#238 – AMA #43: Understanding apoB, LDL-C, Lp(a), and insulin as risk factors for cardiovascular disease
In this AMA episode, Dr. Peter Attia and Nick Stenson discuss atherosclerotic cardiovascular disease (ASCVD), its risk factors like apoB, Lp(a), and hyperinsulinemia, and their interrelation. They explore how metabolic dysfunction contributes to residual ASCVD risk and the importance of early prevention.
Deep Dive Analysis
5 Topic Outline
Understanding ASCVD Risk with a Race Car Analogy
Differentiating ApoB, LDL-C, and LDL-P Measurements
Hyperinsulinemia's Impact on ASCVD Risk via ApoC3
Hyperinsulinemia's Role in Endothelial Dysfunction
Using the Oral Glucose Tolerance Test (OGTT) for Insulin Levels
6 Key Concepts
LDL-C
LDL-C is a laboratory measurement that quantifies the concentration of cholesterol contained within low-density lipoprotein (LDL) particles. While it predicts ASCVD risk, it is considered less comprehensive than ApoB.
ApoB
ApoB (apolipoprotein B) measures the concentration of all particles that carry the ApoB lipoprotein, which includes LDL, VLDL, and Lp(a). It is a better predictor of ASCVD risk than LDL-C because it captures the total number of atherogenic particles, not just the cholesterol within them.
ApoC3
ApoC3 (apolipoprotein C3) is a lipoprotein whose increased expression, often linked to hyperinsulinemia and insulin resistance, blocks the activation of lipoprotein lipase (LPL). This blockage leads to higher triglyceride levels and an increase in triglyceride-rich LDLs, ultimately raising ApoB concentration and ASCVD risk.
Lipoprotein Lipase (LPL)
LPL is an enzyme located on cells that plays a crucial role in controlling lipolysis, the breakdown of fats. When its activity is inhibited, such as by elevated ApoC3, it results in reduced utilization of triglycerides and an increase in their circulating concentration.
Endothelial Dysfunction
Endothelial dysfunction refers to the impaired functioning of the endothelium, the inner lining of blood vessels. This dysfunction makes it easier for ApoB particles to penetrate the subendothelial space, contributing to the initiation and progression of atherosclerotic cardiovascular disease, and hyperinsulinemia appears to drive this process.
Oral Glucose Tolerance Test (OGTT)
The OGTT is a diagnostic test used to assess how well the body processes glucose and insulin. It is particularly useful for identifying hyperinsulinemia in a postprandial state, where glucose levels may be normal but insulin levels are elevated, indicating early insulin resistance.
5 Questions Answered
ASCVD risk can be understood as driving a race car towards a cliff (death), where factors like Lp(a) and hyperinsulinemia act as the 'throttle' accelerating progress, and lowering ApoB acts as the 'brake' slowing it down.
LDL-C measures the concentration of cholesterol within LDL particles, while ApoB measures the concentration of all particles carrying the ApoB lipoprotein (including LDL, VLDL, and Lp(a)), making ApoB a better predictor of ASCVD risk as it reflects the number of atherogenic particles.
Hyperinsulinemia is unequivocally associated with worse ASCVD outcomes, primarily by increasing ApoC3 expression which blocks lipoprotein lipase, leading to higher triglycerides and triglyceride-rich LDLs, thereby increasing ApoB concentration.
Hyperinsulinemia also appears to drive endothelial dysfunction, making it easier for ApoB particles to penetrate the subendothelial space and initiate the inflammatory cascade that propagates ASCVD.
An Oral Glucose Tolerance Test (OGTT) can reveal hyperinsulinemia, especially in a postprandial state, where glucose levels remain normal but insulin levels are elevated, serving as an early indicator of insulin resistance.
6 Actionable Insights
1. Prioritize Early Risk Intervention
Address atherosclerotic cardiovascular disease (ASCVD) risk factors like ApoB, hyperinsulinemia, smoking, and hypertension early in life, as prompt action allows for more effective interventions and slows disease progression.
2. Monitor ApoB Over LDL-C
Prioritize measuring and monitoring ApoB concentration over LDL-C for assessing ASCVD risk, as ApoB is a better predictor that captures all atherogenic particles and serves as a key goalpost for risk reduction.
3. Detect Hyperinsulinemia Early
Look for postprandial hyperinsulinemia, characterized by elevated insulin 30-60 minutes after a glucose challenge, as a “canary in the coal mine” for early insulin resistance and increased ASCVD risk, even if fasting glucose is normal.
4. Utilize Oral Glucose Tolerance Test
Consider undergoing an Oral Glucose Tolerance Test (OGTT) to assess your postprandial insulin levels, which can help detect early insulin resistance and provide insight into your current metabolic state, even if you don’t have type 2 diabetes.
5. Actively Manage ASCVD Drivers
Focus on actively lowering high blood pressure, ceasing smoking, and reducing ApoB levels, as these are identified as the three primary and most impactful drivers of atherosclerotic cardiovascular disease (ASCVD).
6. Understand Lp(a) Baseline Risk
Recognize that Lp(a) levels are largely genetically determined and not directly modifiable, serving as a “low level of maintenance throttle” that contributes to baseline ASCVD risk.
5 Key Quotes
your lifespan is the length of time it takes you to drive a race car from point a to point b where point b is driving it off a cliff and you have two feet and two pedals right so you have the accelerator and you have the brake and your feet are always on both pedals so it's really just a question of how hard are you pressing on each one
Peter Attia
the more you're lowering apob the harder you're pushing on the brake
Peter Attia
apob is a better predictor of risk because it captures not only the concentration of ldl and we know that it's the number of particles more than the cholesterol concentration of the particles that drives risk but also because it includes the other atherogenic particles namely the vldl
Peter Attia
the observation that is unequivocal is hyperinsulinemia is associated with worse outcomes in ascvd
Peter Attia
the true canary in the coal mine is it's a postprandial challenged glucose response where glucose is normal but insulin is distorted insulin is elevated
Peter Attia