Expert consensus focuses on individualized planning to lower elevated LDL.

An orange plastic rack holds blood test tubes of different colors;  Yellow tip on the tube in the front "LDL test"

I recently met with Nancy, a 72-year-old woman with coronary artery disease, to review her latest cholesterol findings. Despite taking statins, following a healthy diet and exercising regularly, our LDL cholesterol remained above our target. “what can I do?” She asked. “When I increase my stats, I get a lot of leg pain. But I don’t want to have another heart attack!”
When the level of low-density lipoprotein (LDL) is high, it contributes to cardiovascular disease, which can cause a heart attack or stroke. Taking statins can lower LDL levels in most people by about 30%, which greatly reduces this risk. Usually, these commonly prescribed medications work effectively with tolerable side effects. But what if a person’s LDL level remains too high at their maximum tolerated dose? The Expert Consensus Report from the American College of Cardiology charts a clear path for next steps.

What is the health goal of bad cholesterol?

Target LDL depends on many factors, including age, family history, and personal history of cardiovascular disease. For people at average risk, LDL should be lowered by 30% to 50%. For those who have already had a heart attack, the LDL target is no more than 70 mg/dL (note: automatic download).

What non-statin treatments are recommended first?

Five non-statin therapies described in this post are intended to help people achieve their LDL-targeted goals while minimizing side effects. They can be combined with statins or given instead of statins.
Each helps lower LDL cholesterol when diet and statins aren’t enough, such as when there is a family history of high cholesterol (familial hypercholesterolemia). But so far, only two options have been shown to reduce the risk of cardiovascular disease – the risk of heart attack, stroke, heart failure and other problems that affect the heart and blood vessels.

ezetimibe (Zetia)

what’s he doing: It reduces LDL and cardiovascular risk by decreasing cholesterol absorption.
How it is presented: daily pill
It is relatively inexpensive and is often given in combination with statins.

PCSK9 . inhibitors

leucomab (Praluent) and evolocumab (Repata)

what’s he doing: A protein called PCSK9 controls the number of LDL receptors on cells. These drugs are monoclonal antibodies against PCSK9 that increase LDL receptors in the liver, helping to remove circulating LDL from the bloodstream.
How it is presented: An injection every two to four weeks
Very effective for lowering LDL, but it is expensive and may not be covered by insurance.

Three new treatments that do not contain statins

Three new non-statin therapies approved by the Food and Drug Administration (FDA) are highly effective in lowering LDL cholesterol. It is not yet known whether these agents reduce the risk of cardiovascular disease.

bempedoic acid (nicyltol)

what’s he doing: Like statins, bempedoic acid tells the liver to lower cholesterol.
How it is presented: daily pill
Bempedoic acid is activated only in the liver, while statins are activated in the liver and muscle tissue. Experts hope this difference will translate into a similar LDL-lowering effect, but without the muscle pain reported by some people taking statins. In fact, early trials showed that this drug lowers LDL cholesterol by about 20% to 25% compared to a placebo.
Possible downsides include the high cost and possible increased risk of tendon rupture, gout, and a heart arrhythmia called atrial fibrillation. Results from larger trials are expected in late 2022.

Evinacumab (Evkeeza)

what’s he doing: Rare individuals born without a cholesterol-processing protein called ANGPTL3 have extremely low levels of LDL and triglycerides, which reduces the risk of coronary heart disease by about 40%. Inspired by nature, scientists have developed evinacumab, a monoclonal antibody that turns off ANGPTL3, mimicking this rare condition and producing a dramatic reduction in LDL by nearly 50% in one trial.
How it is presented: Monthly intravenous infusion
Currently, the Food and Drug Administration has only approved evenacumab for people with familial hypercholesterolemia. Evinacumab appears safe in early trials, but it is very expensive and can only be given in a doctor’s office.

Inclirisan (Lakeview)

what’s he doing: Inclirisan blocks PCSK9. However, unlike alirocumab and evolocumab, which inactivate PCSK9 after its production, inclirisan inhibits PCSK9 production in the liver. Inhibition of PCSK9 increases the number of LDL receptors on the surface of the liver, which speeds up the removal of LDL from the bloodstream and the dropping of LDL by about 50% (see here and here).
How it is presented: injection every six months
Possible downsides include an increased rate of urinary tract infections, joint and muscle pain, diarrhea, and shortness of breath. This medication is expensive and may not be covered by insurance.

What does the report recommend?

It reinforces the importance of tailoring a plan to lower LDL by accounting for individual risks, drug cost, and genetics. A combination of lifestyle changes and medications can help people achieve better LDL control. Therefore, if you have high LDL cholesterol, try to follow healthy eating patterns, exercise regularly, avoid smoking and vaping, and maintain a healthy weight.

  • Statin drugs are the first choice for treating anyone with high cholesterol and cardiovascular risk factors, such as diabetes and high blood pressure.
  • If statins are not enough to help you reach your LDL target, or if side effects are unacceptable, ezetimibe should be added afterward. PSCK9 inhibitors are then considered for those who remain at increased risk after adding ezetimibe.
  • If LDL targets are still not achievable in people with cardiovascular disease, bempedoic acid and inclirisan are considered.
  • For those with familial hypercholesterolemia, efinacumab may be appropriate.

Cardiologists are eagerly awaiting the results of studies looking at whether the three new LDL-lowering drugs also reduce the risk of heart attack, stroke, and other poor cardiovascular outcomes. Until then, their use will likely be restricted to high-risk people for whom less expensive, proven drugs cannot achieve their LDL targets.

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