#03 - Ron Krauss, M.D.: a deep dive into heart disease
Guest Dr. Ron Krauss, a globally recognized lipidologist, discusses atherosclerosis, the causal role of LDL and inflammation, and the nuances of lipid-lowering therapies. He delves into the distinction between LDL-C and LDL-P, the impact of metabolic syndrome, and the complex evidence surrounding statins and niacin.
Deep Dive Analysis
15 Topic Outline
Pathophysiology and Early Onset of Atherosclerosis
Understanding Lipids, Cholesterol, Lipoproteins, and ApoB
LDL Particle Size vs. Particle Number: Which Drives Risk?
Metabolic Syndrome and Atherogenic Dyslipidemia
Evidence for LDL as a Causal Factor in Heart Disease
Genetic Insights: Familial Hypercholesterolemia and PCSK9 Mutations
LDL Particle Residence Time and Remnant Lipoproteins
Safety of Very Low LDL Levels from Genetic Data
Statin Mechanisms, Off-Target Effects, and Adverse Events
Statin Pharmacogenetics and Personalized Treatment
Role of Inflammation in Atherosclerosis and Statin Pleiotropic Effects
Statin Efficacy in Primary Prevention for Men and Women
Critique of Past ATP Cholesterol Guidelines
Revisiting Niacin as a Therapeutic Option
The HDL Paradox and Niacin's Specific Effects
7 Key Concepts
Atherosclerosis Pathophysiology
A 'smoldering inflammatory condition fueled by lipids' that begins in childhood as fatty streaks and can progress to more complex plaques. This process involves cholesterol buildup, oxidative changes, inflammation, and potential plaque rupture, ultimately leading to acute events like heart attack and stroke.
Lipoproteins
Complex spherical macromolecules that act as 'packages' or 'trucks' to transport lipids, including cholesterol and triglycerides, through the bloodstream. They are necessary because cholesterol is hydrophobic and cannot dissolve directly in water.
LDL Cholesterol (LDL-C)
A measure of the total mass of cholesterol contained within low-density lipoprotein (LDL) particles. While commonly used clinically, it can sometimes under-represent the actual number of atherogenic particles.
LDL Particle Number (LDL-P) / ApoB
ApoB is a key protein, with one molecule per LDL particle, making it a good measure of the total *number* of LDL particles. The number of particles is considered a more direct and accurate predictor of cardiovascular risk than LDL-C, especially in cases of discordance.
Atherogenic Dyslipidemia
A constellation of lipid changes characterized by higher triglycerides, lower HDL cholesterol, and a predominance of smaller, more atherogenic LDL particles. This pattern is often associated with the metabolic syndrome.
Mendelian Randomization
A research principle that uses naturally occurring genetic variants, which are randomly distributed in the population, as 'natural randomized trials.' This method helps to establish the causal effect of a modifiable risk factor, like LDL cholesterol, on disease outcomes by observing the association between the genetic variant and the disease.
HDL Paradox
The observation that pharmacological interventions designed to raise HDL cholesterol levels (e.g., niacin, CETP inhibitors) have generally failed to reduce cardiovascular disease risk in clinical trials, and in some cases, have even shown adverse effects, suggesting that simply increasing HDL-C levels is not necessarily beneficial.
8 Questions Answered
Atherosclerosis is the underlying process, starting in childhood as fatty streaks and progressing to more malignant plaques fueled by lipids and inflammation, ultimately leading to arterial blockage and acute events.
Sudden death is estimated to be the first presentation for about 30% or more of individuals, highlighting its nature as a 'silent killer' due to the lack of premonitory symptoms.
LDL-C measures the total mass of cholesterol within LDL particles, while LDL-P or ApoB (a protein on each particle) measures the actual number of these particles, with the particle number being a more direct indicator of atherosclerotic risk.
While particle size can be a marker for metabolic syndrome, the data strongly suggest that cardiovascular risk tracks more closely with the number of LDL particles (LDL-P or ApoB), especially in cases of discordance between LDL-C and LDL-P.
Genetic evidence from individuals with naturally very low LDL (e.g., due to PCSK9 loss-of-function mutations) suggests that lifelong low LDL is safe and protective against heart disease, providing confidence in the safety of pharmacologically lowering LDL, though long-term effects of drugs are still being studied.
No, statins also have pleiotropic effects, including anti-inflammatory actions (e.g., lowering C-reactive protein) and potentially improving endothelial health, which contribute to their overall cardiovascular benefit beyond just LDL lowering.
Major clinical trials (AIM-HIGH, HPS2) tested niacin primarily as an HDL-raising agent in patients already on intensive statin therapy, and these trials showed no additional cardiovascular benefit, leading to the conclusion that simply raising HDL-C is not protective.
Niacin can be beneficial for patients with high levels of small and very small LDL particles, and those with elevated Lp(a), as it effectively lowers both, complementing the effects of statins which primarily target medium and larger LDL particles.
21 Actionable Insights
1. Measure LDL Particle Number
Measure LDL particle number (LDL-P or ApoB) instead of just LDL cholesterol (LDL-C) to accurately assess cardiovascular risk, as the particle itself, not just the cholesterol mass, is the causal agent for plaque formation.
2. LDL is a Causal Factor
Recognize that LDL is a causal factor for heart disease, and lowering it is generally beneficial for reducing risk. However, remember that LDL particle number is the true causal agent, and LDL-C alone may not always reflect risk or treatment benefit.
3. Target Very Low LDL
Consider very low LDL levels (e.g., 10-20 mg/dL) as safe and beneficial, based on genetic evidence from individuals with lifelong low LDL due to PCSK9 loss-of-function mutations who do not develop heart disease.
4. Address Metabolic Syndrome
Actively address metabolic syndrome, characterized by high triglycerides, low HDL cholesterol, and a predominance of smaller LDL particles, as it is a significant underlying factor for cardiovascular disease.
5. Reduce Visceral Fat
Focus on reducing visceral fat, especially around internal organs, as it is a prevalent underlying factor contributing to metabolic syndrome and overall cardiovascular disease risk.
6. Monitor Inflammatory Markers (CRP)
Monitor C-reactive protein (CRP) levels as a marker for inflammatory risk, and aim to lower both LDL (or LDL-P/ApoB) and CRP for maximal cardiovascular protection, as they each contribute to risk.
7. Learn Heart Disease Signs
Educate yourself on the first signs of heart disease, as it is often a ‘silent killer’ with no premonitory symptoms, and early recognition can be critical for intervention.
8. Minimize Lipoprotein Residence Time
Be aware that the length of time lipoproteins circulate in the blood (‘residence time’) is critical; longer circulation, especially of smaller or remnant particles, increases their opportunity to cause arterial damage.
9. Monitor Glucose on Statins
If taking statins, monitor glucose levels regularly, as statins can increase the risk of developing diabetes, particularly in women and with higher doses.
10. Consider Pitavastatin for Myalgia
If experiencing statin-induced myalgias or concerned about diabetes risk, discuss trying pitavastatin (Livolo) with your doctor, as it appears to have a lower association with diabetes risk and potentially fewer muscle side effects.
11. Don’t Abandon Statins Prematurely
Do not abandon statins in favor of PCSK9 inhibitors unless truly statin intolerant, as statins provide additional anti-inflammatory and endothelial health benefits not necessarily replicated by PCSK9 inhibitors.
12. Niacin for Specific Lipid Profiles
Consider niacin as a therapeutic option for patients with high Lp(a) and/or a high number of small LDL particles, especially if statin intolerant or if PCSK9 inhibitors are not an option, as it specifically targets these risk factors.
13. Don’t Rely on HDL Raising
Do not rely on simply raising HDL cholesterol levels as a primary strategy for cardiovascular protection, as clinical trials have shown that increasing HDL alone does not consistently translate to reduced event risk.
14. PCSK9 Inhibitors for High Risk
If you have very high LDL and are statin intolerant, or if maximum statin therapy is insufficient, consider PCSK9 inhibitors as a potent option for lowering LDL and Lp(a).
15. Statin Caution: APOE4 Carriers
If you are an APOE4 gene carrier, exercise greater caution and discuss statin use with your doctor, due to theoretical concerns about potential interactions with brain cholesterol transport, though conclusive evidence is lacking.
16. Re-evaluate Elderly Statin Use
For elderly patients (over 75-80) on high-dose statins, discuss with your doctor whether reducing the dose or discontinuing might be appropriate, weighing the benefits against potential long-term risks like sarcopenia.
17. Address VLDL Remnant Cholesterol
Pay attention to VLDL remnant cholesterol levels, as these particles are highly pathogenic and often missed by standard lipid panels, especially in hypertriglyceridemia.
18. Ubiquinol for Statin Myalgias
For statin-induced myalgias, consider trying ubiquinol (CoQ10), potentially a highly absorbable liquid form, although the evidence for its efficacy in reversing symptoms is not conclusive.
19. Atorvastatin and Diabetes Risk
If on atorvastatin (Lipitor) and concerned about diabetes risk, discuss with your doctor if a switch to another statin like pitavastatin or rosuvastatin (Crestor) might be appropriate, as atorvastatin appears to carry a higher risk for diabetes.
20. Niacin for Elevated Triglycerides
For patients with moderately elevated triglycerides (150-400 mg/dL), niacin can be an alternative approach to lowering triglycerides and small LDL.
21. PCSK9 Inhibitors Target Larger LDL
If using PCSK9 inhibitors, be aware that they primarily lower medium and larger LDL particles, and may have less impact on smaller LDL particles, suggesting a potential complementary role for other therapies in some cases.
5 Key Quotes
Atherosclerosis... described it quite eloquently as a smoldering inflammatory condition fueled by lipids.
Peter Attia
It's a cumulative process that can progress at various rates depending on the condition.
Ron Krauss
Statins are tools. And the most important thing when you have a tool is knowing how to use it and knowing when to use it.
Peter Attia
The fact is that LDL is causal, but there are other circumstances that modify that causality to the extent that some forms of LDL under certain conditions, and this may not be uncommon, can be elevated without pathologic consequences.
Ron Krauss
The failure of those trials speaks to the success of statins and the failure of HDL raising. Those are the two things I take away.
Ron Krauss