It's not the LDL cholesterol, stupid!

Health Professional

The recent fuss with the Enhance Study that failed to demonstrate a difference in carotid plaque with Vytorin ® (simvastatin and Zetia ®) vs. simvastatin alone has raised some serious questions about LDL cholesterol. Some have argued that statin drugs exert benefits through means other than reducing LDL cholesterol, while others have argued that statin drugs fail to provide the benefits in survival that most previously believed.

Lost in the discussion, however, is an important point about LDL cholesterol: It's not a real measured value.

That's right: LDL cholesterol is virtually never measured. When you go to your doctor to have a cholesterol ("lipid") panel drawn, total cholesterol, HDL cholesterol, and triglycerides are measured; LDL cholesterol is calculated from these three other values. How did this come about?

Back in the 1960s, it was clear that higher levels of cholesterol were predictive of heart disease. But it also became clear that the low-density fraction of cholesterol, or LDL, was somewhat better than total cholesterol in predicting heart attack.

Total cholesterol was easily measurable in the 1960s. LDL was not. So, Dr. Friedewald, a noted lipid researcher at the National Institutes of Health, proposed an easy method to calculate LDL cholesterol from total cholesterol, HDL, and triglycerides:

LDL cholesterol = Total cholesterol - HDL cholesterol - triglycerides/5

This simple manipulation would put LDL cholesterols into the hands of the practicing physician and the American public. Dr. Friedewald recognized that this calculation only represented an approximation of LDL cholesterol and that it was thrown off, sometimes substantially, by any abnormal rise in triglycerides or reduction in HDL. But it served its purpose at a time when most doctors hadn't even heard of cholesterol and the public was still sold on whole milk and "farm-fresh" butter, and Chesterfields were the cigarette of choice for most doctors.

The world has since changed. Most doctors have heard about cholesterol and, along with the public, have been inundated with marketing for cholesterol-reducing drugs. Most people with some level of common sense and health awareness no longer fry their meat in lard and no longer believe that the brand of cigarette you choose can be healthy. But we're still using Dr. Friedewald's original calculation for LDL cholesterol.

I had a patient in my office this week. (Actually, one among many.) LDL cholesterol by the Friedewald calculation: 134 mg/dl. True LDL when measured:** 223 mg/dl-a 66% difference.**

Why are we using this outdated method for obtaining LDL cholesterol? Is it because there's nothing better available?

No, there are several tests that are superior to calculated LDL. But two reasons persist to explain why your neighborhood primary care physician or cardiologist is still using this dinosaur of testing called LDL:

  1. The lag in science to practice is 20 years.

  2. Insurance companies vigorously discourage testing beyond conventional lipids.

The array of objections we get from insurance companies is mind-boggling. It would be funny if human life and finances weren't at stake. These "new" tests are "experimental," "unproven," not endorsed by standard guidelines, not approved by some internal committee, or simply "We don't know what this test is."

What are the tests that are superior to Dr. Friendewald's calculated LDL? There are several, listed here in order of best to worst:

  1. LDL particle number-the value generated by NMR lipoprotein testing. This is the gold standard, most reliable test available, and the one I recommend. (Ask your doctor about "NMR lipoprotein testing.")

  2. Apoprotein B-More widely available even from conventional laboratories. It's not as accurate as NMR LDL particle number, but a pretty good choice. Apo B is the principal protein in LDL and is a better reflector of risk.

  3. "Direct" LDL-This is LDL that is actually measured. Unfortunately, it ignores the issues of LDL size and has some other pitfalls, but it's still better than calculated LDL

  1. Non-HDL cholesterol-So-called because it incorporates all undesirable cholesterol-containing lipids except good HDL, thus "non-HDL." This is another calculation, though better than LDL (because it sums up the risk from other apoprotein B-containing lipoproteins). Non-HDL is calculated from Total cholesterol - HDL. It's therefore available from any standard lipid panel. It's little used in everyday practice, however, because most people and their physicians find it confusing.

Imagine your realtor tells you your house's estimated value is $200,000 and that's what you sell it for to an eager buyer. After closing, you find out your house was really worth $350,000. You'd be upset. But that's what you're getting with LDL cholesterol: a bum deal.

It's part of the reason people will say, "My doctor said my cholesterol was fine and that no cause for my heart disease can be found. He said it was genetic." In reality, they could have sky-high LDL cholesterol revealed by LDL particle number or apoprotein B. This enormous inaccuracy of calculated LDL cholesterol therefore diminishes its usefulness in analyzing data from studies, including studies like Enhance.

Calculated LDL cholesterol is a seriously flawed tool to diagnose your initial level of risk. Ask for better.