Who should take a statin drug?

Before 1984, three years before the first statin was introduced in the US, many doctors did not believe that lowering cholesterol helped prevent heart attacks and death. But in that year, the Lipid Research Clinics Trial showed that for every 1% drop in cholesterol, there would be a 2% drop in the risk of heart attack and death.

The important thing about the LRC Trial is that it was a randomized controlled trial (RCT): that means each patient’s treatment was chosen at random, and neither the patients nor the researchers knew whether any patient was receiving the drug (cholestyramine) or a placebo. A RCT eliminates nearly all potential bias from a study, and yields results that are very reliable. Well done RCTs are the closest we can ever get to the TRUTH in medicine.

While the LRC Trial was truly ground-breaking, it didn’t take us very far in treating cardiovascular disease, because cholestyramine is a pretty yucky drug to take, and its effect on cholesterol lowering is modest. Something better was needed.

The first statin drug, Mevacor (lovastatin), was released in the US in 1987, soon followed by Zocor (simvastatin). The FDA approved statin drugs because they lowered cholesterol far more than cholestyramine, and they were incredibly well tolerated by comparison.

In 1994, the first large RCT of statins, the 4S Trial, showed truly amazing benefit in reducing cholesterol numbers. But much more importantly, simvastatin dramatically lowered the risk of heart attack, bypass surgery, and death. Over subsequent years, every single RCT of both old and new statins showed basically the exact same thing: A 25-45% reduction in risk, whether a patient already had heart disease or not.

As more trials were done, it also became clear that the higher the dose of a statin, and the stronger the statin used, the greater the reduction in risk. Higher doses and strengths of statin were also associated with a greater chance of muscle aches (myalgias) and other annoying — but rarely serious — side effects.

The success of statins in preventing serious life threatening events in tens of millions of patients, and the relative safety of the drugs, has become ever more evident over the last 30+ years.

The latest cholesterol treatment guidelines, published November 2013 by the American Heart Association and the American College of Cardiology, are based on the results of the numerous randomized controlled trials (RCTs) done since 1994.

The guidelines are grounded on two principles:

• First, the benefit of statins is proportional to the intensity of the therapy (dose and strength of the drug chosen)
• Second, the side effects are also proportional to the intensity of therapy.

So, high intensity therapy is justified for patients at high levels of risk, and moderate intensity therapy should be given to patients at moderate levels of risk. But patients at low risk should not receive statin drugs at all. In this way, the overall benefits are maximized and side effects are minimized.

The new guidelines identify patient risk from the randomized clinical trials performed to date. The guidelines identify four groups of moderate and high risk patients aged 40-75 who should be on statin drugs:

• Patients who already have clinically important cholesterol deposits (atherosclerosis) in the arteries of the heart, brain or legs are at high risk.
• Diabetics turn out to have virtually the same risk as those who already have cholesterol deposits in their arteries, so they are treated as a high or moderate risk.
• People with extraordinarily high levels of LDL (“bad”) cholesterol, are also considered high risk. The cutoff “high risk” LDL level was defined as 190 mg/dL.
• The fourth group is identified by using a risk calculator developed by the guidelines committee. The calculator estimates the risk of death, heart attack, bypass surgery, stenting, stroke and ministroke (TIA). ). Patients who have a calculated ten year risk of 7.5% or more should be treated.

The risk calculator can be found online. You will need to enter your age, sex, race, blood pressure, diabetes status, smoking status, total cholesterol, and your HDL (“good”) cholesterol to calculate your risk. If your ten year risk exceeds 7.5%, then statin therapy is considered beneficial.

Other factors not in the risk calculator should also be considered in the evaluation of individual patients. These include:

• A family history of premature coronary heart disease in a first degree relative (siblings or parents).
• A C-reactive protein (CRP) of >2mg/L.  CRP is a blood test that shows the level of inflammation that may be seen in atherosclerosis. Please be aware that lots of other conditions can cause a high CRP, so this test is not terribly specific.
• Peripheral arterial disease with a vascular test severity index called ABI that is less than 0.9.
• A computerized tomogaphy (CT) calcium score of >300 Agaston Units or >75th percentile score for age, sex and ethnicity.

The 2013 guidelines discarded the notion that therapy should be adjusted to meet a “target” LDL number like 70 or 100 mg/dL. It turns out that the randomized controlled trials (RCT) show that statin benefit is related to the percent reduction of the baseline LDL cholesterol, no matter what the LDL starting point. If your starting LDL was 200 and it is lowered to 100, it’s the same thing as if your LDL is lowered from 100 to 50. It turns out that none of the RCTs of statin therapy were designed to treat to a “target LDL”, so de-emphasizing the notion of targeted LDL treatment was long overdue. As long as your starting LDL is more than 70, there is benefit to be had by lowering your LDL if you are in a high or moderate risk group.

High intensity statin treatment is defined in the new guidelines as lowering the LDL by more than 50%. Moderate intensity statin treatment is defined as lowering LDL by 30-50%.

The stronger statins, such as Lipitor (atorvastatin) and Crestor (rosuvastatin), are the most effective in producing big drops in LDL.

The bottom line is that high intensity statin treatment should be given to high risk patients, and moderate intensity statin therapy should be given to moderate risk patients.

Non-statin lipid therapy gets short shrift in the 2013 guidelines because randomized controlled trials done with most of these drugs failed to show convincing benefit. Tricor®, Trilipix® (fenofibrate), and Niaspan® (niacin) have not been shown to give additional benefit in preventing cardiovascular disease when added to statin therapy. There are good reasons to use these drugs when the triglyceride level is over 500, but that is a pretty unusual situation.

Many patients take fish oil (omega-3 fatty acids) to prevent heart disease. However, the American Heart Association reviewed all the evidence up to 2017 and did not recommend the use of fish oil for heart disease prevention. They did find borderline evidence that fish oil may slightly reduce death rates in patients who already have coronary heart disease or heart failure. Since there is little risk in using fish oil, they felt it was reasonable to use it in these cases. More study is needed to see if these recommendations hold up in the future.

Zetia® (ezetimibe) is the second ingredient with Zocor (simvastatin) in the combination drug Vytorin.  Zetia can also be given as a separate pill with other statins. A large randomized clinical trial in 2014 showed that Zetia does indeed reduce adverse outcomes when added to a statin. But with only one large trial showing the benefit of Zetia, and many trials showing the benefit of statins alone, we reserve the use of Zetia for patients who cannot achieve their cholesterol lowering goal with a statin alone.

The newly introduced injectable drugs Praluent® and Repatha®, when added to statins, will lower LDL cholesterol to almost unheard of low levels. They are extraordinarily expensive and are to be used in patients with established cholesterol deposits who cannot tolerate adequate doses of statin and those with genetic familial hypercholesterolemia.

Read more about the AHA/ACC Cholesterol Guidelines .