Bempedoic Acid Reduces Cardiovascular Events

[AnUser]

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.

[Neo]

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.

Genetic insights into the association of statin and newer nonstatin drug...

[AnUser]

@Neo

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)

Outcomes in RCT’s is way more important. A drug can target a genetic longevity pathway in a way that is harmful.

[Neo]

Both sources of data in this situation seems to better than one only source (even if that source is better), if you were forced to only look at one source for some arbitrary reason.

Seems like an and and not an or case.

[DeStrider]

You can always take a low dose statin + Ezetemibe + Bempedoic Acid. The improvements are cumulative.

And for those of us who are intolerant to statins, Bempedoic Acid + Ezetemibe is our cost-effective solution.

[adssx]

I thought it was you @AnUser who posted the paper saying that we needed a trial with something like 100k+ participants to be able to reach a conclusion on all cause mortality and that everything else was just noise?

Ezetimibe might have pro longevity effects in men btw: Higher LDL-Cholesterol is Associated with Greater Longevity? - #146 by adssx

And yes, bempedoic acid is so new, with so few RCTs, that it’s hard to conclude.

[adssx]

@AnUser

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

Also: what’s the source? And is it an apple to apple comparison? Most trials of ezetimibe and bempedoic acid (alone or in combination) use these drugs in addition to statins or as first line therapy in statin-intolerant people. If we want to compare the effects on mortality of statins vs BA or EZE we need to look at RCTs that considered drug naive patients with dyslipidemia.

[AnUser]

JUPITER, among others for other statins, have detected decrease in ACM, so it is possible to have enough statistical power. If ACM has been detected, it is obviously superior as it explains risk vs. reward benefit (net benefit), and that there isn’t side effects which negate the benefits. There has at least been one statin that has been withdrawn from the market, and of course many other drugs.

So a drug that has detected ACM benefit is superior to one that hasn’t.

@adssx

Ezetimibe might have pro longevity effects in men btw: Higher LDL-Cholesterol is Associated with Greater Longevity? - #146 by adssx

Even though a drug can target a longevity pathway, the effect depends on the molecule, so a drug can be harmful even though it targets a longevity pathway.

@adssx

If we want to compare the effects on mortality of statins vs BA or EZE we need to look at RCTs that considered drug naive patients with dyslipidemia.

I don’t think any bempedoic acid trial have detected effects on mortality. If they haven’t studied BA in such a trial, that worsens the case for BA compared to statins?

[L_H]

The Jupiter trial shows an ACM benefit from statins compared to placebo, but the data looks very odd. Im sure this has been covered to death. But its worth remembering that in the Jupiter trial the death rate of people taking statins was much higher than you’d expect in a similar match population of healthy individuals.

“The all-cause mortality in JUPITER was more than twice that of the average of primary prevention studies”

Extreme All-Cause Mortality in JUPITER Requires Reexamination of Vital Records

[scta123]

We discussed some of the controversies in another thread. But just discussing ACM if I remember correct the authors were first publish this graph for ACM excluding some later data and were forced to retract it and change it:

The JUPITER trial is challenging to use as proof of statin primary prevention, as it did not demonstrate a reduction in ASCVD mortality. In my opinion, it was halted prematurely because it was becoming apparent that the net benefit of rosuvastatin was being offset by the increased incidence of new-onset diabetes cases in the rosuvastatin group, among other factors. Additionally, the ACM graph seemed to be showing convergence. Overall, JUPITER serves as a notable example of how statistics can be misleading and how financial interests can influence scientific outcomes.

[KFISH]

Also may help more to reduce Lp(a) and trials suggests this effect on apoB.

[AnUser]

@scta123

But just discussing ACM if I remember correct the authors were first publish this graph for ACM excluding some later data and were forced to retract it and change it:

What retraction? Can you link?

@scta123

The JUPITER trial is challenging to use as proof of statin primary prevention, as it did not demonstrate a reduction in ASCVD mortality.

Where did you see that it did not reduce ASCVD mortality?

@scta123

Additionally, the ACM graph seemed to be showing convergence. Overall, JUPITER serves as a notable example of how statistics can be misleading and how financial interests can influence scientific outcomes.

At the end of the graph, the difference between placebo and rosuvastatin was pretty much greater than at other points in the graph, excluding the period about 3.3-4 years into the study were there were a greater difference. You can also look through the entire graph and see a dozen convergences.

[scta123]

@AnUser

Where did you see that it did not reduce ASCVD mortality?

sample size was about 17+k
CV mortality

placebo: 37 events
MI 6 events
Stroke 6 events
other CV death 25 events

rosvustatin: 31 events
MI 9 events
Stroke 3 events
other CV death 19 events

[AnUser]

All-cause mortality is a more precise measurement, so it doesn’t matter (for example, deaths might be misreported as not CVD related).

[adssx]

@AnUser

So a drug that has detected ACM benefit is superior to one that hasn’t.

Yes.

@AnUser

Even though a drug can target a longevity pathway, the effect depends on the molecule, so a drug can be harmful even though it targets a longevity pathway.

Yes. But here we have pathway (MR) + animal study + RCT in humans hinting at potential longevity effects in men. It’s just a “hint”. TBC.

@AnUser

I don’t think any bempedoic acid trial have detected effects on mortality. If they haven’t studied BA in such a trial, that worsens the case for BA compared to statins?

I agree that the case for BA is not extremely strong (due to the low number of studies), except in statin-intolerant people (and maybe in people with T2D). I was interested in BA, but the +14.8% increase in serum uric acid levels is concerning to me:

• Efficacy and safety of bempedoic acid lipid-lowering therapy: a systematic review and meta-analysis of randomized controlled trials 2023: “There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. […] However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment.”
• Effect of bempedoic acid on uric acid and gout in 3621 patients with hypercholesterolemia: pooled analyses from phase 3 trials 2020: “At week 12, mean (SD) serum uric acid levels (% change from baseline) increased from baseline with BA treatment by 0.82 (0.97) mg/dL (14.8%) vs –0.02 (0.82) mg/dL (0.67%) for placebo. Elevations in serum uric acid levels typically occurred within the first 4 weeks of treatment, remained stable during treatment, and returned to baseline after treatment discontinuation. Gout was reported in 1.4% (BA) and 0.4% (placebo) of patients, and hyperuricemia was reported in 1.7% (BA) and 0.6% (placebo) of patients.”

[AnUser]

@adssx

“There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. […]

That’s good, so there is probably a net benefit. But it is a meta analysis, and that is worse than a large RCT detecting ACM benefit.

[adssx]

I disagree, but it’s OK because here’s a recent review that confirms your point on statins’ benefits: Lipid-lowering therapies for cardiovascular disease prevention and management in primary care PEER umbrella systematic review of systematic reviews 2023 ( Bempedoic acid was not analyzed as part of the review )

Statins remain the lipid-lowering drugs with the most consistent benefits, with a relative risk reduction of approximately 25% for major adverse cardiovascular events (MACE) and approximately 10% for mortality. Although MACE was also reduced with ezetimibe (about 7% relative), fibrates (about 15% relative), and proprotein convertase subtilisin-kexin type 9 inhibitors (about 15% relative), these drugs had no effect on cardiovascular mortality or all-cause mortality.

(still, in primary prevention, ezetimibe and PCSK9 seem interesting, TBC. I’d like to see results stratified by gender as well)

In PCSK9i, alirocumab but not evolocumab reduces ACM (and by a lot more than statins: 0.6 OR!): PCSK9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: a systematic review and meta-analysis 2023

After a median of 26 months, Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, OR 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, OR 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE, OR 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, OR 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality OR 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality OR 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE OR 0.35 (0.16, 0.77, p = 0.01). Insufficient MACE data has been reported for Inclisiran.

(@Neo: which one are you taking?)

This shows that concluding about one class can be irrelevant. We shouldn’t necessarily look at all statins but at the best in class (rosuvastatin?).

Also, lipid-lowering therapies might shift mortality from CVD to cancer in people >75yo: Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis 2024

[AnUser]

@adssx

This shows that concluding about one class can be irrelevant. We shouldn’t necessarily look at all statins but at the best in class (rosuvastatin?).

Yes it’s not enough to to only look at mechanism of action (i.e reducing apoB), but also class of drugs and outcomes (i.e statins) and best in class (maybe rosuvastatin). Ultimately the comparison is between different drugs. Like alirocumab vs. rosuvastatin, or even a combination, like for reducing apoB further, basically the question is what is the best way to reduce apoB? I would still place higher value on drugs detecting effects in large RCT’s compared to systematic reviews summating different values.

Although the data for ACM in the Alirocumab trial was good, they didn’t calculate because they ran into a non-stat sig result before it, which still makes for example rosuvastatin slightly better IMO.

[L_H]

@scta123

sample size was about 17+k
CV mortality

placebo: 37 events
MI 6 events
Stroke 6 events
other CV death 25 events

rosvustatin: 31 events
MI 9 events
Stroke 3 events
other CV death 19 events

Yes the Jupiter data is surprisingly weak, considering they stopped it. Do you know when the staree trial is due to report?

https://www.monash.edu/medicine/staree/home

[Neo]

@adssx

(@Neo: which one are you taking?)

Evolocumab / Repatha. Think the liver risks were smaller.

Was considering a potential shift to Alirocumab / Prauluent recently after some weird Lp(a) numbers and when seeing a cost difference emerge in Praulents favor.

Above makes me want to look into that further. Thank you for sharing.