#2262

I would be cautious about reducing acetyl-CoA levels even in the liver.

I am not aware of to what extent it is active in other tissues.

In the end have the study above which concluded it did not reduce ACM, but did reduce non-fatal heart attacks.

Activating AMPK should be good.

#2263

Higher acetyl-CoA in the liver leads to negative effects though, as evident by the massive amounts of people dying from dyslipidemia etc. Removing LDL from the blood by inhibiting synthesis of LDL’s is good.

It needs to be converted to Bempedoyl-CoA to inhibit ACLY, which requires Very long-chain acyl-CoA synthetase or ACSVL1 which apparently is mostly in the kidney and liver.

Bempedoic acid (that does not inhibit ACLY) activates AMPK and lowers CRP and it is in other tissues, decrease in CRP shows in clinical trials, it might also be a HDAC 6 inhibitor, what do you think of that since I’ve seen you post about that before?

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#2264

Absence of evidence is not evidence of absence.

#2265

So it would reduce acetyl-CoA in the kidneys as well. Hence CKD.

Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18 200 patients (9765 on bempedoic acid, 8435 on placebo). Bempedoic acid significantly reduced MACEs compared with placebo (OR 0.84 [95% confidence interval (CI) 0.76–0.96]; P < 0.001; I 2 = 0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69–1.08]; P = 0.20, I 2 = 0%) and all-cause mortality (OR 1.19 [95% CI 0.73–1.93]; P = 0.49; I 2 = 18%).

I read this as ACM going up, but not statistically significantly.

#2266

You make several good points John. Too many people advocate for popping these pills like they’re candy without a full understanding of the complex biochemistry involved and the ramifications.

The goal should always be absolute reduction of total mortality rates. It’s ludicrous to reduce CV mortality while increasing the mortality from something else. The exception would be if you’re at high risk from CV disease but perhaps very low cancer risk. In that scenario, the risk may well be worth it.

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#2267

I don’t personally have a horse in this race. If I were to wish to reduce cholesterol (ApoB or LDL-C) I would not use this approach.

My own ApoB is at the high end of OK and my LDL-C floats around the 3 mmol/l threshold used in the UK. Hence I see no reason to do anything about it.

#2268

Yes that is how it is with a p-value of 0.49, just noise.
I will have to read more about this mechanisms, but I am very skeptical right now of your acetyl-CoA hypothesis and how to even compare it with proven decreases in LDL and of course also AMPK activation (decrease in CRP etc).

You have a patent related to increasing acetyl-CoA?

Once I understand the acetyl-CoA hypothesis better and the mechanism of action of bempedoic acid I would personally able to compare treatments with each other.

Of course but very few interventions can ever detect a difference in mortality rates as fortunately it is so rare (time & size of trial).

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#2269

There was an increase in cancer in one trial of bempedoic acid, and the cancers were early on in the trial which the authors suggest probably is due to preexisting cancers. But a mendelian randomization study of lifelong ATP citrate lyase levels decrease and showed no increase in cancer and a decrease in rate of cardiovascular events:

A greater number of deaths occurred in the bempedoic acid group than in the placebo group. The deaths from cancer generally occurred early in the course of the trial, a finding that probably represents preexisting cancers. No patterns or imbalances in nonfatal neoplasms were observed in our trial, and nonclinical data have not shown evidence of such neoplasms with bempedoic acid treatment to date (unpublished data). Hence, the observed imbalances in deaths from cancer are likely to be a chance finding. No significant between-group differences were observed in the incidence of cardiovascular events or mortality. A mendelian randomization study modeling the effects of lifelong lowering of ATP citrate lyase levels, the results of which are reported in this issue of the Journal ,16 suggests an association with a lower risk of cardiovascular events and no excess risk of cancer. Safety data with longer-term exposure are being assessed in a long-term, open-label extension of the present trial and in an ongoing cardiovascular-outcomes study.

https://www.nejm.org/doi/full/10.1056/NEJMoa1803917

Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer.

https://www.nejm.org/doi/full/10.1056/NEJMoa1806747

#2270

I have a patent application relating to acetyl-CoA, but I don’t have a horse in the race as to whether to take bempedoic acid or not. It may be good for some people in very limited circumstances, but I am doubtful.

The issue about mRNA transcription (and translation) is detailed on my blog. This gives a good start:

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#2271

The normal reason why ACLY does not produce enough Acetyl-CoA is a shortage of citrate not a shortage of ACLY. However, if you are setting out to reduce Acetyl-CoA production then that will impact on ac-CoA availability.

#2272

Two recent papers:

Clinical Benefit of Bempedoic Acid in Randomized Clinical Trials

The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. 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.

and

Bempedoic Acid: A Contemporary Review of Its Pharmacology, Efficacy, and Safety Profile, Including Recent Data from the CLEAR Outcomes Clinical Trial

Recent findings: The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women.

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#2273

I found a study showing bempedoic acid is also an mTOR inhibitor, but it seems everything is nowadays so I am skeptical.

#2274

quote=“John_Hemming, post:2250, topic:1434”]

Personally I would not wish to take an ACLY inhibitor as this would cause difficulties with histone acetylation

This is a risk with the bempedoic acid part of that two drug combo right, not related to the ezetimibe component?

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#2275

Yes it is related to bempedoic acid and not ezetimibe.

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#2276

Thank you @AnUser (extra characters)

#2277

How does one best increase citrate intake - perhaps by taking potassium or magnesium citrate?

#2278

It appears bempedoic acid is better suited as an adjuntive therapy to statins similar to ezetimibe.

#2279

I take a high dose magnesium citrate and a low dose potassium citrate every day. Potassium is hard on the kidneys so better keep that dose low.

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#2280

I wrote about it here:

It is quite complex because if you want to get it right you need to take a few grams every half hour or hour or somewhere in between.

I tend to want to finish with citrate by 3pm at the latest.

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#2281

I just purchased some of the Bempadoic + Eztamibe combo drug and wasn’t able to get a price back from Guru Baba though they appeared to have the lowest price upon searching. A few other companies had it for about 40 cents a pill before shipping. Nilkanth had the Zydus version, so I went with that. Also bought some 5 mg Rosuvastatin for like 5 cents a pill.

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