Hundred Years of Cholesterol Research: Who Are the Best Lipid-Lowering Statins?

2019-12-30 | Back to Park original |

Medicine, eat or not, this is not a simple problem, and you need to carefully weigh the pros and cons.

1970s, Japanese chemist Akira Endo isolated the first statin lipid-lowering drug from penicillium citrinum: mevastatin compactin, ML-236B, an HMG-CoA reductase inhibitorA clinical trial of mevastatin was conducted in Japan in the late 1970s, but has never been marketed.

In 1987, the first human statin lovastatin was approved for marketing by the FDA.

Six statins have subsequently been launched, the most famous of which is Lipitor from Pfizer Inc., the highest-selling drug in the world from 1992 to 2017.

HMG-CoA reductase is an important enzyme for the synthesis of cholesterol in the human body. The basic mechanism of action of statins is to inhibit this enzyme, thereby inhibiting the production of cholesterol and reducing cholesterol in the body. However, more and moreEvidence that statins may also work through other mechanisms [1, 2].

The table below lists the brand names and generic names of 7 statins currently on the market. Atorvastatin and simvastatin are also used in combination products. For example, Caduet in the last two rows of the table isA combination of atorvastatin and amlodipine, a calcium channel blocker, while Vytorin is a combination of simvastatin and ezetimibe, an inhibitor of intestinal cholesterol absorption.

According to the statistics of the Centers for Disease Control and Prevention CDC, from 2015 to 2016, 50% of men ≥60 years old and 38% of women ≥60 years old are taking cholesterol-lowering drugs.

Figure 1: Percentage of people taking cholesterol-lowering drugs at various ages in the United States CDC. Statistics show that the number of people who need to take cholesterol-lowering drugs increases significantly with age, and most users are over 40 years old.

The widespread use of statins has also opened up a new round of controversy: Are there any health benefits of cholesterol-lowering statins? Who needs to take them? Are doctors overusing statins?

Efficacy of statins

The Scandinavian Simvastatin Survival Study referred to as the 4S trial, a clinical trial that is a milestone in cardiology, has proved the effectiveness of statins in reducing cholesterol levels and cardiovascular disease risk in patients with coronary heart disease [3].

The table below compares the results of the 4S trial with the results of the "Coronary Primary Prevention Trial CPPT" mentioned in the previous article. The 4S trial uses simvastatin,CPPT uses cholestyramine a compound that prevents the intestine from reabsorbing cholesterol and promotes its excretion to reduce cholesterol in the blood [4].

* Note: RR is commonly known as Risk ratio. Use the line "risk rate of death caused by cardiovascular disease" as an example. If RR = 1 means that the control group and the medication group have the same risk rate of death due to cardiovascular disease. RR= 0.58 is the point estimate: Compared with the control group without medication, the risk of death due to cardiovascular disease after taking the medication is reduced by 42% 1-0.58; the point estimate can be approached but never willTrue risk ratio. 95% CI 95% confidence interval: According to statistics, there is 95% confidence that the true risk ratio is between these two values. Because 95% CI does not include 1, it can be determined that the risk is reduced.

4S test proves that for patients with a history of coronary heart disease, simvastatin can not only effectively reduce cholesterol in the blood, but also reduce cardiovascular disease mortality and all-cause mortality. Effects on women and patients over 60 years of ageAll are significant.

How about the preventive effect of statins for people who have not had cardiovascular disease but who have high risk?

Jupiter trial in 2008 found that taking statins can reduce the risk of heart attack by 54% and the risk of stroke by 48% [5].

26 subsequent randomized clinical trials have proven the benefits of statins. There are many comprehensive meta-analyses that summarize the data from these clinical trials. A meta-analysis in 2010 was of high quality [6], and it used thisData from 170,000 patients in 26 trials, the conclusions are basically consistent with the US Preventive Services Task Force USPTSF [7]: statins can not only reduce low density lipoprotein LDL cholesterol,Heart attacks and strokes can also reduce mortality for any reason.

Controversy over statins

Although there are so many data that prove that statins can reduce the incidence of cardiovascular disease by lowering LDL cholesterol in the blood, some people still doubt that it works by lowering high levels of LDL cholesterol in the blood.

One of the more well-founded arguments is that perhaps the benefits of statins are not related to the ability to lower LDL cholesterol in the blood, but other pleiotropic effects. For example, statins may have anti-inflammatory properties.Function to prevent a heart attack.

Two pieces of evidence do not support this argument :

1 Looking closely at clinical data, the efficacy of statins is directly proportional to the ability to lower LDL cholesterol in the blood [8, 9].In other words, the drugs that lower LDL cholesterol the most have the greatest cardiovascular protection.

2 Following statins, there are two cholesterol-lowering drugs on the market that are completely different-Ezetimibe and PCSK9 inhibitors.Ezetimibe can inhibit the intestinal absorption of cholesterol, while PCSK9 inhibitors can regulate the degradation of "low density lipoprotein receptor LDL receptor".Both drugs lower LDL cholesterol in the blood and prevent cardiovascular disease, although the benefits of ezetimibe are relatively small.But importantly, their mechanism of action is completely different from statins.

There are many drugs that reduce LDL cholesterol in the blood through different mechanisms, and the protective effect of all these drugs on the cardiovascular is directly proportional to the ability to reduce "LDL cholesterol" see Figure 2 [10]. Therefore, cholesterol is questionedThe theory seems less reliable.

Figure 2: Correlation between the ability of various therapies to reduce the risk of cardiovascular disease and the amount of low-density lipoprotein cholesterol.

Although there is a lot of evidence showing that statins have other mechanisms of action, according to the existing evidence, its effect on the cardiovascular system is largely related to its ability to reduce "LDL cholesterol". Other mechanisms may haveSupporting role.

Other theories that are often heard against taking statins :

1 Statins have great side effects.

Undeniably, like any other drug, statins do have side effects.

Statins may cause muscle pain, which is usually not serious, and will disappear after stopping, without causing irreversible damage. In 10,000 cases, only 1 patient will have severe pain and muscle damage. MoreA few people have liver problems. The use of statins seems to be associated with elevated blood sugar, which in some cases leads to the diagnosis of diabetes. There are also reports linking statin use to memory problems, butThe evidence is insufficient.

Some reports claim that 18-20% of people taking statins will have adverse reactions. This argument is mainly based on two articles published in the British Medical Journal BMJ in 2013 [11, 12]. However, many people ignore it,Subsequently, BMJ and the authors of both articles found that this data was based on an observational study with significant limitations, and issued corrections, withdrawing this statement http://www.bmj.com/about-bmj/independent-statins-review-panel.

The most common side effects of statins are muscle soreness and weakness. The incidence of this side effect in observational studies is much higher than in clinical randomized double-blind trials. There are few randomized trials that specifically study muscle-related results, and some critics believe that it is pharmaceuticalThe company intentionally ignored this. A trial called STOMP [13] looked at the effects of statins on muscles and found that statins did not reduce muscle strength or exercise capacity, but compared to placebo, they ate morePeople complain of muscle pain 9.3% vs. 4.6%. The American College of Cardiology concludes that statins may cause some muscle problems, but the risk of serious muscle or liver damage is very lowhttp://www.acc.org/latest-in-cardiology/articles/2016/11/17/09/03/summarizing-the-current-state-and-evidence-on-efficacy-and-safety-of-statin-therapy.

In addition, statins appear to have an anti-placebo effect [14]. The anti-placebo effect is the opposite of what is commonly referred to as the placebo effect: people who take the drug feel that it has side effects, I scared myself, and there were no or serious side effects, which were also hinted in myself or more serious than normal.

You can eliminate these side effects by changing the dosage or switching to different drugs, because the molecular structure of different statins may be very different, and usually a drug can be found that a patient can tolerate without obvious side effects.

Previously, statins were the only drugs on the market to lower cholesterol. Patients with statin intolerance were troublesome and no drugs were available. But now, with the emergence of new drugs with different mechanisms of action, these patientsThere are also options, such as PCSK9 inhibitors. However, new drugs like PCSK9 are much more expensive than statins.

If the media blindly exaggerates the side effects of statins, it will only make more patients choose to take more expensive drugs. There is a worrying report that the negative news reports of statins have prompted many patients to discontinue the drug, perhaps indirectlyThis led to an increase in heart attacks. [15] Although the increase in heart attacks may be related to other factors, this article reminds us that incomplete factual reports can sometimes have serious negative effects on society as a whole.

Note: Another such example is about the side effects of vaccines. Many people listen to false rumors and choose not to vaccinate, which has led to the resurgence of some epidemics that should soon go extinct.

All in all, taking any medicine should balance the benefits and risks. Don't rely too much on drugs, and don't taboo against illness. The correct way is to find the best treatment for you according to each person's different circumstances.

B Lifestyle changes are the best, statins are "overtreatment".

In the previous article on cholesterol, the clinical trials on diet regimens conducted in the 1960s were introduced, and the results were very inconsistent.

New research finds that for most people, eating more cholesterol does not increase cholesterol levels in the blood.

However, some studies have found that a balanced diet such as the Mediterranean diet and Deshu diet can improve blood cholesterol levels more effectively than a diet that does not eat cholesterol and saturated fats 16, 17.

Also, aerobic exercise for at least 30 minutes a day for 5-7 days a week can also improve cholesterol reducing "bad" cholesterol and increasing "good" cholesterol " [18].

Although changes in living habits are slightly worse than statins in lowering cholesterol Figure 2 compares the effects of diet and drugs, there are no side effects of statins.

The first step in preventing or treating high cholesterol is to change your diet and lifestyle. However, changes in lifestyle are also limited :

For some patients, changes in living habits may be difficult to maintain;

For some patients, changes in living habits can have little effect;

Figure 2 shows that perhaps the more the LDL cholesterol level in the blood is lowered, the greater the benefit to the cardiovascular system. And changes in lifestyle habits alone can only reduce the amount.

If lifestyle changes do not achieve the goal, you need to rely on medications. Lifestyle changes and medications are not mutually exclusive and can be performed at the same time, sometimes it is best to do so.

C statins are not suitable for primary prevention.

Statins can be used as primary prevention of cardiovascular disease, or secondary prevention. Introduce the concept of several levels of prevention :

Primary prevention: It is commonly referred to as a precautionary plan, preventing it from happening before it gets sick.

Secondary prevention: designed to reduce the impact of an already occurring disease or injury. This is to detect or treat the disease or injury as early as possible, so that it can be treated in a timely manner to stop or slow its progress, and to develop a strategy suitable for individuals to prevent re-injury orRelapse, and implement long-term programs to gradually restore people to their original health and activity.

Tertiary prevention: designed to reduce the impact of persistent illness or injury on quality of life.

There are many clinical evidences for statins as secondary prevention, and the effect of primary prevention is definitely less than that of secondary prevention, although it still has a certain effect. [19]. When it is not certain that you will get sick in the future, taking medicine is justIn order to prevent it, it is especially necessary to consider the possible side effects of the drug, such as increasing the risk of muscle pain, diabetes and liver problems.

Analysis estimates that if 100 people take statins for five years, it is estimated that about 1-2 of them can avoid a heart attack. 250 people need to take statins for 1-6 years before one person can avoid it because of anyCause of death [7].

Thus, considering whether to use statins as a primary prevention method is like a number game, you need to weigh the benefits and risks. The higher the risk of heart disease or stroke, the greater the benefit after taking the drug, the more you need to consider whetherMedication.

What kind of people are at high risk? I will talk about it later.

IV Statins have not been proven effective for women or the elderly.

This is often said, but incorrect. Early clinical trials of statins have been conducted only in men. But since the 4S trial, thousands of women have been included in statin trials. Analysis shows the effect of the drug on womenSimilar to men. Analysis of people over 75 years of age also shows some benefits.

5 Statins are too expensive.

Most statins have generic drugs. Although brand drugs are more expensive, generic drugs are already cheaper than common vitamins.

Who should take statins?

In the past many years, doctors decided whether to use statins for patients. Basically, they only looked at the cholesterol level in the body: the value before and after the medication. The doctor will adjust the medication according to the situation until the cholesterol in the blood reaches a specificTarget value.

In 2013, the American College of Cardiology and the American Heart Association published a new medication guide. This guide was updated again in 2018, emphasizing the comprehensive consideration of the amount of LDL cholesterol and otherRisk factors for cardiovascular disease, not just looking at a specific value.

People with a lower risk of heart attack or stroke do not need to take statins. Statins are intended for people at high risk for heart disease.

The amount of cholesterol in the blood is the first value that needs to be screened. There are two values ​​to look at :

1. Total cholersterol: Most people should try to keep the total cholesterol below 200 mg / dL or 5.2 mmol / L.

2. Low density lipoprotein LDL cholesterol. The ideal level of this "bad" cholesterol is preferably less than 130 mg / dL, or 3.4 mmol / L. If you have had a heart attack, you need to be at 100 mg / dLdL or below 2.6 mmol / L. If you are at high risk for heart disease or stroke, you may need to target lower values, <70 mg / dL, or 1.8 mmol / L.

However, it is definitely not to say that the total cholesterol or low-density lipoprotein cholesterol in the blood exceeds this standard, you must take medicine to control it.

More important is the long-term risk of heart disease or stroke :

? If your risk is very low, you don't need medicine unless LDL cholesterol is higher than 190 mg / dL 4.9 mmol / L.

? If your risk is very high, for example, you have had a heart attack in the past, you may need statins, even if your blood cholesterol levels are normal.

Emphasis again, everyone's situation is different. Before choosing a drug, you should discuss the possible benefits and risks with your doctor carefully.

Guide for those who apply statins

Figure 3: Population distribution of cholesterol-lowering drugs among people over the age of 40 in the United States from 2011 to 2012.

From: 2011-2012 National Health and Nutrition Survey http://www.cdc.gov/nchs/products/databriefs/db177.htm.

I mentioned the risk of heart disease or stroke many times before. This risk usually refers to the risk of having a stroke or heart disease within 10 years. It is calculated in the United States using this ASCVD risk estimator Atherosclerotic Cardiovascular Disease Risk Estimator:

http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

risk categories include :

  • low risk: risk value <5%

  • borderline risk: 5% ≤risk value <7.5%

  • intermediate risk: 7.5% ≤risk value <20%

  • high risk: risk value ≥20%

This ASCVD risk estimator is a good starting point, but it also has limitations. As you age, the risk of cardiovascular disease also increases. By the age of 65, almost everyone's risk value will exceed 7.5.%.

After knowing your risk value, how do you decide whether you need to take cholesterol-lowering drugs? Different authorities in different countries have guidelines for the use of statins. However, these guidelines are not exactly the same, leading toThe number of potential recommended medications also varies widely.

It should be emphasized that these guidelines are not rules that patients must follow. They just remind the public that if these conditions are met, they should pay more attention to blood cholesterol levels, consider changing lifestyle habits, and discuss with the doctor whether they need to take statins.drug.

The following are examples of suggestions from several authoritative organizations for your reference.

1 American College of Cardiology and the American Heart Association ACC / AHA

The guidelines issued by these two organizations in 2013 recommended that the following groups consider taking cholesterol-lowering drugs [20] :

  • Anyone who has had a cardiovascular disease, including angina chest pain caused by exercise or stress, someone with a history of heart attack or stroke, or other related illness.

  • Anyone with a high level of LDL cholesterol in the blood ≥190 mg / dL 4.9 mmol / L

  • Any diabetic patient between 40 and 75 years old, LDL cholesterol ≥70 mg / dL

  • Anyone between 40 and 75 years old, LDL cholesterol between 70-189 mg / dL, with a risk of ≥7.5% in the next 10 years calculated with ASCVD risk estimator Have heart disease or stroke or otherPeople with forms of cardiovascular disease.

This guide covers approximately 26.4 million Americans.

The 2018 updated guideline further emphasizes the need for multiple ethnic groups to consider and personalize treatment differently from whites. Current research on risk factors for cardiovascular disease is mainly derived from the aforementioned "Flemingham City HeartResearch ". But the majority of the subjects in this study are whites and are not diverse enough. Different races have very different estimates of risk.

A typical example is diabetes. A great risk factor for diabetes is height and body mass index BMI. The higher the BMI, the higher the risk of diabetes and hypertension. However, compared with whites,Asian and American Asians have diabetes at a lower BMI, and as long as they are Asian, no matter where they live in the world, the exact reason for this difference is not clear.

2013 guidelines point out that people of African descent tend to have a higher risk of cardiovascular disease than white people. The updated 2018 guidelines also include the situation in South Asia. However, there is currently no good large-scale studyResearch and quantify the risk factors of cardiovascular disease in Chinese people. Hope this situation will change in the near future.

2 US Preventive Services Task Force USPTSF

http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/statin-use-in-adults-preventive-medication1

In 2016, the U.S. Government's Preventive Services Working Group issued updated guidelines. They believe that statins are most effective for this population: a risk factor of at least 10% calculated using the ASCVD risk estimator + at least one explicitRisk factors for cardiovascular disease such as high blood pressure, diabetes and smoking.

It is also pointed out that the existing evidence is "not enough" to recommend statins to people aged ≥76 years without a history of heart attack or stroke.

The statement does not mean that people who have already taken statins stop taking them when they are 76 years old, nor does it mean that statins are completely useless for this group of people. It does mean that for these people, the benefits may be relatively small.Personal circumstances determine whether to take medication.

This guideline covers approximately 17.1 million people in the United States. Far below that number

It's not just the U.S. authorities that are divided, it's the same in other countries. For those aged 40-75 years without a history of cardiovascular disease, the USPTSF and ACC / AHA guidelines include 31% and 42%, respectively; Guidelines from the Canadian Cardiovascular Society and the European Society of Cardiology and the European Atherosclerosis Society cover approximately 44% and 15% of the same population sample.

Maybe none of the guidelines are perfect now, but they can serve as a good warning. The sooner you start trying to prevent heart disease, the more likely you are to effectively reduce this risk. For some people, it is safe and effectiveDrugs may be required.

Coronary artery calcium scan

Here is a valuable tool to predict the future risk of heart disease—Coronary artery calcium CAC scan.

This non-invasive imaging test uses mammography screening for similar radiation doses and can measure calcified plaque deposition in the coronary arteries. For patients with ASCVD risk estimates that are intermediate-risk, but close to 20It may be a struggle to start statin therapy immediately. However, if the CAC scan score is zero and there are no other cardiovascular risk factors, then statin use can be temporarily postponed.

Conclusion

Cholesterol has been proposed as a risk factor for cardiovascular disease since the early 19th century. Since then, there have been many controversies about cholesterol research, some of which are reasonable criticisms, and some of them are not so reasonable: the rabbit research conclusionSimple extension to humans; most of the cholesterol interventions by diet have no significant effect; early drug clinical trials were conducted in men only; treatments did not reduce the incidence of cardiovascular events but did not reduce mortality; the mechanism of action of statinsIt may not be as simple as lowering cholesterol; statins are too expensive.

However, the times have improved, and most of the controversies about cholesterol have been answered: there have been many randomized double-blind clinical trials in humans that prove that reducing the level of LDL cholesterol in the body through different mechanisms is beneficial to the cardiovascular system; a balanced dietPrograms and moderate exercise can lower cholesterol. In addition, there are several drugs that can effectively lower blood lipids; clinical trials include women and the elderly; some drugs also improve mortality; several drugs that reduce LDL cholesterol in the blood through different mechanisms areIt is good for cardiovascular. Many statins have generic drugs and are cheaper. If there are adverse reactions to certain drugs, there are other options to consider.

In recent years, the controversy over statins has mainly focused on its role in primary prevention. And these controversies have been misunderstood by some people as statins have no benefit. This is incorrect. For some high-risk groups, statinsIt is a life-saving medicine.

At the other extreme, many statin users mistakenly believe that after taking statins, there is no contraindication, so they can eat anything at will. [21]. This is also very dangerous and undesirable!

No pill can replace a healthy lifestyle: a balanced diet, regular exercise and avoiding smoking.

No medicine has no side effects. You should carefully weigh the pros and cons before deciding whether to use the medicine.

However, drugs are also life-saving and should not be rejected blindly.

Last important point to emphasize :

It is important to treat the results of correlation research in medical research carefully. They cannot be used to prove causality, they cannot be used to prove that a hypothesis is correct, and can only be used to reverse the hypothesis.

The results of correlation studies need to be cautiously interpreted. It cannot be used to indicate causal relationship. It cannot be used to prove a hypothesis, only to disprove one.

References

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[14] A. Gupta et al., Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm ASCOT-LLA: a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. The Lancet 389, 2473-2481 2017.

[15] SF Nielsen, BG Nordestgaard, Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. European Heart Journal 37, 908-916 2015.

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Shi Ye

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