Trying to lower stubbornly high LDL cholesterol?

Recently I 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 remained above our target. "What else can I do?" she asked. "When I increase my statin dose I get terrible leg pains. But I don't want to have another heart attack!"

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

What is a healthy target for LDL cholesterol?

Target LDL 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, 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 aim to help people achieve target LDL goals while minimizing side effects. They may be combined with a statin or given instead of statins.

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

Ezetimibe (Zetia)

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

How it's given: A daily pill

Relatively inexpensive 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 medicines are monoclonal antibodies against PCSK9 that increase LDL receptors on the liver, helping to clear circulating LDL from the bloodstream.

How it's given: A shot every two to four weeks

Highly effective for lowering LDL, but expensive and may not be covered by insurance.

Three newer non-statin therapies

Three newer, FDA-approved non-statin therapies are highly effective for lowering LDL cholesterol. Whether these lessen cardiovascular risk is not yet known.

Bempedoic acid (Nexletol)

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

How it's given: A daily pill

Bempedoic acid is activated only in the liver, whereas statins are activated in liver and muscle tissue. Experts hope that this difference will translate to a similar LDL lowering effect, but without the muscle aches that some people who take statins report. Indeed, early trials show this medication lowers LDL cholesterol by about 20% to 25% compared to placebo.

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

Evinacumab (Evkeeza)

What it does: Rare individuals born without a cholesterol-processing protein called ANGPTL3 have extremely low LDL and triglyceride levels, which lowers their risk for coronary heart disease by about 40%. Taking a cue from nature, scientists developed evinacumab, a monoclonal antibody that turns off ANGPTL3, mimicking this rare condition and resulting in dramatic LDL lowering of almost 50% in one trial.

How it's given: Monthly intravenous infusion

Currently, the FDA has only approved evinacumab for people with familial hypercholesterolemia. Evinacumab appears safe in early trials, but is very expensive and can only be given 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 production of PCSK9 in the liver. Inhibition of PCSK9 leads to an increase in the number of LDL receptors on the surface of the liver, speeding clearance of LDL from the bloodstream and dropping LDL by about 50% (see here and here).

How it's given: A shot every six months

Potential downsides include increased rate of urinary tract infection, joint and muscle pain, diarrhea, and shortness of breath. This medicine is expensive and insurance may not cover it.

What does the report recommend?

It reinforces the importance of personalizing a plan to lower LDL by accounting for individual risk, cost of medication, and genetic factors. A combination of lifestyle changes and medicine can help people achieve better control of LDL. So, if you have elevated 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 to treat anyone who has elevated cholesterol and cardiovascular risk factors, such as diabetes and high blood pressure.
• If statins aren't sufficient to help you reach your LDL target, or if side effects aren't tolerable, ezetimibe should be added next. 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, bempedoic acid and inclirisan are considered.
• For those with familial hypercholesterolemia, evinacumab may be appropriate.

Cardiologists eagerly await the results of studies looking at whether the three new LDL-lowering medications also lower risk for heart attack, stroke, and other poor cardiovascular outcomes. Until then, their use is likely to be limited to people at high risk for whom proven, less costly drugs cannot achieve LDL goals.