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On November 15, the American College of Cardiology and the American Heart Association released an updated guideline for the use of statins to prevent and treat atherosclerotic cardiovascular disease (ASCVD). The full report is available online. It has already generated a lot of controversy. The news media have characterized it as a “huge departure” from previous practice and have trumpeted that it will lead doctors to prescribe statins to millions more people. As usual, the truth is much more nuanced. There are some problems with the guidelines, but on the whole they represent an improved, more rational approach to prescribing statins.

Statins have always been a source of controversy: people seem to either love them or hate them, and discussions about them generate a lot of emotion. The International Network of Cholesterol Skeptics denies that cholesterol has anything to do with cardiovascular disease. An article on HuffPo calls statins “an unsafe, unnecessary product that will now be recommended to healthy people to make them sicker.” Mercola says they can actually make heart disease worse and cause premature aging, and no one should take them unless they have the genetic defect of familial hypercholesterolemia. A website collects patient self-reports of adverse effects; but like the vaccine reports on VAERS , these are only anecdotal reports of correlation, not evidence for causation.

At one time the evidence only supported using statins for secondary prevention and for men. We now have better evidence showing that they are effective for both primary and secondary prevention in patients of both sexes and all ages, and that they are more effective for those with higher risk factors.

What are the new guidelines?

Under the previous guidelines, doctors aimed to keep LDL cholesterol below 160 mg/dL for low-risk patients, below 130mg/dL for people at moderate risk (10 year risk of cardiovascular event between 10 and 20%) and to reduce it to 100mg/dL for those with a history of cardiovascular disease or diabetes, or with a 10-year risk of greater than 20%. For high-risk patients, doctors often aimed for less than 70mg/dL.

An expert panel evaluated all the available published evidence. They found that there was no good evidence to support the current target levels for LDL cholesterol, so they recommended an approach that disregards target levels and is based only on risk level and intensity of statin therapy. In essence, they switched from treating lab tests to treating patients. They identified 4 groups of individuals for which an extensive body of RCT evidence demonstrated a reduction in ASCVD events with a good margin of safety from moderate- or high-intensity statin therapy:

Individuals with clinical ASCVD Individuals with primary elevations of LDL–C ≥190 mg/dL. Individuals 40 to 75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher.

The guidelines are the same for women as for men.

They found no evidence to support adjusting treatment to achieve specific target levels of LDL-C. They found no evidence that using non-statin therapies for prevention would provide acceptable risk reduction compared to their potential for adverse events.

They provided a risk calculator to identify those with a risk of 7.5% or higher for having a cardiovascular event in the next 10 years. It quantifies risk based on age, sex, race, cholesterol, blood pressure, diabetes, and smoking. They pointed out that the data are inadequate to quantify risk for some racial, sex, and age groups, for instance those over the age of 75. The guidelines are not intended to be a cookbook, one-size-fits-all approach. Clinicians are expected to rule out secondary causes of hyperlipidemia, to take other individual patient factors into consideration, and to discuss risks/benefits and patient preferences before starting therapy. They stress that lifestyle modification (adhering to a heart healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) is critically important for everyone, both before and during treatment.

For both primary (patients with clinical ASCVD) and secondary prevention, they recommend high-intensity statin treatment below age 75, and moderate intensity statin treatment for those over age 75. Table 5 in the report defines high, moderate, and low intensity statin dosages. High intensity includes atorvastatin (Lipitor) 40-80 mg and rosuvastatin (Crestor) 20 mg daily; these have been shown to lower LDL-C by 50% or more.

They provide guidelines for monitoring patients on statins:

Regular assessment of adherence to medication and lifestyle

Re-testing lipid levels at intervals as long as 12 months

Other safety measures as clinically indicated

They no longer recommend routine monitoring of liver function tests unless there are symptoms suggesting liver toxicity.

They provide safety recommendations, listing patient characteristics that might increase the risk of side effects and advising how to manage patients who report symptoms that might be side effects of the drugs.

For patients not in the 4 groups, other factors may be considered to inform decision-making: primary LDL–C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative, high-sensitivity C-reactive protein >2 mg/L, CAC score ≥300 Agatston units or ≥75 percentile for age, sex, and ethnicity, ankle-brachial index <0.9, or elevated lifetime risk of ASCVD. Additional factors may be identified in the future.

Criticism of the new guidelines

The risk calculator was based on old data and it overestimates risk. Out of 46 recommendations, 20 were based only on expert opinion. Too many people will be put on statins. The American Academy of Family Physicians is not willing to endorse the new guidelines. Conflict of interest: six out of the 15 authors reported having recent or current ties to manufacturers of statin drugs.

These objections can be answered:

Those who say the risk calculator overestimates risk are relying on studies that underestimate risk because they used research subjects who were much healthier than the average American (the Nurses’ Health Study, the Women’s Health Initiative, and the Physicians’ Health study). And the risk calculator is only a starting point; clinicians are expected to take other factors into account, and a risk over 7.5% doesn’t automatically engender a prescription. The major recommendations were based on high-quality evidence from RCTs; the ones based on expert opinion were about minor details. The new guidelines may put more patients on statins, but it will put more appropriate patients on statins and will make sure that those who are not appropriate will not be given statins. There are a lot more people at risk today because of changes in the population: the population is older, and there is more obesity, hypertension, and metabolic syndrome. The AAFP is only exercising its usual rigorous scientific caution. It tries to make independent decisions based on its own assessment of the evidence rather than slavishly following the recommendations of other groups. It has said it will not endorse the new recommendations until it has had time to thoroughly review the hundreds of pages of supporting evidence as well as evidence from other sources. There is no evidence that those with ties to drug companies influenced the findings of the panel. The majority of the panel had no conflicts of interest, and the panel leaders said no one with industry connections could vote on the recommendations.

Even those who criticize the new guidelines say they support the majority of the recommendations.

How Safe Are Statins?

Mercola cites an article that says 17% of patients stopped taking them because of side effects. But that study concluded “most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other causes, are tolerable, or may be specific to individual statins rather than the entire drug class.” It’s easy to find horror stories on the Internet from patients who are convinced statins have harmed them, but they don’t necessarily mean that the drugs were at fault in those cases. The way to find out, of course, is to do controlled studies. The evidence is mixed. The JUPITER study, with 17,802 subjects, reported a greater number of serious side effects in the placebo group than in the statin group (!), as well as fewer deaths from cancer; but only one difference was statistically significant: an increase in newly diagnosed diabetes in the statin group. The most common side effect is muscle pain, which is often mild and manageable. The most serious reported side effect is rhabdomyolysis, but it is rare: in the JUPITER trial there was only one nonfatal case reported in a 90-year-old patient after the study, and he also had febrile influenza, pneumonia, and trauma-induced myopathy. Increases in liver enzymes, digestive problems, rashes, and neurological side effects have also been reported, often in patients who are susceptible to those problems for other reasons. The neurological effects are memory loss and confusion, which can be reversed by stopping the medication; but on the other hand there is evidence that statins may actually improve brain function in patients with dementia or Alzheimer’s disease. There is a slight risk of increased blood glucose levels that prompted the FDA to include a warning on package labels. The risk of side effects is greater for women, those on multiple cholesterol-lowering meds, with a smaller body frame, aged 65 or older, diabetics, and people who overuse of alcohol.

All drugs with effects have side effects, and most cardiologists consider statins one of the best drugs we have ever had and consider them remarkably safe compared to most other drugs. The new guidelines include a section that objectively evaluates the evidence for risks. Those who object to Big Pharma and prefer natural alternatives may be reassured to learn that the first statin (lovastatin) was isolated from a fungus and can still be obtained from red yeast rice, although products sold in the US no longer contain the active ingredient since the FDA mandated its removal.

Conclusion

It is the overall management of risk factors, regardless of blood cholesterol levels attained, that is important for heart disease and associated mortality. The new guidelines are based on the best evidence we have today from RCTs; they simplify treatment by basing it on risk rather than chasing target levels, and they require fewer blood tests for monitoring. They are meant to be taken as recommendations, not as inflexible requirements; and they will undoubtedly evolve as more evidence comes in. Cardiologist Harlan Krumholz summarized the changes nicely: “The new message is don’t chase targets, know your risk, and — if you need drug therapy — use statins.”