Improving your health is a popular New Year’s resolution, and the first step to making it happen is often a diagnostic test. The important thing to understand with test results like this is which markers show correlation and which show causation. For example, HDL cholesterol correlates with a lower risk of cardiovascular (CV) disease. However, the often-repeated warning that “correlation is not causation” is often repeated.
There is a lot of confusion regarding these two terms and the logical behavior that follows. Much of the confusion exists because correlations predict risk. However, they do not identify the root cause of the disease.
Correlation, causation, and intervention
A common example to illustrate this confusion is the association between ice cream sales and shark attacks. Perhaps a model could predict the number of shark attacks based on ice cream sales on the beach. The two datasets are correlated because more ice cream sales mean bigger crowds and hotter days at the beach. That means more people will get into the water and be attacked by sharks. But ice cream sales do not cause shark attacks, so no one would suggest banning ice cream as a strategy to reduce shark attacks.
The important point is that if two parameters are simply correlated, there is no identifiable intervention strategy (for example, to reduce ice cream sales). Intervention is only logical if the cause is established.
Popular media compounds this confusion with headlines such as “Coffee is associated with lower risk of cardiovascular disease” and “Chocolate is associated with lower mortality.” The words “linked” and “associated” refer to a relationship. Therefore, there is no guarantee that interventions such as increasing coffee intake will reduce the risk of cardiovascular disease.
For HDL-C
HDL-C (high-density lipoprotein cholesterol) is one of the most confusing markers. The negative correlation between HDL-C and CV disease is so strong that HDL-C is referred to as “good” cholesterol, indicating a desire to have high levels of cholesterol. After this association was discovered during an initial study in Framingham, USA, many drugs that increase HDL-C were tested in clinical trials to prove a causal relationship with CV disease. However, despite showing an increase in HDL-C, these trials did not show a reduction in cardiovascular disease risk.
Colloquially, lipids and cholesterol are discussed as LDL, HDL, and triglycerides. Better acronyms are LDL-C and HDL-C. LDL and HDL refer to particles, while LDL-C and HDL-C refer to the cholesterol in these particles, the part that correlates with or causes cardiovascular disease. These particles also contain other molecules such as triglycerides, other fats, and proteins.
The main difference between LDL and HDL is the protein that “binds” all of these different elements together. LDL and HDL are not fixed entities with a defined composition throughout their lifetime. They are constantly exchanging cholesterol (and other elements) in their bodies with their surroundings and are constantly changing. The association between HDL-C and CV disease is due to the role of HDL particles in a pathway known as reverse cholesterol transport (RCT). Cholesterol is an important component of all cells and tissues. Problems occur when it becomes trapped in the “wrong” place, such as the inner wall of a coronary artery. These deposits can eventually cause a heart attack. The RCT pathway removes cholesterol from cells and tissues via HDL that enters the bloodstream (known as cholesterol efflux) and can be measured as HDL-C. In the bloodstream, HDL exchanges cholesterol with other particles and eventually returns the cholesterol to the liver for removal, completing the RCT.
outflow rate
Therefore, an important factor to understand is the rate of removal (efflux rate) of cholesterol from these tissues via HDL. However, the only routinely available measurement is HDL-C concentration in the blood, which does not provide any indication of flux rate.
After several failed clinical trials, additional studies were conducted to understand the rate of elimination, and some drugs were shown to increase elimination. Paradoxically, however, CV risk is not affected. Therefore, the details of HDL’s role as a transporter of cholesterol and a contributor to cardiovascular risk remain enigmatic. HDL-C is currently considered an indicator of overall health status (e.g., exercise increases HDL-C and smoking decreases HDL-C), and its correlation with CV risk is reflects the association between health status and lower CV risk. .
HDL-C intervention trials have revealed the complexity of the HDL-C pathway and demonstrated the risk of correlated factors as intervention targets. A high HDL-C number is welcome as it correlates with lower CV risk (it is important to pay attention to other parameters rather than looking at this number in isolation). But there’s no need to worry if your HDL-C is low. That’s because there are other modifiable factors such as LDL-C, apolipoprotein B (ApoB), and overall health interventions such as exercise and diet that reduce CV risk.
As with other correlation markers, pay attention to it when you’re drinking your morning coffee and read another headline about the drink’s benefits. Not because coffee reduces the risk of disease, but simply because of the benefits of your morning cup. It’s fun.
Tushar Gore is the Managing Director of Resonance Laboratories, a niche pharmaceutical company. He studied at IIT Bombay and the University of Minnesota and has worked at McKinsey and Novo and his Nordisk.His specialty is pharmaceuticals
