As a result, the medical community’s consensus has been to help people reduce LDL cholesterol levels to lower the risk of atherosclerotic cardiovascular disease.
However, more recently, experts have been questioning the cholesterol hypothesis. This article explains the theory, its implications, and factors besides cholesterol that researchers are considering.
What Is the Cholesterol Hypothesis?
The cholesterol hypothesis is based on several observations:
Cholesterol and plaque: Pathologists showed a long time ago that cholesterol deposits are a significant component of atherosclerotic plaques. Cholesterol and heart disease: Epidemiological studies—particularly the Framingham Heart Study—showed that people with high blood cholesterol levels have a significantly higher risk of cardiovascular disease. Cholesterol-lowering medication: In the 1990s, randomized clinical trials demonstrated the value of cholesterol-lowering medication. In those trials, select people with elevated cholesterol levels achieved improved clinical outcomes by reducing their LDL cholesterol levels with statin drugs. For many experts, these trials proved the cholesterol hypothesis once and for all.
Guidelines
These studies resulted in guidelines encouraging people to reduce their risk of heart disease by lowering their cholesterol. As a result, in 1977, the U.S. Senate Select Committee on Nutrition and Human Needs formally recommended that Americans reduce their fat intake—especially saturated fat.
For decades, experts urged people to alter their diets to reduce cholesterol levels. In addition, pharmaceutical companies spent billions of dollars developing drugs for lowering cholesterol.
The Problem
Many lipid experts and cardiologists are now questioning whether the cholesterol hypothesis is true after all. That’s because trials have failed to show a clinical benefit when using drugs other than statins to reduce cholesterol levels.
The problem is that if the cholesterol hypothesis were true, it should not matter which drugs were used to reduce cholesterol; any method of lowering cholesterol should theoretically improve clinical outcomes. But that has not been shown.
Non-Statin Therapies
Some studies found substantially lowered LDL cholesterol levels with non-statin therapies. However, they did not show improved cardiovascular outcomes.
Treatments used in these studies included:
Niacin Fibrates Ezetimibe Bile acid sequestrants CETP inhibitors Hormone replacement therapy in post-menopausal people
Indeed, despite improved cholesterol levels in some of these trials, a substantially worse cardiovascular outcome was seen with treatment.
Statins
In general, of the cholesterol-lowering trials conducted so far, it is fair to say that reducing cholesterol levels with statins seems to improve cardiovascular outcomes. However, reducing them with other interventions does not.
Statins represent a special case when it comes to cholesterol-lowering therapy. Statins have many effects on the cardiovascular system.
In addition to reducing cholesterol levels, they may also:
Have anti-inflammatory propertiesFight infectionsLower blood pressure
These other effects stabilize atherosclerotic plaques and could explain much of the clinical benefit seen with statins.
Drugs that lower cholesterol without having these other plaque-stabilizing characteristics seem not to result in this kind of benefit. Therefore, it is reasonable to postulate that statins do not improve cardiovascular risk only by reducing cholesterol levels. Instead, they might be doing so through these other effects.
PCSK9 Inhibitors
Trials found that when a PCSK9 inhibitor (an anti-cholesterol drug) is added to maximal statin therapy, it resulted in:
Ultra-low LDL levelsImproved clinical outcomes
In the PCSK9i trials (e.g., the FOURIER trial) both cohorts were on statins, and the cohort that had PCSK9i in addition to statin showed benefit above and beyond the other group that was also on a statin but not on a PCSK9i.
Impact on Guidelines
The growing doubts about the cholesterol hypothesis became public in 2013, with the American Heart Association’s new guidelines on cholesterol treatment. In a significant break with prior cholesterol guidelines, the 2013 version abandoned the recommendation to reduce LDL cholesterol to specific target levels.
Instead, the guidelines focused on deciding which people should treat their condition with statins. In fact, for most people, these guidelines generally recommend against using non-statin drugs to lower cholesterol.
These guidelines created tremendous controversy within the cardiology community.
Potential Solutions
While cholesterol has a role in the formation of atherosclerotic plaques, other factors are also at play.
Some questions experts are considering include:
Why do some people with high LDL cholesterol levels never develop significant atherosclerosis?Why do some people with “normal” LDL cholesterol levels have widespread cholesterol-filled atherosclerotic plaques?Why does lowering LDL cholesterol levels with one drug improve outcomes, while lowering LDL levels with another drug does not?
Experts have different ideas for how to move forward. Some think it’s time to abandon the cholesterol hypothesis altogether, while others believe the medical community should revise it.
Abandoning the Cholesterol Hypothesis
Those in this camp believe that if high LDL cholesterol was a direct cause of atherosclerosis, then lowering LDL cholesterol levels by any method should improve cardiovascular outcomes. They suggest that after the cholesterol-lowering clinical trials using many different cholesterol-reducing agents did not find those expected results, the cholesterol hypothesis must be wrong.
Many healthcare providers and a fair number of cholesterol experts seem to be ready to accept this line of thinking and abandon the cholesterol hypothesis altogether.
Revising the Cholesterol Hypothesis
Other experts—likely the majority—still agree with the idea that cholesterol levels are important. They hold this view because no matter how you cut it when it comes to atherosclerotic cardiovascular disease, cholesterol does matter.
Atherosclerotic plaques are loaded with cholesterol. There is also strong evidence that the cholesterol that ends up in the plaques is delivered there by LDL particles. Reducing cholesterol may shrink plaque. There is at least some evidence that when you lower LDL cholesterol in the blood to very low levels, you can begin to reverse the atherosclerotic process—and make plaques shrink.
Any hypothesis is a working model. As you learn more, you change the model. By this reasoning, it makes sense for the cholesterol hypothesis to be revised.
The Role of Lipoproteins
It is now quite apparent that it’s just not cholesterol blood levels alone that are important. It’s also the type and behavior of the lipoprotein particles that carry the cholesterol.
In particular, how and when various lipoprotein particles interact with the endothelium of the blood vessels impacts how the blood vessels promote or hamper plaque formation.
Scientists are rapidly learning more about the various lipoprotein particles and what influences how they behave.
For instance:
Size: Some are small, dense particles, and some are big, “fluffy” particles. The small particles are much more likely to produce atherosclerosis than the larger particles. Oxidized: Oxidized LDL particles are relatively toxic to cardiovascular health. These particles are more likely to worsen atherosclerosis.
The makeup and the “behavior” of LDL particles seem to be influenced by activity levels, diet, hormone levels, and medications.
At some point, there will likely be a new, revised cholesterol hypothesis that considers new understandings about the behaviors of LDL, HDL, and other lipoproteins.
New ways of changing the behaviors of these lipoproteins may help reduce cardiovascular disease.
Summary
The classic cholesterol hypothesis is that the lower your cholesterol levels, the lower your risk for cardiovascular disease. But, recently, more experts are suggesting that the hypothesis is too simplistic. That’s because the range of results from cholesterol-lowering trials is inconsistent.
Namely, some studies have found that lowering cholesterol alone does not consistently improve outcomes. Some studies indicate that statins’ additional benefits may play a role in why they work.
Experts are in an uncomfortable place where the hypothesis and associated guidelines may need modification. There is not a replacement yet.
A Word From Verywell
If you have high cholesterol or heart disease, you may wonder how this impacts you. Remember that lifestyle changes and medications you take to treat coronary disease, including lipid-lowering drugs, have proven benefits. Talk to your doctor about your concerns, and never stop a course of treatment without speaking with your healthcare provider first.
