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Insights from the world's best medical minds

PCSK9 And Ezetimibe: Non-statin Agents For Dyslipidemia

Dyslipidemia accounts for 50% of coronary heart disease

Dr. PC Manoria

Dr.P.C.Manoria, Cardiologist and Phyisicain,Bhopal on Dyslipidemia Issues in India
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Dr. PC Manoria

Cardiologist and Physician

Manoria Heart and Critical Care Hospital, Bhopal


Studies have shown that the prevalence of dyslipidemia is very high in patients presenting at coronary heart disease (CHD). According to Dr. PC Manoria, an eminent cardiologist from Bhopal, it is 60-70%. “The Indian population is characteristic of high incidence of diabetes, high triglyceride, low HDL and elevated LP. High cholesterol and LDL is a problem, but not as much as it is in the West,” he says in an interview with Dr. Manish Verma. “LDL level as high as 190, xanthomas, premature arcus senilis in the eyes, premature coronary artery disease or a history in the family are pointers towards familial dyslipidemia, in which, even high dose statins cannot bring down LDL.” “Among the non-statin lipid-lowering agents, ezetimibe has shown benefit in trials” “Diet only constitutes 20% of the total cholesterol, 70% is manufactured in the liver. Diet restrictions cannot dilapidate the plaque as well. So, statin use is mandatory in CHD patients,” Dr. Manoria talks about diet for patients of dyslipidemia.” Regarding the role of PCSK9 in pan-LDL control, he says, “Diet control can cut cholesterol by 10-15%. Adding statins gives a further 50% reduction. PCSK9, in addition to that, produces another 50% reduction.” “Those who have high risk factors like obesity and are destined to become diabetic develop it with the use of statins. But statins do not make a non-diabetic patient diabetic,” he allays fears of diabetes developing due to use of statins. “In primary prevention, a statin therapy of 5 years can be enjoyed for the next 20 years but once you develop a heart disease, a life-long therapy is mandatory to prevent an event.”


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Complete Transcript

Dr. Manish Verma

Today, we have Dr. P. C. Manoria, an eminent cardiologist from Bhopal. Thank you so much sir for joining us and taking our time. We are going to discuss a very important topic dyslipidemia and which forms a major component of metabolic syndrome as well as puts the person on huge risk of coronary artery disease. Sir, can you tell us about dyslipidemia issues in India.

Dr. PC Manoria

Dyslipidemia is a very common problem in the Indian context and it accounts for 50% of CHD events. So, these risk factors must be modulated so as to minimize the risk of coronary heart disease.

Dr. Manish Verma

Sir, any particular differences between Indian dyslipidemia and Western population.

Dr. PC Manoria

In the Indian context, diabetes is rampant, triglyceride levels are high, HDL levels are low, total cholesterol and LD levels are also high but not to the extent compared to the West.So, Indian dyslipidemia is a little different and LP is also elevated which is genetically determined.

Dr. Manish Verma

What type of strategies, the monitoring should be done,means any particular patient should be monitored or any particular type. You already said about diabetes, other than diabetes any other conditions where dyslipidemia should be specifically looked at.

Dr. PC Manoria

There are several secondary causes of dyslipidemia also for example, hypothyroidism is one of them, but majority of them are primary dyslipidemia.

Dr. Manish Verma

You see patients with coronary artery disease almost every day, so in them what percentage of patient present with dyslipidemia and which are the specific type of factors which are very….?

Dr. PC Manoria

The prevalence of dyslipidemia is virtually 60% to 70%, although the exact statistics are not available on a national level in the Indian context but some studies have shown that the prevalence of dyslipidemia is very high in patient presenting at CHD.

Dr. Manish Verma

What percentage of patient you see they are controlled with…?

Dr. PC Manoria

Although we prescribe drugs when they come for our consultation, but after a lapse of a few months or year, the compliance is decreased may be because of cost or because the patient feels better. Long-term compliance is not seen in large number of patients over the months and years it declines.

Dr. Manish Verma

What percentage of patient will be typically get control with medicines available as of now?

Dr. PC Manoria

We usually use high dose or high intensity statin therapy either atorvastatin 80 mg or 40 mg and this controls LDL levels to a great extent, but there are some percentage of patients where LDL level still cannot be controlled either the drug is not able to control them to its fullest extent or the patient gets intolerance and other side effects. Particularly for example, you see familiar dyslipidemia. Even 80 mg atorvastatin will not bring down the LDL level to target.

Dr. Manish Verma

Familial dyslipidemia is another important subject you mentioned sir. It is often undiagnosed and people are not able to diagnose it, any particular reason for that?

Dr. PC Manoria

Because the incidence and prevalence of familial dyslipidemia is low, so it is not a common practice to screen for it, but if the LDL level is very high say 190 or more, you should suspect it.

Dr. Manish Verma

So if the patient is presenting with very high LDL.

Dr. PC Manoria

Or you have xanthomas, you have premature arcus senilis in the eyes, or premature coronary artery disease and history in the family, all this will point towards the familial dyslipidemia.

Dr. Manish Verma

You also mentioned about intolerance. In your practice how frequently you see patients having intolerance.

Dr. PC Manoria

See muscle symptoms may be seen in 10 to 15,but the real intolerance which means CPK more than 10 is less common.So,you want to know where the CPK elevated 10 times,then declare it as statin intolerance, may be 1%, 2%,or at the most 5%,but muscle symptoms 10 to 15%.

Dr. Manish Verma

What is the role of non-statin lipid-lowering agents at this part of time?

Dr. PC Manoria

Only one drug ezetimibe has shown outcome benefit in the improved trial which was released a year back.Triglyceride lowering agent although we know triglyceride high is associated with coronary artery disease, but there is as yet no randomized dedicated prospective trial which has shown that you lower triglyceride levels, the CAD or CHD comes down.

Dr. Manish Verma

So, non-lipid lowering agents you said what is ezetimibe and anything about fibrates?

Dr. PC Manoria

It blocks the absorption of the cholesterol from the gut,so the LDL levels are decreased.Fibrates although the diabetologist commonly use, we always say triglycerides are very important,but the only evidence of fibrate at the present time is the ACCORD LLE is subgroup study, which showed that in the subset of patients the triglycerides are more than 200 and HDL is low. There is a benefit, but overall trial was negative, but subgroup studies as we see are only hypothesis generating and this has to be tested in a large prospective randomized style which is not investigated at the present time. So at the moment, the rational bases of loading triglycerides from the point of view changing the outcome are not there. This should have been investigated but as you said triglycerides have not been properly investigated and still there is a big question mark whether triglyceride lowering will alter the outcome of CAD, for prevention of pancreatitis of course they are mandatory.

Dr. Manish Verma

Patients often asked about diet also. Any particular advice you give to them when you see patients with dyslipidemia.

Dr. PC Manoria

Diet is very important, but one should have a very clear concept that diet only constitutes to 20% of the total cholesterol, 70% of the cholesterol is manufactured in the liver. So, even if you are on a stringent diet, you cannot drastically reduce the cholesterol levels, you have to use statins and that is very important to remember or you may even on diet restrictions if the body manufactures more, your LDL levels may still be elevated, but diet alone will not delipidate the plaque also. It is statins which delipidate the plaques. So, statin use is mandatory if you are CHD patient or if you are at a high risk of CAD.

Dr. Manish Verma

The latest AHA guidelines do not recommend any particular target, they only say that you give higher metastatin depending on the risk factors and subsequently you expect a particular standpoint so what should the Indian ……?

Dr. PC Manoria

When the ACC guidelines were introduced at that time the data of improvement in CV outcome was available only with statins. Later on, when this improved trial came in, the data was available that if you have a lower cholesterol in a combination with statin plus ezetimibe the benefits is still there. So in times to come, it is very likely that the ACC will issue a focused update that LDL levels are mandatory. The other reason for reviseing the guidelines again LDL levels are mandatory as the PCSK-9. Now when you use diet alone, cholesterol may be decreased by 10% or may be 15%. If you use statins, it decreases LDL-cholesterol by another 50%, so if you use diet plus statin, it is 60% or may be 65%. If you use PCSK-9 on top of that, it produces an additional 50% reduction. Suppose you have LDL level after say high-dose strength 70, another 35 mg will be reduced. So, now we have a Pan LDL control, you can decrease in the intake, you can block the absorption, you can block the senses by statin and these PCSK-9, they are the only pathway for clearance of the cholesterol through the LDL receptors. So now we have data from two trials. The Odyssey long term and the Osler, although these were not outcome trial, but they have shown reduction in the cardiovascular event and on the basis of this, the FDA and EMA has approved two PCSK-9 inverter evolocumab and alirocumab and is very likely that the long-term three outcome trials which are going are likely to be positive. So, in today’s scenario, you cannot avoid LDL target. You have to measure LDL target, although no statin trial has been done looking at the targets. So that was the reason, but now we have the 09:00 improved trial, we have the PCSK-9 data and we have a sort of pan LDL control over it. Statin, diet control, ezetimibe and PCSK-9, you can virtually squeeze LDL to very low levels and the interesting part is that low LDL levels are not harmful that we know we have data from the previous prove trial also LDL less than 40. TNT trials 5 years for a less than 30 or 40 and the normal LDL is also low. So when we are trying to lower LDL say from 130, 140 to 160, 150, or 140, we are reaching normal LDLs and no low LDLs which is a physiological range when the new born is born. So one should not have scare.

Dr. Manish Verma

Sir, you are saying even if the doctors are seeing levels of 45 to 55, they do not have to change any therapy?

Dr. PC Manoria

You are bringing it to near normals, then lowering, this is physiological lowering and not pathological lowering, because you are born with LDL somewhere 40 to 50.

Dr. Manish Verma

That improved trial also clearly showed that they lower the level, so any particular thing you will say about the levels going back to the level again. Do the physicians should target the levels based on the risk factors or for anybody who is presenting with coronary artery disease or even a single risk factor the level should be…..?

Dr. PC Manoria

See, another peculiar feature of statin is whatever is your LDL level, the CTT meta analysis it brings out 25% of the coronary events where your LDL to begin with is less than 70 or 80, 90 or 100 whatever because statins are drugs which do not improve CV outcome by just lowering LDL, they have pleiotropic effects. So from the point of view initiating statins if your patient has CHD which means stroke, PVD, or coronary artery disease, high-dose statin right from the word go. If you are at high risk of coronary artery disease, still high dose of statins. If you have moderate or low risk, you may have use low dose. So, from the point of you have atherosclerotic CVD, high-dose statins to begin, you may not monitor LDL right before initiating, but after you have initiated statins whether PCSK-9 would be useful or not because at the present state of time, the dicta is if the LDL goals are not achieved less than 70, we would like to add PCSK-9 inhibitors and then when you add a PCSK-9, there is another 50% to 60 % reduction, so monitoring is mandatory.

Dr. Manish Verma

Below 70 if the patient is what you suggested, especially if the patient has risk factor and if they are not ……?

Dr. PC Manoria

Classical example is familial hyperlipidemia. Why we use PCSK-9? There are three indications; one familial hyperlipidemia besides LDL apheresis, statin, ezetimibe, still you are not able to control and they had very high risk of premature coronary artery, many of them die. Second is you develop intolerance to statin and third you are a high-risk individual, you have used maximum dose of LDL, the target is still not achieved. Target at the movement is 70, but I am sure this is going to decrease to 40 or 50. Many people would agree, although guidelines take lot of time because they are based on trials, very difficult to conduct trial for every small. Surely, targets will be lowered.

Dr. Manish Verma

One of the fears with physicians have about statin is they may impair the glucose control or they may actually prediabetic patients may get converted into full grown diabetic. So any particular thing you would like to….?

Dr. PC Manoria

See if you really look at the data of the diabetogenicity of statins what happens those who are destined for diabetes, diabetes develops at 6 months or may be little more earlier. It is not that a nondiabetic individual will develop diabetes. By this, I mean suppose you have high body mass index, your waistline is more, you are obese and other risk factors for diabetes, those who are destined to become diabetic they develop diabetes with statin. Suppose you are a normal individual, normal BMI, nothing, he will not develop diabetes. So it hastens the development of diabetes rather than brings up diabetes in a totally nonpredisposed individual.That is important. Time and again, people say diabetes. It has a diabetogenicity, but this is for the person who is destined, they will get even if you do not start statin, they will develop diabetes in six months so that should be remembered.

Dr. Manish Verma

Statin should not be only …….?

Dr. PC Manoria

No they benefit diabetic patients also, but the reality is this.

Dr. Manish Verma

One final question often if there is a tendency for the patients and doctors to stop a therapy once the control is achieved which happens with blood pressure, it happens with diabetes, you might be seeing that happening even with the statins when it comes to lipid lowering, so what should we do if the levels are normal can we stop?

Dr. PC Manoria

See for primary prevention, we have now very good data from the WOSCOPS 20-year follow-up. You take statin five years and enjoy the benefit for the next 20 years, so we have now a documented data with this WOSCOPS trial, which is a primary prevention trial, so we may say you take statin for 5 years and continue your documentation that events continue to decrease, may be good but for secondary prevention, we do not have such long-term data and secondary prevention is very important to assess and reassess the risk. If your risk continues to be high, say after 5 years, I do not think it makes a point in stopping statin because he has already developed the disease and if you allow him to develop second event, this may be, so secondary prevention of our policy is a little strict. We continue to reassess. We do not have a pinpoint answer you will take for 5 years, 10 years or 15 years just like diabetes. If you want to control diabetes, you have to continue, because he has already developed the disease, it has to be a long term therapy, but if you have pinpoint question number, we continue to reassess if he is 5 years, he is still, but if the patient is tolerating the drugs, better to have the statin because the plaques are delipidated only by statins at the present. What the PCSK-9 do, we will know a little later.

Dr. Manish Verma

Thank you so much for your time.



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