only dropped by 1 percent. So, in effect, “your chance to avoid a nonfatal heart attack during the next 2 years is about 97% without treatment, but you can increase it to about 98% by taking a Crestor [a statin] every day.” Another way to say that is that you’d have to treat 100 people with the drug to prevent a single heart attack. That statistic may shock a lot of people.

    If you ask patients what they’ve been led to believe, they don’t think the chance of avoiding a heart attack within a few years on statins is 1 in 100, but 1 in 2. “On average, it was believed that most patients (53.1%) using statins would avoid a heart attack after statin treatment for 5 years.” Most patients, not just 1 percent of patients. And this “disparity between actual and expected effect could be viewed as a dilemma. On the one hand, it is not ethically acceptable for caregivers to deliberately support and maintain illusive treatment expectations by patients.” We cannot mislead people into thinking a drug works better than it really does, but on the other hand, how else are we going to get people to take their pills?

    When asked, people want an absolute risk reduction of at least about 30 percent to take a cholesterol-lowering drug every day, whereas the actual absolute risk reduction is only about 1 percent. So, the dirty little secret is that, if patients knew the truth about how little these drugs actually worked, almost no one would agree to take them. Doctors are either not educating their patients or actively misinforming them. Given that the majority of patients expect a much larger benefit from statins than they’d get, “there is a tension between the patient’s right to know about benefiting from a preventive drug and the likely reduction in uptake [willingness to take the drugs] if they are so informed,” and learn the truth. This sounds terribly paternalistic, but hundreds of thousands of lives may be at stake.

    If patients were fully informed, people would die. About 20 million Americans are on statins. Even if the drugs saved 1 in 100, that could mean hundreds of thousands of lives lost if everyone stopped taking their statins. “It is ironic that informing patients about statins would increase the very outcomes they were designed to prevent.”

    Michael Greger M.D. FACLM

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  • Should You Take Statins?  | NutritionFacts.org

    How can you calculate your own personal heart disease risk to help you determine if you should start on a cholesterol-lowering statin drug?

    The muscle-related side effects from cholesterol-lowering statins “are often severe enough for patients to stop taking the drug. Of course, these side effects could be coincidental or psychosomatic and have nothing to do with the drug,” given that many clinical trials show such side effects are rare. “It is also possible that previous clinical trials”—funded by the drug companies themselves—“under-recorded the side effects of statins.” The bottom line is that there’s an urgent need to establish the true incidence of statin side effects.

    “What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug?” That’s the title of a journal article that reports that, even in trials funded by Big Pharma, “only a small minority of symptoms reported on statins are genuinely due to the statins,” and those taking statins are significantly more likely to develop type 2 diabetes than those randomized to placebo sugar pills. Why? We’re still not exactly sure, but statins may have the double-whammy effect of impairing insulin secretion from the pancreas while also diminishing insulin’s effectiveness by increasing insulin resistance.

    Even short-term use of statins may “approximately double the odds of developing diabetes and diabetic complications.” As shown below and at 1:49 in my video Who Should Take Statins?, fewer people develop diabetes and diabetic complications off statins over a period of about five years than those who do develop diabetes while on statins. “Of more concern, this increased risk persisted for at least 5 years after statin use stopped.”

    “In view of the overwhelming benefit of statins in the reduction of cardiovascular events,” the number one killer of men and women, any increase in risk of diabetes, our seventh leading cause of death, would be outweighed by any cardiovascular benefits, right? That’s a false dichotomy. We don’t have to choose between heart disease and diabetes. We can treat the cause of both with the same diet and lifestyle changes. The diet that can not only stop heart disease, but also reverse it, is the same one that can reverse type 2 diabetes. But what if, for whatever reason, you refuse to change your diet and lifestyle? In that case, what are the risks and benefits of starting statins? Don’t expect to get the full scoop from your doctor, as most seemed clueless about statins’ causal link with diabetes, so only a small fraction even bring it up with their patients.

    “Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.” But that’s for you to decide. Before we quantify exactly what the risks and benefits are, what exactly are the recommendations of current guidelines?

    How should you decide if a statin is right for you? “If you have a history of heart disease or stroke, taking a statin medication is recommended, without considering your cholesterol levels.” Period. Full stop. No discussion needed. “If you do not yet have any known cardiovascular disease,” then the decision should be based on calculating your own personal risk. If you know your cholesterol and blood pressure numbers, it’s easy to do that online with the American College of Cardiology risk estimator or the Framingham risk profiler.

    My favorite is the American College of Cardiology’s estimator because it gives you your current ten-year risk and also your lifetime risk. So, for a person with a 5.8 percent risk of having a heart attack or stroke within the next decade, if they don’t clean up their act, that lifetime risk jumps to 46 percent, nearly a flip of the coin. If they improved their cholesterol and blood pressure, though, they could reduce that risk by more than tenfold, down to 3.9 percent, as shown below and at 4:11 in my video.

    Since the statin decision is based on your ten-year risk, what do you do with that number? As you can see here and at 4:48 in my video, under the current guidelines, if your ten-year risk is under 5 percent, then, unless there are extenuating circumstances, you should just stick to diet, exercise, and smoking cessation to bring down your numbers. In contrast, if your ten-year risk hits 20 percent, then the recommendation is to add a statin drug on top of making lifestyle modifications. Unless there are risk-enhancing factors, the tendency is to stick with lifestyle changes if risk is less than 7.5 percent and to move towards adding drugs if above 7.5 percent.

    Risk-enhancing factors that your doctor should take into account when helping you make the decision include a bad family history, really high LDL cholesterol, metabolic syndrome, chronic kidney or inflammatory conditions, or persistently high triglycerides, C-reactive protein, or LP(a). You can see the whole list here and at 4:54 in my video.

    If you’re still uncertain, guidelines suggest you consider getting a coronary artery calcium (CAC) score, but even though the radiation exposure from that test is relatively low these days, the U.S. Preventive Services Task Force has explicitly concluded that the current evidence is insufficient to conclude that the benefits outweigh the harms.

    Michael Greger M.D. FACLM

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  • Statins and Muscle Pain Side Effects  | NutritionFacts.org

    Why is the incidence of side effects from statins so low in clinical trials while appearing to be so high in the real world?

    “There is now overwhelming evidence to support reducing LDL-C (low-density lipoprotein cholesterol)”—so-called bad cholesterol—to reduce atherosclerotic cardiovascular disease (CVD),” the number one killer of men and women. So, why is adherence to cholesterol-lowering statin drug therapy such “a major challenge worldwide”? Researchers found “that the majority of studies reported that at least 40%, and as much as 80%, of patients did not comply fully with statin treatment recommendations.” Three-quarters of patients may flat out stop taking them, and almost 90 percent may discontinue treatment altogether.

    When asked why they stopped taking the pills, most “former statin users or discontinuers…cited muscle pain, a side effect, as the primary reason…” “SAMSs”—statin-associated muscle symptoms—“are by far the most prevalent and important adverse event, with up to 72% of all statin adverse events being muscle-related.” Taking coenzyme Q10 supplements as a treatment for statin-associated muscle symptoms was a good idea in theory, but they don’t appear to help. Normally, side-effect symptoms go away when you stop the drug but can sometimes linger for a year or more. There is “growing evidence that statin intolerance is predominantly psychosocial, not pharmacological.” Really? It may be mostly just in people’s heads?

    “Statins have developed a bad reputation with the public, a phenomenon driven largely by proliferation on the Internet of bizarre and unscientific but seemingly persuasive criticism of these drugs.” “Does Googling lead to statin intolerance?” But people have stopped taking statins for decades before there even was an Internet. What kinds of data have doctors suggested that patients are falsely “misattribut[ing] normal aches and pains to be statin side effects”?

    Well, if you take people who claim to have statin-related muscle pain and randomize them back and forth between statins and an identical-looking placebo in three-week blocks, they can’t tell whether they’re getting the real drug or the sugar pill. The problem with that study, though, is that it may take months not only to develop statin-induced muscle pain, but months before it goes away, so no wonder three weeks on and three weeks off may not be long enough for the participants to discern which is which.

    However, these data are more convincing: Ten thousand people were randomized to a statin or a sugar pill for a few years, but so many more people were dying in the sugar pill group that the study had to be stopped prematurely. So then everyone was offered the statin, and the researchers noted that there was “no excess of reports of muscle-related AEs” (adverse effects) among patients assigned to the statin over those assigned to the placebo. But when the placebo phase was over and the people knew they were on a statin, they went on to report more muscle side effects than those who knew they weren’t taking the statin. “These analyses illustrate the so-called nocebo effect,” which is akin to the opposite of the placebo effect.

    Placebo effects are positive consequences falsely attributed to a treatment, whereas nocebo effects are negative consequences falsely attributed to a treatment, as was evidently seen here. There was an excess rate of muscle-related adverse effects reported only when patients and their doctors were aware that statin therapy was being used, and not when its use was concealed. The researchers hope “these results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter…exaggerated claims about statin-related side effects.”

    These are the kinds of results from “placebo-controlled randomised trials [that] have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution.)” Now, “only a few patients will believe that their SAMS are of psychogenic origin” and just in their head, but their denial may have “deadly consequences.” Indeed, “discontinuing statin treatment may be a life-threatening mistake.”

    Below and at 4:46 in my video How Common Are Muscle Side Effects from Statins?, you can see the mortality of those who stopped their statins after having a possible adverse reaction compared to those who stuck with them. This translates into about “1 excess death for every 83 patients who discontinued treatment” within a four-year period. So, when there are media reports about statin side effects and people stop taking them, this could “result in thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided. Seldom in the history of modern therapeutics have the substantial proven benefits of a treatment been compromised to such an extent by serious misrepresentations of the evidence for its safety.” But is it a misrepresentation to suggest “that statin therapy causes side-effects in up to one fifth of patients”? That is what is seen in clinical practice; between 10 to 25 percent of patients placed on statins complain of muscle problems. However, because we don’t see anywhere near those kinds of numbers in controlled trials, patients are accused of being confused. Why is the incidence of side effects from statins so low in clinical trials while appearing to be so high in the real world? 

    Take this meta-analysis of clinical trials, for example: It found muscle problems not in 1 in 5 patients, but only 1 in 2,000. Should everyone over a certain age be on statins? Not surprisingly, every one of those trials was funded by statin manufacturers themselves. So, for example, “how could the statin RCTs [randomized controlled trials] miss detecting mild statin-related muscle adverse side effects such as myalgia [muscle pain]? By not asking. A review of 44 statin RCTs reveals that only 1 directly asked about muscle-related adverse effects.” So, are the vast majority of side effects just being missed in all these trials, or are the vast majority of side effects seen in clinical practice just a figment of patients’ imagination? The bottom line is we don’t know, but there is certainly an urgent need to figure it out.

    Michael Greger M.D. FACLM

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  • The 411 on Statins | NutritionFacts.org

    The 411 on Statins | NutritionFacts.org

    The cholesterol-lowering statin drug Lipitor has become the best-selling drug of all time, generating more than $140 billion in global sales. This class of drugs garnered so much enthusiasm in the medical community that some U.S. health authorities facetiously proposed they be added to the public water supply like fluoride is. One cardiology journal even offered the tongue-in-cheek suggestion for fast-food restaurants to offer “MacStatin” [sic] condiments along with ketchup packets to help neutralize the effects of unhealthy dietary choices.

    What Are Statins and How Do They Work?

    Statins are drugs that can lower cholesterol. They work by blocking a substance that our body requires to make cholesterol.

    Are Statins Bad for You?

    Although statins may be effective at lowering cholesterol and potentially helping to reduce the risk of heart disease and even stroke, they come with a host of possible side effects that may do much more harm than good.

    What Possible Side Effects?

    As I discuss in the video Who Should Take Statins?, muscle-related side effects from cholesterol-lowering statin drugs “are often severe enough [to make] patients stop taking [them]. Of course, these side effects could be coincidental or psychosomatic and nothing to do with the drug,” given that many clinical trials show such side effects are rare. Of course, it is also possible that studies funded by the drug companies themselves may under-report side effects. The bottom line is that there’s an urgent need to establish the true incidence of statin side effects.

    Researchers have found that those taking statins are significantly more likely to develop type 2 diabetes than those randomized to placebo sugar pills. Why? We’re still not exactly sure, but statins may have the double-whammy effect of impairing insulin secretion from the pancreas, as well as diminishing insulin’s effectiveness by increasing insulin resistance.

    Even short-term statin use may approximately “double the odds of developing diabetes and diabetic complications,” and increased risks may persist for years after stopping statins.

    Who Should Take Statins?

    How should you decide if a statin is right for you? “If you have a history of heart disease or stroke, taking a statin medication is recommended.” Period. Full stop. No discussion needed. However, if you don’t have any known cardiovascular disease, then the decision should be based on calculating your own personal risk, which you can easily do online if you know your cholesterol and blood pressure numbers, with the American College of Cardiology risk estimator or the Framingham risk profiler. (My favorite is the ACC estimator because it gives your current ten-year risk, as well as your lifetime risk.)

    Under the current guidelines, if your ten-year risk is below 5 percent, unless there are extenuating circumstances, you should stick to diet, exercise, and smoking cessation to bring down your numbers. In contrast, if your ten-year risk hits or exceeds 20 percent, then the recommendation is to add a statin drug on top of making lifestyle modifications. Under 7.5 percent, the tendency is to stick with lifestyle changes unless there are risk-enhancing factors; above 7.5 percent, move towards adding drugs. What are the risk-enhancing factors to take into account when making the decision? A bad family history, really high LDL, metabolic syndrome, chronic kidney or inflammatory conditions, and persistently high triglycerides, C-reactive protein, or LP(a).

    Relative Risk vs. Absolute Risk

    One of the problems with communicating statin evidence to support shared decision-making is that most doctors have a poor understanding of concepts of risk, probability, and statistics, but that understanding is critical for preventive medicine. As discussed in my video Are Doctors Misleading Patients About Statin Risks and Benefits?, when doctors offer a cholesterol-lowering drug, they’re doing something quite different from treating a patient who is sick.

    When drug companies say a statin reduces the risk of a heart attack by 36 percent, that’s the relative risk. In a large clinical study, 3 percent of patients not taking the statin drug had a heart attack within a certain amount of time, compared to 2 percent taking the drug. So, the drug dropped heart attack risk from about 3 percent to 2 percent, which is about a one-third drop—hence, the 36 percent reduced relative risk statistic. Another way to look at the change from 3 percent to 2 percent is that the absolute risk only dropped 1 percent. So, in effect, one’s chance of avoiding a heart attack over the next few years may be about 97 percent without treatment, but it can be increased to about 98 percent by taking daily statin drug. Yet another way to look at it: A hundred people would need to take the drug to prevent a single heart attack.

    The Myth vs. the Reality

    If you ask patients what they were led to believe, they think the chance of avoiding a heart attack within a few years on statins is 1 in 2, when it’s really 1 in a 100. And, if you ask, they want an absolute risk reduction of at least 30 percent or so to take a cholesterol-lowering drug every day, whereas the actual absolute risk reduction is only about 1 percent. So, the dirty little secret is that if patients knew the truth about how little these drugs actually worked, almost no one would agree to take them. So, doctors are either not educating their patients or they’re actively misinforming them.

    Weighing the Risks and Benefits of Statins

    If all those numbers are blurring together, the Mayo Clinic developed a great visualization tool. For individuals at average risk who do not take a daily statin, 10 out of 100 may have a heart attack over the next ten years. However, if all 100 people took a statin every day for those ten years, 8 would have a heart attack and 2 would be spared. That’s about a 1 in 50 chance that taking the drug would help you avert a heart attack over the next decade. What if you have no known heart disease and you take statins for a few years? The chance statins will actually save your life is about 1 in 250.

    What are the downsides? The cost and inconvenience of taking a pill every day, which can cause some gastrointestinal side effects, muscle aching and stiffness in maybe 5 percent, reversible liver inflammation in 2 percent, and more serious damage in perhaps 1 in 20,000 patients.

    Mayo Clinic's visualization tool for the benefits and risks of statins

    If you want a more personalized approach, calculate your ten-year risk. I cover this in more detail in my video The True Benefits vs. Side Effects of Statins.

    Alternatives to Statins?

    As I discuss in my video How Much Longer Do You Live on Statins?, taking statins can enable you to live years longer because, for every millimole per liter you drop your bad LDL cholesterol, you may live three or even six years longer, depending on which study you’re reading. A millimole in U.S. units (mg/dL) is 39 points. Drop your LDL cholesterol about 39 mg/dL or 1 mmol/L, and you could live years longer. Exercise your whole life, and you may only increase your lifespan by six months, whereas stopping smoking may net you nine months. So, how can you drop your LDL cholesterol by about 39 points? You can accomplish that by taking drugs every day, or you can achieve that within just two weeks of eating a diet packed with fruits, vegetables, and nuts.

    table showing the effects of a vegetable diet on cholesterol levels

    A plant-based diet has been shown to substantially reduce cholesterol levels and cardiovascular risk, as well as obesity, hypertension, and systemic inflammation—without negative side effects.

    Michael Greger M.D. FACLM

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  • America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

    America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

    Statins, one of the most extensively studied drugs on the planet, taken by tens of millions of Americans alone, have long had a perplexing side effect. Many patients—some 5 percent in clinical trials, and up to 30 percent in observational studies—experience sore and achy muscles, especially in the upper arms and legs. A much smaller proportion, less than 1 percent, develop muscle weakness or myopathy severe enough that they find it hard to “climb stairs, get up from a sofa, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. He’s had patients fall on the street because they couldn’t lift their leg over a curb.

    But why should an anticholesterol drug weaken muscles in the arms and legs? Recently, two groups of scientists stumbled upon an answer. They didn’t set out to study statins. They weren’t studying cholesterol at all. They were hunting for genes behind a rare disease called limb girdle muscle dystrophy, in which muscles of the upper arms and legs—sound familiar?—become weak and waste away. After both teams tracked the disease through a handful of families in the U.S. and a Bedouin family in Israel, their suspicions separately landed on mutations in a gene encoding a particularly intriguing enzyme.

    The enzyme is known as HMG-CoA reductase, and to doctors, it is not obscure. It is, in fact, the very enzyme that statins block in the process of halting cholesterol production. And so, the answers to two mysteries suddenly became clear at once: Dysfunction in this enzyme causes muscle weakness from both limb girdle muscular dystrophy and statins.

    This connection between a rare disease and a common drug stunned the researchers. “It seemed too good to be true,” says Joel Morales-Rosado, a pathologist who worked on one of the studies as a postdoctoral researcher at the Mayo Clinic. “One of the first things you learn in medical school is association between statins and myopathy.” Now the answer as to why— along with a potential treatment for it—has emerged from the DNA of just a few patients living with a seemingly unrelated genetic disease.

    The first patient the Mayo team studied had been showing signs of limb girdle muscular dystrophy since he was a child, and his symptoms worsened over time until he lost the ability to walk or breathe with ease. (The disease can also affect large muscles in the torso.) Now in his 30s, he wanted to know the genetic cause of his disease before having children and potentially passing it on to them. His two brothers had the disease as well. So the team looked for genes in which all three brothers had mutations in both copies, which is how they zeroed in on the gene for HMG-CoA reductase.

    Six more patients from four other families confirmed the link. They too all had mutations in the same gene, and they too were all diagnosed with some degree of limb girdle muscular dystrophy. (Interestingly, for reasons we don’t entirely understand, they all have normal or low cholesterol.)

    Unbeknownst to the Mayo team, a group of researchers halfway around the world was already studying a large Bedouin family with a history of limb girdle muscular dystrophy. This family also carried mutations in the gene encoding HMG-CoA reductase. Those afflicted began experiencing minor symptoms in their 30s, such as muscle cramps, that worsened over time. The oldest family members, in their late 40s or 50s, had lost all movement in their arms and legs. One bedridden woman had to be ventilated full-time through a hole in her windpipe. Another had died in their mid-50s, Ohad Birk, a geneticist and doctor at Ben-Gurion University of the Negev, in Israel, told me. When his team saw that this family had the mutations in HMG-CoA reductase, they too immediately recognized the potential link to statins.

    This pair of studies in the U.S. and Israel “really strongly suggests” that statins cause muscle damage via the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in either study. The enzyme’s role had been suspected, he told me, but “it had never been proven, especially in humans.” (Questions still remain, however. The enzyme, for example, is found in tissues throughout the body, so why do these common side effects show up in muscles specifically?) Rosenson, at Mount Sinai, wondered if variations in this gene could explain why statins don’t affect everyone the same. Perhaps patients who suffer particularly severe muscle side effects already have less functional versions of the enzyme, which becomes problematic only when they start taking statins, which reduce its function even further. This research might end up concretely improving the life of at least some of the patients most severely affected by statins.

    That’s because Birk’s team in Israel did not stop at simply identifying the mutation. For two decades, he and his colleagues have been studying genetic disorders in this Bedouin community in the Negev and developing genetic tests so parents can avoid passing them on to their children. (Cousin marriages are traditional there, and when two parents are related, they are more likely to carry and pass on the same mutation to a child.) With limb girdle muscular dystrophy, his team went one step further than usual: They found a drug to treat it.

    This drug, called mevalonolactone, allows muscle cells to function more normally even without the HMG-CoA reductase enzyme. Birk’s team first tested it in mice given doses of statins high enough to weaken their limbs; those also given mevalonolactone continued to crawl and even hang upside down on a wire just fine. They seemed to suffer no ill effects. When that experimental drug was given to the Bedouin woman bedridden with limb girdle muscular dystrophy, she also started regaining control of her arms and legs. She could eventually lift her arm, sit up by herself, raise her knees, and even feed her grandchild on her own. It was a dramatic improvement. Birk told me he has since heard about dozens of patients with limb girdle muscular dystrophy around the world who may benefit from this experimental drug.

    Mammen and others think the drug could help a small subset of patients who take statins as well. However, the majority of patients—those with relatively minor pains or weaknesses that go away after they switch statins or have their dosage reduced—probably don’t need this new treatment. It probably even undermines the whole point of taking statins: Mevalonolactone eventually gets turned into cholesterol in the body, so “you’re basically supplying the building blocks for making more cholesterol,” Mammen said. But for some people, numbering in the thousands, severe muscle weakness does not go away even after they stop taking statins. These patients have developed antibodies to HMG-CoA reductase, which Mammen suspects continue to bind and disable the enzyme.

    Mammen is eager for these patients to try mevalonolactone, and he’s been in touch with Birk, who unfortunately doesn’t have enough of the drug to share. In fact, he doesn’t even have enough to treat all of the other family members in Israel who are clamoring for it. “We’re not a factory. We’re a research lab,” Birk told me. Mevalonolactone is available as a research chemical, but that’s not pure and safe enough for human consumption. Birk’s graduate student Yuval Yogev had to manufacture the drug himself by genetically engineering bacteria to make mevalonolactone, which he then painstakingly purified. Making a drug to this standard is a huge amount of work, even for commercial labs. Birk is looking for a pharmaceutical company that could manufacture the drug at scale—for both patients with limb girdle muscular dystrophy and those with the most severe forms of statin-associated muscle damage.

    Back in 1980, the very first person to receive an experimental dose of statins suffered muscle weakness so severe, she could not walk. (She had been given an extremely high dose.) Forty years later, muscle pain and weakness are still common reasons patients quit these very effective drugs. This recent breakthrough is finally pointing researchers toward a better understanding of statins’ toll on muscles, even if they still can’t fix it for everyone.

    Sarah Zhang

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