Trying to lower stubbornly high LDL cholesterol?

Expert consensus focuses on individualized planning to lower elevated LDL.

I recently met with Nancy, a 72-year-old woman with coronary artery disease, to review her latest cholesterol results. Despite taking a statin, following a healthy diet, and exercising regularly, her low-density lipoprotein (LDL) cholesterol remains above our goal. “What else can I do?” she asked. “When I increase my dose of statins, I get terrible leg pain. But I don’t want to have another heart attack!”

When elevated, LDL contributes to cardiovascular disease, which can cause heart attack or stroke. Taking statins can lower LDL levels in most people by about 30%, greatly reducing this risk. Usually, these commonly prescribed drugs work effectively with tolerable side effects. But what if a person’s LDL level remains too high for their maximum tolerated dose? An expert consensus report issued by the American College of Cardiology outlines a clear path for next steps.

What is a healthy goal for LDL cholesterol?

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

Which non-statin therapies are recommended first?

Five non-statin therapies described in this post are designed to help people reach their target LDL goals while minimizing side effects. They can be combined with a statin or given instead of statins.

Each helps lower LDL cholesterol when diet and statins are not enough, such as when there is a family history of high cholesterol (familial hypercholesterolemia). But so far, only two options have been proven to reduce cardiovascular risk – the risk of heart attack, stroke, heart failure and other problems affecting the heart and blood vessels.

Ezetimibe (Zetia)

What it does: Reduces LDL and cardiovascular risk by reducing cholesterol absorption.

How to give: A daily pill

Relatively cheap and often given with statins.

PCSK9 inhibitors

alirocumab (Praluent) and evolocumab (Repatha)

What it does: 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 clear circulating LDL from the bloodstream.

How to give: Injection every two to four weeks

Very effective at lowering LDL, but expensive and may not be covered by insurance.

Three newer non-statin therapies

Three newer FDA-approved non-statin therapies are very effective in lowering LDL cholesterol. It is not yet known whether they reduce cardiovascular risk.

Bempedic acid (Nexletol)

What it does: Like statins, bempedic acid tells the liver to make less cholesterol.

How to give: A daily pill

Bempedic acid is activated only in the liver, while statins are activated in the liver and muscle tissue. Experts hope that this difference will lead to a similar LDL-lowering effect, but without the muscle pain that some people taking statins report. Indeed, early studies show that this drug lowers LDL cholesterol by about 20% to 25% compared to a placebo.

Potential disadvantages include high cost and a possible increase in the risk of tendon rupture, gout, and a heart arrhythmia called atrial fibrillation. Results from larger trials are expected in late 2022.

Evinacumab (Evkeeza)

What it does: Rare people born without a cholesterol-processing protein called ANGPTL3 have extremely low LDL and triglyceride levels, reducing their risk of coronary heart disease by about 40%. Taking a cue from nature, scientists developed evinacumab, a monoclonal antibody that shuts down ANGPTL3, mimicking this rare condition and leading to dramatic LDL lowering of nearly 50% in one study.

How to give: Monthly intravenous infusion

Currently, the FDA has only approved evinacumab for people with familial hypercholesterolemia. Evinacumab appears safe in early studies, but it is very expensive and can only be administered in a doctor’s office.

Inclirisan (Leqvio)

What it does: Inclirisan blocks PCSK9. However, unlike alirocumab and evolocumab, which inactivate PCSK9 after it is produced, inclirisan inhibits the production of PCSK9 in the liver. Inhibiting PCSK9 leads to an increase in the number of LDL receptors on the surface of the liver, accelerating the clearance of LDL from the bloodstream and reducing LDL by about 50% (see here and here).

How to give: Injection every six months

Potential disadvantages include increased rates of urinary tract infections, joint and muscle pain, diarrhea and shortness of breath. This drug is expensive and insurance may not cover it.

What does the report recommend?

It reinforces the importance of customizing an LDL-lowering plan by considering individual risk, drug cost, and genetic factors. A combination of lifestyle changes and medication can help people achieve better LDL control. So if you have elevated LDL cholesterol, try to follow healthy eating patterns, exercise regularly, avoid smoking and cigarettes, and maintain a healthy weight.

  • Statin drugs are the first choice of treatment for anyone who has elevated cholesterol and cardiovascular risk factors, such as diabetes and high blood pressure.
  • If statins are not enough to help you reach your LDL goal or if the side effects are intolerable, ezetimibe should be added. PSCK9 inhibitors are then considered for those who remain at increased risk after adding ezetimibe.
  • If LDL targets still cannot be achieved in people with cardiovascular disease, bempedic acid and inclirizane are considered.
  • For those with familial hypercholesterolemia, evinacumab 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 is likely to be limited to high-risk people for whom proven, less expensive drugs cannot meet LDL goals.

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