Tune in to hear Dr. Norman Lepor from the UCLA Geffen School of Medicine discuss the role of LDL-C and comorbidities in atherosclerotic cardiovascular disease (ASCVD) risk assessment as well as the limitations of statin treatment.
Cardiometabolic Considerations: The Role of LDL-C in ASCVD Risk Assessment & Insights into Optimal Managementclose
Cardiometabolic Considerations: The Role of LDL-C in ASCVD Risk Assessment & Insights into Optimal Managementclose
Cardiometabolic Considerations: The Role of LDL-C in ASCVD Risk Assessment & Insights into Optimal Managementclose
Welcome to ReachMD. This medical industry feature, titled, "Cardiometabolic Considerations: The Role of LDL-C in ASCVD Risk Assessment & Insights into Optimal Management" is sponsored by Novartis Pharmaceuticals Corporation.
Hello, my name is Dr Norman Lepor. I am a cardiologist, Clinical Professor of Medicine at the Geffen School of Medicine at UCLA, attending cardiologist at the Cedars- Sinai Smidt Heart Institute.
My pleasure to be making this very important presentation. And to let you know, as a cardiologist I’ve had an over 30-year history of being involved in the care of the diabetic patient with cardiovascular disease, most of this either in the clinic or the cath lab as an interventional cardiologist. And the treatment of the diabetic patient has always been a significant challenge, but these are very, very exciting times, both as a cardiologist taking care of diabetics, as an endocrinologist taking care of diabetics, or primary care physician taking care of diabetics, because certainly there have been so many new discoveries, so many new approaches to mitigating risk in the diabetic patient with cardiovascular disease. So, to me, these are very exciting times, and no better time to be making this presentation to you all.
There are certainly overlapping risk factors for both the development of type 2 diabetes and cardiovascular disease. We see in this particular figure overweight, obesity are driving forces for developing the insulin resistance syndrome.
We can see that genetics, as well as age represent further factors for increasing the risk of insulin resistance, and we all know that the insulin resistance syndrome, which consists of the dyslipidemia, hypertension and diabetes are very important cardiometabolic risk factors that increase the risk for not only developing cardiovascular disease, but also complications of cardiovascular disease. In addition to the abnormal lipid metabolism associated with the insulin resistance syndrome, we know that there are increased risks that are associated with aging, various races, sex, family history, therefore, genetics, unrecognized or perhaps under-recognized emerging risk factors, such as Lypoprotein(a), inflammation or hypercoagulation very commonly associated with the cardiometabolic risk increase the risk of developing complications, as well as smoking, physical inactivity and hypertension.
So, we can see that what we call the cardiometabolic risk, the risk for developing diabetes as well as cardiovascular disease has a variety of inputs in terms of risk factors, many of them common to type 2 diabetes and cardiovascular disease.
Really, what they represent, diabetes and cardiovascular disease, it is like first cousins in terms of the codependencies on these risk factors, as well as the effect of these risk factors on mortality and cardiovascular events.
Now, atherosclerosis is the main underlying cause of cardiovascular, of coronary vascular disease, and we know that LDL cholesterol is a major culprit in terms of developing atherosclerosis and complications of atherosclerosis.
So, what we see here in this cartoon, which is we are looking, actually, at the, on the top would be the endothelium and the lumen, and what we are looking at in the white is the actual within the wall of the blood vessel. We can see here, which is lipid-rich necrotic core, that’s the bad actor, that’s the necrotic core that leads to the development of predisposition to plaque rupture and thrombosis. So atherosclerosis is a lipoprotein-driven inflammatory disease characterized by the build-up of fatty deposits in the wall of large and medium-sized arteries, and just so you know, we can actually do a very good job of seeing the development of this lipid-rich necrotic core using, for instance, coronary CT angiography, and the coronary vasculature or using a specialized MRI techniques.
Now there is a set number of events in terms of atherosclerosis that leads to the acute vascular syndrome, whether it be an acute coronary syndrome, an acute stroke, etc. Plaque rupture and formation of the thrombi are the major factors responsible for the clinical manifestations of atherosclerosis, so, again, the major driver towards the development of the plaque is cholesterol. The sentinel event that leads to the acute vascular event is the thrombotic complication on top of either a plaque rupture or a plaque fixture.
A number of lipid abnormalities are caused by type 2 diabetes and many of these are really looking at in terms of research at having an effect. We know there is increased production by the liver of VLDL, increased chylomicron production from the gut. There is reduced catabolism of chylomicrons and VLDLs, leading to increased substrate available for LDL production and the small LDL particle in particular.
There are reduced LDL receptors on the hepatocyte. This leads to less LDL cholesterol being taken out of circulation. We know that there is increased number of glycated and oxidized LDLs, which are taken up by the macrophages and this leads to macrophage activation and the release of metalloproteinases, and the effects in terms of the plaque, which lead to a more likely predisposition to thrombosis. We know there’s an increased transfer to LDLs and HDLs by CETP in terms of a variety of compounds that will lead to low HDL levels in particular.
We also know that there is low levels of adiponectin, which drives increasing HDL catabolism. This leads to that syndrome of low HDLs in the diabetic population, increased predisposition to small dense LDL particles, and increased triglycerides.
Here we looked down, perhaps taking more of a detailed view on the issues related to effects on LDL metabolism. What we see here is the increased production of ApoB-48, as well as the increased secretion through the gut of chylomicrons, leads potentially to an increased concentration of triglyceride-rich lipoproteins. These are lipoproteins which have ApoB-100 and ApoB-48. Now lipoprotein lipase actually plays a very important role in terms of the metabolism of these remnants and therefore their destruction.
So, what we see here there are actually compounds that can activate LPL as well as compounds that reduce LPL activity, and the compounds that reduce LPL activity would actually have an adverse effect in terms of increasing concentrations of these triglyceride-rich lipoprotein remnants which are atherogenic, as well as the other atherogenic molecules, such as VLDL, IDL and LDL cholesterol.
So, this is looking at the effect on ApoB-containing lipoproteins, but we also see there is an effect on HDL, because very common in the diabetic patient, in the patient with metabolic syndrome. They actually have low levels of HDL, and this is related to the transfer of triglycerides and cholesterol esters to and from the HDL molecule, making the HDL molecule more likely to be catabolized, and this catabolism leads to lower levels of HDL, and by virtue of lower levels of HDL, presumably leads to decreased reverse cholesterol transport from the plaque, reducing the atherogenic nature of the vascular plaque.
So, what we see in the diabetic patient, interestingly enough, is these low HDL levels that we just talked about by virtue of increased HDL catabolism, and then HDL levels less than 40mg/dL, and in women less than 50mg/dL. We see elevated triglyceride levels. We talked about the reasons for those, increased chylomicrons, a decreased VLDL catabolism, LDL triglyceride elevations of 150 mg/dL above, are felt and accepted to be a major cardiovascular risk factor.
Oftentimes these patients with diabetes have ‘normal’, or only modestly elevated LDL cholesterol levels. Sometimes that even leads to physicians being less likely to treat an LDL because ‘it’s normal’. To me, there is no such thing as ‘a normal’ LDL level. If a patient has evidence of atherosclerosis by either a cardiovascular event or imaging-based identification of atherosclerosis, that level is too high for that patient, so, to me, there is no such thing as a ‘normal’ cholesterol level and we have to be very patient-centric. In addition, we know that there is also a higher prevalence of the small dense LDL particle. This is the particle that’s more likely to accumulate in the arterial wall and activate macrophages to do their thing to enhance plaque formation, as well as reduce plaque stability, making it more likely for plaque rupture.
So, let’s look at attributable risk in terms of all these various risk factors in the diabetic patient. And what we can see here is that the highest attributable risk for developing cardiovascular disease would be the non-HDL cholesterol level, which is really an important level for us to assess in the diabetic patient, even more important in the diabetic patient than the non-diabetic patient because these patients have higher levels of VLDL, and, therefore, that needs to be taken into account when assessing cardiovascular risk.
So, we see here the non-HDL cholesterol, which we calculate quite simply as the total cholesterol minus the HDL, remains the number one factor for attributable risk for the development of cardiovascular complications in the diabetic population, so being that it is the highest attributable risk factor we need to make sure that we are targeting the dyslipidemia in the diabetic population to mitigate risk.
So, this is a really important trial and I think this should really serve to motivate us who treat the diabetic patient to be very assertive in terms of taking a global approach or a holistic approach to reducing risk in the diabetic population. This is looking at 21-year follow-up from the Steno2 trial. What this basically says that if you take an intensified, multifactorial, target-driven treatment of type 2 diabetics with microalbuminuria, so we are talking about treating their lipids, treating their hypertension, trying to treat their obesity, it’s associated with a median of nearly eight years of gain of life versus conventional treatment. So, this should really serve as an important motivator that we really spend the time, expend the effort to identify these risk factors, to treat these risk factors, and to maintain these treatments by motivating the patient to comply with therapy. It really does make a difference, this holistic approach to the diabetic patient, and you know, you don’t have to be a cardiologist to treat hypertension and to treat other cardiovascular risk factors, so I think this is important for the primary care physician, for the diabetologist, for the endocrinologist, as well as the cardiologist to really partner in terms of this multi-factorial target-driven risk factor mitigation process.
And we see here again from this same trial comparing intensive therapy to conventional therapy, looking at cumulative mortality versus cumulative incidence of mortality or cardiovascular event, it really does make a difference and we really see these curves in this particular study published in 2016, that particularly for mortality, the curves really seem to really spread apart at around eight years. This means that we have to be persistent in terms of our risk-mitigating strategies and we have to ensure compliance in terms of our patients to be sure that they are continuing in this effort to partner with mitigating those risk factors.
The Cholesterol Treatment Trialist Collaboration really played an incredibly important role in terms of really bringing home the fact of two things: LDL cholesterol plays an incredibly important role in the development of atherosclerotic disease, as well as vascular complications, and also that lower is better. And what we can see from this particular slide is we are able to achieve event reductions in a whole host of populations: previous vascular disease, diabetics, male versus female, a whole variety of age groups, and we are able to basically achieve event reduction in the 25% range, and I think a good rule of hat is that lowering LDL cholesterol by 39mg/dL, or as the Europeans would say, 1mmol/L, using a standard statin regimen, reduces the incidence of major vascular events by about 20%, so it’s about two to one. For every 2mg/dL reduction of LDL you achieve about a 1% reduction of major vascular events. We also note from this slide and this figure from the Cholesterol Trialist, that this reduction of risk occurs both in the primary prevention trials as well as the secondary prevention trials. And what we are doing here is we are comparing the incidence in the placebo group to the incidence in the group of patients who received the statin therapy, so what’s clear in this linear regression line that lower is better. That’s where we get the term, lower is better. The lower we get the LDL cholesterol, the greater the incremental benefits in terms of preventing coronary heart disease events, and what’s important is that we don’t necessarily reach a floor. There is no LDL level that we say that we no longer get cardiovascular event reduction from further LDL reduction. So I think that is very important; lower is better and we have not seen a floor under which there is no incremental benefit by further reductions of LDL cholesterol. 65 to 75% of patients with ASCVD do have LDL cholesterols greater than 70mg/dL. And remember, when we talk about the diabetic population, they are generally not the patients who come in with LDLs of 160/170mg/dL. They may be coming in 110/120mg/dL, but that does not make their relatively modest increases in LDL cholesterol less important to treat to guideline-based treatment goals.
So, we know from both the guidelines here in the United States, as well as across the pond in Europe, that LDL reduction really plays the central role in ASCVD risk reduction. We’ll get into these guidelines a bit more, but some of the key points would be the following: the most recent AHA/ACC guidelines recommend adding nonstatin LDL-lowering drugs in patients with ASCVD, so we are talking about secondary prevention if their LDL is greater than or equal to 70mg/dL. So therefore, you have a patient come into your clinic, they are LDL 73mg/dL or higher. Don’t stop there. You really want to further reduce cardiovascular events by adding non-statin LDL-lowering drugs, and for the most part, non-statin LDL-lowering drugs would include PCSK9 inhibitors, as well as ezetimibe.
The Europeans are even more aggressive. And I actually practice more akin to the European guidelines and I was present during this presentation of the 2019 ESC/EAS guideline. And what they recommend is that you achieve at least a 50% reduction of LDL cholesterol, with an LDL cholesterol goal less than 55mg/dL in these very high-risk patients, and, of course, the very high-risk patients would include diabetics with evidence of significant coronary or other vascular atherosclerosis, or patients who have diabetes and cardiovascular events, and that you reduce cholesterol to less than 70mg/dL in the high-risk patient population, which, for the most part, includes diabetics. So, we see here this new goal of actually reducing LDL to below 55mg/dL, and we will get into that a little bit more.
Now, what’s important to understand is that the benefits of LDL cholesterol lowering actually continue below the AHA/ACC guideline recommended levels. So therefore, you may not want to stop at an LDL cholesterol of 68mg/dL, which is under the 70mg/dL goal from the ACC/AHA, particularly in patients who have a more aggressive, more malignant personality to their atherosclerosis, who are patients who have a more malignant presentation, patients who have a recent acute coronary syndrome, patients who have breakthrough events on high intensity statin therapy. Patients who have multi-vascular disease, so they have carotid disease and coronary disease, peripheral vascular disease, so multivascular disease, young patients who develop complications of atherosclerosis at an earlier age, so I look at atherosclerosis as not a cookie cutter. I actually try to assess the relative malignancy of the atherosclerotic condition, and by virtue of assessing that risk in each individual patient, the risk in terms of a malignant complication of which you certainly would consider a mortality, a stroke, or an acute coronary syndrome as a malignant presentation, I will then achieve much greater LDL reduction in those patient populations, if they are felt to have a significant higher risk, or what we would even call extreme risk.
And this is, actually, what this graph shows, looking at the FOURIER trial, which evaluated evolocumab in patients with cardiovascular disease. The IMPROVE-IT trial looking at ezetimibe in patients with acute coronary syndrome and the REVEAL trial. We see that as you go from LDL levels in the 60s down to 21mg/dL, even in that population, which I think the vast majority of people treating LDL would feel is perfectly fine, you are able to get further LDL, your further risk reduction in terms of cardiovascular events by about 20% relative to not achieving further LDL reductions. So, this goes along again with that notion that lower is better and perhaps we should think about assessing the malignant risk in that particular patient, in terms of trying to identify how low we should go in terms of LDL reduction below that defined by the different societies and colleges, because what they are saying is that you should achieve an LDL less than 70, for instance. That doesn’t mean you necessarily have to stop if you achieve an LDL less than, let’s say, a 69mg/dL.
So, what we are seeing here is lower is better and even lower is even more better. Excuse my grammar! So, the benefit of LDL-cholesterol lowering continues below the guideline-recommended level. So, I think that that’s important for you to realize as you do your individualized risk assessment in your patients with atherosclerotic coronary vascular disease, particularly those that have diabetes, which we know is a risk amplifier and does put these patients into a very high-risk cohort for developing further complications of coronary and vascular disease. LDL lowering reduces the risk of major vascular advance, particularly in the diabetic patient. We can see here in terms of different events, whether it is CHD-death, looking at vascular death, what we see here is that in patients with diabetes, as I mentioned before, lowering LDL by 39mg/dL, now we are talking about mortal events, reduced all-cause mortality by 13%, vascular mortality, as well as a 12% reduction in death from CHD, so it’s clear that not only are we preventing non-fatal events such as stroke and myocardial infarction, we are actually reducing all-cause mortality, as well as mortality related to these vascular events.
Very interesting data looking at actual plaque regression, so a lot of patients will tell me, ‘you know, can you use something to, you know, to reduce the plaque in my arteries?’ The truth of the matter is if we achieve very low LDL levels, generally below about 60mg/dL we can actually see regression of atherosclerotic plaque in the coronary arteries, as we see here, using intravascular ultrasound. Data just presented, actually, at the European Society of Cardiology, have shown that you can actually see reductions of lipid pools in carotid arteries in patients treated to low levels of LDL with a PCSK9 inhibitor as soon as three months. This can actually be a very important motivating factor to patients, because patients when you show them a picture, and as a cardiac imager, we do do a lot of coronary calcium scanning and coronary CT angiography and when you show a patient a picture of their plaque, the first thing they say is, ‘how do I get rid of it?’ And I think motivating them by saying if we really achieve together very low LDL levels and we achieve these low LDL levels on a continuum so that there is not a loss of compliance, we may be able to achieve this kind of regression in those patients. So, we have been able to find reductions of per cent atheroma volume in these patients in coronary arteries, and now we are also seeing in the carotid arteries, we are seeing regression of the fatty plaque, which is actually the malignant part of the plaque, which leads to an increased risk of plaque rupture and plaque thrombosis. So, long-term exposure to LDL really is the culprit here in terms of vascular events. You know there are populations, for instance, who have genetic abnormalities, like heterozygotes? These patients typically have LDLs over 200mg/dL, but the danger isn’t just by virtue of their very high LDL levels, it’s the fact that their arteries have been bathed by high levels of LDL cholesterol basically from birth.
So, there’s two aspects that relate to the effect of LDL cholesterol on cardiovascular events: one is how high is your cholesterol? And number two is, how long has it been high? This is, to me, a very important graph, and I would say one of the more important figures that we will go over today. And what we can see on the x-axis is the age in years. We can see on the y-axis the cumulative LDL exposure, which is mg/dL times years and there’s two dotted lines on the graph. That’s the age at which the risk of MI begins to rise, and then we see at the higher dotted line the actual mean age of myocardial infarction. So therefore, the heterozygotes, for instance, those that have very high levels of LDL, they actually start having MIs in their 20s, and the average patient with a heterozygote who has an MI is in their early 30s. But let’s look at the patient with modest LDLs, let’s say a patient with an LDL of 125. You are going to start seeing them having MIs at the age of 40, and the mean age of MI is only about 62/63 years old, and that’s concerning.
And even in a patient with an LDL of 80, there is still a risk in terms of developing a cardiovascular event, in this case, the risk of MI, but it’s at a much later age. You start seeing the development of MIs in patients in their 60s, but the mean age of an MI in a patient with this lower level of LDL is actually when they are 100 years old, so what we can see is the importance of not just LDL levels, but the actual continuum in terms of the duration of LDL exposure in terms of increasing the risk associated with myocardial infarction and occurring at an earlier age. That’s why it is so important to do what we call bend the curve, bend the mortality curve by treating these patients earlier who are at risk of atherosclerotic coronary vascular disease. And we can see from this graph, as you go from the LDL of less than 100 up to an LDL cholesterol of greater than 190, we can see that the mean reduction in years free of CV death is very important when we actually treat these patients in terms of their lipids. Because we can see that the cardiovascular mortality rate goes up significantly as the LDL levels increase from less than 100 to as high as greater than 190, and this is looking at two decades of follow-up. It shows the importance of early treatment, early identification to the patient at risk, and durable treatment.
Make sure that patients and physicians comply over the long term, because what’s the other question that patients will often ask: ‘Well, how long do I have to be on this particular drug?’. And of course, what we see with LDL reduction, basically, for their entire lives. There is also an important aspect called intra-patient variability in terms of their LDL. This is probably related to a lack of patient compliance with therapies, and what we can see when your patients come to the clinic, when you are seeing LDL levels that are highly variable, those patients place themselves at a significant increased risk of a whole variety of cardiovascular events, including cardiovascular mortality. This variability is probably not much related to variability in terms of your laboratory readings, it is probably more related to the lack of patient compliance and we will get into the implications of the lack of patient compliance in just a bit.
So, now we are looking at the cumulative event rates using the more modern therapies. We were looking here at the PCSK9 inhibitor, evolocumab in the FOURIER trial. The FOURIER trial took patients who had cardiovascular disease and they were on maximally tolerated lipid-lowering therapies. And they were treated either with the PCSK9 inhibitor evolocumab versus placebo, and what we see here comparing the diabetic to the non-diabetic patient is a pretty similar hazard ratio, meaning percent relative risk reduction, 17%, a little bit higher in the diabetic population, 13% in the non-diabetic population. But what’s more striking is the absolute risk reduction being greater in the diabetic population, about 2.7 versus the absolute risk reduction in the non-diabetic patient of 1.6%, so greater absolute risk reduction in the diabetic population, and no surprise because the diabetic patient is more likely to have a cardiovascular event. So, the number needed to treat for the diabetic in order to prevent a cardiovascular event was lower than the number needed to treat in the non-diabetic population.
Looking at the ODYSSEY outcomes trial with alirocumab, some interesting data. Again, this was an acute coronary syndrome trial, maximally tolerated statin, and other lipid-lowering therapies. You can see that in terms of the lipid effects, LDL, non-HDL, triglycerides, very similar effects, whether you are normal glycemic, pre-diabetic or diabetic.
A similar story here as we saw in the FOURIER trial, the ODYSSEY outcomes trial, if you look at the diabetic patients, you get a very similar relative risk reduction, whether you are normal glycemic, pre-diabetic, or diabetes. Okay, it is about a 15% reduction. However, the absolute risk reduction is almost 50% higher, or almost double in patients who are diabetic versus the non-diabetic population. Again, going along with the fact that the diabetic patient has a higher complication rate, and, therefore, would be able to achieve greater event reduction with a therapy that has efficacy.
So, we see a lower number needed to treat again in the ODYSSEY outcomes trial with alirocumab as we saw in FOURIER with evolocumab. There are still safety concerns or people who are still concerned about very low LDL levels. So far, if you are looking at those trials with terms of the duration, the ODYSSEY pooled analysis looked at patients over three years, and what we do find is that there is absolutely no signal of neurologic events. In fact, we can see that there is a lower incidence of neurologic events, neurocognitive disorders — people speculate that that may be related to perhaps a reduction in terms of micro-strokes. Musculoskeletal events were certainly no greater. There really was no concern about the development of diabetes in this patient population on PCSK9 inhibitor in the ODYSSEY outcomes trial. Hepatic disorders did not seem to be an issue and we did see an increased incidence of cataracts, but these cataracts were actually not necessarily greater with alirocumab but did seem to be more greatly associated with very low LDL levels.
The IMPROVE-IT trial, which was much longer duration, was about seven years, again, what we see here is no increased incidence of adverse events over six years following among ezetimibe-treated patients achieving very low LDLs, LDLs less than 30mg/dL. And I use the analogy that neonates, or babies are born with LDL cholesterols about 30mg/dL and babies need a lot more LDL, a lot more cholesterol because they are making cell membranes, etc., but they seem to be doing quite well with the very low levels of LDL that they are born with.
So there do not seem to be safety concerns associated with very low LDLs in the clinical trials. I think we were able to show that in the IMPROVE-IT trial which lasted about six years, as well as the PCSK9 inhibitor trials, which lasted about three years.
There did not seem to be any increase in adverse event risk across the LDL levels, so it didn’t seem to matter if your LDL was between 70 and 100, 50 to 70, 20 to 50, or less than 20. There did not seem to be any difference in terms of adverse events, including new onset diabetes, cancer, intracranial hemorrhage and cognitive impairment. So in conclusion, the long-term effect of elevated LDL cholesterol is causal to ASCVD and is the most readily modifiable risk factor. Long-term elevated LDL increases the risk for ASCVD, including MI. Consistent, long-term LDL lowering is essential in all patients with ASCVD to reduce the risk of cardiovascular events. And further long-term studies are needed to definitively confirm the safety of continuous lowering of LDL to very low levels, but from the studies that we discussed, which have a duration of between three years to six years, we have not seen any signal yet of that particular complication.
Thank you very much for your attention.
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