00:32 brain cholesterol is separate from plasma; most cholesterol in the body is inside cells, not in bloodstream; most cholesterol in blood is in RBCs, not lipoproteins ▶️ so reducing serum cholesterol has little to no effect on cellular cholesterol requirements
00:36 it's not cholesterol in the arterial wall that poses a problem, it's trafficked cholesterol inside lipoproteins (digested by macrophages)
00:41 most people with low HDL-C have high ApoB. this may underlie the positive association btw HDL-C and CVD seen in observational studies
00:42 trials (via diff techniques and mechanisms) have consistently shown a neutral (at best) or detrimental (at worst) effect of raising HDL-C on CV risk
HDL particles may/probably play a role; HDL-C is a 'useless metric'
00:59 OxPL/ApoB measures oxidized phospholipids in apoB particles (predominantly on lp(a)) and may be an additional risk marker, particularly in those with high lp(a)
01:08 antisense oligonucleotides (ASO) in development for elevated lp(a)
01:09 statins can (in some people) raise lp(a), but net effect (via lowering of overall LDLs) is still likely positive
1:10 PCSK9is can lower lp(a) in addition to lowering LDL/LDL-c
TG content of lipoproteins (including LDLs) can determine particle half-life, structure and function
LDL-C is a reasonable yet imperfect metric of CV risk; nonHDL-C is a bit better; but ultimately risk tracks with ApoB (LDL-C and nonHDL-C can be misleading in discordant patients)
bempedoic acid (approved 2020) is a non-statin, cholesterol lowering drug that inhibits the cholesterol synthesis pathway (upstream of HMGCoA reductase, the target of statins)
01:35 bempedoic acid is hepato-selective and doesn't enter the myocyte, avoiding (or at least reducing) the muscle pain secondary effect of statins
01:40 TGs supported by both pharma and mendelian rando as important metric. can be lowered with fibrates or omega 3s (EPA/DHA, high doses required, >2g/d, max=4g, ≤1g likely does nothing)
Re: heart disease in particular, we can find heterogeneity in the literature. Some studies point to a signal of risk for eggs, others find no stat sig effect.
One of the main differences between science and Social Media content is how they deal with heterogeneity.
Social Media feeds you polarization. One FB forum argues eggs are poison, and shows you only the studies reporting risk.
Another argues eggs are a perfect, risk-free superfood, and shows you only favorable studies.
over 2 months, he lost 27lbs. his BMI came down to the normal range
his LDL-C dropped 20%. his triglycerides, 39%
his anecdote illustrates a couple points:
▶️we can lose weight on almost any type of food, as long as we cut calories enough
▶️ some foods make it easier to cut calories. calorically concentrated junk food makes it easier to overconsume calories, so for most people they're not ideal. most people won't achieve the precise control on a day to day basis that the Prof exercised in his experiment
Does high ApoB still raise risk if I´m “metabolically healthy”?
The evidence indicates it DOES.
(thread)
The idea that cholesterol level is completely irrelevant has largely subsided.
As the public is exposed to more scientific evidence, it has become increasingly obvious that blanket denial is not realistic.
So a more nuanced idea emerged.
“it´s about context”
According to this idea, high cholesterol/apoB increases risk in “sick” people (e.g. insulin-resistant/obese/diabetic) but is harmless for the insulin-sensitive & lean