Statins

Nazish: You know, jokingly people say that we should have started drinking water because it has got many more beneficial effects than harmful effects. We might be able in the future to take these preemptive actions, calling it preventative rather than diagnostic afterwards. Why do we need to give them only once they get a heart attack?

Nazish: Let's give it to them to prevent that heart attack.

Brent: Welcome to Death Clock. I'm your host, Brent Franson. The mission of Death Clock is to help 100 million people live ten years longer. We're trying to bring you information that helps you understand your health and the things that you need to do to live longer. So here on Death Clock, we don't run any ads. You're going to hear all of our conversations uninterrupted.

Brent: The show is supported by the app. The app is available on iOS and Android. It's Death Clock AI, so if you want to support the show or you're curious about what we're doing, you can download the Death Clock app. Today we speak with Doctor Nazish Sayed about statins and cholesterol. So if you are considering taking a statin, if you are taking a statin, if your LDL, your HDL, or your cholesterol is high, or if you've had heart attacks in the family, this is an episode for you.

Brent: There's a lot of misconception and bad information online about heart disease, cholesterol, and statins. We use this conversation to cut to the heart of what science and research tell us about cholesterol, statins, and heart disease. Doctor Sayed is currently at Stanford in the Division of Vascular Surgery and is a member of the Stanford Cardiovascular Institute.

Brent: He's an MD, PhD. He became a doctor and then completed his PhD in biomedical sciences. He's spent his career researching cardiovascular health to understand why we get heart disease and what we can do to prevent it. He's a wonderful guest. I hope you enjoy.

Brent: Doctor Nazish Sayed, welcome to the show.

Nazish: Oh, it's such a pleasure to be here.

Brent: You study cardiovascular health and have focused on that for your career. I want to focus the conversation today on statins and cholesterol, but before we do that, can you give us a sense of your bio?

Nazish: I absolutely can. It's such a pleasure to be here, Brent. My name is Doctor Nazish Sayed, and I'm an associate professor at the Stanford Cardiovascular Institute. I am an MD, PhD. I did my clinical training in cardiology and decided to pursue a PhD to understand at a molecular level why patients get heart attacks and high cholesterol.

Nazish: That led me to complete a fellowship in cardiology at Stanford and join as faculty to understand why people get heart failure or heart disease at a more granular, molecular level.

Brent: Wonderful. Let's start with the basics around cholesterol. What is cholesterol? How does it serve us? What is its positive benefit and why do we have it? Then, why are we concerned about it?

Nazish: Our bodies are meant to produce many different lipids because they are necessary for signaling pathways across organs. Lipids are part of the cholesterol system. We have high-density lipoproteins, low-density lipoproteins, and very-low-density lipoproteins. When you get blood tests done, they report your LDL, HDL, and VLDL, which often confuses people.

Nazish: Basically, it measures how many lipids and lipoproteins our bodies are producing. We need these lipoproteins for signaling between organs and to allow for smoother cardiovascular system physiology. However, environmental and dietary factors, such as eating high-fat foods, often cause us to produce more bad lipoproteins that become pathophysiological and harmful.

Nazish: Generally, the lower the density of the lipoprotein, the worse it is. LDL creates more stickiness. When we produce these lipoproteins in copious amounts due to dietary habits or smoking, they tend to stick within the vascular system.

Nazish: The vascular system is like the plumbing of our body. Arteries carry oxygenated blood away from the heart, while the venous system returns deoxygenated blood back. Lipoproteins, hormones, and enzymes flow through it. When you have these lipoproteins in excess, the blood becomes sticky.

Nazish: This sticky blood runs through the vascular system and attaches to the inner lining of these arteries, which is lined by endothelial cells. When excess lipoproteins attach, endothelial cells send out an SOS signal to immune cells to come and clear the material.

Nazish: Immune cells head toward the area to clear up the extra lipoproteins. In doing so, they get stuck to the substance itself. Over time, a buildup of immune cells, dead cells, and sticky material forms plaque, leading to vascular obstruction.

Nazish: Cholesterol is important for biosynthesis, but excess cholesterol impairs physiology and causes the body's immune system to build up plaque, obstructing the arteries—especially the narrow coronary arteries in the heart.

Nazish: This buildup cuts off the blood supply to the heart muscle. The heart muscle pumps involuntarily, and without a proper blood supply due to cholesterol buildup, it goes into ischemia.

Nazish: Lack of blood impairs muscle function and beating, leading to a heart attack, or myocardial infarction.

Brent: So to summarize, when we say cholesterol, we're referring to lipoproteins. Lipoproteins serve a necessary function for the cardiovascular system to work properly. We think about low-density lipoprotein (LDL), often called bad cholesterol, and high-density lipoprotein (HDL), called good cholesterol.

Brent: We need both in appropriate amounts for the system to run properly. When there are too many, they become sticky and build up on artery walls as they pass through.

Brent: Excessive buildup constricts blood flow, causing heart attacks and ischemia due to limited oxygen to the heart muscle. You mentioned that as lipoproteins build up in the coronary arteries, the body sends a signal calling for help.

Brent: Does that distress signal come in the form of inflammation, such as C-reactive protein or another internal inflammatory marker?

Nazish: Yes, that's correct. The SOS signal sent out by vascular cells triggers chronic inflammation over time. That internal inflammation prompts immune cells to respond and try to repair the mechanism.

Nazish: Immune cells like monocytes and macrophages, which are white blood cells, patrol our circulatory system to patch and repair areas. Unknowingly, they become part of plaque formation when platelets and white blood cells attach to the sticky material.

Nazish: Excess lipoproteins trigger an immune response, and chronic underlying inflammation—driven by diet, lack of exercise, or smoking—leads to plaque buildup.

Brent: It sounds like when firefighters or police show up in response to inflammation, they are trying to help, but much like a firefighter breaking windows or spraying water, their presence can inadvertently contribute to the damage.

Brent: It isn't targeted enough to exclusively help without side effects.

Nazish: You put it well; there is collateral damage. In trying to clean up, the immune response leads to plaque formation, obstruction, and potentially irreversible heart damage.

Brent: Online discussions often question the validity of LDL and HDL as markers—whether LDL is truly bad cholesterol and whether higher HDL is always better.

Brent: Are we undergoing a shift in how we view these markers, or is that mostly pop-science speculation?

Nazish: To be direct, that is pop-science nonsense. Decades of research across animal models and human populations prove that LDL, HDL, and VLDL contribute directly to plaque formation and heart disease.

Nazish: I would not give weight to videos questioning these mechanisms, as the science has been repeatedly validated over decades in millions of people.

Brent: So higher LDL correlates with higher risk for heart disease, while higher HDL correlates with lower risk. Why is HDL considered good cholesterol?

Nazish: Without getting overly technical, our cells need lipids and steroids for normal functioning and signaling pathways. Small molecules rely on lipid rafts to enter and exit cells efficiently, a function enabled by lipoproteins.

Nazish: That is why doctors recommend essential fatty acids or vitamin E for normal cellular function. Cholesterol synthesis is an important part of our normal body system, particularly in the cardiovascular system.

Nazish: When cholesterol synthesis becomes imbalanced, LDL and HDL move in opposite directions. To keep cholesterol in check, doctors recommend raising good cholesterol levels through diet and targeted supplements.

Nazish: Cutting down on sugar and saturated fats helps lower bad cholesterol. Maintaining a healthy check depends on the balance between good and bad cholesterol.

Brent: Is it fair to say that HDL helps clear bad cholesterol from the system, perhaps by processing it through the liver, or does it function through another mechanism?

Nazish: Partly, yes. It helps clear low-density lipoproteins, though research is ongoing to fully map how increasing HDL removes bad cholesterol and alters systemic lipid chemistry.

Nazish: It is accurate to say it assists in balancing cholesterol by aiding the removal of bad cholesterol, and further studies continue to explore how to optimize this balance to combat atherosclerosis.

Brent: On a standard lipid panel, LDL is the primary marker of interest, alongside HDL, VLDL, and total cholesterol. We also hear more about ApoB (Apolipoprotein B).

Nazish: So that's a VL DL, which is a very low density. Yes.

Brent: Some experts suggest ApoB is a more accurate predictor of heart disease risk than LDL. One doctor mentioned focusing primarily on ApoB via a simple blood test. What is the distinction between ApoB and LDL?

Brent: He just cares about ApoE. B that's that's the marker that he's. And that's also a very simple blood test, although not ordered as commonly. It's a new marker that we're looking at. And so what do you think about the distinction between apolipoprotein B, A, B and LDL, the quote unquote bad cholesterol?

Nazish: As research progresses, we are discovering genetic factors that explain why some individuals have high cholesterol despite maintaining healthy lifestyles. ApoB provides valuable insight into genetic risk, as confirmed by knockout animal models.

Nazish: ApoB testing is grounded in solid science. As research advances, new biomarkers offer greater precision in identifying individuals at higher risk of developing elevated cholesterol and atherosclerosis. Although ApoB is not yet part of a standard blood panel, it is becoming more recognized.

Nazish: ApoB variations can indicate a higher genetic propensity for elevated cholesterol. Researchers are also examining other lipid markers, such as Lp(a) and various subfractions, to build a more comprehensive picture.

Nazish: Genetic background can significantly influence cardiovascular risk. Certain populations show higher rates of hypercholesterolemia due to specific genetic polymorphisms, such as variants in the ApoB gene, despite adhering to healthy habits.

Nazish: Over time, standard lipid panels will likely incorporate these refined genetic markers to enable more personalized risk assessments.

Brent: To summarize: standard lipid panels backed by decades of research remain essential. For additional context, patients can ask their doctor for an ApoB test via routine blood work.

Brent: Another genetic marker is Lp(a), or Lipoprotein(a), which remains largely static regardless of diet or exercise changes. If it's elevated, it indicates an underlying genetic risk for heart disease.

Brent: Would you place Lp(a) alongside ApoB as valid, clinically relevant biomarkers rather than speculative markers?

Nazish: Yes. Lp(a) plays a significant role. Extensive research demonstrates that certain demographic groups, such as South Asian populations, display higher average Lp(a) profiles, contributing to an elevated baseline risk for high cholesterol and cardiovascular disease.

Nazish: While further research will help integrate these markers into standard practice, standard measures like LDL and HDL remain robust initial indicators of cardiovascular health.

Nazish: When someone has elevated cholesterol, initial steps include increasing physical activity and adjusting diet. Exploring markers like ApoB and Lp(a) provides deeper insight for developing a long-term preventive management plan.

Brent: Standard lipid panels measuring total cholesterol, LDL, and HDL remain foundational. Adding ApoB and Lp(a) testing offers additional clinical detail. Before discussing statins, let's address lifestyle factors like diet, exercise, and sleep.

Brent: It is often overlooked that the vast majority of circulating cholesterol is produced endogenously by the body, independent of dietary intake.

Brent: Why do lifestyle behaviors like diet and exercise significantly influence cholesterol management if most cholesterol is synthesized internally?

Nazish: That is an important distinction. While most cholesterol is synthesized endogenously, dietary choices remain critical—especially for individuals with genetic predispositions.

Nazish: Atherosclerosis risk can stem from genetic polymorphisms that elevate baseline cardiovascular cholesterol load. Dietary management helps prevent compounding factors, such as combining high genetic risk with a high-fat diet.

Nazish: Managing intake prevents adding dietary stress to an underlying genetic tendency. Past guidelines discouraged butter in favor of synthetic alternatives, but updated research indicates real butter in moderation supports essential fatty acid synthesis better than processed substitutes.

Nazish: Eggs can be included as part of a balanced diet. Egg whites provide protein without the concentrated cholesterol found in yolks. Animal models demonstrate that high-fat diets lead to fatty liver and elevated systemic cholesterol over time, even without genetic variants.

Nazish: Beyond diet, regular exercise improves skeletal and cardiac muscle function, helping break down and clear circulating lipoproteins while reducing oxidative stress.

Nazish: Combining balanced nutrition and exercise with avoiding external hazards like smoking protects vascular cells and preserves cellular signaling integrity.

Nazish: Overall, combining lifestyle management, physical activity, and avoiding harmful exposures helps maintain optimal systemic cellular health.

Brent: Is there a direct proportion between lifestyle factors and internal production? If roughly 75% of cholesterol is generated endogenously, does lifestyle account for controlling the remaining 25%?

Nazish: Controlling that modifiable 25% is vital to avoid adding to endogenous production. In severe inherited conditions like familial hypercholesterolemia, dietary management is essential to lower overall systemic load.

Nazish: Elevated cholesterol impacts not only the cardiovascular system, but also organ function across the liver and other tissues.

Brent: This brings us to medical intervention. Since body chemistry accounts for most cholesterol production, statins are widely prescribed to help regulate endogenous production.

Brent: Is moderate internal production the primary mechanism by which statins lower overall cholesterol?

Nazish: Precisely. Statins are among the most frequently prescribed medications globally alongside antibiotics. They serve as a critical tool for patients with prior cardiovascular events to prevent further vascular thickening.

Nazish: Statins inhibit HMG-CoA reductase, a key rate-limiting enzyme in hepatic cholesterol synthesis. Inhibiting this enzyme directly decreases endogenous production.

Nazish: Research demonstrates that statins offer pleiotropic benefits beyond lowering lipid numbers, including anti-inflammatory properties and improving mechanical transduction within cardiac tissue.

Nazish: In short, statins exert powerful protective effects while primarily controlling systemic cholesterol levels.

Brent: What side effects are associated with statins, and why might someone hesitate to start therapy?

Nazish: Statins maintain a strong safety profile over extensive clinical use. Common minor side effects include mild nausea and, in some cases, skeletal muscle soreness or inflammation.

Nazish: Some long-term users report localized myalgia or tenderness, particularly in large muscle groups like the gastrocnemius.

Nazish: Severe adverse events requiring hospitalization are rare. The broad therapeutic value outweighs side effect risks for most patients.

Nazish: Newer-generation statins continue to optimize safety profiles and minimize muscle-related discomfort.

Brent: I spoke with a physician who half-jokingly suggested that given the high prevalence of heart disease in certain genetic populations, routinely starting low-dose statins by age 35 could prevent widespread cardiovascular events.

Brent: There is logic behind preventive interventions for high-risk demographics.

Nazish: There is truth to that perspective. South Asian populations, for example, demonstrate elevated rates of early cardiovascular disease linked to Lp(a) variants. Proactive statin therapy can help prevent plaque formation before symptoms appear.

Nazish: People often wait for an acute event before seeking treatment. Expanding research into genetic drivers will help us shift toward preventive cardiology rather than reactive care.

Nazish: Rather than waiting for a cardiac event to start treatment, identifying early risk factors allows us to prescribe statins proactively to prevent heart attacks.

Brent: How should we think about disease burden versus isolated biomarkers? High LDL or ApoB indicates elevated risk, but it isn't a direct diagnosis of heart disease on its own.

Brent: For example, I have elevated LDL and ApoB, but my CCTA scan shows zero calcium or plaque buildup in my coronary arteries.

Brent: I have no phenotypic disease present. In cases with visible arterial plaque, starting a statin is clear-cut. But when biomarkers are high without detectable plaque, how should clinicians weigh statin therapy?

Brent: Distinguishing between predictive biomarkers and active structural disease is an important distinction when considering long-term care decisions.

Nazish: That is a fair question. Current medical guidelines rely on population data showing a strong statistical link between elevated cholesterol and heart attacks, rather than tailored individual assessments for every patient.

Nazish: While you received a CCTA, routine advanced imaging is not universally ordered due to resource and access constraints. Physicians rely on broad population risk models to initiate treatment.

Nazish: Statins are prescribed based on demonstrated population risk reductions. Moving toward precision medicine will ideally allow detailed individual cardiovascular phenotyping for every patient.

Nazish: Systemic limitations in healthcare prevent universal advanced imaging at this time, but expanding genetic and structural profiling will help refine risk categories.

Nazish: Imaging confirming clear arteries is reassuring. Some populations maintain high cholesterol without developing plaque. Overall, however, statins remain a low-risk intervention backed by robust population evidence.

Brent: So healthcare systems rely on standard lipid panels because they efficiently categorize risk at scale. Statins offer proven benefits with low adverse effect profiles across large populations.

Brent: While effective for population health, this approach may miss individual nuances unless paired with detailed diagnostic testing.

Brent: A CT scan provides direct visual evidence of whether disease is physically present, moving beyond reliance on surrogate markers alone.

Brent: While advanced screening is ideal for individual decision-making, population-level management continues to rely on lipid markers and statin therapy as the primary standard.

Brent: If patients have access to advanced diagnostics through their physicians, it provides valuable clinical clarity.

Nazish: Absolutely. You nailed it. Well, Brent.

Brent: What drives public skepticism around statins in online media? Some claim statins are overprescribed or cause significant harm. How do you distinguish fact from fiction regarding statin therapy?

Nazish: I have seen those claims. Having researched statins extensively, I can emphasize that ongoing scientific work continues to uncover further therapeutic benefits.

Nazish: Beyond lipid lowering, statins exert beneficial systemic effects, including improving blood flow sensing and vascular responsiveness throughout the arterial tree.

Nazish: Blood vessels constantly sense shear stress and mechanical forces from circulating blood, sending signals to endothelial cells to adapt vessel tone.

Nazish: Our research shows that statins enhance mechanical sensing and chemical signaling in blood vessels, promoting healthy vasodilation.

Nazish: Vasodilation increases oxygenated blood delivery to skeletal muscle and heart tissue. Sensational social media claims often lack rigorous scientific backing.

Nazish: Peer-reviewed literature on NIH PubMed contains robust, multi-year clinical trials involving thousands of patients, consistently confirming the broad health benefits of statin therapy.

Nazish: I encourage patients to rely on reputable scientific evidence. Statins effectively reduce LDL while delivering valuable anti-inflammatory and vascular benefits.

Brent: Statins have been thoroughly studied over decades. Double-blind, randomized controlled trials consistently compare statin therapy against placebos.

Brent: Trial data demonstrates significant reductions in cardiovascular and all-cause mortality among patients receiving active statins compared to control groups.

Brent: The evidence is conclusive: individuals with high LDL face lower mortality risk when taking statin therapy.

Nazish: Absolutely. This is supported by rigorous research, and I personally take a statin because the therapeutic benefits are well established.

Brent: Even with a zero CCTA score, an elevated LDL and ApoB profile at age 43 warrants serious consideration of preventive therapy, given the high prevalence of heart disease.

Brent: Taking a low-dose statin proactively can reduce long-term risk. How would you advise a patient presenting with high LDL but minimal visual plaque?

Brent: If somebody is ahead of the curve and there's there isn't any plaque build up or it's a very small amount of build up, how would you think? How would you advise on a, on a statin?

Nazish: In that clinical scenario, I would opt for low-dose statin therapy to lower circulating LDL and mitigate future cardiovascular disease risk.

Nazish: Systemic high cholesterol also affects metabolic function across hepatic and digestive organs. Initiating low-dose statin therapy offers long-term systemic protection.

Nazish: Beyond protecting coronary arteries, suppressing excess cholesterol prevents lipid accumulation in hepatic tissues that leads to fatty liver disease.

Nazish: In my clinical view, starting low-dose therapy for elevated LDL effectively inhibits synthesis and reduces systemic cholesterol levels.

Brent: If someone has elevated LDL, discussing statins with their primary care physician is a reasonable step to gather personalized medical advice.

Brent: What dietary patterns do you follow or recommend to manage cholesterol health?

Nazish: I focus on increasing dietary fiber through leafy green vegetables. You do not need to eliminate meat entirely, but higher dietary fiber assists in binding and clearing excess cholesterol through digestion.

Nazish: A significant amount of cholesterol is excreted through the digestive system when supported by adequate dietary fiber, keeping it from accumulating in organs.

Nazish: In addition to leafy greens, over-the-counter antioxidants like vitamins C and E provide general anti-inflammatory support alongside consistent meal timing.

Nazish: Limiting ultra-processed fast foods is beneficial because they lack dietary fiber. Maintaining a sustainable long-term pattern allows room for occasional cheat meals.

Nazish: The key takeaway for dietary cholesterol management is maximizing dietary fiber and green vegetables to enhance natural clearance pathways.

Brent: Thank you for your time. Where can listeners find more trustworthy information or follow your work?

Nazish: The American Heart Association is an excellent resource for evidence-based information on cardiovascular disease, vascular health, and cholesterol guidelines.

Nazish: I also recommend speaking directly with your primary care physician to discuss preventive options and personalized testing.

Nazish: Your doctor can help guide you through individual health decisions.

Brent: Doctor Sayed, thank you so much for your time and for sharing your expertise.

Nazish: It was a pleasure to join you, Brent.