#43

If I understand things correctly, looks like a mini dose of 50mg (normal US approved dose is 180mg) would add an additional ~20% lowering on top of statin or PCSK9

(see paper below and similar magnitude to the paper I quoted from above)

You can look at the model inputs here and run other scenarios (Tables 1 and 2):

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#44

I’m taking a generic comb of bempedoic acid and ezetimibe from India, but I’m considering looking for a source of branded bempedoic (Nexletol) to make sure it’s up to par for quality/safety. Is it naive to think that a branded prescription from India is unlikely to be fake?

Either way, sounds like I’d get virtually the entire benefit of both meds by just taking half a tablet of the combo med daily.

#45

I don’t know. The good news is you can easily check if its working well via a lipid blood test.

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#46

They could fake it by putting a statin in instead.

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#47

Treatment intensification with bempedoic acid to achieve LDL-C goal in patients with ASCVD: A simulation model using a real-world patient cohort in the US 2024

This simulation shows that adding BA + EZE (FDC) to maximally tolerated statins would result in more patients achieving LDL-C goal than adding EZE alone or NOAT.

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#48

Apologies if this has been raised elsewhere, but it may be best to avoid bempedoic acid + statin

“Tendon rupture, a severe adverse effect of bempedoic acid, results in approximately 0.5% of cases** . All instances of tendon rupture were associated with high-dose statin co-administration, with no reported events of tendon rupture in statin-intolerant patients.”

Bempedoic Acid - StatPearls - NCBI Bookshelf.

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#49

That’s why you would use bempedoic acid plus a statin to avoid using high-dose statin if the statin alone wasn’t doing it.

#50

How much of an extra benefit do you gain using a low dose statin along with Bempedoic Acid + Ezetemibe?

#51

“Studies have shown that adding bempedoic acid to low- or moderate-dose statin therapy provides an additional 15-18% reduction in LDL cholesterol compared to statin therapy alone.”

With no statin but with BA + ezetimibe alone:
“At week 12, BA + EZE FDC therapy lowered mean LDL-C levels by 38.8%, significantly more than ezetimibe alone (19.2%; difference, 19.5% [95% confidence interval ]”

It would be interesting to see what the combo BA +EZE+Pantethetic acid would do.
I can find no published studies evaluating the combination of bempedoic acid, ezetimibe and pantethine.

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#52

Thanks @L_H

(seems that there is no actual source for the statement though, for other statements the educational material was citing things; but not here)

#53

I saw something on the Peter Attia subreddit which got into my brain and I think I like it.
Statins are superior to bempedoic acid because they detected a decrease in all cause mortality and cardiovascular mortality. So statins are superior to bempedoic acid @adssx
The same would be true regarding statins > PCSK9 inhibitors?
It would also improve the case for higher dose statins.

It was not, that was a combined endpoint.

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So statins are better than bempedoic acid.

Apparently no trial have shown decrease in ACM for ezetimibe, so statins are better than ezetimibe as well, though ezetimibe have shown decrease in ASCVD mortality. This would also make me more bearish on CETPi as initially we won’t have this type of data compared with statins.

#54

The problem with Bempedoic Acid is that it is a new drug (Approved in 2020). Statins have been around for 40+ years, so there’s a lot more data. The median length of studies for BA was about 4 years. However, the results, listed below, are quite impressive. With such a marked result in fewer cardiovascular events, I have to believe that BA is as good as a statin and that BA + Ezetemibe is probably superior.

Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6 months. The mean baseline LDLc was 129.4 (22.8) mg/100 ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6) mg/100 ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm.

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#55

There was no significant reduction detected for cardiovascular death or all cause death. That means it is worse than a drug with a significant reduction detected for both.

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#56

I think it just means that we don’t know yet (especially re all cause death where - as you laid out in the past - those trials were not powered for it [Edit: I think, but am not sure in the Eze case, you would have to know that it was - and with a similar degree of powered trial, in a similar at risk, uncontrolled Apo B trial as the statin trial(s) you want to compare again for apples to apples ]).

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#57

How do you know it was not powered for it? There were 17000 patients in the study above combined. This discussion is also about which drug is superior.

#58

Might be wrong on this but think one of the PCSK9i trials (pradulent?) actually did show all cause mortality improvement (even if that was not the goal or power of the study?)

More importantly, how do you weigh the Mendelian Randomization (and mechanistic) data?

Same re CETPi.

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Most importantly, I still think we want to approach this as personalized medicine, including whether a given person is a high producer or high absorber (simple blood test) could make a big difference in which Apo B lowering med is optimal for that person vs just going after crude averages from the trials alone?

(Or - while not you Anuser, eg for 20% of people with high Lp(a), PCSK9i will often have an additional edge)

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(Re Peter Attia: he seems to personally think that PCSK9i, Bemp A and Eze might be better for him and his patients based on most recent interviews/his most recent understanding, etc? Even if he still thinks statins play a key role and understand the cost considerations)

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#59

It was a post-hoc analysis.

You prioritize the intervention that has detected a decrease in ACM or if that wasn’t detected, at least a decrease in cardiovascular death. Even though it decreases a causal factor, it might negate it in other ways.

#60

See my edit above (extra char)

#61

I don’t have anything more to add at the moment. If I am reducing my apoB I will of course pick the strategy which have detected decrease in ACM or if that isn’t detected at least cardiovascular death.

Not sure what you mean with ezetimibe.

#62

No worries no need to spend time on it. We both agree that Apo B down is the bigger order of magnitude as long as you are not experiences negative side effects that you can observe in blood work or subjectively when choosing from the main well tested drugs.

Which one or combo among them is a bit of a secondary level decision at this point.

Last comment is to perhaps looks at these types of studies to inform your decision if goal is longevity (I haven’t read it, but seems to be a good example)

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis

This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

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