Recommending ezetimibe, “The lower the LDL-C, the better”

[Interview] Professor Kim Hyo-soo (Seoul National University Department of Internal Medicine)

Believing in ‘the lower the better’, cholesterol target level will change

Targeting LDL-C level of 55mg/dL needs ezetimibe combination therapy as first-line treatment

김효수 교수

With robust evidences of efficacy, ezetimibe is now one of major options for treating dyslipidemia.

 

“The lower the better.” The result of clinical trial IMPROVE-IT, with the slogan claiming the lower the low-density lipoprotein cholesterol (LDL-C) is the better the health benefit, earned its recognition when it was announced in 2015.

 

Numerous pharmaceutical companies in Korea raced each other to release combination drugs with ezetimibe plus either atorvastatin or rosuvastatin.

 

The products landed themselves on the market safe and sound.

 

Given the positive response, some wondered about the unexpected recommendation addressed in Guidelines for the Management of Dyslipidemia 2018 published by Korean Society of Lipid and Atherosclerosis’ (KSoLA).

 

While American Association of Clinical Endocrinologists (AACE) updated its guideline in 2017 with new ‘extreme risk’ category and advised medical professionals to bring the LDL-C level down to under 55 mg/dL, the KSoLA’s latest guideline maintained the target treatment level of LDL-C for ultra-high risk group at 70 mg/dL.

 

Meanwhile, European Society of Cardiology (ESC) has recently recommended setting treatment target LDL-C level for extreme risk group at under 40 mg/dL.

 

With an expectation of more assertive use, ezetimibe was also listed as second-line treatment option following statin treatment.

 

Despite the release of new medicine like PCSK-9 inhibitors, the Korean guideline generally took the conservative approach.

 

And what are the thoughts of Korean clinical doctors on dyslipidemia treatment strategy after the newest edition of the guideline was published more than a year ago?

 

Daily Pharm interviewed Kim Hyo-soo, the then Professor at Department of Internal Medicine of Seoul National University Hospital, on the issue.

 

At the time of publishing, he was the chairman of the society and has actively supported prescription of ezemitib at any time.

 

- About setting 'treatment target of LDL-C level 55 mg/dL' and 'ezetimibe as first-line treatment,’ did you think it was too soon?

 

In my opinion, ezetimibe is not in any way insufficient to be a first-line treatment.

 

But many did not see a good reason to add ezetimibe to the first-line treatment option, when a patient can reach the target level with statin monotherapy.

 

So the guideline recommended medical professionals to prescribe the medicine to patients struggling to manage the cholesterol level only with statin.

 

Treatment target level of LDL-C actually differs among many clinical trials.

 

When setting 70 mg/dL as an idealistic level, the needs for ezetimibe as a first-line treatment are low to be honest.

 

But it’s another story when setting the level at 55 mg/dL.

 

Usually the level is unreachable with statin monotherapy.

 

It needs a combination therapy with ezetimibe.

 

Personally, I prescribe statin-ezetimibe combination therapy as first-line treatment.

 

In other words, each doctor’s level of lowest value varies, so the guideline had to take a rather careful approach.

 

On a side note, I did suggest setting 55 mg/dL as target LDL-C level when we were updating the guideline.

 

Now I’m looking into 35 mg/dL, even.

 

- What had enabled ezetimibe to lower LDL-C level and to ultimately prevent cardiovascular events?

 

LDL-C can be divided into apolipoprotein B (ApoB)-48 and ApoB-100.

 

Previously, only ApoB-100 was considered to be accumulated as plaque, but apparently studies have found ApoB-48 also works the same.

 

Now it’s more convincing that statin’s ApoB-100 synthesis inhibition combined with ezetimibe’s ApoB-48 absorption inhibition is lowering LDL-C level more effectively.

 

For a long time, hyperlipidemia treatment was solely dependent on statin and the practice has prescribed a high dose of it.

 

Combination therapy with non-statin class, previously quite unpopular, is now gaining the attention and PCSK-9 inhibitor, expensive but powerful in dropping LDL-C level, is also used more often.

 

The time has changed, eventually.

 

- Is there a particular patient group you would especially recommend ezetimibe combination therapy?

 

Cholesterol absorption is accelerated in diabetic patients.

 

With more favorable condition for cholesterol absorption than non-diabetic patient, ezetimibe could deliver more dramatic effect.

 

Ezetimibe would also be effective for patient group with high blood sugar level, because it does not increase chance of diabetes onset when used, whereas statin does.

 

Postprandial hyperglycemia is a vital issue for a diabetic patient, but newer studies say postprandial lipidemia is also as bad.

 

Ezetimibe inhibits postprandial lipidemia, which would be beneficial to diabetic patients.

 

For my clinical practice, I have often used ezetimibe to lower diabetic patients’ cholesterol level.

 

As a matter of fact, I conducted a research on less explored area of effect of the drug on blood glucose.

 

The researchers are currently analyzing data collected from about 200 people.

 

- Many have mentioned of PCSK-9 inhibitor, but apparently it tends to be administered once-monthly (originally indicated for once-biweekly) as the drug use is mostly non-reimbursed, despite its outstanding efficacy.

 

Is it alright to change the interval?

 

For a patient, relapsed disease like acute coronary syndrome (ACS), myocardial infarction (MI) and peripheral artery disease (PAD) are critical to their condition.

 

And those patients’ LDL-C level has to be lowered more aggressively.

 

And if adding ezetimibe does not work, then PCSK-9 inhibitor has to be used.

 

But, it is expensive.

 

And that is why many of them are administered once a month, but their LDL-C level ranging from 70 mg/dL to 80 mg/dL is usually halved or more.

 

A patient that ticks off more than two of high-risk conditions—diabetic, hypertension, age 65 and up, cigarette smoking, hypercholesterolemia—is advised to take PCSK-9 inhibitor.

 

I personally consider using PCSK-9 inhibitor when a patient’s cholesterol level is not controlled with rosuvastatin-ezetimibe combination therapy.