And it's an area where there is legitimate nuance: we only measure LDL-C partly because it's easy and available, there are other ways of looking at blood lipid particles we could be measuring that might be more effective (like ApoB), it interacts with other things like insulin, inflammation, metabolic health, blood pressure.
But all that said, the case for high LDL being bad for heart attacks and strokes is very strong.
To me the strongest short list of evidence is simply:
- People who have familial hypercholesterolemia, from different genetic causes/pathways, all have massively increased heart disease at young ages.
- People who naturally have a disabled PCSK9 gene have extremely low LDL levels, where PCSK9 is directly involved in the liver's ability to clear LDL from blood, and these people also have incredibly low incidence of heart disease.
- Modifying cholesterol levels via PCSK9 or statins both have very strong evidence that they work on people who have heart disease, we have many RCT involving people who have already had one heart attack, and they have clear dose response curves: the amount of LDL reduction is directly proportional to risk reduction. We have less clear evidence on healthy people and from diet but those people are just a lot harder to study.
It's true that not everyone with high LDL develops plaque and we don't know why, but I feel a lot of "lipid hypothesis skeptics" tend to swim around in the gray areas and just don't interact with the more smoking gun bits of evidence that have to be explained away if you are going to say that LDL has no effect.