Rapamycin and risk of cardiovascular disease

[Neo]

@L_H

Fourier trial isn’t convincing to me

Thanks for your response.

Have you read about/are your familiar with

• people that genetically naturally high vs low PCSK9?

• Mendelian Randomization studies on PSCK9 across the population and the casuals evidence from that in support of PSCK9 down = really good?

• other PCSK9i clinical trials

Each of these alone and combined suggested that the risks reward of PCSK9i is good and likely better than that of statins.

It might be good to take a look at those three other buckets of evidence if you want to evaluate PCSK9i and Repatha

[LaraPo]

It was a great discussion with both sides presenting their interpretation of the study on Repatha. I enjoyed it . It helped me to make a decision not to use Repatha at this time and try other methods (rosuvastatin + ezetimibe, supplements like Nattokinase and Lumbrokinase, Alma fruit, French bark, B5, aspirin, and possibly Cavadex). I regret that I didn’t do a calcium score test earlier and wondering why none of my providers ever mentioned it to me.

[scta123]

@Neo

Each of these alone and combined suggested that the risks reward of PCSK9i is good and likely better than that of statins.

Rapamycin and risk of cardiovascular disease

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/full#CD011748-sec-0067

[John_Hemming]

I tried (not particularly hard) to get a calcium score and the medics in the UK said it was too invasive unless you had good reasons for doing the test. I did not push it although I had an ultrasound test which did not indicate any calcium in the wrong places.

I have started going to the gym with my older son (who is 30). I intend trying to find out how fast I can build my heart rate up to. On my first visit (last week) I was a bit careful because I did not want to ache for a number of days. In fact I did not ache at all - which surprised me. I hit 144 bpm which is not that high, but is higher than I did in my 40s. (I am 63).

[LaraPo]

Calcium score test is not invasive - it’s a short 10 min scan procedure. There’s of course a radiation concern, but if a scanner is CT-C3000 the radiation is minimal. Insurance doesn’t cover it, but it’s not that expensive ($150). I plan to do a carotid arteries ultrasound. My previous one 5 years ago was clean.

[desertshores]

Where is this discussion going? Are people disputing that lower LDL is not better at reducing all-cause mortality?

There is NO compelling evidence to dispute this.

Doctors who study lipidology and its effects think that lower is better.

“There are about 700 board-certified lipidologists in the US and Canada, but only about 50 “dedicated” lipidologists, who work exclusively with cholesterol and atherosclerosis.”

Leading Lipidologists Endorsing Lower LDL Targets
Dr. Michael Miller - Professor of Cardiovascular Medicine at the University of Maryland School of Medicine
Dr. Christie Ballantyne - Professor and Chief of Cardiology at Baylor College of Medicine
Dr. Seth Martin - Director of Advanced Lipid Disorders Center at Johns Hopkins Hospital
Dr. Pamela Morris - Director of Preventive Cardiology at New York-Presbyterian Hospital

For me, the preponderance of the evidence indicates that lower is better.
The evidence for the lowest possible LDL being best is just not there.

As far as ASCVD-Risk is concerned, blood pressure seems to be a more important factor according to this calculator. (Which actually kind of sucks because it won’t accept my age or LDL levels)

Of the variables the calculator uses is BP. Fairly small changes in BP produce a bigger change in the outcome than LDL levels.

https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate

[L_H]

Hi Anuser,

1. You’ve just requoted the full quote that I quoted earlier in the thread. The reason I cut it in half was merely because my post was already very long and so i only included the directly relevant part. The second half of the quote merely eliminates one legitimate reason why they might have made the change halfway through the study. I repeat: I’ve never made any claims as to why they did this. If you don’t believe me, go back and read what I’ve posted. The fact that you are resorting to “tinfoil” conspiracy allegations, suggests that it’s actually you who is being intellectually dishonest.

2. The divergence is a point of numerical fact. It is also a point of fact that they terminated the study early before any statistical significance could be determined. That’s not to say statistical significance would have emerged over time - it’s simply saying that we won’t ever know because the trial was terminated early.

3. Again you’re using a straw man argument. I never said that I “believe in” anything. I am merely saying that their negative findings are partly why I am not “convinced” by this Fourier study. Where you’ve made another factual error is that the independent commitee was also blinded. It seems silly making things up just to fit your narrative of “Rogue doctors”. They had access to the narrative in the CSR and the original team failed to respond to all communications from the reviewing team - another yellow flag.

I suspect you’re “convinced” by the Fourier study because you want to believe it. But I am simply putting for forward factual reasons why I’m not personally “convinced” by it. The fact that you find this so hard to accept is probably worth mulling on. My motivation is that I’m keen that anyone reading this board isn’t given a once-sided argument to lower their ldl-c to extremely low levels (c.30 mg/dl) without understanding some of the fact and questions surrounding this trial.

[Virilius]

While lower LDL-C/apoB is always better (until 20-38mg/dL is reached), not every medication that lowers LDL-C necessarily provides a benefit when it comes to all-cause mortality. The atorva-/rosuvastatin+ezetimibe combination has proven itself in clinical trials so far while PCSK9i (at least in the study above) showed a (statistically not significant) trend towards higher all-cause mortality.

[L_H]

@Neo

Have you read about/are your familiar with

• people that genetically naturally high vs low PCSK9?
• Mendelian Randomization studies on PSCK9 across the population and the casuals evidence from that in support of PSCK9 down = really good?
• other PCSK9i clinical trials

Hi Neo,

Thank you, yes I am aware of the evidence, but I haven’t gone into it sufficiently throughly to overcome my ‘first do no harm’ bias. Are there any particular studies you’ve found to be strong? I’d love to have a look.

[AnUser]

@Rapamycin and risk of cardiovascular disease

While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals.

This is misleading when out of context, because “adverse signals” for or against, is related to only a few specific diseases which they studied there.

To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.

@L_H

Where you’ve made another factual error is that the independent commitee was also blinded. It seems silly making things up just to fit your narrative of “Rogue doctors”.

I didn’t read their report, but thanks for pointing that out.

@L_H I kind of appreciate the discussion if I learn something from it, and if this study is concerning to you, then there is simply Praluent which is a PCSK9 inhibitor too but where a detection of a decrease in all cause mortality was shown.

@Virilius

while PCSK9i (at least in the study above) showed a (statistically not significant) trend towards higher all-cause mortality.

Praluent detected a decrease in ACM.
https://www.nejm.org/doi/full/10.1056/nejmoa1801174

[L_H]

@Rapamycin and risk of cardiovascular disease

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/full#CD011748-sec-0067

Yes I think it’s the safety data that puts me off acting now. Both on PCSK9i and targetting an extremely low apoB.
Having said that - the risk reward profile for each person is different. I’m lucky to have below 70 mg/dl apoB naturally (without any pharma help). And I’m hopeful that I should be able to get close to 50 with just microdosing rosuvastatin and ezetimibe (2.5 mg of each eod). My intention is to trial this for 6 months and test every three months.

[L_H]

@AnUser

Praluent detected a decrease in ACM.
https://www.nejm.org/doi/full/10.1056/nejmoa1801174

That looks interesting thank you. Just shows you can look through the “noise” of all cause mortality if you keep going for long enough!
I note that the treatment group in that study had relatively high ldl-c compared to the levels we’ve been discussing though. Ldl-c at 66 mg/dl by the end of the period (40 at the beginning). So apoB higher than that. The placebo group was at 90 to 103 mg/dl over the period.
So I don’t think it adds to the argument to go extremely low.

@AnUser

I didn’t read their report, but thanks for pointing that out.

Seriously? We had that huge debate about Fourier and the report criticising it - and you never read the report criticising it??? What were you basing your reasoning on?

[AnUser]

Children and newborns have very low LDL, does that convince you that it’s safe?

@L_H

Seriously? We had that huge debate about Fourier and the report criticising it - and you never read the report criticising it??? What were you basing your reasoning on?

I probably have looked at it, but I didn’t read it in detail.
There are those who suggest that it wasn’t blinded:

To TCTMD, Nissen said the Cleveland Clinic’s academic research organization, known as C5Research, which he heads up, has a professional, experienced team of adjudicators, just like the TIMI group, with all clinical outcomes analyzed according to rigorous standards. An unblinded post hoc analysis introduces its own significant bias, he said.

And in the report, there is a “validation committee” that wasn’t blinded:

The Validation Committee also confirmed that all potential cases for readjudication had been evaluated, and that readjudications achieved by consensus of the Readjudication Committee were consistent with the information in the CSR narratives.

So I was wrong that I was wrong, and it wasn’t blinded after all.

[L_H]

@AnUser

Children and newborns have very low LDL, does that convince you that it’s safe?

No. Sadly I’m neither.

[Virilius]

Appeal to nature fallacy. Safety data should be derived from rpcs only.

[scta123]

@Virilius

rpcs

What did you mean here? Randomized control trial? RCTs?

[Virilius]

Randomized, placebo-controlled (rpc) trials.

[AnUser]

Lowering cholesterol to 'levels of a new-born' cuts heart attack risk |...

[Bicep]

Newborns don’t have the microbial burden the oldsters have. They don’t need the LDL’s to clean up the mess. We do.

[AnUser]

Too bad the data is from lowering LDL in 60 year olds then.