Last updated: Aug 12, 2008
As our genes evolve, our risk factors for high LDL cholesterol increase.

Robert S. Rosenson, MD, is the director of lipoprotein disorders and clinical atherosclerosis research at the University of Michigan in Ann Arbor.

Q: Is the "total cholesterol" number my doctor talks about obsolete, or does it still have some value?

A: It has some relevance because, typically, the higher the cholesterol, the higher the bad cholesterol—but it also could be the higher the good cholesterol. And thats why we focus on HDL and LDL cholesterol. By focusing on the total cholesterol, people can often be misled about their risk [for cardiovascular disease] being too high or too low. One can have total cholesterol of 175 and HDL cholesterol of 25 and be at incredibly high risk for a cardiovascular event. By contrast, one can have total cholesterol of 240 and HDL cholesterol of 65 and not be at increased risk. So its the components that comprise the total cholesterol that are important.

Q: The thinking about cholesterol has changed rapidly in recent years. Has it stalled, or is it likely to continue to evolve?

A: People misunderstand the concept of cholesterol. Cholesterol is a fat that is easy to measure analytically. But cholesterol is carried in lipoproteins, and lipoproteins are what contribute to atherosclerosis. So we need to start thinking in terms of lipoproteins, and therapies that modify lipoproteins, instead of just the cholesterol carried in the lipoproteins.

This is very relevant because individuals who are obese and insulin-resistant—such as those with the metabolic syndrome or type 2 diabetes—do not have elevated LDL cholesterol levels but they have an increased number of LDL particles that puts them at a substantially increased risk for cardiovascular events. So this is where the terminology needs to change from a cholesterol concept to a lipoprotein concept.

Q: Are lipoproteins harder to test for?

A: They are, but commercial tools are available to measure lipoproteins or apolipoproteins, the major protein on the particles. Apolipoprotein tests are available in all hospital laboratories. Lipoprotein subclasses can be measured through three methodologies: nuclear magnetic resonance, ultracentrifugation, and gradient gel electrophoresis.

Q: What about triglycerides?

A: Triglycerides have emerged as a significant independent risk predictor for coronary heart disease (CAD). There was a large meta-analysis of 263,000 individuals that showed that high triglycerides were associated with a 1.72-fold increased risk of CAD events. LDL cholesterol was about 1.8–2.0, so elevated triglycerides are not so far behind LDL cholesterol. High triglycerides often predate or antedate the development of type 2 diabetes and are often a predictor of CAD.












Q: Do people with high LDL cholesterol generally have other risk factors for heart disease?

A: Yes, theres often overlap. You can have a family history and high LDL genetic disorder; you can be obese and have high LDL cholesterol. About half the people with high blood pressure have high LDL cholesterol or other lipid abnormalities (such as high triglycerides or low HDL cholesterol). Cigarette smoking is not associated with LDL cholesterol but it is associated with a low level of HDL cholesterol, which may be one of the major mechanisms whereby it mediates its cardiovascular toxicity.

Q: Other than family history, what are some of the most important mechanisms that cause high LDL cholesterol?

A: Being overweight, trans-fat intake, dietary composition. Those are the major mechanisms.

Q: Is diet generally more important than family history?

A: No. Family history is very important, and the response to diet is probably under genetic control. New research has shown that our genes are evolving as we become more industrialized. As we eat more processed food, were gaining more weight and the risk factors are becoming worse. So it becomes a moving target, but genes are very important.

Q: Lately theres been a lot of attention placed on the relative importance of inflammation over cholesterol. Is inflammation potentially a more important risk factor?

A: Atherosclerosis is lipids and inflammation—its both. Its not one or the other. So I dont think we can separate them out. You can dissect a plaque, and youll find that it has cholesterol in it, that it comes from lipoproteins, and that it has inflammatory cells in it. Theyre both important.



Q: What type of patient is a good candidate for cholesterol-lowering statin medications?

A: Anybody who has established cardiovascular disease is placed on a statin. Its shown to reduce cardiovascular events regardless of the entry LDL cholesterol level. We target the therapy based on how high-risk that individual is.

For people who are free of cardiovascular disease, the initiation of therapy depends on where the LDL cholesterol level is in relation to their overall cardiovascular profile. For the people who are at lowest risk, we intervene at higher levels of LDL cholesterol. For people who are at the highest risk, we intervene when the LDL cholesterol is lower. You match the intensity of therapy not based on cholesterol alone—not in a void—but in the context of the other risk factors.

Q: Do you find that many patients dont take their statin medication?

A: I dont think adherence to statins is any different than for any other medication that treats an asymptomatic condition, such as blood pressure. In preventive therapy people need to understand how important it is to take their medications regularly.

We deal with this all the time. For example, if someone who has heart failure doesnt take his water pill, hes going to feel short of breath—theres going to be a very clear signal. But when we treat a condition like high cholesterol, theres less compliance because its asymptomatic.

Q: Are patients able to stop statin therapy easily once they start?

A: If you stop the medication, your cholesterol will return to baseline after a very short period of time, about four to six weeks. The whole point is that you get placed on a statin if your risk and LDL cholesterol is high enough. And we have to think about the lifetime risk of cardiovascular disease. The fact is, cardiovascular disease is the leading cause of death in industrialized societies. People with persistently high LDL cholesterol should expect to go on a statin for a lifetime—unless its somebody who ate a poor diet and didnt have the motivation, and now they do have the motivation to change their diet and lose weight. If theres a change in therapeutic lifestyle, you can always reevaluate.

Q: How has the availability of generic medications changed statin therapy?

A: The models that evaluated the use of statins in people with high cholesterol were based on a time when the statins were not generic. Since we have cheaper medications now, we should be using statins more frequently, not less frequently, because the burden of heart disease is so high in industrialized societies.