I take Repatha, 140 every two weeks. No adverse reactions and it has gotten my Lp(a) down from 40 to 29 and also reduced LDLC and APOB. I wrote a longer response on a thread I started about high HDL.
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RobK
#86
As of Feb 20th, one month on Repatha, , my LDL is 17 which is superb; apoB is 28 also super.
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Neo
#87
What were the levels before? Any other Apo a lowering meds?
Any change in Lp(a)?
I’m on-board with trying a PCSK9 inhibitor for my high LDL which I’ve had for years (164 in November, but because of my overall good health i don’t qualify for a statin via insurance). But what am i shooting for? LDL under 70? LDL of 20 permanently? LDL of 20 for a time and then relax?
I recently head an interview with Thomas Dayspring in which he said an LDL measure of zero should not be an issue (i assume this is hyperbole?). So what’s recommended?
PCSK9 inhibitors appear to be very safe, and with fewer side effects than statins if I’m reading the papers correctly.
AnUser
#89
Statins are dirt cheap, you don’t need insurance for them. 180 doses of 5 mg rosuvastatin is $7.70 if split in half. So $15 a year.
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I’ve been taking Praluent for a few months now with no noticeable side effects. My cholesterol (and apoB specifically) has never been better.
Now I’ve noticed this link in another thread with a Mendelian randomization showing PCSK9 decreases increases risk for Alzheimer’s.
Even if the above is true it seems that another study shows preliminary evidence that APOB increases risk for Alzheimer’s disease.
I plan to keep taking Praluent, but hope that my blood brain barrier provides some protection from Praluent so I can enjoy the many benefits of a low apoB without worrying about unintended consequences of the medication.
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Scientists shut off Pcsk9 in mice, via epigenetic editing:
Discussion
In this study, we show that LNP-mediated delivery of mRNAs encoding ETRs to the liver of mice can lead to durable (nearly one year of follow-up) epigenetic silencing of Pcsk9. Notably, epi-silencing proved to be stable also after partial hepatectomy, further confirming the heritable nature of the epigenetic marks deposited by the ETR technology and indicating that epi-silenced hepatocytes remained competent for liver regeneration. When compared with RNAi, for which multiple administrations are required31, our approach is configured as a one-and-done treatment, a feature shared only with other genome-editing technologies. Unlike the latter approaches, however, the ETR technology does not require the induction of potentially genotoxic DNA breaks to inactivate the desired gene32,33,34. This feature represents a safety advantage, especially when aiming at multiplex epi-silencing, as both gene editing, and to a lesser extent, base editing can cause reciprocal chromosomal translocations33,35,36. Moreover, epi-silencing differs from genome editing in that it can be reverted by either pharmacological intervention or treatment with editors equipped with a transcriptional activator, as previously shown in cell lines15,22. As such, epi-silencing would allow for temporally controlled silencing of the targeted gene and the reversal of treatment-related adverse effects. Here, we also show that the ETR technology can establish substantial levels of epi-silencing in vivo, at values that are already compatible with several experimental and therapeutic applications. In our experimental settings, epi-silencing performed as well as conventional gene editing (up to 75% of Pcsk9 inhibition).
https://www.nature.com/articles/s41586-024-07087-8
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Update to my January post on taking Repatha. I started in May 2023. I have now paused it. Here’s why:
I got the script because I had moderately high Lp(a) – so refused to take a statin. Also, I have the C;C phenotype on the gene 9p21 which significantly raises risk. CAC score of 0.96. Total Chol about 232 but very high HDL and low Trigs. Normal BP and BMI, good cardio function Depending on what you read/believe, I had low-moderate risk.
Blood glucose increased. This can happen in some patients on statins. Recent H1AC was 5.8 – just barely prediabetic. But insulin down to 2! Studies (mouse studies) shows that PCSK9i’s can cause insulin to drop and also raise glucose. The lowering of PCSK9 occurs in the liver. which leads to more LDL receptors and lower cholesterol. But it also leads to more LDL receptors in the pancreas and that somehow leads to the Beta cells putting out less insulin. Once again: in mice.
I had two minor symptoms that can also be caused by Repatha – an annoying skin sensitivity and mild upper respiratory short of breath sensation. These have both abated. But just another bit of information that makes me think the Repatha was the cause of the low insulin.
My cholesterol levels (including Lp(a) ) had decreased significantly while on Repatha. But I decided to take a break from the Repatha. At about the same time that this was happening I came across a paper that showed a U-shaped phenomenon whereby both lower and higher total cholesterol (total, not LDL) correlated with higher all cause mortality. Before starting Repatha, I was at the sweet spot of 232 of total cholesterol, with very high HDL and low Trigs. I am still concerned about the Lp(a) but my plan is to double down on efforts to reduce inflammation. Have read that if you can keep inflammation very low, the risk from Lp(a) is reduced. My Lp(a) was 40 and went down to 29. My CRP was 2.2 so not ideal.
My glucose is now down from about 100 to 90, HbA1C from 5.8 to 5.5. Insulin from 2 to 3. But I have been calorie restricting, so???
I will re-asses in a few months. Give all the above, my current mindset is to forgo lipid lowering drugs entirely, focus hard on inflammation through diet and exercise. Was already doing that but will amp it up. To be continued . . .
Would appreciate reactions, questions, suggestions.
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Neo
#93
@Deborah_Hall : Would def work on getting inflammation levels down, have you measured inflammation in other ways than CRP? What has the CRP trend been over time?
Re a U shaped association of cholesterol and mortality - those studies are just correlations and likely driven by reverse causation. For instance, cancer often drives cholesterol down, and cancer of course drives mortality - in those cases it’s clear that it’s not low cholesterol driving mortality but cancer driving the mortality. Association studies are a very weak for of evidence, while clinical trials and Mendelian Randomization studies are much stronger forms of evidence and generally suggest that lower Apo B/LDL is better. You can read what I and @AnUser have extensively written and provided evidence for on this forum on that.
In general, would mostly care about Apo B and Lp(a) and perhaps LDL and less about total cholesterol numbers.
Lower insulin might actually be a feature and not a bug or side effect in the context of longevity - as long as you find other ways to lower the glucose levels (and spikes). There are many, many ways of accomplishing lower glucose (often with evidence of having other additional longevity benefits - eg dietary optimization, food sequencing, Acarbose, SGLT-inhibitors, adding extra fiber to your diet, etc - all of these are discussed a lot on this forum).
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Hi
I dont know if anyone is interested or if I can do it, but some of you guys know that I work in a pharmacy, we’ve got a Praluent 150mg that is going to the destruction, not cause it is perishable, but because is has been payed by someone but has never come back to take it. We can’t sell it a second time. 120€ is anyone wants it. Retail price in France : +/- 420€
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Maybe not relevant but if you can’t sell it a second time, how can you charge €120 for it? Just curious.
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Novel PCSK9 Inhibitor Reduced LDL by 50%
Lerodalcibep, a novel, third-generation proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, reduced low-density lipoprotein cholesterol (LDL-C) by more than 50% after 1 year in patients with or at a high risk for cardiovascular disease (CVD), new phase 3 results showed.
Newer, more stringent LDL targets in 90% of patients receiving lerodalcibep vs only 16% of those on placebo, despite concurrent treatment with a statin or statin plus ezetimibe.
“This hopefully gives doctors a more practical PCSK9 antagonist that’s small volume, can be administered monthly, and is an alternative to the every 2 week injection of monoclonal antibodies and probably more effective in LDL cholesterol–lowering compared to the small interfering RNA” medicines, study author Eric Klug, MBBCh, MMed, associate professor, Division of Cardiology, University of the Witwatersrand, Johannesburg, South Africa, told theheart.org | Medscape Cardiology.
https://www.medscape.com/viewarticle/novel-pcsk9-inhibitor-reduced-ldl-50-2024a10007hi
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As always, the issue with berberine si not efficacy, but quality and price. It’s a supplement, which means it’s not manufactured and tested in a place meets fda standards.
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True, but Consumerlab.com does a good job of testing supplements, and they do a new round of berberine testing every year. I’m currently taking the Solaray version because they’re a well-established company and passed CL testing with flying colors.
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Here is my N=1 experience with Repatha
I started it in May 2023. My lipids were somewhat high, but the main concern was Lp(a) of 50.
After a year, all lipids were much lower and Lp(a) had dropped to 29.
But, I asked to have insulin tested and found it was very low, about 1-3.
A shortage of PCSK9 can impact the pancreas to produce less insulin. I was concerned so decided to take a break from the Repatha, then retest.
After about 8 weeks, lipids had gone up some but still low enough. LDLC of 72. And, Lp(a) now 27. And, insulin still very low and HA1C went up slightly to 5.9 But inflammation dropped a bit to 1.0
During the Repatha break, I continued to take 5 mg Ezitimibe, added plant stanols, and also went from 2 to 3 days a week hot tub+swimming (hot/cold/hot shock). Still exercise “moderately” on other 4 days. Reduced wine to no more than about 4 ounces per week.
I do not understand this at all. I have trouble believing that the two “lifestyle interventions” made that big a difference. Not going back on Repatha but am probably going to try BA. Cardiologist will no longer let me have Repatha since lipids are “OK” now so will get BA “elswhere”.
Concerned about glucose. PCP says increase metformin from 1000 to 2000 but I don’t think the metformin is doing much at all. Not moving the needle on glucose which has been borderline too high for many years.
So, that is my experience with Repatha. Would welcome insights . . . .
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Any idea what your visceral fat levels are? Ever had a DXA scan? If your glucose is too high because you’re insulin resistant, it may be a relatively straight (albeit not necessarily easy) fix by losing some visceral fat.
My BMI is 18.4. I weigh101 pounds.
Neo
#103
Adding muscle mass can help act as a sink for glucose. See eg the Peter Attia AMA that came out on Monday this week.
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Your BMI and body weight are definitely lower than average and suggest that you probably have low to no visceral fat, but a DXA scan could be helpful to accurately assess body composition (visceral fat, lean mass, etc) if there’s any question, since BMI alone often doesn’t give the full picture.
Your idea to try BA sounds reasonable, especially since it may also increase insulin sensitivity. Analysis with references from Dr. Oracle:
Question: Does bempedoic acid affect insulin sensitivity?
[Literature Analysis]
The meta-analysis (PMID: 32827596) found that bempedoic acid therapy is associated with a significant reduction in new onset or worsening diabetes (Odds Ratio: 0.66, 95% CI: 0.48-0.90). This suggests that bempedoic acid may improve insulin sensitivity or reduce the risk of developing diabetes, which is directly related to the question.
The prespecified analysis from the CLEAR Outcomes trial (PMID: 38061370) found that bempedoic acid did not increase the risk of new-onset diabetes or worsen HbA1c levels in patients without diabetes at baseline. Additionally, in patients with diabetes, bempedoic acid reduced cardiovascular events compared to placebo. This suggests that bempedoic acid does not negatively impact insulin sensitivity and may have beneficial effects in patients with diabetes, which is relevant to the question.
The pooled analysis of phase 3 trials (PMID: 34981622) found that bempedoic acid significantly reduced HbA1c levels in patients with diabetes or prediabetes, and did not increase the incidence of new-onset diabetes compared to placebo. This indicates that bempedoic acid may improve glycemic control and insulin sensitivity, directly addressing the question.
The review article (PMID: 36386319) discusses the potential mechanisms by which bempedoic acid may improve insulin sensitivity and glucose metabolism, including decreased gluconeogenesis and activation of AMPK. However, it does not provide direct evidence from clinical studies, so its relevance to the question is limited.
[Answer generated by www.DrOracle.ai]
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