#23 - Tom Dayspring, M.D., FACP, FNLA – Part IV of V: Statins, ezetimibe, PCSK9 inhibitors, niacin, cholesterol and the brain
Dr. Thomas Dayspring, a renowned lipidologist, joins Peter Attia, MD, in Part IV of their series to discuss the history and current use of drugs for cardiovascular disease prevention, including statins, ezetimibe, PCSK9 inhibitors, fibrates, fish oil, and niacin. They also delve into cholesterol's role in brain health and the futility of using CKs and LFTs for statin adverse effects.
Deep Dive Analysis
14 Topic Outline
Introduction to Lipid-Lowering Drugs and Episode Topics
Early Cholesterol-Lowering Drugs: Niacin and Bile Acid Sequestrants
Statins: Discovery, Mechanism, and Early Clinical Trials
Limitations of Short-Term Clinical Trials in Atherosclerosis
Lessons from Triparinol: The Importance of Cholesterol Synthesis Pathways
Statin Selectivity and the Role of LDL Receptor Upregulation
Ezetimibe (Zetia): Mechanism of Action and Trial Challenges
Fibrates: Fenofibrate and Gemfibrozil, Their Mechanisms and Trials
Fish Oil: EPA vs. DHA for Triglyceride and ApoB Lowering
Niacin Revisited: Historical Trials, Side Effects, and Efficacy Debate
PCSK9 Inhibitors: Genetic Discovery and Remarkable Clinical Impact
Cholesterol, Statins, and Brain Health: Desmosterol as a Biomarker
Statin Selection, CNS Penetration, and Individualized Therapy
Futility of CK and LFT Monitoring for Statin Toxicity
8 Key Concepts
Bile Acid Sequestrants
A class of drugs that bind to bile acids in the gut, forcing the liver to use more endogenous cholesterol to make new bile acids. This process depletes the liver's cholesterol pool, leading to increased LDL receptor expression and subsequent lowering of cholesterol metrics.
HMG-CoA Reductase
An enzyme early in the cholesterol synthesis pathway. Statins inhibit this enzyme, which reduces cholesterol production and, more importantly, causes the liver to upregulate LDL receptors to scavenge more cholesterol from the blood, thus lowering LDL cholesterol.
LDL Receptor Upregulation
The process by which liver cells increase the number of LDL receptors on their surface. This mechanism, enhanced by drugs like statins, ezetimibe, bile acid sequestrants, and PCSK9 inhibitors, is crucial for safely and effectively reducing clinical cardiovascular events by clearing ApoB-containing lipoproteins from the bloodstream.
Neiman-Pick C1-like protein (NPC1L1)
A protein that facilitates the absorption of sterols, including cholesterol, in the gut and also allows the liver to reabsorb cholesterol from bile. Ezetimibe's main mechanism of action is inhibiting this protein, thereby reducing cholesterol entry into enterocytes and the liver.
Macrophage Reverse Cholesterol Transport (RCT)
A functional aspect of HDL where it removes cholesterol from foam cells (cholesterol-laden macrophages) in the arterial wall. This process, which involves ABC transporters like ABCA1 and ABCG1, is critical for delipidating plaque but has no direct relationship to serum HDL cholesterol levels.
Fibrates
A class of drugs, including fenofibrate and gemfibrozil, that primarily reduce the synthesis of VLDL particles in the liver by depleting triglyceride pools. They can lower LDL particle count and have shown benefits in reducing microvascular endpoints in diabetic patients.
PCSK9
A protein that binds to LDL receptors and promotes their degradation, preventing them from recycling back to the cell surface. Inhibiting PCSK9 (with drugs like Repatha and Praluent) leads to a longer half-life for LDL receptors, dramatically enhancing the clearance of ApoB particles from the blood.
Desmosterol
A precursor molecule in the cholesterol synthesis pathway, particularly prominent in the brain's cholesterol synthesis. Serum desmosterol levels can serve as a biomarker for brain cholesterol synthesis, and low levels, often due to statin use, have been correlated with cognitive impairment.
10 Questions Answered
Niacin was used for a long time, but the first drug with outcome evidence for lowering cholesterol and reducing clinical events was the bile acid sequestrant, which works by forcing the liver to use endogenous cholesterol to make new bile acids.
Statins inhibit HMG-CoA reductase, an enzyme in the cholesterol synthesis pathway, leading to reduced cholesterol production and, more importantly, upregulation of LDL receptors in the liver, which enhances the clearance of ApoB particles from the bloodstream.
These trials are often short (e.g., 5 years) for a disease like atherosclerosis that develops over decades, making it challenging to demonstrate a significant impact on hard outcomes like mortality within the trial's limited duration.
Triparinol lowered cholesterol but caused severe side effects like atherosclerosis and cataracts because it inhibited a late step in cholesterol synthesis, leading to the accumulation of desmosterol, a molecule with other harmful roles in the body, highlighting the importance of understanding the entire synthetic pathway.
Ezetimibe blocks the Neiman-Pick C1-like protein (NPC1L1), which reduces the absorption of cholesterol from the intestine and prevents the liver from reabsorbing cholesterol from bile, leading to depletion of liver cholesterol and subsequent upregulation of LDL receptors.
Fibrates work best in patients with elevated ApoB and elevated triglycerides, particularly diabetics, by reducing VLDL particle synthesis and potentially improving microvascular endpoints like retinopathy, amputations, and renal disease.
Despite lowering atherogenic ApoB and raising HDL-C, niacin trials failed to reduce clinical events and showed increased toxicity, possibly due to adverse effects like worsening insulin resistance and other hematologic disruptions.
PCSK9 inhibitors prevent the degradation of LDL receptors, allowing more receptors to recycle to the liver cell surface. This dramatically enhances the clearance of ApoB particles (LDL and remnants), leading to very low LDL cholesterol levels and significant event reduction even in patients already on statins.
While statins generally improve vascular health, over-suppressing cholesterol synthesis in the brain in some individuals could contribute to cognitive impairment. Serum desmosterol levels can serve as a biomarker for brain cholesterol synthesis, with low levels indicating excessive suppression.
According to Tom Dayspring, CK elevation is generally not a useful biomarker for statin toxicity unless it's extremely high (e.g., 10,000-fold elevation), and LFTs also have no correlation with statin toxicity. These tests often cause unnecessary alarm and lead patients to stop beneficial statin therapy.
37 Actionable Insights
1. Individualize Statin Therapy
Tailor statin therapy by carefully selecting patients based on their individual risk profiles, avoiding extreme views of universal use or complete avoidance.
2. Drugs as Tools Mindset
Adopt a mindset where drugs are viewed as tools, aiming to have a broad range of therapeutic options and understanding the appropriate use and limitations of each.
3. Educate on Lipids and Statins
Physicians should thoroughly educate themselves and their patients on the complexities of cholesterol and statin therapy to counter misinformation and ensure appropriate treatment decisions.
4. Use Biomarkers, Target ApoB
Utilize biomarkers and advanced risk assessment tools to precisely define an individual’s disease risk and effectively attack atherosclerosis by focusing on ApoB levels.
5. Prioritize LDL Receptor Upregulation
When selecting lipid-lowering drugs, prioritize those that enhance LDL receptor expression (e.g., statins, ezetimibe, PCSK9 inhibitors) as this mechanism has consistently shown to safely reduce clinical events.
6. Maintain Statins for High-Risk
Do not discontinue statins in high-risk patients, as these drugs are proven to save lives when directed at the right patients at the right times, despite common misconceptions.
7. Don’t Monitor CK for Statins
Do not routinely monitor CK levels for statin toxicity; instead, rely on myopathic symptoms like aches or weakness to determine if a statin should be stopped, as minor CK elevations are not indicative of toxicity.
8. Don’t Monitor LFTs for Statins
Do not routinely monitor liver function tests (aminases) to judge statin toxicity or liver issues caused by statins, as there is no established correlation in package inserts or guidelines.
9. Monitor Serum Desmosterol
Monitor serum desmosterol levels as a biomarker for brain cholesterol synthesis, especially in patients on statins, as statin use is the biggest reason for suppressed desmosterol synthesis.
10. Adjust Statin for Low Desmosterol
If serum desmosterol levels fall below a certain threshold, consider adjusting statin therapy, as further statin use may not provide additional ApoB lowering benefit and could indicate excessive cholesterol synthesis inhibition.
11. Low-Dose Statin + Ezetimibe
Consider using a low-dose statin combined with ezetimibe to achieve similar ApoB reduction as high-dose statins, potentially with fewer side effects and less suppression of cholesterol synthesis in the brain.
12. Choose Hydrophilic Statins for CNS
If concerned about statins crossing the blood-brain barrier and potentially affecting the brain, choose hydrophilic statins like pravastatin, rosuvastatin, or pitavastatin, as they penetrate less easily than lipophilic ones.
13. Measure Key Sterol Biomarkers
When administering lipid-lowering therapy, measure phytosterols, stanols, and desmosterol to gain a comprehensive understanding of cholesterol absorption and synthesis pathways.
14. Reduce Phytosterols with Ezetimibe
If phytosterols are considered injurious, ezetimibe is the only way to effectively prevent their absorption into the body.
15. Ezetimibe for Reverse Cholesterol Transport
Utilize ezetimibe as it is the most effective pharmacologic agent for increasing the excretion of cholesterol from the body via stool, thereby supporting reverse cholesterol transport.
16. Ezetimibe for Normal Absorbers
Consider ezetimibe even for patients who are not hyperabsorbing cholesterol, as it can still provide additional ApoB-lowering and help keep phytosterols out of the body, mimicking a genetic model of longevity.
17. Assess Phytosterols for Ezetimibe
To identify optimal candidates for ezetimibe, assess phytosterols or other absorption proxies, as the drug specifically targets cholesterol absorption.
18. Fenofibrate for Elevated ApoB/Triglycerides
Consider fenofibrate for patients with elevated ApoB and elevated triglycerides, especially if statins or ezetimibe have not normalized these levels.
19. Fibrates for Diabetic Microvascular Complications
Consider fibrates for diabetic patients to potentially reduce microvascular complications such as retinopathy, amputations, peripheral neuropathy, and renal disease, based on secondary outcome data.
20. Choose Fenofibrate with Statins
When using a fibrate in combination with a statin, choose fenofibrate over gemfibrozil to avoid drug interactions that can raise statin levels and increase the risk of myositis and rhabdomyolysis.
21. Monitor Omega-3s, Supplement DHA
Monitor omega-3 levels in patients, as not everyone can convert EPA to DHA, and DHA is crucial for brain health and other functions, potentially requiring direct supplementation.
22. High-Dose EPA for ApoB Lowering
If the primary goal is additional ApoB lowering, consider prescribing high-dose EPA.
23. Stop Smoking, Manage Blood Pressure
Advise patients to stop smoking and actively manage their blood pressure, as these are foundational interventions for preventing heart disease.
24. Don’t Fear Very Low LDL
Do not be concerned that very low LDL cholesterol levels (e.g., 10-30 mg/dL) will impair hormone production or lead to other diseases, as genetic studies show no such deficiencies.
25. Awareness of Statin Cognitive Impairment
Be aware that cognitive impairment is listed as a potential side effect in the FDA package insert for all statins, indicating it can occur in some patients.
26. Discontinue Statins for Cognitive Impairment
If a patient complains of cognitive impairment while on a statin, consider discontinuing the drug, as it is a potential cause and often the first explanation for such symptoms.
27. Thoughtful Statin Use
Continue to use statins as the backbone of antilipid therapy, but apply them thoughtfully and with individualized consideration for each patient’s unique profile and potential sensitivities.
28. Migrate Patients to Crestor
Consider slowly migrating patients from Lipitor to Crestor, especially if they tolerate it well, as a preferred statin choice based on current practice trends.
29. Pravastatin for Statin Intolerance
Consider using pravastatin more frequently for patients who do not tolerate other statins or experience slight CK elevations, even without pain, due to its favorable profile.
30. Understand Lab Test Mechanics
Gain a deeper understanding of how laboratory tests are performed to better interpret results and identify potential blind spots in patient assessment, enhancing clinical acumen.
31. Alternative Drugs for Statin Intolerance
For highly statin-intolerant patients or those with specific conditions where statins have not shown benefit (e.g., aortic stenosis, chronic renal failure), consider alternative lipid-lowering therapies.
32. Statin Reduction with Ezetimibe/PCSK9i
If concerned about statin side effects or over-suppression of cholesterol synthesis, consider reducing statin dose and adding ezetimibe or, if affordable and indicated, a PCSK9 inhibitor.
33. Skepticism on Niacin Efficacy
Be skeptical of claims extolling niacin’s efficacy for cardiovascular outcomes, as current evidence from well-designed trials has not consistently demonstrated positive results.
34. Niacin: Be Aware of High Doses
If considering niacin, be aware that clinical trials used massive pharmacological doses (e.g., 4 grams/day of immediate release), which are associated with significant side effects like flushing and pruritus.
35. Caution with Immediate-Release Niacin
Exercise caution with immediate-release niacin due to its high doses and common side effects, which make it largely intolerable for most people.
36. Understand PCSK9 Mechanism
Understand that PCSK9 degrades LDL receptors, and inhibiting it (with PCSK9 inhibitors) improves LDL clearance, leading to lower LDL and reduced cardiovascular events, providing a strong rationale for its use.
37. Target Liver for Cholesterol Synthesis
Ideally, cholesterol synthesis inhibition should be targeted primarily to the liver, as it is the main tissue for upregulating LDL receptors and clearing LDL particles, minimizing inhibition in other tissues.
8 Key Quotes
The only drugs that have ever shown to both reduce cholesterol, but more importantly, reduce events, have either been in isolation or in compounds or in combination, where they are enhancing clearance.
Tom Dayspring
The industry is now going to always be a victim of the success of statins. It is unethical to take high-risk patients and take them off statins, despite what the internet wants to tell you, that statins are evil and all that nonsense, which I don't want to get into.
Peter Attia
If you're a big believer in this reverse cholesterol transport process, which I've certainly expounded on now, what is the number one pharmacologic agent that increases the amount of cholesterol that's winding up in your toilet bowl because it's in your stool? ... Azetamide by far.
Tom Dayspring
I always made the case, what? Fibrates reduce amputations, neuropathic ulcers, improve renal disease, save your eyes. Why the hell are you not on a fibrate if you're a diabetic, you know?
Tom Dayspring
I just don't like people out there who want to extol niacin. Niacin, fine, but don't start telling them niacin has a lot of data. It's got zero data.
Tom Dayspring
If you tell me you've never seen cognitive impairment in a patient you've started on a statin, you're a liar or you're a fool or you're not questioning your patients when they come back because it does occur.
Tom Dayspring
You know when you should stop a statin with a CK? When there's like a 10,000 fold elevation of CK, then you might start to worry.
Tom Dayspring
I mean, if the listener is sort of saying, what the hell is the takeaway from this? I think it's a couple things. One is statins are not bad. Statins are still the mainstay backbone of antilipid therapy. Be thoughtful about which ones you use.
Peter Attia