This is an excerpt from the recent webinar 'How and when to consider PCSK9 inhibitors in practice' by Dr. Jamshed Dalal hosted by M3 India. Dr. Dalal explains the studies and data on PCSK9 inhibitors, their role in lowering LDL cholesterol, how effective they are alongside other relevant drugs, and who they can be prescribed to.

The M3 India team recently hosted a webinar with renowned Cardiologist and Director of Centre for Cardiac Sciences at a prominent Mumbai hospital, Dr. Jamshed Dalal. He presented studies and data to educate cardiologists and physicians on the use and effectiveness of PCSK9 inhibitors in managing ASCVD.

PCSK9 inhibitors are the new-age drugs with monoclonal antibodies that inhibit pro-protein convertase kexin/sutilisin type 9. They help reduce the risk of MI and other CV events, caused due to high LDL levels, and promote carriage of PCSK9 loss-of-function alleles once the LDL levels are brought down.

Here’s an excerpt from the webinar, where Dr. Dalal explains the studies and data on PCSK9 inhibitors, their role in lowering LDL cholesterol, how effective they are alongside other relevant drugs like statins and even standalone, and who can you prescribe it to.

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Which are the target populations for PCSK9?

Of course, the first problem group of patients would be those with familial hypercholesterolaemia. As you know familial hypercholesterolaemia can be either homozygous or heterozygous. These people usually have LDL cholesterol of 200 to 300. They have very early premature coronary artery disease and most of them often have infarcts or die in their teenage or early adult life.

There is no separate group for this and there are no other options. Statins benefit this group but cannot help them to a great extent and PCSK9 inhibitors are virtually life-saving for this group of patients. But if we leave that group aside and we simply consider patients we see in day to day practice- the ones with coronary artery disease, then you’ll see patients who have inadequate LDL response.

Everybody doesn’t respond well to statins, some people don’t take statins and some experience side effects of statins. Plus, there are a lot of myths surrounding harm from statins; so patient keep stopping statins and then face problems. Then you may have patients who keep having cardiovascular events despite tolerance because of the residual risk. That residual risk can be taken care of with the use of PCSK9 inhibitors. And of course, if someone has very high LDL LP (a) levels or lipoprotein b levels, then they will definitely experience additional benefits.

Now if you look at the patients with familial hypercholesterolaemia, the earlier the patient gets the cholesterol down, the better their life span will be. So, if statins are started late or if PCSK9 inhibitors are started late, these people will not survive. They will die in about 12 years, 12.5 years. However, if treatment is given early, it can prolong their life considerably. Therefore, early detection and proper treatment of these patients can yield very good results.

Statins help these patients, no doubt, but if someone has an LDL cholesterol of 250 and is given statins, it will come down to 200 or say, 180, but it is still considerably high. And to bring it further down from those levels of 180 to 200, despite giving statins, a PCSK9 inhibitor would be an absolute essential part of treatment. And it has produced dramatic benefits!

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As far as cardiologists or clinicians are concerned; who should we target?

We should target patients who have had prior myocardial infarctions, who have multi-vessel coronary artery disease, associated diabetes or CKD, or those who have had recent coronary syndromes, the poor risk factors and there are others. They have family history, or they have diabetes, hypertension and multiple other problems. And there are people with associated peripheral vascular disease.

Anyone with coronary artery disease or peripheral vascular disease has a much higher incidence of vascular problems and death; patients who are above 65 years of age with known coronary artery disease; patients who have CAD and stroke; or TIAs and familial hypercholesterolaemia. And then of course, there can be statin intolerance and high Lipoprotein A.

What is the 10-year mortality risk?

The type of patients mentioned above would be considered as highest risk. They have about 20 to 30, 35 percent 10-year risk and that is considerable for the possibility of future events. So these are the patients who should be targeted, even if they are on statins and even if their LDL cholesterols are 70 or 80.

Earlier, the 2016 ESC guidelines mentioned that below 70 for patients with high risk, should be adequate but that is clearly changing now. The LAI, which is the Lipid Association of India, suggested that it should be below 50 and in fact. So clearly, there is a shift in paradigm and treatment of patients with LDL, patients with ischaemic heart diseases, patients with high risk or very high risk, which means patients who have had myocardial infarction before, had another ACS, peripheral artery disease, diabetes, hypertension, basically, a family history.

All patients, in fact, 50% of my patients have all these problems, and there is nothing unusual. It’s not one or two percent, who are high-risk. A vast majority of patients seen by cardiologists fall into this high risk or very high risk category.

Earlier, the guidelines formed by the American College of Endocrinology mentioned that patients with low risk i.e. no risk factors at all, should try and keep their LDL below 130. But, this concept of letting LDL be at 160 or 170 is no longer warranted. And patients with moderate risks, which means two risk factors and a 10-year risk of less than 10%, should keep LDL below 100. So, in a majority of our Indian patients with any sort of a risk factor, it is wise to keep LDL cholesterol below 100, as a primary prophylactic treatment.

If a patient has diabetes, hypertension, heart failure, CKD or any evidence of coronary, carotid or peripheral vascular disease, an LDL below 70 is recommended. And then you have the very high risk group, which means the patients who have had premature cardiovascular diseases, which is a large number of Indians, patients with established heart diseases and diabetes stage 3 and 4, CKD, heart failure patients, and those who have unstable angina for example. In all of these patients, it is recommended to keep the LDL below 50 or 55.

Usually you will find that if the LDL has been in the range of 80, the LDL will still be in the range of 60-65 with Ezetamibe and 20 mg or 40 mg of Rosuvastatin. Unfortunately, doubling the dose of Rosuvastatin from 20 to 40 produces a small fall in LDL, doesn’t produce very dramatic falls in LDL. Now if this patient comes back and his LDL cholesterol is still 65, cholesterol levels need to be brought down further. Because if the lipids are brought down with a PCSK9 inhibitor, may be to 30 or 40, it will sufficiently benefit as has been seen from previous trials – the Fourier Trial and the Galgov trial.

So, one needs to concentrate on multi-vessel disease patients, recurrent MI patients, young patients with cardiovascular disease, and patients with associated stroke. We also often ignore stroke, patients with a coronary artery disease or diabetes and hypertension and having a TIA or stroke or having peripheral vascular disease or having CKD. These are the patients, who have an extremely high risk of problems and it is a must to aim to keep their LDLs below 50.

Patients with statin intolerance

The other problem is the small number of patients, who have statin intolerance. Generally about 5 to 10% are intolerant, and that doesn't only mean vague muscle pain; but real intolerance, where there is rise of enzymes. One thing that can be done for these patients is to correct the vitamin D levels as they are often vitamin D-deficient. It is good to try co-enzyme Q10. In spite of that, if they refuse to take statins because of side effects, then they become an important target for PCSK9 inhibitors.

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This article is a transcript of the webinar by Dr. Jamshed Dalal, titled, 'How and when to consider PCSK9 inhibitors in practice'. Click here to watch.

Stay tuned for the next two parts of the transcript:

Do PCSK9 inhibitors cause sugar to rise?

Q&A session on PCSK9 inhibitors

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To read Dr. Jamshed Dalal's article on PCSK9 inhibitors, click Role of PCSK9 inhibitors in the aggressive management of atherosclerotic vascular disease: Dr. Jamshed Dalal