Allan Sniderman, M.D.: Cardiovascular disease and why we should change the way we assess risk

In this episode of the Drive podcast, host Peter Attia speaks with Dr. Alan Snyderman, a prominent cardiologist and researcher, about advancements in understanding cardiovascular disease. They discuss the importance of Apolipoprotein B (APOB) as a superior predictor of atherosclerosis risk compared to traditional metrics like LDL cholesterol. Snyderman emphasizes the need for early intervention based on long-term risk models rather than short-term risk calculators, advocating for a shift in clinical guidelines to incorporate APOB measurements. The conversation also touches on challenges in disseminating cutting-edge research amidst entrenched medical guidelines and consensus-driven recommendations.

• The podcast focuses on translating the science of longevity into accessible content for everyone.
• Dr. Alan Snyderman, a senior scientist and professor at McGill University, is the guest.
• Dr. Snyderman is a mentor to Peter Attia and an expert in cardiovascular medicine.

"Our goal is to provide the best content in health and wellness full stop, and we've assembled a great team of analysts to make this happen."

• The podcast aims to provide high-quality health and wellness content.

• The discussion centers on the complexities of cardiovascular medicine, particularly APOB and risk management.
• The podcast aims to elucidate why APOB is a superior metric for predicting atherosclerosis risk compared to LDL cholesterol and non-HDL cholesterol.
• The role of triglycerides, HDL cholesterol, and total cholesterol in understanding cardiovascular disease is also discussed.

"What I mean is clear thinking of complex concepts that you'll ever hear anybody talk about with respect to APOB and risk management."

• The podcast intends to clarify complex cardiovascular concepts, particularly APOB and its role in risk management.

• Atherosclerosis is a disease in the tissue, and understanding its natural history is crucial for prevention strategies.
• Current guidelines focus on ten-year risk, which makes preventing premature disease challenging.
• The disease develops over decades, often before risk becomes apparent in traditional models.

"For the first three decades or so of life, the disease begins, gets a foothold in the artery, but it's only in the fourth decade that you start to develop delusions that can actually precipitate a clinical event."

• Atherosclerosis begins early, and understanding its progression is essential for effective prevention.

• Current models focus on ten-year risk, which often misses early prevention opportunities.
• Many cardiovascular events occur before age 60, but risk models often don't account for this.
• A causal benefit model, focusing on long-term risk and APOB measurements, can provide more accurate predictions.

"Rather than what sterry taught me, and it took some years before we could develop the methodology, of course, risk is a good concept. Of course it is. But we should be selecting people also based on causes."

• Current risk models have limitations, and focusing on causes like APOB levels offers better prevention strategies.

• Cholesterol is essential for cell structure, but its transport in the body is complex.
• Cholesterol travels in particles that contain ApOB, which is crucial for understanding cardiovascular risk.
• The number of APOB particles is more important than the cholesterol level for assessing risk.

"Any cholesterol in the artery only got there within an APOB particle. It doesn't just float in, it gets there within an APOB particle, either VLD or LDL, that gets into the arterial wall and gets stuck there."

• APOB particles are central to the development of atherosclerosis, making them a key metric for risk assessment.

• The relationship between cholesterol levels and cardiovascular risk was first noted in the 1950s.
• Later research in the 1970s and 1980s highlighted the importance of APOB particles over cholesterol levels.
• Studies showed that the number of APOB particles is a more accurate predictor of risk.

"The one with the increased number of particles has higher atherogenic risk because any cholesterol in the artery only got there within an APOB particle."

• Historical research has shifted the focus from cholesterol levels to APOB particle count for predicting cardiovascular risk.

• Despite evidence, guidelines have been slow to adopt APOB as a primary metric.
• Cost and assay standardization have been cited as barriers, though APOB tests are affordable and standardized.

"This cost argument has been used without documentation as a killer argument."

• Guidelines have been slow to change due to misconceptions about cost and assay standardization.

• LDL cholesterol is often calculated, not directly measured, leading to potential inaccuracies.
• Non-HDL cholesterol and triglycerides provide additional context but are not as precise as APOB measurements.

"LDL cholesterol can also be measured directly. That assay has never been validated in disease patients."

• LDL cholesterol is typically estimated, and direct measurement methods lack validation in disease contexts.

• The discussion highlights the need for a shift in focus from cholesterol levels to APOB particles in cardiovascular risk assessment.
• Future guidelines should incorporate APOB measurements for more accurate and early prevention strategies.

"It's the particle. And when you're measuring the triglyceride, you're just measuring a blob of liquidity in a bunch of particles, and you need to know the number of them."

• Understanding the role of APOB particles is crucial for advancing cardiovascular disease prevention and management.

• Dyslipoproteinemia is a condition characterized by abnormal lipid levels, specifically involving cholesterol and triglycerides.
• Type 3 dyslipoproteinemia is a highly atherogenic condition with high triglycerides and cholesterol but low APOB levels.
• Diagnosis of this condition is challenging without measuring APOB, a practice not commonly performed in the U.S.

"In type three, that process breaks down. And for reasons that are not well understood, under age of 30, 35, or 40, people develop high triglycerides and high cholesterol."

• Type 3 dyslipoproteinemia involves a breakdown in the normal metabolism of VLDL particles, leading to high cholesterol and triglycerides.

"But type three cannot be diagnosed in most patients in the United States because APOB is not measured."

• The lack of APOB measurement in routine medical practice makes diagnosing type 3 dyslipoproteinemia difficult.

• APOB is a key marker in assessing the risk of atherosclerosis and lipid disorders.
• The number of atherogenic particles, not just their concentration, is crucial in evaluating risk.

"For normal patients that I'm treating with statins, I only have to get one number right."

• APOB measurement simplifies monitoring and treatment of patients on statins.

"APOB was a more accurate index on statin treatment than on HDL cholesterol."

• APOB is a superior marker compared to non-HDL cholesterol for assessing treatment efficacy.

• Mendelian randomization helps establish causality by linking genetic variants with disease outcomes, minimizing confounding factors.
• APOB has been shown to incorporate information from triglycerides and LDL cholesterol, supporting its causal role in atherosclerosis.

"What a number of Mendelian randomizations have shown is that APOB includes all the information in triglycerides, LDL cholesterol, and even HDL cholesterol."

• Mendelian randomization studies confirm APOB's comprehensive role in lipid metabolism and its superiority over traditional lipid measurements.

"Mendelian randomization allows you to do is to come a lot closer to causality."

• This technique provides stronger evidence for causality compared to observational studies.

• Traditional lipid measurements may not capture the full risk profile, especially in the context of metabolic disorders.
• There is resistance in the medical community to shift from LDL cholesterol to APOB as a primary metric.

"It's another example, an unfortunate, sad example, that trying to quantify lipoproteins based just on lipids is not adequate."

• Reliance solely on lipid measurements without considering APOB can lead to underdiagnosis and undertreatment.

"The world has remained. It's a phenomenon that I'm. That I don't really understand how resistant the lipid world has been to change."

• The medical community's reluctance to adopt APOB as a standard measure is puzzling given the evidence.

• Hypertension is a major risk factor for atherosclerosis, though its pathophysiology is not fully understood.
• The proximal aorta may play a significant role in the development of systolic hypertension.

"The proximal aorta is elastic, and if you look at a flow curve, a hydrostatic pressure curve, when we're young, it's rounded."

• Changes in the proximal aorta's elasticity may contribute to hypertension and subsequent cardiovascular risk.

"Once I got hypertension, okay, then I've got a driving force to push particles into the wall."

• Hypertension increases the mechanical force on blood vessels, facilitating the entry of atherogenic particles.

• Smoking is a well-established risk factor for atherosclerosis, though the exact mechanisms remain unclear.
• Treatment decisions often prioritize smokers due to their elevated risk profile.

"Smoking gets you up the category to have your life saved, so bad behavior gets you closer to having your life saved."

• Smoking significantly increases cardiovascular risk, impacting treatment prioritization.

"What is it about smoking that drives risk of atherosclerosis so much?"

• The mechanisms by which smoking exacerbates atherosclerosis risk are not fully understood but are significant.

• There is a need for better understanding and management of lipid disorders, particularly in the context of genetic and metabolic factors.
• Research should focus on improving diagnostic tools and treatment strategies to address the complexity of lipid metabolism.

"I don't know. I think that's where research needs to be done."

• Further research is needed to understand the genetic and environmental factors influencing atherosclerosis.

"Are we doing a better job treating hypertension than dyslipidemia?"

• Ongoing evaluation of treatment efficacy and strategies is crucial in addressing cardiovascular disease.

• Family history can influence treatment decisions, especially when considering lipid levels.
• A low APOB may reduce the impact of family history on treatment decisions.
• Individual patient goals and objectives are crucial in clinical decision-making.
• The relationship between statins and diabetes is not fully understood.

"If the APOB is actually low, I'd be less inclined to let it influence me."

• A low APOB level can reduce the influence of family history on treatment decisions.

"A lot of these decisions at the individual level actually aren't that difficult when you're speaking to a particular patient, because they have their own objectives and goals."

• Individual patient goals and preferences play a significant role in clinical decisions.

• CAC is a cardiovascular imaging technique to detect calcification in coronary arteries.
• Calcification indicates advanced atherosclerosis and is linked to higher heart attack or stroke risk.
• The frequency of positive CAC increases with age, making it less informative for older individuals.
• A negative CAC does not rule out the presence of disease, especially in those with high APOB.

"Coronary calcium is an important step forward in cardiovascular imaging, and it's a process where you can accurately and pretty safely determine, using x-ray techniques, whether there's calcium bone in the coronary arteries."

• CAC is a significant advancement in detecting coronary artery calcification.

"The frequency of a positive coronary calcium goes up as we age, so does the risk of disease."

• Positive CAC results become more common with age, paralleling increased disease risk.

"If somebody has a high APOB, the fact that their coronary calcium is negative doesn't mean they don't have a lot of disease and that the disease isn't developing at a rapid rate."

• A negative CAC does not eliminate the possibility of significant disease in individuals with high APOB.

• Risk assessment should consider long-term health beyond immediate years.
• A 5% ten-year risk can be significant, especially when considering long-term outcomes.
• Confidence intervals in risk predictions are often not published, complicating risk assessment.
• Science should embrace diverse views and challenge consensus to improve understanding.

"If a person's ten-year risk is 5%, how can you get somebody excited about a 5% event in the next decade if somebody's 50?"

• A 5% ten-year risk may not seem significant, but it becomes more relevant when considering long-term health.

"The bounds of our knowledge are really quite limited, and it's important that we admit that to ourselves and to our patients as well."

• Acknowledging the limitations of current knowledge is essential in medical practice.

"Any process that has unanimous recommendations has a weakness."

• Unanimous recommendations may indicate a lack of diverse perspectives and can hinder scientific progress.

• Experiments are crucial for testing hypotheses and advancing scientific understanding.
• Consensus in science should allow for diverse views and continuous challenge.
• Guidelines should reflect a multiplicity of views to avoid stagnation and ensure progress.
• Doctors need better tools to present information without compromising on truth.

"An experiment is done to test a hypothesis. If the hypothesis is sustained, you can continue to hold the hypothesis."

• Experiments are the foundation for testing and validating scientific hypotheses.

"Science is about change. If we're still saying the same things we said 30 years ago could be a problem."

• Science should evolve and adapt as new evidence and perspectives emerge.

"I think we need to learn more about how we present information. I don't think we should ever compromise on truth."

• Improving the presentation of information to doctors and patients without compromising truth is essential.

• Physicians often face uncertainty in decision-making, especially when it comes to complex conditions like appendicitis.
• There is a need to present a range of thoughts on a subject rather than a simplified consensus, acknowledging the uncertainty in determining the correct approach.

"You'd like to be able to give them the range of thoughts on a subject, acknowledging that you can't tell them which one is correct."

• Physicians need to present multiple perspectives to patients, allowing them to make informed decisions despite uncertainty.

• Different medical professionals, from family doctors to academic internists, should have a range of opinions.
• Unanimous agreements can oversimplify complex issues, potentially leading to outdated or incorrect conclusions.

"I think at a minimum, you've got to have a range of opinion in the experts in the field, and I don't think we meet that minimum."

• A diversity of expert opinions is crucial to avoid oversimplification and ensure more comprehensive decision-making.

• Algorithms assist in medical decision-making, but should not replace clinical judgment.
• Advanced healthcare professionals use algorithms as tools, integrating them with clinical insights.

"When we treat algorithms just by algorithms, then that isn't what's called clinical medicine or clinical surgery."

• Algorithms are valuable tools but should complement, not replace, the nuanced decision-making of skilled healthcare professionals.

• The COVID-19 pandemic has highlighted the challenges in managing dissenting views and the push for a uniform voice in medical recommendations.
• There is a need for open debate among experts to prevent mistakes.

"I'm not good with someone just shrieking. What I'm against is saying, because we can't have somebody shrieking, we can't have any debate."

• Open debate is necessary to avoid mistakes and ensure a comprehensive understanding of complex medical issues.

• The culture of scientific debate and discussion has weakened over time, leading to a dilution of the process.
• Consensus and unanimity have become more emphasized, potentially stifling diverse viewpoints.

"I think that's the weakness. I think that's the crucial weakness. I think inside the room, that's what's not occurring as I judge that by the product that comes out."

• The emphasis on consensus can limit the discussion of diverse and potentially valuable scientific viewpoints.

• Guidelines can sometimes overshadow individual scientific contributions, leading to a focus on consensus rather than evidence.
• The composition of guideline committees and the ability to critique their outputs need reevaluation.

"Now, if you're on the guidelines, that's your science. You're very prominent because you're on the guidelines, not that you did the science."

• The current guideline process may prioritize consensus over individual scientific evidence, necessitating a reevaluation of committee compositions.

• The cost of medical tests, such as APOB, is often misrepresented, affecting their adoption despite their potential benefits.
• Awareness among physicians is crucial to overcoming these misconceptions.

"The guidelines presented as a cost issue. That's the argument against APOB."

• Misrepresentation of costs can hinder the adoption of beneficial medical tests, highlighting the need for increased awareness among physicians.

• Short-term risk calculators may not adequately capture the long-term risks of diseases like atherosclerosis.
• A 30-year causal model provides a more comprehensive understanding of disease progression and prevention.

"I have an objective for how long a person might be able to live disease-free. And I also tend to be influenced by people like you who have taught me how long it takes for this disease to take hold."

• Long-term risk models offer a more complete picture of disease progression, aiding in more effective prevention strategies.

• APOB is identified as a causal, necessary factor in atherosclerosis, though not solely sufficient for disease development.
• Targeting necessary factors like APOB can be more effective in prevention than addressing multifactorial causes.

"Necessary means you have to have an APOB particle traffic a lipid into an artery wall. If that doesn't happen, you don't get atherosclerosis."

• Understanding necessary factors in disease development aids in focusing prevention efforts on the most impactful targets.

• The nonlinearity of disease progression and risk reduction can be counterintuitive, emphasizing the importance of early intervention.
• Compounding effects over time highlight the benefits of early preventive measures.

"Starting early pays off later. And when you start later, what you're doing, essentially, is to try and modify the disease that's already present."

• Early intervention in disease prevention can lead to significant long-term benefits, underscoring the importance of understanding nonlinearity and compounding effects.