Wednesday, April 3, 2024

LDL vs Heart-Attack Risk

I feel great, I work out almost every day, and my biomarkers are all in terrific shape, except for one: the amount of LDL in my bloodstream. My doctor is so concerned that he wanted to put me on statins (a class of drug) and refer me to a cardiologist right away. I wanted to do some research before going on any pharmaceuticals, but I did proceed to meet with the cardiologist who did further testing (ECG, physical checks for cholesterol near elbows and achilles, blood pressure check) but nevertheless echoed my family doctor that I should go on statins right away. So I've been digging into the research to figure out if this is what I should be doing.

The first thing I'm trying to figure out is whether I am indeed at high risk, as the doctors believe me to be. For that, I'm looking for any evidence that links high LDL (by itself, as my other markers are quite positive) with vascular risk, or some sort of correlation between LDL and heart attacks or death. I couldn't find any on my own, so I asked the cardiologist for the evidence he was referring to when he said "We actually see higher LDL leads to higher heart attacks" and the first place he pointed me to was here:

In the final paragraph, the article makes the claim that the lipid hypothesis (that LDL cholesterol has a causal role in the development of coronary heart disease and other cardiovascular diseases) has been confirmed. It does so by referencing the 4S study and a meta-analysis conducted by the Cholesterol Treatment Trialists (CTT). I read these both so that I could understand the basis of this claim.

1) 4S

In this trial, the group receiving statins had fewer adverse events and deaths, and also developed lower LDL than the control group. This trial opened my eyes as to how useful statins can be in some specific cases. But it does not establish any causation between LDL and vascular risk, which is what I'm looking for. It showed that statins lowered risk and lowered LDL, but not neccessarily that lowering LDL is what caused the lower risk.

2) CTT meta-analysis

In this meta-analysis of 21 controlled trials, statins once again showed themselves to lead a reduction in adverse events and deaths, along with a reduction in LDL. At this point I cannot dispute that statins reduce LDL and often times reduce deaths as well. But I'm still unable to see any evidence that the relationship between LDL and risk is causal.

But the authors seem to imply causation in their interpretations, with statements like "Each 1 mmol/L LDL cholesterol reduction reduces the risk of occlusive vascular events by about a fifth". That looks like sloppy wording to me, as it suggests that if I lowered LDL some other way (diet? exercise?) that risk would go down. But that's not what they showed. All they showed was that the statin lowered LDL and lowered risk, and then assumed that the lowered risk was the result of the lowered LDL, which it may or may not be.

There was some addional extra info in this meta-analysis, however, that gives me pause. The authors broke down who got the heart attacks by various factors, and when it came to LDL there didn't seem to be a strong relationship between a patient's LDL level and whether or not they had an adverse event:

That is, 3.9% of people in the highest LDL control/less category had a negative event over the course of the trial, while 4.6% of those in the lowest LDL control/less category did. So wouldn't this seem to suggest heart attack risk is independent of one's LDL level, or negatively correlated?

This was not true of other risk factors, as diabetes, hypertension, blood pressure, BMI, HDL and smoking status were all predictors of heart events in the directions you would expect.

It's important to note that almost all of the studies (both that I've discussed above, and that have been done in this area in general) have been conducted and/or financed by drug makers who have a vested interest in selling these drugs. While controlled trials are the gold-standard, there are still tricks that can be played with them. For example, they can shelve (i.e. not publicize) studies that don't show what they want them to. In meta-analyses, they can select criteria such that they don't include studies that contain results they're not happy with.

I will continue the search to determine whether high LDL is indeed risky, and needs to be brought under control. If any of you have any evidence that shows high LDL is risky, I'd be happy to check it out.


Anonymous said...

I was also told I need to be on statins due to high LDL and Total Cholesterol. Luckily my lipid specialist(Ontario) suggested a coronary calcium score test. Takes minutes and is a non-invasive CT scan of the coronary arteries. If your score is zero (mine was) then the research is clear that your 10 year risk of a coronary event is low. The specialist was then Ok with me not taking a statin, and doing a coronary calcium score test in 8 years. Even in the US this test is not done routinely even though it costs under $200.

Saj Karsan said...

Thanks, Anon. I'm on a waitlist for one (BC). My cardiologist feels that such a scan can be clean and can change quickly though, so even though I requested the test because I felt it would be helpful, he doesn't put much stock in it for my particular case.

Interestingly, I read an article yesterday about how these scans are late indicators ( Nevertheless, from what I've gathered so far (and this changes all the time as I continue to learn more about this topic), the scan results are still more useful than simple LDL-C measures.