Friday, June 26, 2009

When Friedewald Attacks

I don't get very excited about nitpicking blood lipids. That's not to say they're not useful. There's definitely an association between blood lipids and certain health outcomes such as cardiovascular disease. The thing that tires me is when people uncritically interpret those associations as evidence that lipids are actually causing the problem.

Low-density lipoprotein, or LDL, is the cholesterol fraction that typically gets the most attention. High LDL associates with heart attack risk in Americans and some other groups. Statins reduce LDL and reduce heart attack risk in a subset of the population, and this has been used to support the idea that elevated LDL causes heart attacks. This is despite the fact that lowering LDL via diet doesn't seem to reduce heart attack risk (typically by reducing total fat and/or saturated fat). Statins may in fact work because they're anti-inflammatory, rather than because they reduce LDL. But both explanations are speculative at this point.


The fact remains that if you want to know if Mr. Jones is going to have a heart attack in the next five years, measuring his LDL will give you more information than not measuring his LDL. This association doesn't seem to apply to all cultures or to Americans eating atypical diets. Then you can get into the fractions that associate more tightly with heart attack risk, such as low HDL, high triglycerides, small dense LDL, etc. Triglycerides vary with HDL (that is, when trigs go up, HDL generally goes down) and the ratio also happens to be a predictor of insulin sensitivity. Total cholesterol is virtually useless for predicting heart attack risk in the general population. This is something I'll discuss in more detail at another time.

When you walk into the doctor's office and ask him to measure your cholesterol, the numbers you get back will generally be total cholesterol, LDL, HDL and triglycerides. All of those except LDL are measured directly. LDL is calculated using the Friedewald equation, which is (in mg/dL):
LDL = TC - HDL - (TG/5)
Low-carb advocates have known for quite some time that this equation fails to accurately predict LDL concentration outside certain triglyceride ranges. Dr. Michael Eades put up a post about this recently, and Richard Nikoley has written about it before as well. The reason low-carb advocates know this is that reducing carbohydrate generally reduces triglycerides, often below 100 mg/dL. This is the range at which the Friedewald equation becomes unreliable, resulting in artificially inflated LDL numbers that make you have a heart attack just by reading them.

I had a
lipid panel done a while back, just for kicks. My LDL, calculated by the Friedewald equation, was 131 mg/dL. Over 130 is considered high. Pass the statins! But wait, my triglycerides were 48 mg/dL, which is quite low. I found a paper through Dr. Eades' post that contains an equation for accurately calculating LDL in people whose triglycerides are below 100 mg/dL*. Here it is (mg/dL):
LDL = TC/1.19 + TG/1.9 - HDL/1.1 - 38
I ran my numbers through this equation. My new, accurate calculated LDL? 98 mg/dL. Even the U.S. National Cholesterol Education Panel wouldn't put me on statins with an LDL like that. I managed to shave 33 mg/dL off my LDL in 2 minutes. Isn't math fun?

*This equation was designed for individuals with a total cholesterol over 250 mg/dL.

23 comments:

MangoManDan said...

Thanks for this post, Stephan. I was hoping this new formula would calm me down, but if I did the formula right it left me with higher LDL rather than lower.
My numbers: TotalChol 170, Trigl 55, HDL 31, with a computed (old formula) LDL of 170.
Under the revised formula I get (170 / 1.19) + (55 / .81) - (31 / 1.1) - .98 = 181.59.

For a good while I've been telling myself that my low HDL is an artifact of my low triglycerides.
I've read that a low carb diet can raise your HDL, but that has never been true for me.

Another question related to this formula. If the new computation changes your LDL, does that mean you also have an incorrect number for HDL or total cholesterol or triglycerides? (I'm an English major; math is not my forte.)
Dan

Carl Breth said...

Try this one ...
LDL (mg/dL) = TC/1.19 + TG/1.9 – HDL/1.1 – 38

Comes out to LDL = 105.62

per http://www.ams.ac.ir/AIM/08113/0014.pdf

Mat said...

MangoManDan

My HDL use to run below 30 until I started 10,000iu Vitamin D3 gelcaps per Dr. Davis:

"Actos, Avandia, and vitamin D"
http://heartscanblog.blogspot.com/2008/02/actos-avandia-and-vitamin-d.html

This got my HDL up to his recommended 60. 10,000iu Vitamin D is my max winter
dose. I use my home cholesterol meter's HDL reading to set my Vitamin D intake.

Matt W

Anna said...

Stephan,

I think the formula you posted is for mmol/L measurements. The formula Carl Breth posted is for the mg/dL measurement.

Kiwi Geoff said...

Hi Stephan,

I was amused to see that you made the same mistake as I did when I first read the "Iranian" paper.

We read the "superscript" (which is actually the reference for the equation) as ^2 (square command):

LDL = TC - HDL - (TG/5)^2

Friedewald should be:

LDL=TC - HDL - (TG/5) (mg/dL)
LDL=TC - HDL - (TG/2.17) (mmol/L)

Folk need to be careful that they use the right equation to match the units used by their lab results.

For people on a low carb diet (leading to hopefully low TG's) using the Iranian equation can reduce the "estimated" LDL. My partner's LDL went from 3.1 down to 2.26 (mmol/L). In other words Friedewald "increased" the value by 37%

Regards, Kiwi Geoff.

Stephan Guyenet said...

Wow, I really misread those equations. Thanks for correcting me, folks.

Dan, try calculating your LDL again using the corrected formula.

Nick said...
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Nick said...

No fun with math!

I sure liked my 'calculated' LDL number of 105 better than my 'adjusted' number of 177.2!

Did I get that right?

195/1.19 + 81/1.9 - 74/1.1 - 38 = 177.2.

That makes my LDL number very close to my TC number. At LDL of 177, knowing what VLDL is seems critically important, especially knowing that my hsCRP came back at 2.43.

I hate to be reactive, but wonder if this suggests getting a NMR lipoprotein test or a heart scan?

Kenny Kball said...

The macro implications of the breakdown of Friedewald's formula at the low end of the TG scale are fascinating. I'd love to study how much money is being spent on statins nationally, on the basis of mis-estimated LDL.

But of course the bigger grievance is that yet another systemic bias against traditional diets is been lurking in our blood work... and has been for nearly three decades. Thanks again for a terrific blog Stephan.

Anna said...

Nick, I get 127 for your recalculated LDL.

164+68-67-38=127

Everyone is having fun with numbers: I pulled my last two cholesterol panels:

2006 from my HMO lab - these results had my HMO endo concerned at my first appt with him, but he dropped the subject when I said "fine, order a detailed lipoprotein test to count and type my LDL particles - I'm not worried about it". I know my diet is low in omega 6, low in carbs, and high in naturally saturated fats, so I expect my LDL pattern to be the light, fluffy kind not associated with atherosclerosis.

My coronary calcium scan score in Dec'08 was 0 (mostly I did the scan to get my husband to also get a scan - as a longtime smoker who's been unable to sustain quitting, he's the one with the risky factors). At 47 yoa, I'm about the recommended age for women to a baseline CAC scan and there is CVD is my family history, so there were plenty of reasons to do the scan (also I wanted a pre-menopause baseline, as well as a simultaneous comparison for my husbands score so that no one could blame my food at home for his higher risk level!). Wish I had gotten an earlier baseline scan when I was eating high carbs & less sat fat and not yet on thyroid hormones for hypothyroidism. I could have had some plaque growing then for all I know.

3/2006 - TC 246, TG 77, HDL 66, LDL-Calc (Friedewald) 165, TC/HDL ratio 3.7

Recalculated LDL 150

2/07 (done at the local health food store and diet included yet more butter and cream in the previous year, plus the addition of home-rendered lard)

TC 230, TG 59, HDL 72, LDL-calc (Friedewald) 146

Recalculated LDL 121

My LDL still isn't considered low, but with all the other factors to consider, it doesn't concern me.

I just had some other labs done and my ferritin level is fine, too, despite the high amount of red meat I eat (pastured bison, mostly).

Nick said...

Whew, thanks Anna.

I just did a recalculation and don't see how I got my number. But doing it once again, I now get:

164+46-67-38=105, which matches my calculated number.

Much more fun math! Now I'd like some better math for my golf scores.

Carl Breth said...

Nick,

It's even better....

I calculate your LDL as 101.217

163.86 + 42.63 - 67.273 - 38

Jonathan said...

Stephan, is LDL still associated with coronary risk if you leave out the folks with familial hypercholesterolemia? If so, do you know a trustworthy reference documenting this fact?

Thanks!

Anna said...

Yes, I made a mistake; I divided the TG by 1.19 instead of 1.9. Oops. No, I wasn't a math major, either....

Paula said...
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Paula said...

Just a note of caution in applying the formula from the Archives of Iranian Medicine article: the study from which the formula was developed only included patients with total cholesterol greater than 250 mg/dL.

MangoManDan said...

Thank you to Carl and all. My new LDL number makes me feel healthier than ever.

Mat, I did start taking Vitamin D 2 or 3 months ago, right around when I came across Stephan's blog. I'm not sure if the blog led me to the vitamin, or vice versa. Also taking Vitamin K oil now. I bet my tests will be better in the fall.

I do have to worry about my numbers because I'm in my mid fifties and have been a poster child for metabolic syndrome for 40-some years. I don't think any particular regime can undo the damage I've done to my system, but a late start is better than none.

Dan

Jim said...

I'm a skeptic.

I'm skeptical about the "normal" ranges for lab tests, if they're just based on averages, and not optimal health.

I'm skeptical about the accuracy of the tests.

And I'm very, very skeptical about the whole idea that every unusual lab result needs a chemical to correct it.

Kiwi Geoff said...

I note that some people have had some problems using the various formula.

So this evening I wrote a quick
LDL Calculator:

If above does not work try:

http://homepages.slingshot.co.nz/~geoff36/LDL_mg.htm

- that allows inputting the raw lab results, it then calculates both the Friedewald and Iranian LDL estimates.

It may be useful for those on a low carb lifestyle, to quickly see how the two formula give different answers when TG's are nice and low.

Regards, Kiwi Geoff.

Stephan Guyenet said...

Jonathan,

That's an interesting question. I don't feel qualified to answer it at this point. I've been reading Dr. Harumi Okuyama who states that the association between total cholesterol and CHD is probably due to familial hypercholesterolemia. I think he makes a good case that it's at least a partial explanation.

I would assume that would also apply to LDL, but I haven't looked into it.

Paula,

Thanks, I've written a note about that at the bottom of the post. It's hard to say how well the equation will fit Americans too, it needs to be validated here.

Geoff,

Nice work, your calculator works great!

Alfredo E. said...

The way to avoid insuline resistance, obesity, diabetes, hypertension, etc. is to control HDL cholesterol and Triglycerides.

The 2 main markers when talking about heart disease are: HDL cholesterol and triglycerides, not total cholesterol. If your HDL cholesterol is above 60 and your triglycerides are below 100, you don’t have to worry about your total cholesterol.

In order to get to those 2 markers you have to: exercise 30 minutes everyday at a medium high level of exertion, eat a low carbohydrate diet (paleo diet) and take 3.000 mg of fish oil everyday.

Please read more at: Fish Oil and Heart Disease

JOSEPH said...

Stephan, what are the studies that show the Friedewald calculations overestimate the LDL numbers? I've seen an Iranian study, but wonder if this has been followed up with subsequent research?

Also, is there any way to estimate the LDL-c subtypes based on TG, HDL-c & Total-c?

We've been seeing a trend of conflicting blood work with the Paleolithic diet crowd, many who report HDL, TG, BP improvement, but poorer performance in the LDL category. I suspect that the increase in LDL levels in our low-carb, no-grain diet may be due to both the low TG effecting the calculations, as well as an increase in the lighter "fluffier" LDL vs the smaller denser 'bad' LDL.

Stephan said...

Hi Joseph,

There is a new formula in the works that should be able to replace Friedewald and the Iranian formula at all TC, HDL and trig levels. It was developed by Ricardo Carvalho of the Portuguese blog Canibais y Reis. We're collaborating on a paper together but it has been stagnating. Hopefully we'll get it out this year.

I'm not totally comfortable with the sky-high LDL that some people get on low-carb paleo diets. I seriously doubt paleolithic humans had LDL like that, given that modern-day HGs have extraordinarily low total cholesterol. I don't know how very high "pattern A" LDL will influence CHD risk over the long term, but I see that pattern as potentially pathological.