Are you trying to lower stubbornly high LDL cholesterol?

Expert consensus focuses on individual planning to reduce high LDL.

I recently met Nancy, a 72-year-old woman with coronary artery disease, to review her latest cholesterol findings. Despite taking statins, a healthy diet and regular exercise, her low-density lipoprotein (LDL) cholesterol remained above our target. “What else can I do?” she asked. “When I increase the dose of statins, I have terrible pains in my legs. But I don’t want to have another heart attack!”

When high, LDL contributes to cardiovascular disease, which can cause heart attack or stroke. Taking statins can lower LDL levels in most people by about 30%, substantially 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 above the maximum tolerated dose? An expert consensus report published by the American College of Cardiology lays out a clear path for the next steps.

What is a healthy goal for LDL cholesterol?

Target LDL depends on many factors, including age, family history, and personal history of cardiovascular disease. For people at intermediate risk, LDL should be reduced by 30% to 50%. For those who have already had a heart attack, the target LDL does not exceed 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 can be combined with a statin 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 cardiovascular risk: the risk of heart attack, stroke, heart failure, and other problems affecting the heart and blood vessels.

Ezetimibe (Zetia)

What does he do: It reduces LDL and cardiovascular risk by reducing the absorption of cholesterol.

How it is given: A daily pill

Relatively inexpensive and often given with statins.

PCSK9 inhibitors

alirocumab (Praluent) and evolocumab (Repatha)

What does he do: A protein called PCSK9 controls the number of LDL receptors on cells. These medicines are monoclonal antibodies against PCSK9 which increase LDL receptors on the liver, helping to clear circulating LDL from the bloodstream.

How it is given: One shot every two to four weeks

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

Three new non-statin therapies

Three new FDA-approved non-statin therapies are highly effective for lowering LDL cholesterol. It is not yet known whether these reduce cardiovascular risk.

Bempedoic acid (Nexletol)

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

How it is given: A daily pill

Bempedoic acid is activated only in the liver, while statins are activated in the liver and muscle tissue. Experts hope this difference translates into a similar LDL-lowering effect, but without the muscle aches reported by some people taking statins. In fact, early studies show that this drug lowers LDL cholesterol by about 20% to 25% compared to placebo.

Potential drawbacks include high costs and a possible increased risk of tendon rupture, gout, and a cardiac arrhythmia called atrial fibrillation. Results from larger studies are expected by the end of 2022.

Evinacumab (Evkeeza)

What does he do: Rare individuals born without a cholesterol processing protein called ANGPTL3 have extremely low LDL and triglyceride levels, which reduces the risk of coronary heart disease by about 40%. Taking a cue from nature, scientists developed evinacumab, a monoclonal antibody that deactivates ANGPTL3, mimicking this rare condition and causing a dramatic drop in LDL by nearly 50% in one trial.

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

How it is given: One shot every six months

Potential drawbacks include an 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 tailoring a plan to reduce LDL taking into account individual risk, drug cost and genetic factors. A combination of lifestyle changes and medications can help people gain better LDL control. So, if you have high LDL cholesterol, try to follow healthy eating patterns, exercise regularly, avoid smoking and vaping, and maintain a healthy weight.

  • Statins are the first choice for the treatment of anyone with high cholesterol levels and cardiovascular risk factors, such as diabetes and hypertension.
  • If statins aren’t enough to help you reach your LDL goal, or if the side effects aren’t tolerable, you need to add ezetimibe later. PSCK9 inhibitors are therefore considered for those who remain at increased risk after the addition of ezetimibe.
  • If it is still not possible to achieve LDL goals in people with cardiovascular disease, bempedoic acid and inclirisan are considered.
  • For those with familial hypercholesterolaemia, evinacumab may be appropriate.

Cardiologists eagerly await the results of studies that will examine 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, cheaper drugs cannot meet LDL goals.

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