Exploring the Effect of Long-Term Exposure to LDL-C on ASCVD Risk

Host:

Hello, and welcome to this podcast, where we will be discussing the effect of long-term exposure to persistently elevated LDL cholesterol on ASCVD risk.

This podcast was sponsored by Novartis Pharmaceuticals Corporation, and the speakers were compensated for their time. Statements in this podcast reflect the medical expertise and opinions of the presenters.

Today, we will hear the perspectives on this topic from four health care practitioners spanning multiple specialties, including cardiology, family medicine, internal medicine, and endocrinology. We will hear from Dr Guy L. Mintz, Director of Cardiovascular Health and Lipidology at the Sandra Atlas Bass Heart Hospital at North Shore University Hospital in Manhasset, New York. We will also hear from Dr James Underberg, a lipid specialist in New York City, and Dr Kari Uusinarkaus, a family medicine doctor, lipid specialist, and medical director at Centura Health Physician Group in Colorado Springs, Colorado. Finally, we will end with a note from Dr Yehuda Handelsman, an endocrinologist who is also the Medical Director and Principal Investigator of the Metabolic Institute of America.

First, Dr Mintz describes the risk hypothesis of exposure to persistently elevated LDL cholesterol.

Dr Mintz:

We know the clinical benefit of lowering LDL cholesterol and other apoB-containing lipoproteins is important in terms of reducing clinical events.¹ LDL cholesterol is not just a biomarker but really is a causal factor in the pathophysiology of atherosclerosis.¹ The effect of lowering LDL cholesterol in atherosclerotic cardiovascular disease is independent of the mechanism by which the LDL cholesterol is lowered, meaning if we are talking about pharmacologic therapy or genetic polymorphism, we see that this is a clear benefit in reducing LDL cholesterol, and we have seen from a variety of recent studies with PCSK9 inhibitors and statins that lower LDL cholesterol is certainly better.^2,3

So, I think it’s important for us to look at the patients at a much younger age. Certainly now, with the epidemic of obesity in adolescents and young adults, and the insulin resistance and inflammation associated with obesity, these are all challenges for us to reduce risk at a much earlier age than we would have considered in the past. So, it’s critical to identify patients with increased LDL cholesterol levels, and I will also add in non-HDL cholesterol levels, at an earlier age because prolonged exposure to lower LDL cholesterol beginning early in life has been associated with a three-fold greater clinical benefit for each unit of lower LDL than treatment with statins started earlier in life, and this may explain why patients certainly have a residual risk later in life.⁴

Typically, the American Heart Association and ACC guidelines talk about a group of patients between the age of 40 to 70, and using the risk calculator to assess them,⁵ but really we want to look at all patients’ risks throughout a lifetime. Cumulative risk to LDL cholesterol can certainly be used as an estimate of total plaque burden.⁶ Reducing long-term exposure to high LDL cholesterol can delay the onset and modify the course of the atherosclerotic disease.⁴

Host:

Dr Underberg further emphasizes the importance of exposure time to LDL cholesterol towards ASCVD risk, highlighting the need for earlier diagnosis and treatment to reduce cardiovascular events and reduce risk. 

Dr Underberg:

So, one of the most important things we have recognized when it comes to the association of LDL cholesterol and risk for ASCVD events is that time matters. Exposure to LDL cholesterol over the lifespan increases the risk: the area under the curve is key, and so the longer you are exposed to a risk factor, the greater impact that risk factor has on events.⁷ And the longer you have that risk factor removed or decreased or treated, the greater the benefit.

But also, just as important, newer data suggest that the earlier the intervention, the greater the potential benefit. And so, again, why is this key? Well, one of the things we often see in our clinical practice is patients with inherited high cholesterol – familial hypercholesterolemia. The inherent risk in familial hypercholesterolemia is not just the degree of LDL cholesterol elevation but the fact that, by making the diagnosis, we know the patient has been exposed to that high cholesterol from early in life. And so, that’s what determines the extensive risk associated with it is the lifetime of exposure.

And so, cumulative exposure to LDL cholesterol can be used as an estimate of total plaque burden and reducing long-term exposure to elevated LDL can delay the onset and modify the course of ASCVD.⁶ Diagnosis is key and early intervention is important.

Host:

It is apparent from the perspectives of Dr Mintz and Dr Underberg that increased length of exposure to elevated LDL cholesterol is associated with increased ASCVD risk. Dr Uusinarkaus suggests considering long-term exposure to persistently elevated LDL cholesterol as analogous to a concept that providers are very familiar with, namely pack-years of smoking history.

Dr Uusinarkaus:

So, I think a lot of my colleagues in the primary care arena have gotten comfortable with the idea of pack-years when it comes to tobacco use. And so, I think, the time is right for us to think about LDL exposure in the same way.

The vascular endothelium is a very dynamic structure, allowing certain things to cross and keeping certain things within the parameters of the blood stream, and we know that cholesterol, and LDL cholesterol in particular, is central to the hypothesis and formation of atherosclerosis.¹ So, if you have a very high LDL cholesterol and a very high atherogenic lipoprotein burden, it adds up over time.

The point to take home here is that why do genetic high cholesterol patients develop MIs in their 30s and 40s? It’s because their vascular endothelium is bathed with a high amount of LDL exposure over time, and so, if you really think about the treatment paradigm, we’re probably not treating our patients early enough nor aggressively enough, akin to recommending smoking cessation early on and not going back to it. So, I think it’s a really important concept. It’s LDL “exposure-years” is my term for it, and it’s very similar to the concept of tobacco and pack-years of smoking history.

Host:

Finally, we end with thoughts from Dr Handelsman on the impact of long-term exposure to persistently elevated LDL cholesterol in high-risk ASCVD patients, from an endocrinologist’s perspective.

Dr Handelsman:

We know that, as more LDL is there, especially in the people with obesity and diabetes, people that smoke, people with high blood pressure, and now we know about people with rheumatoid and different types of diseases with high inflammatory score in the body – these are all the people that LDL can enter into their blood vessels and can cause an uptake by macrophages.^1,7 This is the group of people where the blood vessels are much more vulnerable and therefore the LDL can enter in.⁷ If they are a bit obese and have insulin resistance, and the LDL is smaller, it will come in. So, the longer the time they have, the more time they can have for lipids to be accumulated. Long-term exposure for LDL will increase the risk to have blockages, if you will, of blood vessels of one type or another.⁶

Host:

Thank you for listening to this brief synopsis on long-term exposure to persistently elevated LDL cholesterol in ASCVD. I’m Christina Jones. We hope you’ll join us next time.

References:

1.     Bentzon JF et al. Circ Res. 2014;114(12):1852-1866.
2.     Ray KK et al. Lancet Diabetes Endocrinol. 2019;7(8):618-628.
3.     Sabatine MS et al. JAMA Cardiol. 2018;3(9):823-828.
4.     Ference BA et al. Eur Heart J. 2017;38(32):2459-2472.
5.     Arnett DK et al. Circulation. 2019;140(11):e563-e595.
6.     Ference BA et al. J Am Coll Cardiol. 2018;72(10):1141-1156.
7.     Cannon CP. Am J Cardiol. 2008;102(12A):5L-9L.

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