Statin Intolerance: Pearls for Practice in the PCSK9 Inhibitor Era

In her role directing one of the first and largest dedicated programs for patients with statin intolerance, Cleveland Clinic Section Head of Preventive Cardiology and Rehabilitation Leslie Cho, MD, has collected her fair share of practical nuggets of advice on the condition. She recently fielded the following questions on the topic for her fellow providers.

Q: Can you lay out the essentials of what statin intolerance involves and how common it is?

Dr. Cho: Statin intolerance can mean the inability to take statin therapy due to its effect on muscles, joints or liver function tests. Specifically, it’s the inability to tolerate the lowest dose of two or more different statin medications. Statin intolerance has been debated for years, and its existence was questioned because it generally wasn’t reported in clinical trials. In the real world, however, it affects 5 to 10 percent of people who try statin therapy.

Within about a month of starting therapy, affected patients typically start getting severe muscle aches in the large muscle groups — the arms, shoulders, thighs or buttocks — on both sides of the body. These effects go away within a month after stopping statin therapy.

Statin intolerance is more common in the elderly, in women, and with more-potent statin therapy. So higher the dose, and the more potent the statin, the greater the chance of statin intolerance.

Q: How do you manage a patient who develops symptoms of statin intolerance? Do you try to treat the symptoms? Do you change the medication?

Dr. Cho: The first thing is to see whether something else may be causing the intolerance, including substances that can interfere with the body’s elimination of statins. A common culprit is alcohol, which means patients may have to limit how much they drink. Commonly prescribed cardiac medicines like diltiazem or amiodarone also can interfere with statin elimination, as can some antibiotics and, notably, other cholesterol-lowering medicines, such as fenofibrate. Some patients may be taking certain herbal supplements that can prevent statin elimination. So you have to rule out these things as causes of the statin intolerance. But if they are the cause, management is typically straightforward: You stop the substance that’s interfering with statin clearance or you change other medicines around.

If none of these potential causes is implicated, you can switch the patient to a different type of a statin. Statins are considered either lipophilic or hydrophilic. The hydrophilic statins — i.e., rosuvastatin and pravastatin — are less likely to go to the muscle. Other statins — such as atorvastatin, simvastatin and lovastatin — are lipophilic and more likely to go to a patient’s muscles.

So we tend to put patients on a hydrophilic statin. We start with one dose a week and then slowly titrate to twice a week. If the patient tolerates that for a couple of weeks, we go to every other day or we increase the dose or frequency as tolerated. We tend to use rosuvastatin for this type of intermittent dosing because it has a longer half-life, but pravastatin can be tried as well.

True statin intolerance — when a person cannot take a statin even once a week — is extremely rare.

Q: Over time, Cleveland Clinic has developed a program for patients with statin intolerance. Tell us about it and the outcomes you’ve seen with the above approach.

Dr. Cho: We have the largest experience in the world of treating statin-intolerant patients. We start with a thorough history and physical. If it turns out a patient is truly statin-intolerant, we start them on rosuvastatin once a week at the lowest possible dose, 2.5 mg. If they tolerate that, we go to 2.5 mg Monday and Thursday. Then we go to 5 mg Monday and Thursday. Then we increase the dose as they are able to tolerate.

Of the patients who are intolerant to two or more statins, 70 percent end up being able to take a statin. Sixty percent can take it every day, once we start this slow process. Another 10 percent can take a statin three times a week. It’s only the rare patients — the other the 30 percent (of those who could not tolerate two or more statins) — who really can’t take any statin therapy.

For patients who can’t take any statin, there are other good solutions out there. There is ezetimibe, which lowers cholesterol about 15 percent. But what has really changed the treatment landscape for statin-intolerant patients are the PCSK9 inhibitors, evolocumab and alirocumab.

Q: So for patients in your statin intolerance program, do you aim for a goal cholesterol level, and is the program helping them meet the goal?

Dr. Cho: Yes. The program’s LDL cholesterol goal is less than 100 mg/dL for primary prevention patients and less than 70 mg/dL for secondary prevention patients. Even before the PCSK9 inhibitors were approved a few years ago, we were able to meet those goals in approximately 90 percent of patients. Of course, intervention is more than just medicine — it’s diet, exercise, healthy weight and everything else. Many times, these patients who are statin-intolerant have to be on a statin plus ezetimibe to get reach the goal. But with all of these things, we have had very good success.

And we’ve seen from the Cleveland Clinic-led GAUSS-3 randomized trial of patients with confirmed, lifestyle-limiting statin intolerance that PCSK9 inhibitor therapy yields excellent LDL cholesterol reduction with a low rate of muscle-related adverse effects and a good overall side effect profile. So PCSK9 inhibitors represent a strong additional therapy option for patients in the program who may need them. And for certain patients — such as those who have genetic cholesterol problems, or statin-intolerant individuals who have very aggressive cardiovascular disease with multiple events — it makes sense to put them on a PCSK9 inhibitor early on.

Q: What’s your bottom-line advice?

Dr. Cho: Statin intolerance is more common than previously thought, but it’s still rare. For patients with suggestive symptoms, it is really important to take a careful history and physical and then to eliminate any other causes that could exacerbate muscle aches during statin therapy. If there are no other causes, try intermittent dosing of a hydrophilic statin. If the patient still doesn’t reach goal LDL cholesterol, then consider a PCSK9 inhibitor.