Cholesterol and Heart Disease
Cholesterol is a complex topic, one that often gets over simplified. While research does clearly suggest that if your cholesterol is really high that you have an increased risk of heart disease, the picture gets much more nuanced with moderate elevations.
What is Cholesterol?
Cholesterol is a waxy or fatty substance used primarily in the membranes that surround each of your cells. In addition, it plays a role as a building block for stress and sex hormones along with vitamin D. As such, your body needs a certain amount of cholesterol to function properly.
In the bloodstream, cholesterol is carried as particles of different densities. Generally, lower density particles (called low-density lipoprotein or LDL cholesterol) are considered more harmful to heart health. LDL particles carry cholesterol through the bloodstream, delivering it to the cells and tissues of the body. When LDL cholesterol is highly elevated, cholesterol can get deposited in the blood vessels leading to atherosclerosis and heart disease.
On the flip side, higher density particles (called high density lipoprotein or HDL cholesterol) are typically considered helpful. HDL particles appear to work like a shuttle, carrying cholesterol back to the liver, removing it from tissues. However, there is evidence that when highly elevated, HDL can also have a negative impact on heart health (Franczyk 2021).
Cholesterol and Heart Disease
When it comes to cholesterol and heart disease the picture is a bit more convoluted than generally acknowledged. There are two situations where high cholesterol is well known to correlate with heart disease and lowering cholesterol has clear benefits. The first situation is with very high cholesterol levels. This is often due to a genetic problem that elevates cholesterol, although other causes are possible.
When individuals have really high cholesterol levels, they are at risk for early death from heart disease. Lowering cholesterol in these individuals has been documented to reduce the risk of heart disease to that of the standard population (Mata 2015).
The other clear situation where reducing cholesterol with medication reduces heart disease risks is after a heart attack. If an individual has a serious heart event, like a heart attack, lowering cholesterol has also been clearly established as a way to reduce the risks for further problems (Koskinas 2018).
Primary Prevention of Heart Disease
The biggest question that remains is if lowering cholesterol in patients with only moderately elevated levels is effective for reducing deaths. While controversial, some researchers have argued that the benefits from lowering cholesterol are so minimal in these individuals that they aren’t worth the risks (Byrne 2019).
Cholesterol and Risk of Mortality
While somewhat surprising to hear, high LDL cholesterol is not always associated with an increased risk of death. There are a number of large studies, including in the United States, Finland, Korea and China that have found no relationship between LDL cholesterol and mortality (Ravnskov 2021). This is surprising since heart disease is the leading cause of death. You would expect that if lowering cholesterol was effective that there would be a clear relationship between LDL cholesterol levels and mortality.
Some studies have actually found the reverse, that higher LDL cholesterol is associated with a reduced risk of death (Orozco-Beltran 2017). This association, in part, may be explained by a possible relationship between low LDL cholesterol and cancer. When LDL cholesterol was low, one study found increased rates of cancer deaths. Of note, these low LDL levels are in the range of what is usually considered optimal (Zuliani 2017).
Cholesterol, Mortality and Total Cholesterol
Probably some of the best evidence for cholesterol and mortality comes from a massive study out of Korea. The study evaluated 12.8 million adults. And the results are surprising. Both low and high total cholesterol (LDL and HDL levels combined) is associated with an increased risk of death. The risks for increased mortality appear to primarily occur below 180 mg/dl or above 280 mg/dl of total cholesterol (Yi 2019). This could make an argument that normal total cholesterol levels should span from 180-280 mg/dl.
It’s interesting to note that normal total cholesterol levels are thought to span 125-200 mg/dl. This range is mostly in the range that appears to increase the risk for death. The data clearly calls into question the mainstream approach of lowering cholesterol at almost any cost. Reducing total cholesterol under 180 mg/dl may not necessarily be the best approach.
The other interesting piece to note is in relation to age: the association between cholesterol levels and mortality for individuals over age 75 is significantly reduced. This raises obvious questions about cholesterol lowering strategies in older individuals.
Cholesterol, Mortality and LDL Cholesterol
Since total cholesterol includes both “good” and “bad” cholesterol, it’s worth trying to sort out differences by type of cholesterol. A large study that included over 100,000 individuals out of Denmark did just that. The results are intriguing. They found that death again increases with both low and high LDL cholesterol. The sweet spot with the lowest risk for death from any cause was 140 mg/dl, a level that is normally considered elevated on standard laboratory testing (Johanessen 2020). Once again, we are faced with data that appears to contradict the idea that low cholesterol is always better.
Contradictions and Concerns Over Data
Now to be clear, there is conflicting data that has been published on cholesterol levels and death. However, a lot of the large studies (like the ones referenced above) are hard to dismiss, especially as they contain so many subjects. The cholesterol lowering drug Lipitor has generated more profits than any other drug in history (Kiplinger 2017). As such, the possibility of bias from the pharmaceutical industry in order to protect profits is of real concern. We know industry-funded studies are often biased, which can create problems.
There are also concerns about data integrity with cholesterol research (Redburg 2017). While standard guidelines for clinical trials demand that the raw data be accessible for further analysis by independent researchers, the pharmaceutical industry has stubbornly funneled almost all cholesterol research through a single research body that has ties to the industry. This body historically has been unwilling to release the raw data from any of the published clinical trials. This raises huge conflicts of interest and concerns about the validity of findings from most cholesterol lowering studies. Indeed, researchers have raised concerns that there appears to be problems with bias in the published cholesterol research (DuBroff 2018).
Cholesterol is a controversial medical topic. While really high cholesterol clearly raises risks for heart disease, our current recommendations for reducing what are usually “modest” elevations may not be effective or prudent. Even after all the millions of dollars spent on cholesterol research, there are still very basic questions that haven’t been satisfactorily answered. Hopefully, more unbiased research can help to improve our understanding of when to apply cholesterol-lowering therapies. Ultimately, the goal should be to reduce death and improve overall health, not just reducing cholesterol levels at any cost.