#1
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About to start Rapamycin for the first time
Rapamycin Holidays (Cycling Protocol), and Antibiotic Usage for Acne
#2

Again one of those studies where big pharma pulls one their usual slight of hand tricks: if you give a preventive treatment all cause mortality needs to be lower in the treatment group not just the so called primary endpoints of cardiovascular deaths. I won’t even mention the the rhabdomyelitis and severe infections in the treatment group (which the investigators conveniently deemed not related)

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#3

Afaik it’s difficutl to detect differences in all cause mortality in short term study. With that being said, because bempedoic acid only reduces LDL-C by around 20-25%, it’s better used in combination with a statin or a PCSK9i than as a standalone.

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#5

Well the authors did suggest that in the discussion, 15% less chance of dying from cardiovascular cause but of course since the all cause mortality in the treatment group was slightly higher that just means people died from other causes instead…

The risk of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (the first key secondary end point) was 15% lower with bempedoic acid than with placebo,

#6

What does fatal mean to you?

The ACM sophistry is still going on I see.

Absence of evidence is not evidence of absence.

#7

That’s not sophistry that’s showing the mirrors and wires of the magician. It should be obvious to anyone that if you treat one group against a fatal disease and don’t treat the other group, not only the mortality for that fatal disease should be lower but also the all cause mortality. If the ACM is the same it just means the treatment kills people of other causes

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#9

Again what do the authors conclude:

The risk of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (the first key secondary end point) was 15% lower with bempedoic acid than with placebo,

but since there was ACM was slightly higher in the treatment group you don’t even need a course in statistics, just common sense to know that therefor the treatment made people die from other causes. You cannot have your cake and eat it too, either there was no difference in one of the endpoints (death from cardiovascular causes) between treatment and placebo or the treatment reduced cardiovascular deaths but causes deaths by other causes

#10

No it was not ‘slightly higher’ since there was no statistical significance. You are making fake patterns out of noise.

The null hypothesis is that there is no difference in all cause mortality, the default assumption, and you need statistical significance to disprove the null hypothesis.

It was proven that the intervention decrease risk of death from cardiovascular disease, etc.

#11

Why all-cause mortality should not be the primary outcome measure for trials of cancer screening

Prasad accepts that all-cause mortality is an insensitive outcome in the assessment of the efficacy and harm arising from medical screening programmes, but says it is necessary. The use of insensitive and uninformative endpoints in clinical trials is bad science. It would delay and possibly prevent effective programmes from being adopted (and prolong trials of ineffective interventions). Disease specific outcomes need to be examined.

All-cause mortality will generally be dominated by causes of death that are unrelated to the screening and any intervention that follows, so that any benefit (or harm) from screening will be concealed. This is not to say that a direct assessment of all-cause mortality should be ignored. It may indicate possible benefit or harm but failure to reveal either does not exclude the existence of clear and sufficient evidence of benefit or harm. It is the insensitivity (and lack of specificity) of all-cause mortality as an outcome that is the problem, not the outcome itself.

Traditionally, innovations in cardiovascular medicine (including preventive therapies) have been assessed in terms of cause-specific morbidity and mortality. More recently, some have argued that such therapies should not be used unless they have been shown to reduce all-cause mortality. Here, we argue that such an approach is bad science and makes a mockery of evidence-based medicine.

Cardiovascular therapeutics should aim to reduce mortality, but it is not necessary to demonstrate a reduction in all-cause mortality when assessing them. It is, in general, misguided to attempt to demonstrate such an effect because it is too crude a measure of either benefit or harm. Results are dominated by causes of death unrelated to the intervention—the signal-to-noise ratio is low. Most effective interventions in public health and preventive medicine that have together led to substantial improvements in life expectancy would not have been introduced had policymakers required direct evidence of an impact on all-cause mortality.
Suppose a particular cause (X) is responsible for 5% of all deaths in the target population over the next 15 years, and consider an intervention that prevents 70% of deaths from X (see Figure A). Suppose 3% of the target population will die over the next 15 years. If all-cause mortality were the end point, it would need 1 095 000 individuals randomized equally between the intervention and no intervention to have 90% power to show the benefit; using cause-specific mortality, it would need only 41 000 individuals. How is it possible to justify conducting a study that is >25 times larger than needed? Conversely, using all-cause mortality to guide decisions regarding futility in clinical trials may be misguided, as shown in (Figure B).

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.023359

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#12

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial !

In conclusion, among patients with diabetes unable or unwilling to take guideline-recommended doses of statins, bempedoic acid used as monotherapy provided significant, clinically meaningful reductions in cardiovascular events. Furthermore, consistent with genetic studies, bempedoic acid did not increase the risk of new-onset diabetes nor worsen measures of glycaemia among those without diabetes. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for patients with and without diabetes who are unwilling or unable to take guideline recommended doses of statins.

New Paper, Open Access

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial:

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(23)00316-9/fulltext

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#13

Jagdish has already sent my 6 month supply of bempedoic acid to my courier. I’ll start taking it in 2024!

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#14

Bempedoic Acid is relatively expensive. Is anyone getting results in terms of blood test metrics that are significantly better than with ezetimibe alone?

#15

It should be better than Ezetemibe and on par with a statin. You can get it cheaper from India.

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#16

Jagdish also carries the combo med (bempedoic+ezetimibe), so one could get the benefits of both in one tablet per day.

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#17

Does anyone know what the dose to effect curve on Apo B from bempedoic acid looks like?

Is it similar to statins where a low dose gives the majority of the effect and even if more effect comes from a larger dose there are significant diminishing effects?

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#18

These papers on Bempedoic Acid may answer your questions.

#19

Thx. Skimmed them but was not able to see the answer.

Btw, I was not aware that it increases AMPK - that is a very nice longevity supporting “side effect”…

From the second paper

In preclinical animal models, free bempedoic acid increased the activity of AMP-activated protein kinase (AMPK) [16]

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#20

Looking at the references it also affects ACLY (ATP - Citrate Lyase)

#21

It has a really small effect on apoB in full dose (around 15% reduction). From what I read it has a negative effect on kidney and liver function… I would think twice to use it as a primary prevention. Similar decrease in apoB can be achieved simply by adding 15 grams of soluble fibre to your diet. Nothing major with probably more benefits than just apoB reduction IMO.

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#22

Liver injury from BA is rare at 1%. Best to check your liver markers regularly to be on the safe side. But it seems incredibly rare.

Since the approval and more widespread use of bempedoic acid, there have been no published reports of clinically apparent liver injury attributed to its use.

Kidneys seem to be OK unless your kidneys are in serious trouble.

BA is likely safe to take if you have mild to moderate kidney problems. But it’s not known if the drug is safe to take if you have severe kidney problems such as end-stage kidney disease and you’re on dialysis.

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