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Twittorial #1; Lp(a) and the real “LDL-C”:

When one looks at your lab report, note the LDL-C says “calculated”. So, believe it or not, the most important risk factor for CVD is actually an estimated value. Hard to believe but true. 1/17
Sometimes it says direct LDL, which is an actual measurement. LDL is a complex particle containing apoB, cholesterol, cholesteryl esters, phospholipids and a bit of triglyceride. LDL-C only reflects the total cholesterol in LDL, that is why there is a “C” at end of it. 2/17
LDL particles are made of about 50% cholesterol by mass (i.e. the human body is 60% water). Lp(a) on other hand is 20-45% cholesterol. The gold standard for measuring LDL-C is ultracentrifugation. 3/17
This places your plasma in a test tube with a salt solution and ‘floats up” the lipids according density and can separate them and measure them separately. Expensive and labor intensive and not done at clinical levels. 4/17
However, because density of LDL and Lp(a) overlap, it can’t separate these so counts them together, but it can separate chylomicrons, VLDL and IDL and HDL. Think of this as swimming in a pool vs ocean, ocean is more buoyant due to salt content. 5/17
What it does not tell you is that both of these metrics are not what they seem to be. Its very difficult to actually measure the LDL without interference of Lp(a), so in general, “LDL” is actually “LDL-C + Lp(a)-C”. 6/17
We have published on this before. ncbi.nlm.nih.gov/pubmed/25943842

In rare cases another lipoprotein class IDL-C, can be in this equation, but in fasting samples it is not present except for some very rare disorders]. 7/17
Total cholesterol in blood = LDL-C + HDL-C + VLDL-C. VLDL-C is estimated by triglyceride/5 (complex topic for another time). So, the lab basically measures TC, HDL-C and estimates VLDL-C and whatever is left over is called “LDL-C”. 8/17
I think it can be appreciated that much error can be introduced with this situation. So, what does this mean for patients with elevated Lp(a)?- if ones Lp(a) is zero or close to zero then the “LDL-C is likely accurate, so no problem 9/17
However, let’s say LDL is 80 mg /dL and your doc is considering to give you more statin to get it <70 mg/dL. Lets say Lp(a) is 150 mg/dL and 30% is cholesterol, the Lp(a)-C is 50 mg/dL, but no one measured it and it is not known. 10/17
So in this subject, the “real” LDL is 30 and the Lp(a)-C is 50 and the total LDL-C is 80. The patient is not likely to respond well to more statin/ezetimibe/PCSK9i with such low LDL. Without understanding this concept, a patient will be labeled “statin resistant”. 11/17
If the Lp(a) is in nmol/L, one can estimate in mg/dL by dividing by 2.5, but this is not accurate and a rough estimate. What we need is better ways to quantitate the real LDL and to also measure Lp(a) to understand what might be happening. 12/17
It very important to know what real LDL-C in high Lp(a) patients to ultimately be able to better individualize therapy to improve outcomes. Efforts are underway in our lab to do this. At practical level, no action is currently needed outside understanding this. 13/17
Ok quiz time: Q1- 5 points
Choose the correct answer: In subjects with elevated Lp(a), one can predict that the laboratory measured LDL-C with be what compared to the real LDL-C: 14/17
Q2- 5- points
Choose correct answer regarding statin resistance:
A-Is worsened by low saturated fat/low cholesterol diet
B-Is seen in patients who take their statin daily
C-Can seen in subjects with high Lp(a)
D-There is no such thing
15/17
Bonus question: 1 point. Chose the correct answer: Which cartoon animal looks most like an Lp(a) particle when looked on straight in profile. Hint: 16/17
Happy Saturday to all, polls close next Friday morning. Feel free to suggest improvements in this forum or other topics of interest. 17/17
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Sam Tsimikas, MD
@Lpa_Doc
The clinical expression of CVD is complex and not due to "one" risk factor. Its a combination of things that can and cannot be measured, layered on environmental factors (diet, exercise, etc). So, if only Lp(a) is present and not other factors, there is less risk of getting CVD
Lp(a) is not a "disease", its a risk factor, so it has to be thought of in probabilistic terms, i.e. if one has elevated levels how much does it increase risk of getting CVD. The majority of people with any one risk factor don't get CVD. Death rates in US from CVD is ~30-40%
Think of it like lung cancer and smoking, if you smoke 1 cigarette vs 3 packs (60) per day, you are more likely to get lung cancer if you smoke 60, but many people that smoke 60 cigs a day dont get lung cancer. But at population level, most lung cancer is seen in (heavy) smokers
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Sam Tsimikas
@Lpa_Doc
I suspect many of my non-physician followers will be confused, so this needs a response. I think we agree that risk rises with higher Lp(a). I do agree if ones Lp(a) is 50 risk is low. I don't agree that saying a risk of >50 mg/dL is either trivial or a slogan.
I think a 20% higher risk (going from a 10% risk of dying, having a heart attack or stroke) to 8% (over 3 years only like in the trial, not a lifetime of 40-80 years!!) is significant to those whose own Lp(a) is elevated, needed one or more procedures or lost a loved one.
This 20% risk in 3 years in a trial will add up substantially as the years go on and curves will continue to separate relative to low Lp(a) patients. We have to look at lifetime risk, not what risk is in a short term trial. The 10 vs 8% could end up being 50% vs 30% in 20 years.
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Sam Tsimikas
@Lpa_Doc
Its not 50, but (>)50, its like saying LDL >130 is associated with higher risk. Of course, the higher the value the higher the risk. The Novartis trial will use >70 mg/dL, which represents 15% of population at risk, ~1B. Point is no matter what metric you use, it a huge number.
Note also, the >50 mg/dL is in patients on statins, ncbi.nlm.nih.gov/pubmed/30293769. In subjects not on statins risk starts at >30 mg/dL (>75 nmol/L) Old papers show this and see most recent Madsen et al in subjects without prior event: ahajournals.org/doi/abs/10.116…
Madsen data: MACE incidence rates per 1000 person-years were 29 for individuals with Lp(a)<10 mg/dL, 35 for 10 to 49 mg/dL, 42 for 50 to 99 mg/dL, and 54 for ≥100 mg/dL. I think above 10-30 mg/dL one can consider risk fairly linear, like LDL-C.
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