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What are the benefits of statins in terms of prolonging life?

What are the benefits of statins in terms of prolonging life?


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Recently the UK government suggested that all adults over the age of 50, without exception, would benefit from taking statins.

I have an elderly female relative who may, or may not have had a minor cardiac event (the diagnosis is still out) and low blood pressure. It has been suggested to them that they would benefit from statins and have asked me (a former biologist) to find out more.

I've had a look at the mechanisms of action, which seem clear. But the clinical data is somewhat confusing.

It seems we can state with certainty that a small but significant number of users report relatively minor side effects, and a very tiny minority have serious ones.

In term of the benefits, however, the picture is much less clear. I have found a variety of statistics about how they reduce cardiac events but what this translates to in terms of length of life and quality of life is not stated.

One article I looked at suggested that on average, someone at high risk of heart disease taking statins for 30 years would only live an extra 9 months.

The author of that site has a book to sell, and may have an axe to grind. But there are several other articles out there - such as this, and this and this - which make worrying claims about statins being both more unsafe and less beneficial than clinical trials suggest. In particular there seems very limited evidence of any benefits to women.

I am inclined to treat these as alarmist nonsense - they have that sense of hysteria about them. But given that the authors look legitimate, that clinical trials data do not appear to agree with one another (widely varying in the percentage of users reporting side effects, for example), and that this is a relative, I wanted to get a second opinion.

So - can someone please crunch the numbers and tell me what the benefits of statin use are in terms of life years and quality of life? Is there any benefit for women with or without heart disease? And is there any basis to some of the alarmism around their use?


I suspect I won't be crunching as much numbers as you'd want me to, however here are some basic points:

  • Statins have shown a clear ability to improve the blood llipid profile.
  • Their use in primary/secondary prevention for cardiac events is justified by the belief that less blood lipid will leave less lipids to clog the arteries with. This is an old paradigm, and it is debated, even if we nowadays indeed give statins to all (potential) cardiac patients. There is evidence for a positive effect of those drugs, but it is not undisputable.
  • An enormous amount of money is made from statins, and the pharma pushes very hard for their use.
  • They do have undesirable effects, but those appear mostly early, so patients are usually well monitored for them and they mostly pose no real threat.

On the subject of women: women before menopause are protected from cardiac events by their hormone profile, and would therefore likely benefit very little from statins at that time. After menopause, women present the same cardiac risk as men do. I do not know if studies have shown a difference in outcome for statins in postmenopausal women. If you want to know more, I advise you to go searching for it on Pubmed

DISCLAIMER: The above does not represent professional medical advice, and is subject to debate.


3 Myths About Cholesterol-Lowering Statin Drugs

If you&rsquove swapped bad habits (hello, nightly takeout and binge-watching your favorite program) for good ones such as going for a jog and cooking a healthy meal at home, you&rsquore on the right track for keeping or getting your cholesterol levels within a normal range.

But sometimes making lifestyle adjustments isn&rsquot enough to reduce your cholesterol. That&rsquos when your doctor may recommend medications.

Statin drugs are prescription medications that lower cholesterol and prevent cardiovascular disease, which is the leading cause of death in the United States. Often the first line of therapy after lifestyle changes, statins can reduce the risk of stroke, heart attack and even death from cardiovascular disease by 25 percent or more. If you&rsquove already experienced a cardiovascular event, statins are a mainstay of long-term preventive therapy to reduce the chance it will happen again.

Although statins benefit those most at risk for cardiovascular disease, many people have concerns about taking this class of drug. &ldquoIn general, there&rsquos been an exaggeration of the dangers of statins,&rdquo says Seth Martin, M.D., M.H.S., associate professor of medicine at the Johns Hopkins University School of Medicine and director of the Advanced Lipid Disorders Center. &ldquoStatins have a solid track record. In monitoring people taking statins for decades, we&rsquove found that they&rsquore safe and most people tolerate them well without any problems. But still, these misconceptions persist.&rdquo


Cholesterol, statins, and longevity from age 70 to 90 years

Background: The importance of cholesterol as a risk factor among older people, particularly among the very old, is controversial. Whether or not hypercholesterolemia warrants medical concern, and whether statins are beneficial among very old people, remain unresolved common clinical dilemmas. This study examines whether increased total cholesterol (TC) was associated with higher mortality from age 70 to 90, and if statins had a protective effect.

Methods: A representative sample (born 1920-1921) from the Jerusalem Longitudinal Cohort Study (1990-2010) was assessed at ages 70, 78, and 85 for fasting serum TC, low-density (LDL), and high-density lipoprotein (LDL) triglycerides statin usage social, functional, and medical domains and all-cause mortality data (1990-2010). TC was analyzed as either continuous (10 mg/dL increments) or dichotomous variable (high TC >200 mg/dL). Cox proportional hazards models determined mortality hazard ratios (HRs), adjusting for TC, statin treatment, gender, self-rated health, smoking, hypertension, diabetes, ischemic heart disease, neoplasm, body mass index, albumin, and triglycerides.

Results: Prevalence of high TC at ages 70, 78, and 85 was 75% (n = 344), 65% (n = 332), and 34% (n = 237), and statin use was 0%, 17.9%, and 45.4%, respectively. Survival was increased (not significantly) among subjects with high TC >200 mg/dL versus ≤200 mg/dL from ages 70 to 78, 78 to 85, and 85 to 90: 79.1% versus 73.3% (log rank P = .16), 68.7% versus 61.5% (P = .10), and 73.4% versus 70.3% (P = .45), respectively. Survival was significantly increased among subjects treated with statins versus no statins at ages 78 to 85 (74.7% vs 64.3%, log rank P = .07) and 85 to 90 (76.2% vs 67.4%, P = .01). After adjustment, TC (continuous or dichotomous) was not associated with mortality from 70 to 78, 78 to 85, or 85 to 90. In contrast, statins at age 85 were associated with decreased mortality from age 85 to 90 (adjusted HR 0.61, 95% confidence interval 0.42-0.89).

Conclusions: Among older people, cholesterol levels were unrelated to mortality between the ages of 70 and 90. The protective effect of statins observed among the very old appears to be independent of TC.

Keywords: Cholesterol longevity longitudinal cohort study oldest old statins.

Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.


Statins do not benefit patients with lung cancer, new study shows

Cholesterol-lowering drugs used alongside chemotherapy have no effect on treatment outcomes for lung cancer patients, according to a new study.

Recent research into statins has claimed a role for the drugs in preventing cancer development, or prolonging the survival of patients with several common cancers, including lung cancer, and so generated much interest in the medical community. But evidence published by a team from Imperial College London and UCL (University College London) shows that the drugs do not, in fact, benefit lung cancer patients at all.

The research team believe the new evidence is so compelling that existing or new planned trials into the use of statins in cancer treatment should be reconsidered.

The study, funded by Cancer Research UK, is published in the Journal of Clinical Oncology.

Statins work by lowering cholesterol levels in patients and are usually prescribed by doctors to help prevent heart attacks or strokes. A number of small-scale studies published over the past five years have investigated the potential for statins to restrict the growth and survival of cancer cells.

Because cholesterol plays a key role in cell growth messages, it was initially thought that lowering the levels of cholesterol could impair the development and growth of cancer cells. Cholesterol was also believed to delay the recurrence of cancer after treatment has been completed. Collectively these effects were thought to improve the survival of cancer patients.

In the largest randomised trial of statin therapy in cancer patients yet completed, the Imperial team measured the effects of a leading statin, called pravastatin, in patients with small cell lung cancer -- a particularly aggressive form of lung cancer where new treatments are desperately needed.

The study included 846 patients from 91 hospitals in the UK and was carried out at the Cancer Research UK & UCL Cancer Trials Centre at the UCL Cancer Institute. Patients were randomly selected to receive either the statin or a placebo alongside their usual chemotherapy treatment, and monitored over two years. The results showed that, although there were no adverse effects from taking statins, there were no advantages either.

"It's becoming increasingly common for patients with increased cholesterol to take statins and many cancer patients will be or have been prescribed these drugs entirely separately from their cancer treatment," explains Professor Michael Seckl from the Faculty of Medicine at Imperial College London, who led the research. "There's no reason for people to stop taking statins to manage their cholesterol, but it's extremely unlikely, for patients with small cell lung cancer, that taking statins will make any difference to their cancer treatment outcome. Because all statins work in a similar way to lower cholesterol, it's relatively unlikely that statins other than Pravastatin would have a different, more beneficial effect."

The Imperial researchers plan to continue their investigations into precisely how statins work at a cellular level, but believe further large-scale trials such as the one just completed may be unnecessary.

"Our results match those of other randomised trials examining different types of cancer, but these were much smaller than our own study, and they have also shown no benefit to using statins in cancer treatment," says senior author Professor Allan Hackshaw, Deputy Director of the Cancer Research UK & UCL Cancer Trials Centre. "Collectively, this evidence seems quite persuasive."

"It is possible that ongoing statin trials of other types of cancers might find a benefit, and so it would be interesting to see their findings when available. However, I think researchers should consider carefully whether to start a new statin trial as part of cancer treatment, without results from further large studies like ours."


What You Should Expect From Statin Therapy

Cholesterol-lowering statin medications have been at the forefront of managing cardiovascular disease for several decades now. Why? It’s because a large body of research supports their benefits in reducing the risk of heart attack and stroke.

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The drugs have become so universally used that if you haven’t been prescribed a statin already, chances are you will at some point.

Preventive cardiologist Luke Laffin, MD, says statins lower your LDL ( or “bad”) cholesterol, which is associated with a reduced risk of atherosclerotic cardiovascular disease. (That’s the buildup of cholesterol, fatty cells and inflammatory deposits on the inner walls of your arteries aka “hardening” or “clogging” of the arteries).

“Additionally, statins lower inflammation, which we know is a factor that causes atherosclerosis and cardiovascular disease,” Dr. Laffin says.

Yet, despite their many benefits, statins (like all medications) have some important side effects you need to know about. So, review the risks and benefits of these important medications with your physician, and discuss your need for statin therapy.

What are the benefits of statins?

Statins inhibit the action of an enzyme that’s responsible for cholesterol production in your liver. In the process, they significantly reduce LDL and total cholesterol, while also having beneficial effects on HDL (“good”) cholesterol, triglycerides and inflammation. Some evidence suggests that high-intensity statin therapy may help to slow, and potentially reverse, the growth of artery-clogging atherosclerotic plaques. They may also make them less prone to rupture and cause heart attacks and strokes.

“There are good data to suggest that the more LDL lowering we can achieve, the lower the risk of adverse cardiac events such as strokes and heart attacks,” Dr. Laffin explains.

Although statins all belong to the same drug class, they differ in how potent they are and how much they can lower LDL cholesterol.

Your doctor will use a tool like the American College of Cardiology/American Heart Association risk calculator and other factors to gauge your long-term risk of atherosclerotic cardiovascular disease, determine if you need statin therapy, and if so, which one.

The statins are generally taken once daily and are available in generic forms. “It’s important to note that atorvastatin and rosuvastatin really are the workhorses of cardiology and statins at this point,” Dr. Laffin adds. “A lot of pharmacies typically will have one of the high-intensity statins. They’re inexpensive and easy to obtain. In my experience, 99% of insurance companies cover at least one of them, and more than 75% cover both of them.”

Are you a candidate for a statin?

Guidelines from the American College of Cardiology and American Heart Association recommend statin therapy for:

  • Secondary prevention in people with established atherosclerotic cardiovascular disease.
  • People with an LDL cholesterol level of 190 milligrams per deciliter (mg/dL) or higher, due to a genetic condition.
  • People with diabetes ages 40 to 75 with an LDL level over 70 mg/dL and no atherosclerotic cardiovascular disease.
  • Non-diabetic adults ages 40 to 75 with a 20% or greater likelihood of developing atherosclerotic cardiovascular disease in the next 10 years (high-risk patients).
  • Non-diabetic patients ages 40 to 75 with an LDL level of 70 to 189 mg/dL and a 10-year ASCVD risk of 7.5% to less than 20% (intermediate risk) if the risk estimate and presence of certain risk-enhancing factors * favor treatment.

* These factors include a family history of ASCVD, LDL levels persistently ≥160 mg/dL, triglyceride levels persistently ≥175 mg/dL, chronic kidney disease, ethnicity, inflammatory diseases, metabolic syndrome, and (in certain people, if measured) results of high-sensitivity C-reactive protein, lipoprotein(a), and apolipoprotein B. Note: The guidelines recommend considering coronary artery calcium scoring for people at intermediate risk in whom a decision about starting statin treatment remains uncertain.

What are the side effects of statins?

Elevated liver enzymes. In addition to more common side effects such as headache and nausea, statins occasionally may cause increases in liver enzymes, suggesting liver inflammation. However, the latest ACC/AHA guidelines recommend liver-enzyme testing only for statin users who are at higher risk or have symptoms that may suggest liver toxicity. Furthermore, statins may cause small elevations in blood sugar, enough to push some people into the range of type 2 diabetes. “But, we know that the benefits of statins outweigh that small increase in blood glucose across multiple populations,” Dr. Laffin notes.

Mental fogginess. While some studies have identified positive effects of statins on cognitive function, some users have reported problems like mental fogginess and forgetfulness, which go away after stopping the drug. Overall, though, large-scale clinical trials don’t suggest an increase in cognitive problems associated with statin use, Dr. Laffin says.

Muscle pain. One of the most noteworthy side effects associated with statin therapy is muscle aching and stiffness, which can be more severe as the statin dose and potency increase and may make some people intolerant to the drugs. Certain statins — in particular, atorvastatin and simvastatin — are more likely to cause these side effects, while others, like rosuvastatin and pravastatin, have less of an effect.

How to minimize side effects

Some treatable conditions (like thyroid dysfunction and severe vitamin D deficiency) may contribute to statin intolerance. So may consuming large quantities of grapefruit (or juice) and taking certain medications. Addressing these factors may ease or prevent statin-related muscle effects. Also, some people have found that taking coenzyme Q10 supplements may help, although the ACC/AHA guidelines don’t recommend their use.

It’s important not to stop taking your statin and to report any muscle side effects to your physician. Your doctor may switch you to a less-potent statin, change the dose, or explore alternative dosing strategies. This may include taking the drugs every other day or less frequently. With some perseverance, you and your physician can develop a statin regimen that works for you.

“Usually, you can find at least some dose of statin that people can tolerate, even if it is just a couple times a week,” Dr. Laffin says. “If you absolutely cannot tolerate a statin at any dose, then we have other medications we can use,” such as ezetimibe (Zetia ® ) or newer drugs known as PCSK9 inhibitors: alirocumab (Praluent ® ) and evolocumab (Repatha ® ).

What you need to know about statin use in older adults

Age is the most significant risk factor for atherosclerotic cardiovascular disease. However, the risks and benefits of statins must be carefully considered in older populations, especially those with health problems.

Older adults, as a whole, may be more likely than their younger counterparts to experience serious side effects from statins. Many seniors take multiple medications, making them more likely to experience adverse medication interactions with a statin. Importantly, seniors with other medical conditions that shorten their life expectancy may not reap the benefits of statin therapy.

So, if you’re over age 75 — and especially if you have other health problems — discuss the pros and cons of statin therapy with your physician, Dr. Laffin advises.

“The effects of statins are usually over the long term—we’re talking five to 10 years in terms of cardiovascular risk reduction,” he explains. “So, you have to balance the risk of taking another medicine versus whether you are going to die from something else in those five to 10 years. I think it’s very reasonable for someone who has other competing comorbidities to talk about deprescribing statins.”

This article first appeared in Cleveland Clinic Men’s Health Advisor.


The uses and risks of statins

Statins are a group of drugs that can lower blood cholesterol levels. They do this by blocking an enzyme in the liver that is necessary for making cholesterol.

Cholesterol plays a role in normal cell and body function. However, very high levels can lead to atherosclerosis. This causes cholesterol-containing plaques to build up in the arteries and block blood flow.

By reducing blood cholesterol levels, statins also lower the risk of heart attacks, strokes, and chest pain, also called angina.

Researchers estimate that nearly 30% of people aged 40 and over in the United States take some form of statin. Below, we describe the uses, risks, and possible benefits of these drugs.

Doctors typically prescribe statins to lower blood cholesterol levels. These drugs block the action of a liver enzyme that helps produce cholesterol. They are also known as HMG-CoA reductase inhibitors.

Statins can reduce the amount of low-density lipoprotein (LDL) cholesterol in the body. People sometimes refer to this type as “bad” cholesterol. Statins can also raise levels of high-density lipoprotein (HDL), or “good,” cholesterol.

In addition, statins can lower the amount of fats, called triglycerides, in the blood.

  • atorvastatin (Lipitor)
  • fluvastatin (Lescol)
  • lovastatin (Mevacor)
  • pitavastatin (Livalo, Livazo)
  • pravastatin (Pravachol)
  • rosuvastatin (Crestor)
  • simvastatin (Zocor)

Atorvastatin and rosuvastatin are the most potent, while fluvastatin is the least.

Combination drugs are also available. For instance, Vytorin is a combination of simvastatin, which is a statin, and ezetimibe, a drug that reduces the absorption of dietary cholesterol.

People who are taking simvastatin, atorvastatin, or lovastatin should avoid grapefruit and grapefruit juice to reduce the risk of an interaction.

Most people who take statins have minor side effects, if any. Minor side effects can include:

The two most serious side effects are liver failure and skeletal muscle damage. These are rare.

Specifically, statins may lead to muscle damage in 1 in 10,000 people who take this type of drug each year. The damage is typically reversible once the person stops taking the statin.

More rarely still, a severe type of muscle damage called rhabdomyolysis may occur, in an estimated 2–3 in 100,000 people taking this type of drug per year.

Also, some research has linked statin use with cataracts. However, a 2017 review found no clear evidence of this.

In addition, statins may slightly increase a person’s risk of type 2 diabetes.

Finally, statins may be linked with memory problems, though the evidence has been mixed. According to a 2018 review , statins may cause temporary memory impairment, but they may also have a protective effect against age-related cognitive decline. Research into this is ongoing.

What is rhabdomyolysis?

Rhabdomyolysis initially causes muscle pain and can worsen to cause significant muscle breakdown or kidney failure. In rare cases, it can be fatal.

The condition is more common in people who take a statin in combination with another drug that carries rhabdomyolysis risk or raises the level of statin in the blood.


The Stats on Statins: Should Healthy Adults Over 50 Take Them?

Everyone over 50 should take statins to lower their cholesterol, an editorial argued last week in The Lancet. The piece based its recommendation on a meta-analysis of 27 clinical trials published in the same issue that concluded statins significantly reduce the risk of heart attacks and other cardiovascular events in healthy people without posing substantial risks. Subsequent articles heralding the meta-analysis's findings were published in the Guardian, Forbes and the U.K. Telegraph. But based on the numbers, many experts still aren't convinced that the drugs' benefits outweigh their risks.

There's no question that statins save lives when they are prescribed to people with cardiovascular disease. But whether the drugs should also be given to healthy people who do not have high cholesterol or other cardiovascular risk factors has been a long-standing and controversial question. One large clinical trial known as JUPITER reported in 2008 that rosuvastatin (Crestor) lowers the risk of heart attacks and other events by 44 percent in healthy subjects but experts have since raised questions about its methodology in part because the trial was stopped early, which might have created the effect of overestimating the drug's benefits. The current meta-analysis was designed to help put the issue to rest. "Our aim was to bring together all the available evidence," explains co-author Colin Baigent, an epidemiologist at the University of Oxford in England.

After pooling the results of 27 trials involving 165,149 people, the meta-analysis reported that people are 21 percent less likely to suffer a serious vascular event such as a heart attack, stroke or bypass surgery after their cholesterol drops by the amount that might be expected after taking statins for a year than are similar people who do not take the pills. But such outcomes are rare in healthy individuals anyway, so the risk reduction actually translated to a small clinical benefit&mdashreducing the overall risk from 4.04 percent to 3.27 percent per year, a difference of 0.77 percent.

In other words, approximately 130 people need to take statins for a year to prevent just one unwanted health outcome, and 500 people have to take them to prevent a single death. "Once you get down to very low levels of risk, the benefits are very small," Baigent admits.

Experts also raise questions about the subjects included in the meta-analysis. Although the review was supposedly designed to assess the effects of statins in people at low risk of vascular disease, 60 percent of its participants in fact already had vascular disease. "Why combine people who have heart disease with people who don't? It's really misleading," says Kausik Ray, a cardiologist at Saint George's University of London. In 2010 Ray and his colleagues published a meta-analysis of 11 statin clinical trials involving 65,229 subjects without cardiovascular disease and concluded that statins do not reduce the risk of death in healthy people. (By including people who had vascular disease, the Lancet meta-analysis overestimated statins' benefits: a subgroup analysis reveals that among people who did not have vascular disease, statins only reduced the absolute risk of a cardiovascular event by 0.4 percent per year.)

And what about side effects? It's long been known that statins increase the risk of hemorrhagic strokes, muscle pain and other severe (but rare) muscle and liver complications. In February 2012 the U.S. Food and Drug Administration warned consumers that the drugs might also increase the risk of diabetes and memory loss. Nevertheless, the Lancet analysis suggests that the probability of these side effects is quite low for instance, only one person out of every 2,000 treated will suffer a hemorrhagic stroke. "The benefits are substantially bigger than the hazards, even at very low levels of risk," Baigent says.

Yet some experts worry the findings underestimate true risk. According to Rita Redberg, a cardiologist at the University of California, San Francisco, and chief editor of the Archives of Internal Medicine, prior to the start of one of the trials included in the analysis, potential subjects were given statins for several weeks to see how well they tolerated them. If any individuals experienced side effects, they weren't invited into the trial. This type of prescreening is "not clean science," says Vinay Prasad, an internist at Northwestern University Feinberg School of Medicine, because it makes drugs look safer than they really are.

There is also the issue of funding and bias. Almost all of the trials included in the meta-analysis were funded in part by pharmaceutical companies, and some of the meta-analysis's co-authors have received honoraria from drug companies, too. Although these facts do not mean that the results are invalid, a 2003 study published in the British Medical Journal suggests that trials funded by drug companies are more likely to report favorable results about their products than are trials funded by independent organizations. "Asking industry to conduct its own studies is like asking a painter to judge his own work as to whether or not it should win an award," Prasad says. "It's another reason to be skeptical."

And even if the findings of the meta-analysis are accurate and the side effects are rare, "one should question whether it is cost-effective" to put millions of people on the drugs for a small potential benefit, says James Liao, an expert in vascular medicine at Brigham and Women's Hospital in Boston. Generic low-cost versions of the drugs are available&mdashWalmart sells a month's supply of low-dose lovastatin for $4&mdashbut many consumers choose costlier brand name options. In 2011, for instance, Americans spent $4.4 billion on AstraZeneca's Crestor and $7.7 billion on Pfizer's Lipitor.

So should more healthy people take statins? Baigent argues that doing so could save millions of lives, because many heart attacks occur in people who are considered low-risk. But at what cost? "There are a lot of people taking statins who are not getting any benefits from them, and they're subject to a lot of adverse events," Redberg says.


Statins Benefit No One

Lowering LDL Cholesterol is a Bad Idea

I t is widely known, and can be found on many major medical web sites, that high LDL cholesterol causes heart disease. However, this is false. There is abundant research available today confirming that this is false, but the notion persists. Small LDL particle size is associated with heart disease so is homocysteine, CRP, high insulin, high glycated-proteins, A1c is an example, high Lp(a), immature HDL particles, high iron stores and more. The list of things associated with developing heart disease is long and none of them are dispositive. As a kind of fun fact, know that low cholesterol is associated with everything from depression to cancer. Lots of excuses for this association are made by the statin apologists but no one actually knows what the link between low cholesterol and these other diseases might be.

American medicine has been on a veritable cholesterol-lowering crusade going on 40 years. People were told to eat low cholesterol food, and take cholesterol-lowering drugs, specifically statins. Knowing, as I do, how the body tends to optimize toward healing disease, I was always suspicious of this. Everything else being equal if the body would be better off with lower cholesterol, that’s where it would already be – no pill needed.

In fact, in 2002, the drug industry came up with a statin substitute, that only lowered cholesterol, called ezetimibe (Zetia, Vytorin). It was specifically developed so that people that could not tolerate statins, could still lower their evil cholesterol. However, exetimibe, if used alone, not only failed to prevent heart attacks, it significantly increased cancer. This dramatic medical misfire was apparently not enough to get the FDA to pull the drug it’s still available and widely prescribed. So, whatever the merits of lowering cholesterol as evidenced by statins lowering cholesterol, it was not as simple as ‘lower cholesterol and everything will be fine.’ The failure of this drug should have put the simple ‘lipid hypothesis’ to rest. By the way ‘the lipid hypothesis’ is the generic term for the whole cholesterol model of disease.

“BUT, BUT, BUT, statins reduce heart ‘events’. There’s surely a benefit.” This is true, but who benefits? If you consider ‘all cause mortality’, rather than considering just heart events, the picture is not so sanguine. No category of women, with or without pre-existing heart disease is helped overall. For men with no pre-existing heart disease, no benefit either. For men over 80, no benefit. We have now ‘sliced and diced’ the benefit group down to “men, under 80, with pre-existing heart disease may get benefit from statins.” For that group, maybe. Even this is controversial. Not quite the wonder drug hoped for. More than that, there is an increase in non-heart related deaths. Hmmmm.

Are there positive uses for statins? Yes. The most striking example, and the secret of its use revealed, is this: if atorvastatin is infused at the time of a coronary catheterization then there are fewer heart complications, including death, from the procedure. Now this immediate benefit is obviously not from lowering cholesterol. It is from calming ‘endothelial inflammation:’ the metabolic fire in the lining of damaged arteries is dampened. This is a good thing. Congratulations statins!

We know that unstable plaque, the damaged area of an artery, is the source of the clotting trigger that brings on a heart attack. We further know that inflammation is what destabilizes these areas of damage. Decrease the intimal inflammation and you get fewer heart attacks and bingo you also now know the real benefit of statins.

However, are the 30,000,000 Americans currently taking statins receiving benefit? In almost all cases, the answer is ‘no benefit:’ by any measure no more than 1 or 2 per hundred and probably much less than that in most populations.

Recent studies show 20% percent of statin users report side effects: 10% have muscle pain and damage, sometimes permanent, the rest are divided between liver damage, kidney damage, adult onset diabetes, cataracts, depression and memory loss.

Summary: Statins are effectively proven to be of no benefit to most, if not all, segments of the population. There are some specific uses, and that’s that.

Even though I question whether any of you would benefit from statin therapy, almost all of you could benefit from inflammation reduction. Do you need to address this? Quantitative Medicine can easily answer that one. C-Reactive Protein, or CRP, is a quite general inflammation marker, easily determined with a blood draw. Is yours high? If so, something is amiss. Could be heart disease. Could be allergy, genetics, cancer, a cold, or a lot of other things. However, you need to figure out the bad actors and reduce them to see if CRP goes down. Diet and exercise can play a strong role here. If you do reduce it, you reduce your heart attack risk enormously, far more than even the wildest dreams of the statin manufacturers. Do your own heavy lifting – don’t outsource it to statins.


Common Side Effects of Statins

The most commonly reported side effects of statins include:

  • a headache
  • belching or excessive gas
  • constipation
  • croaky voice or hoarseness
  • difficulty sleeping
  • heartburn, indigestion, nausea, or stomach discomfort
  • lower back or side pain, tenderness around the eyes or cheekbones
  • nasal congestion or stuffiness, or a runny nose
  • slight muscle pain
  • sweating.

Other side effects, such as liver damage, are rare, and it is not necessary to have ongoing liver tests while you are taking a statin once you have had a baseline liver function test done.


Contents

Statins are usually used to lower blood cholesterol levels and reduce risk for illnesses related to atherosclerosis, with a varying degree of effect depending on underlying risk factors and history of cardiovascular disease. Clinical practice guidelines generally recommend people start with lifestyle modification through a cholesterol-lowering diet and physical exercise. For those unable to meet their lipid-lowering goals through such methods, statins can be helpful. [14] [15] The medication appears to work equally well regardless of sex, [16] although some sex-related differences in treatment response were described. [17]

If there is an underlying history of cardiovascular disease, it has a significant impact on the effects of statin. This can be used to divide medication usage into broad categories of primary and secondary prevention. [18]

Primary prevention Edit

For the primary prevention of cardiovascular disease, the United States Preventive Services Task Force (USPSTF) 2016 guidelines recommend statins for those who have at least one risk factor for coronary heart disease, are between 40 and 75 years old, and have at least a 10% 10-year risk of heart disease, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm. [18] [19] [20] Risk factors for coronary heart disease included abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking. [19] They recommended selective use of low-to-moderate doses statins in the same adults who have a calculated 10-year cardiovascular disease event risk of 7.5–10% or greater. [19] In people over the age of 70, statins decrease the risk of cardiovascular disease but only in those with a history of heavy cholesterol blockage in their arteries. [21]

Most evidence suggests that statins are also effective in preventing heart disease in those with high cholesterol but no history of heart disease. A 2013 Cochrane review found a decrease in risk of death and other poor outcomes without any evidence of harm. [4] For every 138 people treated for 5 years, one fewer dies for every 49 treated, one fewer has an episode of heart disease. [10] A 2011 review reached similar conclusions, [22] and a 2012 review found benefits in both women and men. [23] A 2010 review concluded that treatment without history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex. [24] Two other meta-analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention. [25] [26]

The National Institute for Health and Clinical Excellence (NICE) recommends statin treatment for adults with an estimated 10 year risk of developing cardiovascular disease that is greater than 10%. [27] Guidelines by the American College of Cardiology and the American Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol ≥ 190 mg/dL or those with diabetes, age 40–75 with LDL-C 70–190 mg/dl or in those with a 10-year risk of developing heart attack or stroke of 7.5% or more. In this latter group, statin assignment was not automatic, but was recommended to occur only after a clinician-patient risk discussion with shared decision making where other risk factors and lifestyle are addressed, the potential for benefit from a statin is weighed against the potential for adverse effects or drug interactions and informed patient preference is elicited. Moreover, if a risk decision was uncertain, factors such as family history, coronary calcium score, ankle-brachial index, and an inflammation test (hs-CRP ≥ 2.0 mg/L) were suggested to inform the risk decision. Additional factors that could be used were an LDL-C ≥ 160 or a very high lifetime risk. [28] However, critics such as Steven E. Nissen say that the AHA/ACC guidelines were not properly validated, overestimate the risk by at least 50%, and recommend statins for patients who will not benefit, based on populations whose observed risk is lower than predicted by the guidelines. [29] The European Society of Cardiology and the European Atherosclerosis Society recommend the use of statins for primary prevention, depending on baseline estimated cardiovascular score and LDL thresholds. [30]

Secondary prevention Edit

Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease. [31] Pre-existing disease can have many manifestations. Defining illnesses include a prior heart attack, stroke, stable or unstable angina, aortic aneurysm, or other arterial ischemic disease, in the presence of atherosclerosis. [18] They are also advocated for use in people at high risk of developing coronary heart disease. [32] On average, statins can lower LDL cholesterol by 1.8 mmol/L (70 mg/dL), which translates into an estimated 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment. [33] A greater benefit is observed with high-intensity statin therapy. [34] They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). [35] [36]

No studies have examined the effect of statins on cognition in patients with prior stroke. However, two large studies (HPS and PROSPER) that included patients with vascular diseases reported that simvastatin and pravastatin did not impact cognition. [37]

Statins have been studied for improving operative outcomes in cardiac and vascular surgery. [38] Mortality and adverse cardiovascular events were reduced in statin groups. [39]

Older adults who receive statin therapy at time of discharge from the hospital after an inpatient stay have been studied. People with cardiac ischemia not previously on statins at the time of admission have a lower risk of major cardiac adverse events and hospital readmission two years post-hospitalization. [40] [41]

Comparative effectiveness Edit

While no direct comparison exists, all statins appear effective regardless of potency or degree of cholesterol reduction. [22] Simvastatin and pravastatin appear to have a reduced incidence of side-effects. [5]

A comparison of simvastatin, pravastatin, and atorvastatin, based on their effectiveness against placebos, found no differences in reduction of cardiovascular disease or lipid levels in the blood. [42] A 2015 Cochrane systematic review update reported that rosuvastatin is more than three-fold more potent than atorvastatin. [43]

Females Edit

According to the 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in females than in males compared to rosuvastatin. [43]

Children Edit

In children statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia. [44] Their long term safety is, however, unclear. [44] [45] Some recommend that if lifestyle changes are not enough statins should be started at 8 years old. [46]

Familial hypercholesterolemia Edit

Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those with homozygous deficiencies. [47] These people have defects usually in either the LDL receptor or apolipoprotein B genes, both of which are responsible for LDL clearance from the blood. [48] Statins remain a first-line treatment in familial hypercholesterolemia, [47] although other cholesterol-reducing measures may be required. [49] In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications. [50]

Contrast-induced nephropathy Edit

A 2014 meta-analysis found that statins could reduce the risk of contrast-induced nephropathy by 53% in people undergoing coronary angiography/percutaneous interventions. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus. [51]

Choosing a statin for people with special considerations [52]
Condition Commonly recommended statins Explanation
Kidney transplantation recipients taking ciclosporin Pravastatin or fluvastatin Drug interactions are possible, but studies have not shown that these statins increase exposure to ciclosporin. [53]
HIV-positive people taking protease inhibitors Atorvastatin, pravastatin or fluvastatin Negative interactions are more likely with other choices [54]
Persons taking gemfibrozil, a non-statin lipid-lowering drug Atorvastatin Combining gemfibrozil and a statin increases risk of rhabdomyolysis and subsequently kidney failure [55] [56]
Persons taking the anticoagulant warfarin Any statin The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin. [57]

The most important adverse side effects are muscle problems, an increased risk of diabetes mellitus, and increased liver enzymes in the blood due to liver damage. [5] [58] Over 5 years of treatment statins result in 75 cases of diabetes, 7.5 cases of bleeding stroke, and 5 cases of muscle damage per 10,000 people treated. [31] This could be due to the statins inhibiting the enzyme (HMG-CoA reductase), which is necessary to make cholesterol, but also for other processes, such as CoQ10 production, which is important for muscle function and sugar regulation. [59]

Other possible adverse effects include neuropathy, [60] pancreatic and liver dysfunction, and sexual dysfunction. [61] The rate at which such events occur has been widely debated, in part because the risk/benefit ratio of statins in low-risk populations is highly dependent on the rate of adverse events. [62] [63] [64] A Cochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excess adverse events among those treated with statins compared to placebo. [4] Another meta-analysis found a 39% increase in adverse events in statin treated people relative to those receiving placebo, but no increase in serious adverse events. [65] The author of one study argued that adverse events are more common in clinical practice than in randomized clinical trials. [61] A systematic review concluded that while clinical trial meta-analyses underestimate the rate of muscle pain associated with statin use, the rates of rhabdomyolysis are still "reassuringly low" and similar to those seen in clinical trials (about 1–2 per 10,000 person years). [66] A systematic review co-authored by Ben Goldacre concluded that only a small fraction of side effects reported by people on statins are actually attributable to the statin. [67]

Cognitive effects Edit

Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline. [68] [69] [70] [71] [72] Statins have been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases. [73] [ needs update ] Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study [74] and the Health Protection Study (HPS) demonstrated that simvastatin and pravastatin did not affect cognition for patients with risk factors for, or a history of, vascular diseases. [75]

There are reports of reversible cognitive impairment with statins. [76] The U.S. Food and Drug Administration (FDA) package insert on statins includes a warning about the potential for non-serious and reversible cognitive side effects with the medication (memory loss, confusion). [77]

Muscles Edit

In observational studies 10–15% of people who take statins experience muscle problems in most cases these consist of muscle pain. [6] These rates, which are much higher than those seen in randomized clinical trials [66] have been the topic of extensive debate and discussion. [31] [78]

Serious muscle problems such as rhabdomyolysis (destruction of muscle cells) and statin-associated autoimmune myopathy occur in less than 0.1% of treated people. [79] Rhabdomyolysis can in turn result in life-threatening kidney injury. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as fibrates, and hypothyroidism. [80] [81] Coenzyme Q10 (ubiquinone) levels are decreased in statin use [82] CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking as of 2017 [update] . [83] The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy. [84]

Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. [85] The incidence of rhabdomyolysis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) were combined with a fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001. [86]

Some researchers have suggested hydrophilic statins, such as fluvastatin, rosuvastatin, and pravastatin, are less toxic than lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a connection. [87] Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage. [87] Tendon rupture does not appear to occur. [88]

Diabetes Edit

The relationship between statin use and risk of developing diabetes remains unclear and the results of reviews are mixed. [89] [90] [91] [92] Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes. [93] Use in postmenopausal women is associated with an increased risk for diabetes. [94] The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear. [91] However, recent findings have indicated the inhibition of HMGCoAR as a key mechanism. [95] Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the hormone insulin. [91] One way this is thought to occur is by interfering with cholesterol synthesis which is necessary for the production of certain proteins responsible for glucose uptake into cells such as GLUT1. [91]

Cancer Edit

Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk. [96] [97] [98] [99] [100] Specifically, statins may reduce the risk of esophageal cancer, [101] colorectal cancer, [102] gastric cancer, [103] [104] hepatocellular carcinoma, [105] and possibly prostate cancer. [106] [107] They appear to have no effect on the risk of lung cancer, [108] kidney cancer, [109] breast cancer, [110] pancreatic cancer, [111] or bladder cancer. [112]

Drug interactions Edit

Combining any statin with a fibrate or niacin (other categories of lipid-lowering drugs) increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. [85] Monitoring liver enzymes and creatine kinase is especially prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in kidney function.

Consumption of grapefruit or grapefruit juice inhibits the metabolism of certain statins. Bitter oranges may have a similar effect. [113] Furanocoumarins in grapefruit juice (i.e. bergamottin and dihydroxybergamottin) inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however, it is a major inhibitor of only lovastatin, simvastatin, and to a lesser degree, atorvastatin) and some other medications [114] (flavonoids (i.e. naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). The absolute prohibition of grapefruit juice consumption for users of some statins is controversial. [115]

The U.S. Food and Drug Administration (FDA) notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may increase the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. [116]

Osteoporosis and fractures Edit

Studies have found that the use of statins may protect against getting osteoporosis and fractures or may lead to getting osteoporosis and fractures. [117] [118] [119] [120] A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used. [121]

Statins act by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Because statins are similar in structure to HMG-CoA on a molecular level, they will fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competition reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. A variety of natural statins are produced by Penicillium and Aspergillus fungi as secondary metabolites. These natural statins probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer. [123]

Inhibiting cholesterol synthesis Edit

By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night, [124] so statins with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning, [125] [126] but have shown no difference in the long-acting atorvastatin. [127]

Increasing LDL uptake Edit

In rabbits, liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation. [128] This is accomplished via proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the nucleus and bind to the sterol response elements. The sterol response elements then facilitate increased transcription of various other proteins, most notably, LDL receptor. The LDL receptor is transported to the liver cell membrane and binds to passing LDL and VLDL particles, mediating their uptake into the liver, where the cholesterol is reprocessed into bile salts and other byproducts. This results in a net effect of less LDL circulating in blood.

Decreasing of specific protein prenylation Edit

Statins, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inhibition of protein prenylation for proteins such as RhoA (and subsequent inhibition of Rho-associated protein kinase) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other pleiotropic cardiovascular benefits of statins, [129] [130] [131] [132] [133] [134] as well as in the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in studies as statins, [135] and may also account for some of the benefits seen in cancer reduction with statins. [136] In addition, the inhibitory effect on protein prenylation may also be involved in a number of unwanted side effects associated with statins, including muscle pain (myopathy) [137] and elevated blood sugar (diabetes). [138]

Other effects Edit

As noted above, statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis through so-called "pleiotropic effects of statins." [132] The pleiotropic effects of statins remain controversial. [139] The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy. [140] Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research): [139]

  1. Improve endothelial function
  2. Modulate inflammatory responses
  3. Maintain plaque stability
  4. Prevent blood clot formation

In 2008, the JUPITER trial showed statins provided benefit in those who had no history of high cholesterol or heart disease, but only elevated high-sensitivity C-reactive protein (hsCRP) levels, an indicator for inflammation. [141] The study has been criticized due to perceived flaws in the study design, [142] [143] [144] although Paul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms in length. [145]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

As the target of statins, the HMG-CoA reductase, is highly similar between eukaryota and archaea, statins also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro. [146] Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of statins for management of irritable bowel syndrome has been proposed and may actually be one of the hidden benefits of statin use. [147] [148]

The statins are divided into two groups: fermentation-derived and synthetic. Some specific types are listed in the table below. Note that the associated brand names may vary between countries.

LDL-lowering potency varies between agents. Cerivastatin is the most potent, (withdrawn from the market in August, 2001 due to risk of serious rhabdomyolysis) followed by (in order of decreasing potency), rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. [160] The relative potency of pitavastatin has not yet been fully established, but preliminary studies indicate a potency similar to rosuvastatin. [161]

Some types of statins are naturally occurring, and can be found in such foods as oyster mushrooms and red yeast rice. Randomized controlled trials have found these foodstuffs to reduce circulating cholesterol, but the quality of the trials has been judged to be low. [162] Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling [ citation needed ] branded drug. [163] [164] [165] [166] [167] [168] [169]

Statin equivalent dosages
% LDL reduction (approx.) Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
10–20% 20 mg 10 mg 10 mg 5 mg
20–30% 40 mg 20 mg 20 mg 10 mg
30–40% 10 mg 80 mg 40 mg 40 mg 5 mg 20 mg
40–45% 20 mg 80 mg 80 mg 5–10 mg 40 mg
46–50% 40 mg 10–20 mg 80 mg*
50–55% 80 mg 20 mg
56–60% 40 mg
* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis
Starting dose
Starting dose 10–20 mg 20 mg 10–20 mg 40 mg 10 mg 5 mg if hypothyroid, >65 yo, Asian 20 mg
If higher LDL reduction goal 40 mg if >45% 40 mg if >25% 20 mg if >20% 20 mg if LDL >190 mg/dL (4.87 mmol/L) 40 mg if >45%
Optimal timing Anytime Evening With evening meals Anytime Anytime Evening

The role of cholesterol in the development of cardiovascular disease was elucidated in the second half of the 20th century. [170] This lipid hypothesis prompted attempts to reduce cardiovascular disease burden by lowering cholesterol. Treatment consisted mainly of dietary measures, such as a low-fat diet, and poorly tolerated medicines, such as clofibrate, cholestyramine, and nicotinic acid. Cholesterol researcher Daniel Steinberg writes that while the Coronary Primary Prevention Trial of 1984 demonstrated cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced. [171] Scientists in academic settings and the pharmaceutical industry began trying to develop a drug to reduce cholesterol more effectively. There were several potential targets, with 30 steps in the synthesis of cholesterol from acetyl-coenzyme A. [172]

In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began to investigate this problem. Research had already shown cholesterol is mostly manufactured by the body in the liver with the enzyme HMG-CoA reductase. [11] Endo and his team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell walls or cytoskeleton (isoprenoids). [123] The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.

A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their report in 1976. [173] The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition. [ medical citation needed ] Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs. P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus, first marketed in 1987 as Mevacor. [11]

In the 1990s, as a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between HDL and LDL cholesterol, and various pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo and Bristol-Myers Squibb. In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. [11] [174] In 1995, Zocor and Mevacor both made Merck over US$1 billion . [11]

Though he did not profit from his original discovery, Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008, for his pioneering research. [175] Endo was also inducted into the National Inventors Hall of Fame in Alexandria, Virginia in 2012. Michael C. Brown and Joseph Goldstein, who won the Nobel Prize for related work on cholesterol, said of Endo: "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo." [176]

As of 2016 [update] misleading claims exaggerating the adverse effects of statins had received widespread media coverage, with a consequent negative impact to public health. [31] Controversy over the effectiveness of statins in the medical literature was amplified in popular media in the early 2010s, leading an estimated 200,000 people in the UK to stop using statins over a six-month period to mid 2016, according to the authors of a study funded by the British Heart Foundation. They estimated that there could be up to 2,000 extra heart attacks or strokes over the following 10 years as a consequence. [177] An unintended effect of the academic statin controversy has been the spread of scientifically questionable alternative therapies. Cardiologist Steven Nissen at Cleveland Clinic commented "We are losing the battle for the hearts and minds of our patients to Web sites. " [178] promoting unproven medical therapies. Harriet Hall sees a spectrum of "statin denialism" ranging from pseudoscientific claims to the understatement of benefits and overstatement of side effects, all of which is contrary to the scientific evidence. [179]

Lovastatin (Mevacor) was approved as a generic drug in the US in December 2001. [180]

Pravastatin (Pravachol) was approved as a generic drug in the US in April 2006. [181]

Simvastatin (Zocor) was approved as a generic drug in the US in June 2006. [182]

Atorvastatin (Lipitor) was approved as a generic drug in the US in November 2011. [183] [184]

Fluvastatin (Lescol) was approved as a generic drug in the US in April 2012. [185]

Pitavastatin (Livalo) and rosuvastatin (Crestor) were approved as generic drugs in the US in 2016. [186] [187]

Ezetimibe/simvastatin (Vytorin) and ezetimibe/atorvastatin (Liptruzet) were approved as generic drugs in the US in 2017. [188]

Clinical studies have been conducted on the use of statins in dementia, [189] lung cancer, [190] nuclear cataracts, [191] hypertension, [192] [193] and prostate cancer. [194] There is no high quality evidence that statins are useful for pneumonia. [195] The small number of available trials do not support the use of statins as an adjunctive therapy or as a monotherapy in multiple sclerosis. [196]