adssx
#2992
From last month: Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality
Our findings provide genetic evidence suggesting no threshold of lowering apoB or, equivalently, LDL-C (ie, the main apoB-containing lipoprotein) for reducing risk of CAD, all-cause mortality, and CVD mortality, further supporting the concept of the lower the better.
They didn’t look at below 0.7 mg/dL though:
However, they cite another MR that looked at below 50 mg/dL: Efficacy and safety of low levels of low-density lipoprotein cholesterol: trans-ancestry linear and non-linear Mendelian randomization analyses 2023
Our findings are consistent with a recent MR study showing no threshold in the association of LDL-C with CAD, although that study used a different approach for instrument selection and lacked power to detect a significant association of LDL-C with all-cause mortality.
4 Likes
L_H
#2993
I haven’t access to the full study yet, but interested to understand more from it re:
“There are potential safety concerns (including haemorrhagic stroke and dementia) for people who have low LDL-C levels.”
The summary data is well worth exploring:
4 Likes
adssx
#2994
Indeed, they found:
In the UK Biobank, when restricted to individuals with low concentrations of below 70 mg/dL, LACE estimates demonstrated that genetically proxied lower LDL-C levels were significantly associated with an increased risk of haemorrhagic stroke [OR, 0.72 (95% CI, 0.54–0.96); P = 0.03] and dementia [OR, 0.75 (95% CI, 0.59–0.97); P = 0.03].
In contrast, a non-significant inverse association with dementia was found in Chinese. This non-significant result may be due to the use of the Mini-Mental State Examination (MMSE) to define dementia outcome, which differs from the definition in the UK Biobank.
Finally, the statistical powers of some outcomes (e.g. haemorrhagic stroke and dementia) are relatively low in the UK Biobank and the China-PAR project, which may raise the concern of false negatives in the linear and non-linear MR and less robust evidence of significant associations in the stratified analyses. Further studies with a larger number of participants are needed to validate our results.
The editorial comment for this article says: LDL-cholesterol lowering: to be or not to be too low
However, low genetically proxied LDL-C is inversely associated with diabetes incidence and marginally statistically related to two other outcomes, dementia and haemorrhagic stroke. The authors contend that their findings should raise concern about dementia and haemorrhagic stroke as serious adverse effects when extreme lowering of LDL-C is undertaken.
The Mendelian randomization approach is probably valid but still involves some extrapolation to measured LDL-C and its lowering by medication. The authors excluded the lowest extremes in their LDL-C distributions (<50 mg/dL in the British and <20 mg/dL in the Chinese), which might be the most informative group for detecting adverse effects with extreme lowering of LDL-C. The diabetes finding is opposite to the clinical trial findings for statin use. The haemorrhagic stroke finding was based on only six events regressed across the LDL-C range 50–70 mg/dL in about 800 people among the British; though there were higher case counts in the Chinese, there was no excess risk across the LDL-C range 20–69 mg/dL. Dementia was based on a weak diagnostic tool, low Mini-Mental State Examination score, without additional neurological investigation. Many comparisons were made, weakening statistical inference and yet still finding mostly marginally statistically significant results. These issues further weaken the Mendelian randomization approach. Therefore, we accept their caution about possible adverse effects, but pending further investigation, tend to accept the lack of adverse effects of PCSK9 inhibitors and the known, largely controllable adverse effects of statins as indicated in the individually randomized studies of measured LDL-C.
5 Likes
adssx
#2995
@AnUser @Neo: Can we conclude based on this that, not taking into account the financial aspect, and assuming you can achieve the same LDL target, PCSK9 inhibitors (and maybe ezetimibe) are better than statins for lifespan extension?
1 Like
scta123
#2996
I don’t think there is enough data for PCSK9i at this moment that would warrant PCSK9i in primary prevention as the first line of drug.
Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011748.pub3
adssx
#2997
This is a Cochrane review from 2020. It’s outdated.
2 Likes
scta123
#2998
Do you know are there any new reviews that include any new relevant data?
adssx
#2999
We don’t have something as good as a Cochrane review but we have:
They all point to a high efficacy and safety. But they mostly look at very-high risk patients. I don’t know if we can conclude yet about statins vs PCSK9 inhibitors indeed. It would be great for Cochrane to update their review with the current evidence.
4 Likes
Neo
#3000
There are some signals in that direction, but think it’s again one of those where we just don’t know enough (yet).
One of the problems with the MR of PCSK9 is that we don’t know how much it matters that genetically lower PCSK9 through development and childhood AND in the brain/CNS (that are part of MR analyses) whereas the current PCSK9i antibody based drugs are probably not crossing the blood brain barrier and are not generally started until in adulthood.
For me it was enough that PCSK9i is the only Apo B lowering option that has a somewhat material Lp(a) lowering effect for it to be worth that being my base medication for now. Will keep evaluating as time goes by.
4 Likes
AnUser
#3001
Based on that study, slight yes just because an effect was detected for PCSK9i.
If you can’t monitor desmosterol then it can be better for preventing Alzheimer’s especially if you have an apoE4 allele.
I don’t know how it would compare on vascular dementia and depression. A lipophilic statin might be good for both especially in case of genetically elevated LDL in the brain. Alzheimer’s isn’t the only dementia that exists. Desmosterol hypothesis is kind of weak anyway. Statins also have widespread use like atorvastatin and lots of data.
2 Likes
I found this interesting tidbit from Consumerlab:
Several clinical studies show that adding sterols or stanols, usually incorporated in a margarine or spread, to statins results in an additional 7% to 10% reduction in LDL cholesterol. (Blair, Am J Cardiol 2000; Cabezas, J Am Diet Assoc 2006).
ConsumerLab recommends a product called CholestOff Plus
L_H
#3003
Thought this was interesting. A reminder that one answer may not fit all. Genetics can impact efficacy of cholesterol treatments
“Additionally, apoB was reduced significantly in patients with AA or GA, but not GG, with both pravastatin and policosanol (Liu et al., 2016). Policosanol is typically initiated at 5 mg/day and titrated up to 20 mg/day for hypercholesterolemia.”
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/policosanol
1 Like
AnUser
#3004
I haven’t looked into this in detail, but can the plant sterols be atherogenic?
1 Like
I haven’t looked into it much either, but it’s what ConsumerLab recommended for lowering LDL.
adriank
#3006
I’m on my 3rd week and the most noticeable thing is my blood pressure dropped from 140/90 to 120/80. Previously my blood pressure has always been good but in the last 6 months I’m not sure why it went up. Anyway now it has normalised.
1 Like
Bicep
#3007
You probably aren’t crazy about Paul Mason, but in this video he shows pictures of plaque with what look like cholesterol crystals and says they are camposterol from plant oils. They lower LDL but do the same thing:
1 Like
AnUser
#3008
Yes I do not like Paul Mason’s opinions in general.
There is a genetic condition with hyperabsorption with lots of negative effects:
Ezetimibe works as a treatment and blocks absorption. Anyway I wouldn’t use plant sterols to reduce cholesterol levels.
They are more atherogenic than cholesterol according to Peter Attia and are carried in lipoproteins:
3 Likes
AnUser
#3009
What about pitavastatin?
High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD) 2018
High potency, low drug-drug interactions (based on metabolism), increases HDL a bit, lipophilic, apparently less glucose increasing effect.
About the REPRIEVE trial:
https://www.reprievetrial.org/learnmore/participant-faq/
2.3% had muscle side effects compared to 1.4% for placebo.
5.3% developed diabetes compared to 4.0% for placebo.
REPRIEVE results revealed that pitavastatin, a statin medication and the heart disease prevention strategy tested in the trial, reduced major heart disease events like heart attacks and strokes in people with HIV by 35% compared to placebo. Pitavastatin also reduced major heart disease events or death from any cause by 21% compared to placebo.
Pitavastatin was effective in both men and women, and the study participants experienced very few safety events.
nejmoa2304146.pdf (799.8 KB)
2 Likes
AnUser
#3010
Adding ezetimibe improves LDL better than doubling statin dose, 2020.
Peter Attia says they think probably Pitavastatin, Rosuvastatin probably the best place to go if choosing a statin (3 months ago), but it’s all highly individualized and to try a couple if choosing a statin to the one that does the best without any collateral damage.
I might try Pitavastatin 2 mg after I run out of rosuvastatin, it seems better. He mention to start with only third generation statins, and highly potent ones.
This guy doesn’t like pitavastatin:
It’s not a very popular statin, so rosuvastatin might be better after all…
3 Likes
Nah. I don’t have anything against rosuvastatin, that is the one my daughter takes.
I take atorvastatin plus ezetimibe and see no reason to change based on the studies.
“According to subgroup analysis of the 11 included studies (Fig. (Fig.2),2), the combination of ezetimibe and atorvastatin (10 mg) (Sakamoto K 2017, Sakamoto K 2015, Matsue Y 2013, Okada K 2012) [MD = -16.98 mg/dL, p < 0 .0001] or simvastatin (20 mg) (Le NA 2015, Averna M 2010) [MD = -17.35 mg/dL, p < 0 .0001] also showed stronger ability of reducing LDL-C, while the combination of ezetimibe and rosuvastatin (10 mg2018,) Ran D 2017, Farnier M 2016, Saeedi R 2015) [MD = -9.29 mg/dL, p = 0.05] showed less relevant.”
1 Like
