#508: ASCVD Risk & Lipids Update! PREVENT, ApoB, Lp(a) + Next-Gen Therapies

Summary

The Curbsiders Internal Medicine Podcast

Episode #508: ASCVD Risk & Lipids Update! PREVENT, ApoB, Lp(a) + Next-Gen Therapies
Date: December 15, 2025
Guest: Dr. Lawrence (Larry) Sperling, Katz Professor at Emory, CMO of the Family Heart Foundation

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Episode Overview

This episode delivers an up-to-the-minute review of atherosclerotic cardiovascular disease (ASCVD) risk assessment, lipid management, and next-generation therapeutics. Dr. Lawrence Sperling, world expert in preventive cardiology, guides listeners through nuanced risk prediction methods (including the PREVENT calculator), underutilized labs like ApoB and Lp(a), practical application of non-statin therapies, the growing role of genetics, and patient-centered approaches to cardiovascular prevention. The discussion is woven with clinical pearls, memorable analogies, and a focus on real-world implementation.

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Key Discussions & Insights

1. The Art and Science of ASCVD Risk Assessment

- The Foundational “CPR” Approach to ASCVD Risk

• Calculate risk with validated risk scores
• Personalize risk: layer in "risk enhancers" such as family history, metabolic syndrome
• Reclassify risk with additional tools (e.g., coronary arterial calcium, further labs)

Key Quote:

“CPR: Calculate, Personalize, Reclassify. Risk assessment is not the end—it’s the beginning of clinical decision making.”
– Dr. Sperling [11:44]

[08:39–14:43] Case Example: 52-year-old man with metabolic syndrome

• Non-HDL cholesterol is a critical, underused measure—additive value, no extra cost.
• Cardio-metabolic risk should be explicitly discussed as it broadens the prevention lens to diabetes and other manifestations.

2. Lab Pearls: Non-HDL, ApoB, and Lp(a)

A. Non-HDL Cholesterol

• Simple calculation: total cholesterol minus HDL = non-HDL (captures all atherogenic particles)
• "Do the Math": It's free, comes with every lipid panel.
• Target: For LDL goal <70 mg/dL, non-HDL goal <100 mg/dL ([34:15]).

B. ApoB: When and Why? [26:29–34:41]

• Scientifically more accurate for atherogenic risk, but not front-line for all.
• Most helpful when:
  • Triglycerides are significantly elevated
  • Discordance between LDL and ApoB suspected (rare: ~2% of cases)
  • LDL is very low (<70 mg/dL) on therapy or calculation becomes unreliable (even negative)
• Overuse can confuse patients; focus currently is on improving care with existing LDL targets.

Key Quote:

“Our biggest challenge today is not scientific knowledge—it’s implementation. I’m a selective user of ApoB.”
– Dr. Sperling [28:56]

C. Lp(a): The "Triple Threat" Lipoprotein [36:34–41:37]

• Increases risk through: atherogenicity, inflammation, and thrombosis
• 1 in 5 globally have high Lp(a), higher prevalence in women, Black, South Asian populations.
• Universal screening is done in Canada, Europe; rare (<1%) in US but may soon change.
• Reporting: measured as nmol/L (preferred) or mg/dL; standardization needed.
• Strong familial/genetic component—screen patients/families with early heart disease.

Key Quote:

“Lp(a) is a triple threat—atherogenic, inflammatory, and prothrombotic. We underappreciate its clinical value.”
– Dr. Sperling [36:36]

3. Using Coronary Calcium and Risk Reclassification [15:21–23:56]

• When to consider coronary calcium scoring:
  • As a second step for patients with intermediate risk or unclear decision on statin initiation
  • Not appropriate in very low- or very high-risk patients
• Important counseling:
  • “A score of zero is reassuring, but not an absolute guarantee—could still be non-calcified plaque.”
  • Adjust interpretation for age, gender, ethnicity (MESA tables).
• CCTA (coronary CT angiography): promising, not yet standard for primary prevention.

4. PREVENT Risk Calculator [42:00–48:51]

What’s Different and Why Now?

• Broader age (30–79 years), includes BMI, eGFR, diabetes.
• Uses zip code (social deprivation index) instead of race.
• 10- and 30-year (lifetime) risk estimation.
• Allows “total CVD,” heart failure prediction.
• More accurately calibrated: likely that future statin thresholds will be lowered (e.g., ~3%) based on PREVENT.

Key Quote:

“PREVENT lets us move beyond 10-year risk to 30-year, lifetime risk—and eliminates race as a factor.”
– Dr. Sperling [45:54]

5. Statins, Shared Decision Making & Side Effects [50:39–57:56]

• Explain statins as “CVD risk reducers,” not just as “cholesterol meds.”
• Discuss anticipated benefit, common side effects (myalgias, not true myositis), and risk of not starting.
• Use ultra-low, intermittent dosing where needed (e.g., rosuvastatin every other day).
• Emphasize “the right statin for the right patient” and revisit decisions longitudinally.

Notable Moment:

“For every medicine, we consider indications, contradictions, benefits. We also must weigh the risks of not starting.”
– Dr. Sperling [51:51]

Lifestyle Modification

• Dietary pattern over “diet”—preferably Mediterranean, flexitarian, or “portfolio” (more nuts, oat bran, flax, high-quality dark chocolate [~65% cacao+]).
• Most patients will see modest (<10%) LDL reduction from diet alone.
• For overt familial hypercholesterolemia (FH): immediate medication plus lifestyle (don’t delay).

6. Familial Hypercholesterolemia (FH) and Family Cascade Screening [73:56–88:09]

• Suspect FH in patients with very high LDL (>190 mg/dL) at a young age—especially if family history of early CV events.
• Non-response to max statin/ezetimibe often signals monogenic causes (e.g., LDL-R, ApoB, PCSK9 mutations).
• Physical signs: corneal arcus, xanthelasma, tendinous xanthomas.
• Cascade family screening and consider genetic testing (over 2,000 FH variants described).

Key Quote:

“If you’ve ruled out secondary causes and LDL is >190, don’t bother with risk calculators—go straight to therapy.”
– Dr. Sperling [77:54]

7. Non-Statin and Next-Gen Therapies [81:01–91:52]

Bempedoic Acid

• ACL inhibitor, modest LDL lowering (~20–30%)
• Event reduction shown (CLEAR Outcomes), but not mortality

PCSK9 Inhibitors (alirocumab, evolocumab)

• Potent; first-line non-statin add-on for FH or very high risk

Inclisiran

• siRNA against PCSK9, dosed twice yearly. Awaiting outcome trial data.

Lipoprotein Apheresis

• Reduces time-averaged LDL/ApoB/Lp(a) by up to 80%, considered in severe FH or when refractory to usual therapy.

Lp(a) Lowering Drugs

• Pelacarsen and others: Early trials show 80–100% Lp(a) lowering; outcomes trials now underway (HORIZON trial, etc.).
• Hopeful, but surrogate markers—need confirmation of hard endpoint benefits.

8. Pearls on Patient Conversation and Prevention Philosophy

Memorable Moment:

• Dr. Sperling's contract analogy for prevention:

“We sign a contract to age 100, and then renew one year at a time. This is a partnership—you get more votes than me, you’re the patient.” [13:53]

On Early Statin Use and Lifetime Risk:

• “Cholesterol years” matter—prolonged exposure increases cumulative risk. Discuss with younger, high-risk patients (esp. with strong family history).
• Ok to defer 3 months for lifestyle change in primary prevention if risk is not extreme.

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Timestamps for Key Segments

• Career & Advice: [05:30–07:22]
• Case 1 Discussion (ASCVD Risk): [08:39–14:43]
• Coronary Calcium Scoring & CCTA: [15:21–23:56]
• ApoB & Discordance: [26:29–34:41]
• Lp(a) in Practice: [36:34–41:37]
• PREVENT Risk Calculator: [42:00–48:51]
• Statin Counseling & Lifestyle: [50:39–62:56]
• Familial Hypercholesterolemia, Genetics: [73:56–88:09]
• PCSK9, Bempedoic, Inclisiran, Apheresis: [81:01–88:09]
• Lp(a) Lowering Trials—Future Outlook: [88:54–91:52]
• Take-Home Message: [92:36–93:42]

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Take-Home Clinical Pearls

• Risk assessment is the gateway, not the gatekeeper—partner with patients over time.
• Don’t ignore non-HDL cholesterol—calculate and act on it!
• Screen for Lp(a) at least once, especially with family history, early disease, or intermediate risk.
• PREVENT risk calculator will likely reshape practice—get familiar and be ready for lower medication thresholds.
• FH is underdiagnosed—look for it, confirm, and screen families.
• Statin “intolerance” is rare; use creative dosing and frame benefits as CVD protection, not just cholesterol-lowering.
• Non-statin and next-gen therapies are expanding options, especially for genetic hyperlipidemias and soon, elevated Lp(a).

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Memorable Quotes

“Each visit doesn’t have to be an all-or-none statin decision. Plant seeds. Patients will often circle back when they’re ready.”
– Dr. Sperling [54:53]

"My job is never to convince you to take a medicine … but to translate the evidence for you."
– Dr. Sperling [56:51]

“We’re devoted to cardiovascular disease prevention, which is very possible today and will have greater possibilities in the future.”
– Dr. Sperling [93:36]

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This summary captures the clinical depth and spirit of the episode—useful as a reference for patient care or board review, and perfect for those who want high-yield pearls without listening to the full podcast.

Transcript

[A]

Paul, why did the girl quit her job at the donut factory?

[B]

I don't know. Matt, why did the girl quit her job at the donut factory?

[A]

Because she was fed up with the whole business.

[B]

All right?

[A]

The whole business.

[B]

No, I got it.

[A]

I love donuts.

[C]

The Curbsiders podcast is for entertainment, education and information purposes only, and the topics discussed should not be used solely to diagnose, treat, cure, or prevent any diseases or conditions. Furthermore, the statements expressed on this podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity, aside from possibly cash, like MORAL hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much. We aren't responsible if you screw up. You should always do your own homework and let us know when we're working.

[A]

Welcome back to the curbsiders. I'm Dr. Matthew Frank Watto, here with my great friend and America's primary care physician, Dr. Paul Nelson Williams. Hey, Paul.

[B]

Hey, Matt. How are you?

[A]

I'm doing well. This is an episode on cardiovascular risk reduction and lipids with a true expert, Dr. Lawrence Sperling. And, Paul, before we get to our guest bio, could you tell us what is it that we do on Curbsiders? Because I am tired and I'm struggling a little bit right now.

[B]

You doing all right, Matt? Yeah. Just as a reminder to you and our audience, we are the Internal Medicine Podcast. Believe it or not, we use expert interviews to bring you clinical pearls and practice changing knowledge. Matt, as you mentioned tonight, we talked to Dr. Lawrence Sperling about lipids and evaluation, so I'll get to that in a second. So let me tell you about Dr. Sperling first, Matt. He is the founder and was the director of the Heart Disease Prevention center at Emory. He is currently the Katz professor in Preventive Cardiology and a professor of global health. He serves as the CMO for the Family Heart Foundation, a nonprofit focused on timely identification and care of people living with FH and elevated lp, a name that we talk about. He served as the Executive director of the CDC CMS Million Hearts Initiative from 2019 to 2024, as the president of the American Society for Preventive Cardiology, and as a member of the writing committee of the 2018 guideline on the management of blood cholesterol. Perhaps you have heard of it, Matt. He was also on the writing committee of the AHA Cardiovascular, Kidney, Metabolic Health. That's the CKMH initiative. Today he talks to us about updated ASCVD risk prediction, what some of the new tools that we have to evaluate and sort of categorize risk. We talk about some of the labs that perhaps you're not ordering routinely but maybe should things like lp. We talk a little bit about non statin therapy, so we obviously talk about statins as well. We talk about some of the newer medications, how he thinks about using them, and how he talks to patients about side effects and risks and benefit overall. There's a lot of talk about sort of shared decision making and partnering with patients to to talk about how we can best take care of them. Without further ado, let's get to it.

[A]

A reminder that this and most episodes are available for CME credit for all health professionals through VCU healthurbsiders.vcuhealth.org Larry, thank you for joining us. We just clapped, which always feels great. That syncs things up. And the audience that we got to bring them in, they want to know what is a hobby or interest that you have outside of medicine.

[D]

Yeah. First, just want to say how grateful I am to be invited to join all of you for Curbsiders. My wife is an internal medicine physician and Curbsiders is her Go to Internal Medicine podcast. So have heard a lot about Curbsiders. So in terms of a hobby, thankfully I have a lot of hobbies outside of being a preventive cardiologist. Through photography during the pandemic, I got back into acrylic painting. And once upon a time I was a marathon runner. I actually ran. My very last marathon was the marathon from Marathonia to Athens in Greece. Got a wreath of olive branch around my head when I finished in the Panathenian stadium. Now for full disclosure, I did not win it, but it was an incredible experience.

[A]

So it sounds like you won the way they're outfitting you with all this. That's great.

[B]

Did you have to run in sandals or barefoot or.

[D]

No, no, definitely with my running shoes. But it was a personal win.

[A]

That's great. That's great role modeling as well. That sounds like it was a good thing to do for your heart and your cardiovascular risk, which we're gonna get to. And you told us before that this is. We're recording this on World Heart Day. It's not gonna be released on World Heart Day, but we are recording this on World Heart Day.

[D]

That is correct. Every September 29th is World Heart Day. I work with the World Heart Federation in Geneva, Switzerland, and in addition to my work as a preventive cardiologist, I do population health, public health, and global health. And the end of September also marks the end of National Cholesterol Education Month. So a perfect time to talk about cholesterol management.

[A]

So we will return the favor by releasing this in a month or two. I wish we would have known Paul.

[B]

Well, but still, I mean, I feel like the listeners will appreciate the energy that it brings to the recording today. So it's going to work out great. Larry, I'd like to ask, I always like the advice or feedback question. So can you share with us meaningful advice or feedback that you receive sometime during your career training, perhaps that you now share with with your trainees and learners?

[D]

Yeah. So some of the best advice I received is when I was towards the end of my fellowship, I went to a meeting at the ACC's Hart House with all the superstars in academic medicine. And I remember Valentin Fuster, who to this day is one of my mentors. One of his best pieces of advice was ultimately, you need to find what excites you and interests you each and every day when you wake up. And if you find that you've found the right place in terms of your professional career. I think also besides that, personally, I give advice that my career developed not by design. And so for those young listeners out there, be open to new ideas, be open to new possibilities. I grew up in New York. I was actually a Mets fan, not a Yankees fan, but I like to use Yogi isms, Yogi Bear, the catcher of the Yankees. Yankees Yogi said, when you come to a fork in the road, take it. So there are many opportunities out there that you may not consider. And I started in molecular and vascular biology. In addition to finding out I didn't want to spend the rest of my career doing molecular and vascular biology. I had the opportunity to come to several of these forks which really helped define my career, but most importantly allowed me to serve in very rewarding capacities.

[A]

Paul, this follows the rule that you always say that almost every time you ask someone about their career. It was not by design.

[B]

Yeah, right. And the people that are truly happy with their jobs did not intend on doing that specific job. But they exactly as you say, Larry. They were sort of agile and willing to say yes to things and now are very happy, even though it's not where they expected to end up.

[A]

So, Paul, let's get to our first case because we want to get into a lot of good content tonight on this topic, which is a deep well that we need to go to. So Paul, what is the first case?

[B]

So, Larry, we're gonna talk about a 52 year old male. Why don't we go with the Mr. Smith who presents to our clinic for a routine visit and to discuss his overall heart health. He's concerned because his father had an MI at age 54. Other than well controlled hypertension on lisinopril, he has no other medical issues. He has no personal history of ascvd. He does not have diabetes. He does not have a known diagnosis of familial hypercholesterolemia. No history of tobacco use. His BMI is 29. He enjoys walking on the weekends, but doesn't otherwise exercise and states that he eats as healthy as he can. The last time that we checked his lipid panel, he had a Total cholesterol of 210mg per deciliter, LDL cholesterol 135mg per deciliter, HDL of 42mg per deciliter, triglycerides of 225mg per deciliter, and a non HDL C of 168mg per deciliter. So a lot of information here. But before we sort of unpack the Sad case of Mr. Smith, if you could start broad and let us know how we should start thinking about screening patients for ASCVD risk and how we're calculating that these days.

[D]

So, Paul and Matt, I'm so glad we're starting with this case because this gentleman from Kashlak Memorial is a very common case for internal medicine specialists. In fact, um, this individual, if we, if we start looking at his risk profile, he's got the metabolic syndrome, doesn't he? He's got a BMI of 29. His triglycerides are elevated. I'm assuming this is fasting, but even if it's not, fasting raises a red flag. A lowish HDL cholesterol. And there's a couple of things I'd like to point out before we dive into the concept of risk assessment. First, the non HDL cholesterol is significantly elevated. And many of your listeners may not be familiar with non HDL cholesterol. We wrote a paper about 15 years ago about non HDL versus APOB in comparison, as we use this for risk assessment and we titled it do the math because if you graduated from first grade, you can calculate the non hdl. In fact, it's a question I often ask on teaching rounds. I look at the profile and I say, what's non hdl? It's the total cholesterol. Minus HDL is the non HDL cholesterol This encompasses all of the atherogenic particles. And I think later on we'll talk more about particle number apob. But I still like that non hdl. The other do the math issue for non HDL that I think is very important for the listeners is the cost of non HDL cholesterol is $0.00. It comes with the standard lipid profile and it adds value. It's really important to call out to this gentleman that he has cardiometabolic risk and we often don't do that. One third to two thirds of our patients depends upon the patient population. They are living with some degree of cardiometabolic risk. And so when I have a conversation with this gentleman about his cardiac risk, we also talk about his potential risk for diabetes and other cardiometabolic manifestations. So let's talk about risk assessment. Let's take a step back from this individual patient because risk assessment is foundational for primary prevention. With risk assessment, I like to use a rubric that is called cpr. And I didn't coin the term cpr, but Donald Lloyd Jones did. And Don Lloyd Jones is really a guru of risk assessment. He was at Northwestern. He's now the director of the Framingham Heart Study. As we were building the 2018 cholesterol guidelines, we really thought about this CPR approach. C We calculate risk and there are many risk assessment tools out there. Framingham, there's the pool cohort equation, there's mesa, the MESA risk score, the Reynolds risk score, and now there's the prevent risk score. So we should start with risk assessment. But that is not the end of clinical decision making. It's actually the beginning. So risk assessment is a population based tool that we want to apply to each and every individual patient. By definition, a population based risk assessment will always have limitations. So the C we calculate P, we begin to personalize. How do we personalize? We add what are called cardiovascular risk enhancing factors to this individual patient. I count two. He's got a family history of heart disease and he's got the metabolic syndrome. Now I'd like to even know more about this patient because there are other potential cardiovascular risk enhancing factors that we might want to be aware of. And then we go to the R. So we'll calculate risk in this individual patient. Let's just say he's. By using the pull cohort equation, he's going to be likely in the borderline risk category. Although clinicians do not guesstimate well risk, they actually do as well as throwing darts. So this is why we must anchor our risk assessment with a risk assessment tool. But if we get to the R, which is risk reclassification, we should think of other tools like potentially a cardiac CT calcium score, which, which is our single best tool for cardiovascular risk reclassification because sometimes we de risk, but also we can increase our concern and increase our potential risk for this individual. The last thing I want to mention is cpr. But then now it's all about patient partnered care. I like, I know we talk about patient centered care, but it's a patient partnership. And when I talk to my patients, we talk about this partnership. I always say, you get more votes than me. You're the patient. And I also say preventive cardiovascular care is longitudinal. So we sign a contract to age 100 and then we renew one year at a time. So in terms of this partnership, the key is called the clinician patient risk discussion. And this is all about trust, it's about safety. And it's an ongoing conversation. We don't have to make a decision for this gentleman, this visit. In fact, sometimes I start planting seeds for the conversation that will occur over time.

[A]

I like that. Yeah, that is okay. So CPR calculate risk, it's going to be personalized. We're going to personalize the risk with risk enhancing factors. We're going to reclassify. We might do things like you mentioned a coronary CT where you can get a calcium score or there's also a coronary CT angiogram that also comes with a calcium score. Paul, are you ordering a bunch of these these days? Do you have any questions about those?

[B]

Just that question. Not a ton of them, to be honest with you.

[D]

And then.

[B]

No, man, no questions right now.

[A]

I'm just trying to bring you in, Paul.

[B]

I appreciate it.

[A]

So, so Larry, could you tell us how for Paul and I, who maybe we order these sometimes. Can you tell us a little bit about how we might think about using the CT scans to reclassify people?

[D]

Yeah, I think as we reclassify risk, we should consider a CT non contrast calcium score as the initial study. Now we also want to think about this. In the right individual, the wrong individual would be a 25 year old woman who's a marathon runner, vegetarian, you know, very healthy behaviors. And the other wrong patient would be somebody who in that contract to age 100 has made it to age, you know, 89 or 90 without significant cardiovascular disease. So that non contrast CT for calcium is very valuable. But it also, the caveat is it only detects calcified plaque. So there's the timeline of atherosclerosis and calcification occurs fairly late in that timeline. So when I do have a conversation with a patient, let's just say the good news is your calcium score is 0. And the negative predictive value of a calcium score of 0 is quite high in the right patient for maybe as many as 10 years plus. But I also qualify that the calcium score of zero does not mean that you do not have atherosclerosis. And so with an individual at risk, we focus on, let's just say 10 year risk, absolute risk. But often we extend the risk discussion to lifetime risk because that can be really important in that partnered care about decision making and also decision making about initiating medications not just for that short term risk, but medications accrue benefit over time. It's one of the only things I remember from calculus. It's that integral, right? It's the area under the curve. And so risk accrues risk over time, which is why somebody born with a genetic cholesterol disorder like familial hypercholesterolemia has risk in utero. But the flip side of that is risk reduction accrues benefit over time. The coronary ccta. I'll just mention it for Paul and Matt after, you know, 50 years of investigation about this, the potential for CCTA, we are finally at the point where we can use CCTA in a meaningful way to assess plaque, plaque, volume composition, plaque that is at risk. And then we also can pair that to a ccta, ffr, fractional flow reserve, non invasively. But at this point in time, I wouldn't consider CCTA as a standard tool for cardiovascular risk reclassification.

[A]

Yeah. So the CCTA is coronary CT angiogram. So that's where the reason you can see plaque is because they're doing an actual angiogram with CT and then ffr, the fractional flow reserve. Right. And that's. They do that in cath labs. Right. To try to see how much things change across a lesion, to see if it needs to be intervened upon or not. And so now they're able to. I didn't realize they were able to do this with CT now. So that's exciting, but. So it sounds like you're telling if we're a primary care, maybe we order a calcium score, but the ccta, maybe I'm sending them to you before I'm ordering that test because I'm not sure. I might get myself into some hot water not knowing what to do with the results if I find some soft plastic Plaque, non calcified plaque that you know is gonna, I'm sure the person's not gonna be happy to know they have that.

[D]

I think in the future we may be able to use coronary CCTA as a benchmark, meaning you do it at time point A in a patient and let's say they have a volume of plaque and plaque composition. Ideally, if you rescan in three to five years and you may show beneficial healing of plaque, you might be able to show that plaque composition is heading in the better direction. And then this is a question I get all the time is can you make it go away? And at least in 2025 we don't have liquid Drano, you can't get back to time zero. But we do have significant approaches that can shrink the plaque, heal the plaque and prevent it from disrupting or rupturing. And that's our goal. So it is an exciting time to be a preventive cardiologist and I think it's a really exciting time to be an internal medicine specialist who is committed to cardiovascular disease prevention for their patients.

[A]

I had a follow up question about the calcium score.

[D]

I.

[A]

So people in their 30s, I would imagine, like, like you said, people in their 30s, 20s, 30s that are healthy, active, overall, I would expect they would have a zero calcium score. People in their 40s and 50s, I would expect, I'd say it's good if they have a zero calcium score, but I would expect, you know, some of them might have a positive calcium score. And then people in their 60s, 70s, I'm assuming there's going to be calcium for most people. How do you pre counsel people when they're going for this? Do you tell them? I expect to find some, but I just want to see how much there is. What's the utility if it's someone you expect there to be calcium? You told us for an 80 year old who hasn't had an event yet, it doesn't make sense. But what about people that are younger than that?

[D]

Yeah. So first of all, Matt, I'm glad you asked the question because we should always look at the calcium score in relation to age, gender and ethnicity. It comes from the MESA study and the MESA cohort, the multiethnic study of atherosclerosis. If we look at a calcium score as an absolute number, it's actually a number that adds up each and every calcified plaque, both volume and density, and it's the Agatston score. That score is beneficial to some degree, but it's basically a population based score. The Greater the calcium score, the greater the risk for a population of individuals. We do want to talk to a patient about the likelihood of underlying atherosclerosis. That would be pretest probability. What is interesting, if you look at the data, there are individuals that you would expect to have a calcium score that would be significantly elevated. And still there are individuals that have a calcium score of 0 when you would expect them to have a calcium score that's much greater. So it's very humbling that as much as we think we know about the process of atherosclerosis, we still have a lot to learn. And there are factors that increase the likelihood of atherosclerosis in totality. There are likely genetic factors that are protective, like superoxide dismutase, where, you know, individuals with significant risk factors may have the ability to squelch oxidative stress, reduce inflammation and reduce the process of atherogenesis. The score, though. I'm not a golfer, but you want your calcium score to be just like your golf score, as low as possible. And I frequently have discussions with patients about the absolute score. I put it into context, of course, you should never do a cardiac calcium score in an individual who's having active symptoms. That's a different story. Active symptoms takes you away from thinking about primary risk assessment. Then you have a patient who has symptoms and you want to think about how to address those symptoms.

[A]

Paul, any follow ups to this?

[B]

Just a vague thought. And maybe that'll help us transition, sort of the next stage. I will say I don't know if it's because I'm getting older, more distinguished looking, or if. Because the stigma against statins has kind of faded. But I don't hear as much pushback these days. One statin therapy from patients like I did in the past. So while it's great to have these sort of nuanced tools to assess risk, I will say, if I say I think you should be on cholesterol medication, I don't get as much fight as I used to when there was, I think, a lot of bad press regarding sort of statin assistibias and that kind of thing. But I think even before getting to things like, because very few patients I have will sort of demand. I shouldn't say demand, I shouldn't frame it in that sense. But I don't know that I reach for coronary artery calcium scoring all that often. If I think someone's high enough risk and I think statins are benign enough, I tend to just pull the trigger and patients tend to Be okay with it. But I would like to hear a little bit more about some of the other tools that we have in terms of sort of assessing overall risk, if now is perhaps the time to talk about those things.

[D]

And Paul, your point is well taken. You should only get to the R reclassification of risk if that patient partner discussion would move that risk assessment and the risk related decision making in one direction or another. So in a trusted conversation with one of your patients, if the decision is, look, I'm 52, like this case, I have a family history of cardiovascular disease. You talk about your concern about cholesterol. If the decision is made together to start a statin or other therapies, then it likely wouldn't change that management.

[A]

So I'd like to move the discussion to talk about APOB now. And we're going to get to LP too. But you mentioned APOB already in passing. You said that the non HDL is a essentially free measure that you get. You can calculate it off the standard lipid panel and you're talking. It tells you all the atherogenic particles that are there because it's just taking out the hdl. Everything else is atherogenic. How does APOB add value on top of that? Or is there a reason that we need to order apob? It's starting to appear in guidelines now and I know a lot of people are coming in asking me to order it and I have been ordering it for patients and it doesn't seem like it's costing people a lot of money right now. So how do you talk to people about that?

[D]

Yeah, thanks, Matt. We'll definitely talk about APOB and other risk tools that are cholesterol related. I do want to come back to the prevent risk score because that is one of the leading edge areas that internal medicine docs should be aware of. APOB here, I'm going to share data, but I'm going to share my words of wisdom and expertise. Being a preventive cardiologist for three decades and training for about a decade in preventive cardiology. Scientifically, APOB and LDL particle number are better measures of atherogenic risk than the calculated LDL cholesterol, because unless you order a direct ldl, the LDL is a calculated value. Now, we used to calculate the LDL using the Fried Wald equation, but there are better ways to calculate LDL today, the Martin Hopkins equation, and then there's an NHLBI equation. APOB is, you know, that's a one to one relationship because each atherogenic particle has One apob, apolipoprotein. But I am a selective user of apob. I am personally not ready to embrace APOB for all. And I'm going to explain why. First and foremost, guidelines need to be translated to care. And our biggest challenge today is not scientific knowledge, it's not therapies, it's implementation science in the real world. And unfortunately, despite outstanding guidelines, I served on the writing committee of the 2018 Cholesterol Guidelines. We are not doing so well when we use the scorecard of practice, meaning hypertension control, cholesterol management. We're not doing so well and we have some really basic ways to treat these significant cardiovascular risk factors. Yet we're, we're essentially flailing here. So let's come back to apob. Apob. There are no guidelines right now that use APOB at the front end of this cholesterol related decision making. There are no universal APOB targets. And then our patients finally are learning about, you know, the bad cholesterol. I say the LDL is the lousy cholesterol that you want lower. If all of a sudden I know patients are reading about it and asking about it. But if we have to, for the general population, start educating about APOB and let alone APOB targets, I'm not going to say we're starting all over again, but we're adding unnecessary hurdles to improving care. Now with apob, all APOB containing particles are not the same. Even though they represent the atherogenic particles, an LDL particle and an LP particle, they are not equivalent. LP is much more atherogenic. In fact, it's estimated six times more atherogenic than LDL cholesterol. So we can't just use the APOB number to assess the totality of atherogenesis based upon the APOB and the lipid profile. And then the last point I want to make here is we reserve conceptually thinking about APOB for ideally when there's discordance, meaning the LDL and the APOB or the particle number, which you can get by an NMR analysis, these do not connect. Most of the time we see concordance. And there was a paper published in about 2018 in circulation by the group at Hopkins and they demonstrated using the Martin Hopkins equation that the prevalence of discordance was actually quite low. It was at about 2% or less. And so when do I think about APOB? It's when somebody has significant hypertriglyceridemia, but I still use that non HDL cholesterol. Do the math. You use that as Your secondary goal after your LDL target and the non HDL doesn't cost you anything or cost the patient anything in that decision making. The other area where the APOB may be of additional value is once you've started treating and you get to LDL cholesterols less than 70 milligrams per deciliter, there can be a greater chance of discordance. An example here might be we wrote a paper in the European Heart Journal and it was titled how low is too LDLs under 30 milligram per deciliter in the era of PCSK9 inhibitors. And, and sometimes I'll have a patient who's on very aggressive combination lipid lowering therapy and their calculated LDL comes back a negative value. You know, we know that's not possible. You know, so if you really want to be more accurate here, that's the time to get the apob. But it's likely the APOB is also going to be very low and it wouldn't change management. So I'm not a total APOB nihilist, but I think we need to really align our focus on the care of the patient and not just using the science and the measurement tools to think we're doing a better job.

[A]

So I wanted to recap a little bit. So you're saying that we're not ready to just move right over to apob. Part of it is just we're not even doing that well. We've had LDL around for a long time. We're not even doing that well following that and controlling that. And you can get a lot of the information by just looking at the non HDL cholesterol and trying to get the LDL to target. The discordance between APOB and LDL is not that high. But you said if the LDL is below 70, there's a higher risk of discordance. You said that sometimes if the triglycerides are high, you'll use an apob. And I think there was one other situation. Were you saying if it was a high non HDL that you would potentially order.

[D]

The other one would be when you start getting very, very low LDLs calculated meaning a negative LDL. It's just not feasible to have a negative LDL even when the triglycerides are high. I still like the non HDL. The non HDL should be the LDL target or goal plus less than 30 milligram per deciliter. And I, I use that number because from the Friedwald equation, you know, we use triglycerides divided by 5 is the contribution of triglycerides to the atherogenic burden.

[A]

Give me one more time the target for the non HDL you like?

[D]

Yeah, it would be. Let's just say you have a patient, their LDL Target is under 70 milligram per deciliter. I would like their non HDL target to be less than 100 milligram per deciliter. And it's just based upon the triglycerides of less than 150. Although 150 is still a little liberal. I mean, that's not an optimal fasting triglyceride level.

[A]

Yeah, Paul, I think we can handle that kind of math. I think we can.

[B]

Yeah. I like addition subtraction. You're really right. My wheelhouse here. This is good.

[A]

Yeah, I know. One of the other ratios I've heard out there is the fasting triglyceride to HDL ratio. You want it to be as low as possible. Right. So your fasting triglycerides are in the 50s and your HDL is in the 50s. I guess that would be taken as. As good.

[D]

You know, there are many ratios out there. I would say, you know, maybe stay away from the ratios. Although they. They can be helpful and predictive. Above and beyond hdl cholesterol, we think is more likely to be a marker of risk than a target of therapy through Mendelian randomization trials. It appears to be not necessarily a causative factor like LDL or lp. In fact, we were one of the first groups to publish the U shaped curve related to HDL cholesterol. Having a very low HDL is a marker of risk. It's usually a marker of metabolic risk or somebody who smokes. There is a condition called hypoalphalipoproteinemia. Very low HDL associated with cardiovascular disease. But. But in individuals with a very high HDL cholesterol, we used to think how this was a protective factor, but it may not be. In some people. This is a reason to think about a calcium score, for instance, or just asking an individual about their family history of cardiovascular disease.

[A]

Should we. Paul, where do you want to go next? It's a choose your own adventure here. Prevent or lp? We're going to get to both.

[B]

So I feel like since we're still in lab markers, why don't we. Why don't we finish up with LP and then sort of circle back to prevent? So let's, let's do LP first.

[D]

Great. So LP lipoprotein A is a really important cardiovascular risk. Factor. It was discovered in 1963. So we've been at the understanding of LP for six decades. We often underappreciate the value of measuring at lipoprotein delay. One out of every five people in the world have a high lp. It is much more likely in women, black individuals, people of South Asian origin. And that LP has a skewed distribution. It is not a bell curve distribution, a normative distribution. It actually is skewed to the right and it has a very long tail. So there are many people with completely normal Lp. But when you start getting into Lp values that are 2 times, 3 times, 5 times, 6 times above the upper limits of normal, this is something to pay attention to. Now, some of the challenges with lp LP I call the triple threat because it likely exerts its impact through a pro atherogenic mechanism, greatly oxidizing LDL and phospholipids, an inflammatory mechanism and a thrombotic mechanism. Lp, though, in addition to increasing the likelihood of cardiovascular disease, also increases the likelihood of the progression of aortic stenosis. One of the current challenges in practice is there's not a standard measurement of LP can be measured in nanomole per liter. This is in molar units or milligram per deciliter. This is in mass units. We think the molar units is the better standard. And so unifying standardization of LP measurement will be helpful. The other point I want to make about lipoprotein is Although one out of every five people worldwide are living with a high op, one of our star fellows at Emory, Alex Rozavi, published a paper from the all of Us data set. This is looking at. We looked at over 250,000Americans. The paper was published in JAC Advances this year. And less than 1% of Americans have had their LP measured. And from several other papers, we know that only 2% of individuals or so living with ASCVD have had an LP measured. Universal screening is recommended in Canada, Europe and China, not yet in the U.S. although we're awaiting the publication of the updated cholesterol guidelines, which likely will occur sometime in the year ahead.

[A]

Paul, I'm not gonna shame you on this. I'm just gonna say I checked mine and it was fortunately very low. But I kind of knew that. Cause I don't my family history. I'm gonna die of cancer. Paul, we've talked about this before.

[B]

Sure. I have to think it's a naming issue. Saying little anything is lightly humiliating when you're talking about lab values like the LP is Just not a great name. And I feel like it's just not, because I really do think this is more an issue of marketing than I think, a lack of caring about this type of thing. So, Larry, I'm going to task you, as someone who's esteemed on multiple writing committees and does research in this, to really champion a rebrand like LP Sub A even just sounds so much better. Like, the little A is just. It's a real problem, and I think that's what's keeping us from keeping our patients healthy.

[D]

Yes, I agree with you. Names mean a lot, especially trying to translate medical information to the lay public. So little A probably is not the best name because it's predominantly a genetically determined factor, and it's determined by the lipoprotein big A gene. So it's the big A gene that determines the tail of the lipoprotein A molecule. So it's apob. The tail has squiggles called kringles. These are repeats. The term kringle comes from a Danish pastry, interestingly. And the repeats or the tails are a significant part of the genetics and the atherogenicity of the molecules. So I will spread the word. Paul, we need a new name for lipoprotein to be determined.

[B]

A lipopolycringle, like, it's right there. Like, it rolls off the tongue. I think patients expect us to say things that are hard to pronounce and sound weird. And the little A, I think, is almost too plain English. So, yeah, I appreciate you crusading on my behalf.

[A]

Okay.

[B]

All right. I've been a distraction. We should probably talk about the prevent calculator, because I think that's a relatively new thing that I've seen a lot of local uptake. Matt, I don't know where it's been about you, but a lot of people will. Sort of where I practiced got really excited about it right away, and I've actually started using it almost immediately. So I'd love to hear, Larry, from you, how it sort of differs from the pulled cohort equation and sort of prior risk calculators that we have.

[D]

Yeah, I'm glad to hear about the uptake of prevent. It is one of the major advances in risk assessment. PREVENT stands for predicting risk of cardiovascular events. And I'm grateful that I was part of the AHA team that built the CKMH initiative, Cardiovascular Kidney Metabolic Health Initiative. And as part of that, a subgroup derived and validated the prevent risk score. Why should we be thinking about prevent today versus the pool cohort equation? Let's go back to the case we started with. In that individual, we can calculate a prevent risk score, although we would need his GFR because that's standard now as part of the prevent risk assessment. And we don't know whether, I guess we're assuming he didn't have diabetes. When I calculated that patient's prevent risk score, I assumed he had a normal creatinine clearance. Why is prevent a step up? First of all, it allows a 10 year and a 30 year risk assessment, broadens the age range of risk assessment to ages 30 to 79. The derivation and validation was based upon 6.5 or greater individuals, 46 data sets, and both cohort data and real world health system data. So prevent has a greater ability to discriminate and calibrate. But remember, there's no risk assessment tool that is perfect and risk assessment is a starting point. It's not the end of clinical decision making. Where prevent is really, really helpful is there are, in addition to adding bmi, like in this case, presence or absence of diabetes and egfr, they're optional elements of the pre vet risk tool that includes urinary albumin, creatinine ratio, A1C if available. But where it is really a changed risk score from the pool cohort equation is we no longer use race or ethnicity. Zip code is used, and zip code, I get it right off the patient's chart out of the electronic medical record. I don't have to ask the patient what their zip code is. When they're checked in their zip code, their address is there. But that zip code is a surrogate of the social deprivation index. And again, not perfect because we don't live in the same zip code our whole entire life. And there are some zip codes that have significant variability in terms of the sociodemographic and socioeconomic status. But it's a starting point where we want to remember with prevent as opposed to the pool cohort equation. With the pool cohort equation, there were four buckets of risk, low, borderline, intermediate or high. Those four buckets will likely remain. But because there's greater ability to discriminate risk and calibrate risk. So as opposed to throwing darts, you have a greater chance of hitting the bullseye or around the bullseye for a patient, the risk thresholds likely will be different. And this is a work in progress. And I think about the risk thresholds likely being half of what they were for the pool cohort equation in terms of a decision to start a medication such as a statin. But we should be using prevent to counsel patients on 10 year risk, absolute risk, but also that 30 year lifetime risk, which I think is very valuable. We also with prevent, go beyond calculation of just ASCVD risk. Prevent allows the calculation of total CVD risk and heart failure risk. So you can broaden that conversation with a patient about risk in many different domains. And the other thing about prevent is it is being incorporated the first guidelines, new guidelines to be released in the past month with the hypertension guidelines they embrace Prevent and prevent ideally should be marked on your iPhone or on your computer in clinic. But in the best case scenario, our electronic medical record should be calculating prevent for us as clinicians. Even better, our patients should have their prevent risk score calculated by the electronic record before they come to clinic. They should bring it with them and ask their doctor to discuss it together. And it's a great touch point to begin that clinician patient risk discussion.

[A]

The total cardiovascular disease that you're able to calculate with that, can you define that? Is that the same as just ascvd? Is that what you're.

[D]

No, it goes beyond. So ASCVD is stroke, heart attack. Total CVD brings in the totality of cardiovascular stroke, heart attack and beyond that is going to. It's also mortality for stroke and heart attack. But total CVD encompasses. It doesn't bring in afib. I mean, that's one of the areas that we're not quite able to calculate an AF risk, although they're AF risk assessment tools. So we'll flip back to that patient. I mean, the ascvd risk was 3.1% with prevent, but the total CVD was 4.8 and the heart failure was 1.6. So it does. I mean, it brings the heart failure into the equation. It's still missing, you know, elements of total cardiovascular disease risk and it doesn't really bring in, you know, pad.

[A]

And you're predicting that with the next iteration of guidelines. Instead of our statin threshold being 7.5%, it might be half of that.

[D]

Yeah, it might be around 3%. And the data showed us even when the 2018 cholesterol guidelines were written, the risk thresholds were chosen based upon those that would more greatly benefit from a statin than a risk related to a statin. And that's how those thresholds were chosen. But those thresholds were beneficial down to as low as 3%. And now with prevent, we also want to make medication decisions beyond just statins because we have non statin agents, we have consideration for aspirin in primary prevention. And then for those at significant cardiometabolic cardiorenal risk, we should be thinking about the potential benefits of SGLT2 inhibitors, GLP1 receptor agonists. So we really want to build this risk discussion around optimizing a lifestyle and behavioral approach for all. Of course. But then how do we incrementally think about the potential benefits of other medications over the life course?

[A]

Well, let's get back to our case here and let's say he never had LP tested. He has a family history of early MI, triglycerides are above 200. We opt to test him for LP and APOB and his LP is 35 nanomoles per liter, which is in the normal range. His APOB is 100 milligrams per deciliter, which by this lab is in the normal range. And anything else that you would do at this point or how would you talk to him about statin initiation?

[D]

This is a trusted conversation. This is an individual where I would begin to talk about a statin as first line lipid lowering therapy. If he is wanting a little more data, we could consider a cardiac CT calcium score. But even if this individual had a low calcium score, we're really focusing on lifetime risk. And, and the lifetime risk of total CVD in this patient was 26%.

[A]

Yeah.

[D]

Using the prevent risk score. The way I begin a discussion about statins is we often talk about statins as a cholesterol lowering medication. What I try to emphasize is that we'd like to consider in addition to you're addressing a healthy lifestyle approach, diet, gradual weight reduction, moderate physical activity. We'd like to begin to think about a medication that not only lowers your cholesterol but importantly lowers your cardiovascular disease risk. That's a really important part of that conversation and many patients don't fully understand why you've started a statin. My cholesterol is better, I feel okay, I guess I can stop it. About 50% of patients post MI within six months have stopped their statin. So there also are concerns about statin related side effects. So I do have, as I'm having this conversation with a patient, I start paying attention to nonverbal cues, right? If they're squirming in their chair, getting defensive looking, I often say, look, for every medicine we start, we always want to think about indications, contraindications, benefits, risks and side effects. But we often don't take into account the risks of not starting a medication. I also mentioned to the patient that statins in general are very well tolerated and that we will Find what I call finding the right statin for the right patient. I talk about the most common side effects, which are myalgias but not myositis. And if you have muscle aches, pains and weakness bilaterally across your body, you feel like you have the flu, but you don't, just call me, let me know. We'll change the dose or we'll think about another statin. We were the first in the world to publish using very low doses of statins every other day or Monday, Wednesday, Friday or even twice a week, because an agent like rosuvastatin or atorvastatin, they have a very long half life. Rosuvastatin has a half life of 19 hours. So getting a little bit of statin on board. And we think the statins, besides lowering cholesterol, they lower cardiovascular risk more than likely through additional biologic mechanisms. The statins reduce inflammation, they reduce platelet stickiness, they also will improve endothelial function. So the statins have biologic benefits above and beyond. But today we have non statins in our toolbox and we want to think about the risk of that patient. A potential initial goal, it might be a 50% lowering of LDL cholesterol from baseline. And the 2018 cholesterol guidelines do not give us a specific numerical targeting goal, although the expert consensus decision pathway from the acc, which was published a few years ago, started getting back to a numerical targeting goal, which I still discuss with patients.

[A]

I think it's valuable to say patients like the numbers. They do.

[D]

Yeah. So it's okay to say, let's target an LDL less than 100 milligram per deciliter or less than 70, or in a very high risk patient, less than 55 milligram per deciliter. But one of the I talked about planting seeds. If I see the patient having some concerns, I frequently will just stop right there and say, look, if I was going to start a statin, I would start this statin at this dose. Why don't you read about it? And that way if between now and your follow up visit, you decide you're ready to give it a go, just send me a message and we'll get started on it. Very frequently patients will message me back to say, Dr. Sperling, I reviewed our discussion together and I thought about the statin and you know, I am concerned about my family history and I agree with you, my cholesterol is too high. So let's get started on that medication between now and my next visit. So you know, each and Every visit doesn't have to be in that 15 or 30 minutes. An all or none decision.

[A]

Paul, any follow ups to that?

[B]

No, I love that that's a move I use all the time where I'm like, why don't we you look it up, let me know when we see each other, talk to each other again. We can certainly revisit this. And my philosophy is if they forget to look it up, they care less about the side effects than I do about actually prescribing the medication, which I will, and then I will sort of re broach and oftentimes I can sort of push people. So if someone's concerned enough to look it up, usually they'll usually be on board with it regardless. And if they don't, then I will sort of re bring it up again. And that also proves that I still care about this medication, think it's indicated. So either way, eventually we kind of land on the same page where patients are usually open to being prescribed whatever it is that we're talking about, in this case being statins. But I like that framing of, well, do your research and let's discuss and follow up. Because I think that seems less paternalistic than just trying to foist a medication on someone.

[D]

It's about that trust and safety that is the core of our relationship with our patients. I will often say my job is never to convince you to take a medicine, have a test, have a surgery, but my job is to translate the evidence to this conversation on behalf of you.

[A]

The other question I always get from a patient like this, they might say, you know what, I just want to, I want to give diet and lifestyle a try first. And, and then when I come back in three months, let's check again. And inevitably I notice Maybe there's a 10% drop in LDL if the person was really overfed and just eating a terrible diet. The triglycerides will often change the most, I find, but I don't usually get a huge change in cholesterol. Can you talk about that and how you handle that situation and how much diet and exercise and other non pharmacologic methods might work?

[D]

Yeah, I'm glad you brought this up, Matt, because for all of our patients we should be focusing on a healthy dietary pattern as opposed to a diet. There's a difference, you know, a fad diet, which is extreme healthy dietary pattern, regular, moderate physical activity, and for some people focusing on gradual weight reduction. It is true that for many individuals, diet alone will not significantly lower the LDL cholesterol. It can lower the triglycerides. The three themes I talk about with a dietary approach and I try to individualize these, we can very easily ask our patients on a usual day recognizing you don't eat the same thing every day. What's a typical breakfast, lunch, dinner, snacks and beverages. And I try to make very specific recommendations to start moving that dietary pattern to a healthier place. The three themes I talk about frequently are a Mediterranean dietary pattern, flexitarian, meaning less animal protein, so more plant based, but you don't have to necessarily be a vegan or vegetarian. And the third one is a cholesterol lowering approach versus low cholesterol. It's based upon the portfolio dietary pattern. The original portfolio dietary study was done, oh boy, easily 25 years ago, more. And it looked at people with moderate hypercholesterolemia. They were randomized to a usual diet that they were following an AHA step two diet. And then they also were randomized to lovastatin, which was the very first statin on the market versus the portfolio dietary pattern. So that's right. So it's step two diet, lovastatin, portfolio diet. And these are things you can eat more of that will lower your cholesterol. And these are not herbals and supplements. Oat bran, walnuts, almonds, ground flaxseed and a little bit of dark chocolate. There's actually benefit to high quality dark chocolate, to improving your vascular function, your blood pressure and like your cholesterol a little bit. Now the diet discussion is a really important one because most people equate their cholesterol level with what they eat. And our body is very complex in terms of cholesterol metabolism. Of course there's dietary cholesterol, saturated fat, but our body makes cholesterol, synthesizes cholesterol, recirculates cholesterol, and so our cholesterol level doesn't just equate to what we eat. And there are people living with genetic cholesterol disorders, familial hypercholesterolemia, heterozygous individuals, one out of every 250 people worldwide. We know that diet alone is the wrong answer when we've made the diagnosis of fh, when we diagnose fh. Yes, we're going to talk about a healthy dietary approach and pattern, but we want to talk about somebody living with a genetic cholesterol disorder. And we want to start medical therapy as soon as possible to reduce this individual's risk across their life. And we also want to use the equation F plus H equals suspicion for Familial hypercholesterolemia. So family history of high cholesterol, early heart disease, high cholesterol in that individual and extend that risk. Discussion beyond the individual to family cascade screening. I currently serve as the chief Medical officer of the Family Heart Foundation. This is a fantastic organization providing knowledge, tools, and resources for individuals who are living with FH high LP and LDL cholesterol that is too high for them.

[A]

So the really quick to swing back to the dark chocolate. I think it has to be like 65% cacao. I don't want people to think they're eating the typical dark chocolate. Hershey's dark. And I don't think that's lowering your cholesterol. It has to be the real stuff. It has to have high percentage of cacao in it. Okay, but the FH support.

[B]

Listen, as someone who lives in Hershey, Pennsylvania, I feel obligated to say probably Hershey chocolate does lower your cholesterol, though. So I might have to push back.

[A]

To that a little bit. I have no.

[D]

And I visited Hershey many, many years ago, and I don't know if it's still the case, but the air in Hershey, Pennsylvania is intoxicating with the smell of chocolate.

[B]

Depends on which way the wind blows. It's either chocolate or cow manure. So, yeah, on good days, chocolate for sure.

[A]

Okay, so actually, before we get to the FH so portfolio dietary pattern, you said that would be adding things to the diet like oat bran, oats, bran walnut, almonds, flax. And we said the dark chocolate. And then we should suspect FH if they have family history of, like, premature heart disease or early heart disease and they have high cholesterol themselves.

[D]

That's correct. And often just a family history of high cholesterol. But we have to make that diagnosis. You know, we can't just say you have high cholesterol. And I'm concerned calling it a probable genetic cholesterol disorder helps that individual understand not only their risk, but the risk of their family. The other thing with diet that we have to be aware of is the ketogenic dietary pattern. Yes, there are individuals that can significantly elevate their cholesterol with a strict ketogenic dietary pattern. So have those antennas up when you see somebody with an LDL cholesterol, you know, 200 plus, especially if the last time you saw them, their cholesterol was in a more moderately elevated range. We want to think about secondary causes of hypercholesterolemia. So liver disease, kidney disease, thyroid disease, some medications that can elevate cholesterol. But that ketogenic diet is not among the healthy long term dietary patterns.

[A]

I've seen the ketogenic diet. This is what. Yeah, these hyper responders to the ketogenic diet. And yeah, there's definitely a rabbit hole. You can go down on this because I had a guy whose total cholesterol was 170 and it jumped up to like 500 and his LDL went up to the 2002 and he was on a ketogenic diet and he just changed up his macros and it went right back down. But there are some people out there that are on the carnivore diet or ketogenic diet that are hyper responders. And I think they're doing some. These are like metabolically fit people and they're doing. There's been at least one CT study where they're trying to say that it doesn't. The plaque didn't progress that much over the course of one year. And I don't know, I'm not convinced yet. I'm very worried about that. And I think that's a dangerous.

[D]

I was asked to look at and comment on that CT study, and there are significant methodological concerns. So I would not embrace that one study as kind of a blanket statement to say ketogenic dietary approaches are safe.

[A]

Yeah, we will get to that at another time, Paul, but this is good discussion here. Yeah. And I mean, we have all these patients that have this. You get the LDL, it's 130, 160. They're in this intermediate or borderline risk score. They want to try the lifestyle thing. So we try it and then they come back and maybe it's changed a little bit in a favorable way. And oftentimes other things will change. Like it's easier, I find, to get the blood pressure to come under control or the blood sugar to come under control than the cholesterol. And you said you talked to them about starting statins and so that three month wait, I feel like over the course of a lifetime, that three month wait is okay. If someone who hasn't had an event, is that reasonable to do?

[D]

Very reasonable. It depends on the. Oh, and you said somebody who's not had an event, not having. Yeah, I think if it's secondary prevention, there's greater urgency there. Of course. Yeah. With side effects. If we go to the 2018 cholesterol guidelines, if you read it from beginning to end, and I'm sure Matt and Paul, you've read the 2018 cholesterol guidelines to be Hosts for curbsiders. But if you read the guidelines, in the entire guidelines, there's never once a mention of the term statin intolerance. We use the term statin associated side effects, and the most common being sams statin associated muscle symptoms. We do this because there's a concept of the nocebo effect out there. You know, there's the statin concerned individuals that, you know, there's a whole discourse out there about worries about statins. And the nocebo effect comes from the Latin derivation of noisi, like noisi receptors, meaning pain receptors. So there's a preconceived notion of harm. And where we talk about statin associated muscle symptoms, you know, somebody will say, ow, my shoulder hurts. It must be the statin. Well, no, your shoulder hurts and we need to understand better why your shoulder hurts. So having that right statin for the right patient discussion, I think is really important. Statins can slightly increase the risk of diabetes in people who are living with the genetic predisposition for diabetes or underlying insulin resistance. Statins do not cause diabetes, but through internuclear signaling and they upregulate an increase in blood sugar. But it's never a reason to not prescribe a statin. It's an extra reason to talk about both cardiovascular disease prevention and diabetes prevention in a patient like that initial case we talked about. And you want to have that conversation in a combined effort related to comprehensive prevention.

[A]

And for somebody, let's say this patient was a bit younger, in his 30s and was worried about the family history. I've had the conversation with some people, like some people want to start a statin, a low dose statin, at a younger age. Just be if they've tried the lifestyle thing and their cholesterol's not coming down, thinking about, we talk about this lifetime risk is, is high for this person. So thinking of it almost like compounding interest, like the earlier you start, the more benefit you might reap because you have a much longer lead time and you'll be exposed to the high cholesterol for much less, many fewer years than if you just waited a couple decades until your risk score got high enough to start the statin based on your 10 year risk. Does that factor into counseling or do you think that'll ever make it into guidelines?

[D]

You know, the conversation is really important, that absolute risk as a starting point. But many patients, let alone clinicians, you know, what does it mean to say you have a 7.4%, 10 year risk, but when you start talking about a lifetime Risk approaching with prevent, we might say, you know, 30 years or even frequently I talk about individuals with a 50% lifetime risk. You know, people get that. That's flipping a coin up in the air. You know, heads you're going to have a heart attack or stroke, tails you won't. I mean that you're going to leave that up to chance. And the concept of cholesterol years is a very valuable discussion point. Just like we talk about PAC years, it's exposure over time. And so as we mitigate exposure over time, we hopefully will have benefits that accrue not only in the short term, but in the long term. And although our RCT is related to statins and other cholesterol therapies, you don't often have a two to three to five year timeline. We're never going to have a, you know, a 20 year RCT or a 30 year RCT. But the evidence does show that benefit does accrue over time.

[A]

Yeah. So it would be reasonable if someone's game for starting early or if they wanted to. And because now the cost, there's very few side effects for most people. Put them on a low dose, the cost is not much and you know, they could take it for decades. Theoretically. I don't like the idea of myself of taking medicine for decades, but you know, depends on how worried you are about that ASCVD risk.

[D]

So yeah, I'm often asked about, do I have to take this the rest of my life? And I say, you know, let's get started for the reasons we discussed and we will continue to evolve our approach to your care together. Of course, knowledge will increase over time. Other therapies will be able to potentially be available to patients over time. And so we want to let the evidence evolve and we apply that evidence back to our team decision making.

[A]

Okay, well, we'll conclude this case and for Mr. Smith, I don't know if it's Will Smith or Brad Pitt. Paul. I think they're both in their 50s. Right. It could be either one of those guys. Maybe they're older.

[B]

I think both probably older.

[A]

Actually they're probably older. Okay, so it's not one of them different Mr. Smith. Anyway, we start him on rosuvastatin, 10 milligrams and he improves his lifestyle and lives happily ever after. But we have another case. Paul, would you get to that?

[B]

Sure. So we've got a 62 year old gentleman with a history of high blood pressure, hyperlipidemia, type 2 diabetes and CKD with the last EGFR at 48ml per minute with a 35 pack year history of tobacco use. Although he quit two years prior, he's presenting for follow up. He had been adherent to his maximally tolerated high intensity statin therapy. So we're at atorvastatin 80 milligrams but his LDL remains persistently elevated at around 160 milligrams per deciliter. So we added on his etimibe 10 milligrams at a recent visit. But even with that his LDL only fell to 150 milligrams per deciliter dot so at this point we just haven't achieved what feels like should be our goal for this person. So I would like to hear your kind of overall approach for patients like this because I feel like this is something I see often where they're on medications, they endorse adherence and we just haven't moved the needle as much as we would like. So what is your overall approach then? We can sort of narrow in and talk about specific medications.

[D]

I would want to know about this individual's family history. That would be very valuable to me. And a question I would ask is when was the first time you were told you had high cholesterol and how high was your cholesterol when you were first told it was high? What I'm concerned about with this individual is this individual most likely has severe hypercholesterolemia. But above and beyond that I'm very suspicious. This person has familial hypercholesterolemia. Why do I say that? If we back calculate with that atorvastatin 80 where we would expect approximately a 50% LDL reduction, then his LDL probably was approaching 300 or beyond at baseline. I definitely would want to do a physical exam on this gentleman looking for clues for hypercholesterolemia that is genetic. So fh. So corneal arcus xanthelasma, tendinous xanthomas, also Achilles tendinous xanthomas. But if he came back and said look, I was told I had a high cholesterol when I had my first cholesterol test at age whatever, 25, how high was it? Oh, they told me it was really high. And then I'll ask, tell me about your family history. And often the story plays out about a parent, a grandparent, potentially cousins, and that's that F +H should make us suspicious of familial hypercholesterolemia. But I think a qualifying question for this gentleman is and Neil Stone, who was our co chair for the 2018 cholesterol guidelines taught me how to ask this question in a very non judgmental fashion. I would ask him, how many times a week or month do you miss taking your cholesterol medicine? And if he said, you know, to be honest with you, I miss taking it several weeks at a time. And, and it's interesting the answers you get from patients. I've had patients who are physicians that say, you know, I probably miss it maybe seven to ten times a month because I'm traveling. I forgot to put it in my bag. I've had other patients say, I take it all the time during the week, but not on the weekends. So that's a nonjudgmental way of assessing adherence. But if this patient looked at me and said, I take my statin all the time, then it's really likely he has familial hypercholesterolemia. And then the fact that by adding the statin and the ezetimibe that these values are still significantly elevated. We should be thinking about the genetics of this individual because they may have an LDL receptor abnormality where they're not responding as well as they should to a statin or azidomibe. So they might have a functional abnormality of the LDL receptor or partial null LDL receptor, because the statins and azitimibe, the secondary benefit of these agents are they upregulate the LDL receptors. And so if you have dysfunctional LDL receptors, you often don't respond well. I'd also want to know this gentleman's lipoprotein aa, because in individuals with familial hypercholesterolemia, they have a greater chance of having a high Lp as opposed to that 20%. In the general population, it's more like 30 to even sometimes 50%. And these genetic factors synergistically increase risk for an individual and a family. For this individual, another point I want to make is if we are suspecting he has familial hypercholesterolemia, we don't need to calculate a pre met risk score or a pull cohort equation. If you remember from the 2018 cholesterol guidelines, there were populations where we went straight to therapy. If your LDL cholesterol baseline was greater than 190 milligram per deciliter and you've excluded secondary causes, you go right to treatment. But you also have a conversation about why you think that LDL cholesterol is elevated.

[A]

And when we're saying FH here, are you saying either heterozygous or the homozygous version, does it matter much to us.

[D]

In you know, it does matter. And there are criteria for suspecting fhe. There's the Simon Broom criteria, the Dutch lipid criteria. The medped make an early diagnosis, prevent an early death. They all incorporate to some degree the family history, the LDL cholesterol. Simon Broom and Dutch lipid take into account physical findings, but genetics matters because there are some family members who might have a lower LDL cholesterol or an individual with that strong family history. And their LDL is not 200, 250, 300, it's more like 140 or 160. We know from a great paper from Cara et al that if you have the genes for fh, even if you have a lower LDL cholesterol, your risk is much higher than a matched population with that LDL cholesterol. So this person here, I mean, most likely has heterozygous FH or heterozygous fh. That's where I'm raising that question. Because if they're a non responder or a poor responder, they may have a, a dysfunctional LDL receptor or they may have a blend of heterozygous FH and a high lipoprotein little A.

[A]

Let's talk about what drugs we might go to next here and is this somebody. I'm guessing this is somebody I would refer on, but I would definitely, if there was a long wait time, I might try something else. I'm thinking PCSK9 inhibitor, bempedoic acid. I don't, I've never prescribed inclisiran, so I'm not really too familiar with that. We talked about it with Dr. Mikos a while back but haven't prescribed it. So where we go next? Medication wise?

[D]

Medication wise. Thankfully we have additional therapies that can be used today. You know, for this individual I would definitely be reaching for a PCSK9 inhibitor. With a caveat, but let me just mention bempedoic acid is an ACL inhibitor, an acyl citric lyase inhibitor. If you remember, the pathway of cholesterol synthesis upstream from HMG CoA reductase is ACL. And so Bempedoic acid will lower LDL cholesterol modestly in the range of maybe 20 to 25 or 30%. There is evidence base the Clear Outcomes trial, reduction in events but not total mortality but still evidence based. Inclisiran is a way to inhibit PCSK9 through small interfering RNA. The advantage is you ultimately use it only twice a year. There are outcomes trials in progress related to inclisiran. But let's flip back to the PCSK9 inhibitors. Because these drugs were first FDA approved 10 years ago. I remember having a waiting list of patients that I was ready to start prescribing PCSK9 inhibitors. These drugs are monoclonal antibodies. They inhibit PCSK9, which is a protease involved in the turnover of the LDL receptors. So from a big picture standpoint, if you block the LDL receptors from turning over, the LDL receptors get the hangout longer, soaking up that LDL cholesterol into the cell. So I think it's worthwhile to consider a PCSK9 inhibitor. You know, if this person has a partially dysfunctional LDL receptor, I'm not sure, but they might not respond as well to the PCSK9 inhibitor. This is a high risk individual. Clearly. I mean, hypertension, beyond their genetic lipid disorder, type 2 diabetes, a GFR of 48, former smoker, you know, so I'd really want to get their LDL cholesterol down as low as possible. I mean, at least under 70 milligrams per deciliter or even potentially less than 55 milligram per deciliter through what will be needed as combination therapies. This is an individual where we should think about a unique therapy called lipoprotein apheresis. I helped Emory start 22 years ago, the first and only lipoprotein apheresis program in the state of Georgia. And this is a therapy that will reduce the time averaged LDL cholesterol if needed. It's not quite, but we can think about a little bit of a parallel to hemodialysis. What happens is you have a column, and the column has electrostatic affinity to APOB containing particles, which includes all the atherogenic particles, including the LP. And after a single therapy of three hours, we can reduce these values by, you know, 50, 60, 70, 80%. But they start popping back up. And so, you know, we treat over time. But this is an individual that, you know, really concerns me in terms of their not just lifetime risk, but their short term cardiovascular risk. And it's going to take some time to land on appropriate combination therapy that is aggressive and effective. But we want to extend this conversation to the patient's family cascade screening, because often when I meet somebody who clearly has familial hypercholesterolemia, I'm going to ask about their family. And unfortunately, we often don't think as internal medicine physicians about the complete family. And so really want to focus on family screening Both for LDL cholesterol for lipoprotein. And our U.S. guidelines recommend that all Americans over the age of 20 should have a lipid profile at least once every five years. An initiative we just launched called Lead Peds focuses on our pediatric guidelines recommending all children should have a cholesterol between the ages of 9 and 11. And only 11% of American children have had a cholesterol checked at that age. And we want to even think about checking a cholesterol at a younger age in a suspected family where there's familial hypercholesterolemia or early heart disease.

[A]

Is there genetic testing that if I referred this patient to you with, let's say we found out his LDL did start close to 300 and now it's 150. And I refer to you, is he going to have genetic testing or can we just sort of just operate on the. With the assumption that he has fhh?

[D]

The phenotype alone raises a high suspicion for fh. There is benefit to genotype both for the individual and potentially for the family. There are various platforms for assessing genetics. And so I would have the conversation about genetic evaluation because it's not just checking the genetics like you check in ldl. There's gotta be a really important conversation that occurs before and after genetics are checked. And there's potential cost to genetics or genomic evaluation in terms of, you know, moving gender beyond the genetic evaluation to a better understanding of that individual. There have been over 2000 different variants of FH described. So it's not like you're going to find the fh. The most common form of FH involves the LDL receptor, but there's an APO V variant of FH and then there's a PCSK 9 variant of FH. And then there's even a rare autosomal recessive type of fh, because most FH is autosomal dominant, meaning you know, if you have the gene, then statistically 50% of your children will have high cholesterol.

[A]

Well, I want to, I want to move on and just with the last few minutes, just see where we're at with these LP lowering drugs. So we'll say that our patient here, we did the evaluation, we found out they have heterozygous FH and elevated lp. They've heard that there's some drugs in trials right now that do lower LP. And we talked about this with Dr. Mikos even a couple years ago, that there's these. Pelacarson is one of them. I'm not going to try to say the other one. Some of these are injectable, some of these are. I think there's even an oral agent. So talk to us about that. And what do you think the outcomes will show for these trials?

[D]

This is one of the most exciting areas in cardiovascular disease prevention today. We are truly on the potential horizon of LP directed therapies. The first study likely to report out and be published will be the Horizon trial. This is pelacarson and this agent is an antisense, so it binds to the messenger rna. Your own body's rnase eats up this dimer. And there are other agents in development and phase three RCTs, there's lepidicerin, there's opacirin, these are small interfering RNA agents. And, and there's even an oral agent, as you mentioned. And one of the other mechanisms of action is disconnecting the APOB from that LPA tail. What we know thus far these therapies appear to be effective. They can lower LP 80, 90 or even some of them approaching 100%. So far they appear safe. These clinical trials are in progress and the clinical trials are predominantly focusing on secondary prevention, although several of the clinical trials have a high risk primary prevention arm. And there's Even a phase 2 clinical trial in progress right now looking at progression of aortic valve stenosis. Because I mentioned those living with a high op AA can have progression of AS at a greater rate.

[A]

Yeah. You know, Paul, I was surprised when I was reviewing for this. I keep. Because we've heard about these drugs for quite a while now. And you know, I'm hopeful they'll work. I just, I'm always skeptical because there's all these mechanisms. It seems very promising. And this is lowering LP is a surrogate endpoint. Right. So we just can't say that just targeting a surrogate endpoint is going to translate to hard clinical endpoints that we care about, like mortality and cardiovascular death, strokes, heart attacks, all that. But I'm very hopeful it works because that would be great.

[D]

Yeah, there's definitely a lot of hope out there. And Paul, I don't know if you are encountering or matt. Encountering patients that are asking about these clinical trials. At Emory, where I work, we have a clinical trial team and so frequently we're referring these patients on to our clinical coordinators, study coordinators, to see if they're potentially eligible for one of these novel therapies that are presently in the midst of major clinical trials.

[A]

Well, to conclude this case here, let's say we got lucky. We started this guy on a PCSK9 inhibitor. Actually, he did respond to that. So we didn't have to go further down, we didn't have to go further down the line for other drugs. And he's not yet entered into a trial for LP lowering drug. But he's, we told him he can stay tuned for that. Larry, I want to thank you so much for all your time and all your great teaching. I learned so much from this conversation. But I want you to just tell the audience two or three things that you really want them to remember from all the things we talked about.

[D]

At the top of what I want the audience to remember is cardiovascular disease remains the number one cause of death in our nation and globally. And so as you care for your patients in the office or in the hospital, be attuned to risk assessment. Risk assessment is a starting point, but we talked about risk assessment as not being the end of getting to know your patients. So use that CPR rubric, calculate, personalize, and then if needed, reclassify. I also want the audience to recognize that we have safe and effective therapies that not only can lower cholesterol, but importantly, as you message your patients, the message that needs to be heard is these agents lower cardiovascular risk. And that together through that partnered care, that we should be committed to cardiovascular disease prevention, which is very possible today and will have greater possibilities in the future.

[A]

Thank you so much, Larry. Really great.

[B]

This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole holes. Are we doing this instead of yummy because I hate it even more. Still hungry for more. Join our Patreon and get all of our episodes ad free, plus twice monthly bonus episodes at the patreon.com curbsiders. You can find our show notes at the curbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice changing articles, guidelines and news in internal medicine.

[A]

And we're committed to high value practice changing knowledge and we want your feedback. So email [e-mail] a reminder that this and most episodes are available for CME credit for all health professionals through VCU healtherbsiders.vcuhealth.org Special thanks to our writer and producer for this episode, Ben Fuhrman, and to our whole Curbsiders team. Our technical production is done by podpace. Elizabeth Proto does our social media. Jen Watto runs our Patreon. Chris the Chew Manchu moderates our discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto and.

[B]

As always, remain Dr. Paul Nelson Williams. Thank you and goodbye.

[E]

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