Rapamycin and risk of cardiovascular disease

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#3064

I agree (I didn’t know before btw, learned this thanks to Neo in another thread; I love this community where I learn something new every single day!)

For PD, we have RCT + MR + longitudinal + observational studies showing a decline with statins. But that’s in PD. In healthy individuals, RCTs don’t show anything indeed. But given the link between PD and LBD I found it interesting that this paper looked at LBD. Given the time needed for NDDs to develop and the specific demographic (old people), this cannot be captured by short RCTs on the general population. Do we have RCTs of statins on people with MCI? I’m pretty sure that people with MCI are excluded from most trials because they cannot follow the protocol, and it would be a mess to have them in. I could only find these trials:

Regarding the STAREE trial, the authors noted in early 2023:

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(source)

Yes, 740k is massive. But at the end for LBD it’s 2,591 cases: 4,027 controls. And people with LBD are often undiagnosed or misdiagnosed (source). So there are probably many LBD cases that are not LBD but another kind of dementia or depressive disorder while there might be many LBD cases among controls. How many? I don’t know but that’s why (and combined with the signal for PD mentioned above) I’m not “as strict” in terms of CI and I’m looking for “directions”.

Hm… They write “Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: –0.082; 95% CI: –0.16 to –0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = –0.18; 95% CI: –0.35 to –0.014; P = 0.03).” and “However, our finding of concurrent improved memory performance associated with the HMGCR instrument highlights the complexity of the HMGCR-cognition relationship.” and for these, we can see on the image that for statins (HMGCR): cognitive performance is on the left of the axis, memory performance is on the right, reaction time is on the right, but they used “reaction time DEFICIT” (why on earth did they do that?!), and total cortical surface area is on the left. So I understood that left = negative beta = “bad”. Did I misunderstand? :sweat_smile: Because then they write: “genetic inhibition estimates for PCSK9 were on the beneficial side of null with regression coefficients in the direction of reduced AD progression score, lower amyloid deposition levels, and lower LBD risk” And for PCSK9 they give (Table 2):

  • Disease progression score: 0.0086 (–0.16 to 0.17)
  • Cerebral amyloid deposition: –0.0038 (–0.55 to 0.55)
  • Lewy Body dementia: –0.018 (–0.51 to 0.48)

“on the beneficial side of null” seems quite a big leap of faith but anyway, it means that negative beta for LBD is protective? So statins potentially protective?

Help needed if anyone knows how to understand the results…

Btw, from last week at the Pan American Parkinson’s Disease and Movement Disorders Congress. So it’s not only about me/us a few longevity weirdos here. Some serious folks also have doubts: https://twitter.com/AlbertoEspay/status/1756678599438995951

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Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial (2023)
Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial (2023)
#3065

Yes, both psk9 and hmgcr inhibition genes associated with lower mean lewy body disease risk. But without any statistical significance. So potentially statins still could be protective or harmful or neutral

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#3066

Thanks. Still interesting because another recent MR (preprint) showed that statins may be neutral wrt PD risk but might shift from the freeze of gait subtype to the tremor subtype. Maybe one of these subtype is more associated with cognitive decline than the other.

Anyway, there’s a link between lipid lowering drugs and cognition and it’s probably not as simple as “statins good” or “statins bad” (does it depend on your BMI? Diabetes status? Genes? Age? :man_shrugging:). I hope the ongoing trials will clarify the picture. I contacted the lead clinician behind the statin cessation study (Statins In The Elderly (SITE)): results expected “this summer”. Wait and see…

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#3067

Obicetrapib might come to market the latter part of this year if approved for reducing LDL, based on two phase 3 trials:

“HeFH and ASCVD can be devastating diseases which, if inadequately addressed, can result in myocardial infarction, cerebral infarction, or cardiovascular death,” said John Kastelein, M.D., Ph.D., FESC, Chief Scientific Officer of NewAmsterdam. “It has become increasingly clear that lower levels of LDL-C are directly correlated with a reduced risk for major adverse cardiovascular events. With obicetrapib, we aim to deliver LDL-C reductions that are substantially better than currently available non-statin oral therapies, in a convenient, tolerable formulation. We are pleased to have both BROADWAY and BROOKLYN, the two pivotal Phase 3 trials necessary to support a potential LDL regulatory filing, fully enrolled and look forward to reporting data from both studies in the second half of 2024.”

https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-completes-enrollment-pivotal-phase-3-0?mobile=1

Our product candidate, obicetrapib, is a next-generation, oral, low-dose CETP inhibitor that we
are developing to potentially overcome the limitations of current LDL-lowering treatments. We believe
that obicetrapib has the potential to be a once-daily oral CETP inhibitor for lowering LDL-C, if
approved. In our Phase 2b ROSE trial, obicetrapib demonstrated a 51% lowering of LDL-C from
baseline at a 10 mg dose level on top of high-intensity statins. In all three of our Phase 2 trials, TULIP,
ROSE and OCEAN, evaluating obicetrapib as a monotherapy or a combination therapy, we observed
statistically significant LDL-lowering activity combined with generally moderate side effects and no
drug-related, treatment-emergent serious adverse events (“AEs”). Obicetrapib has demonstrated strong
tolerability in more than 600 patients with low or elevated lipid levels (“dyslipidemia”) in our clinical
trials to date. Obicetrapib is also expected to be relatively low in cost to manufacture compared to most
other branded LDL-lowering therapies on the market with high efficacy. We believe that the estimated
low cost of goods for obicetrapib will enable favorable pricing and position it to significantly improve
patient access to a high efficacy LDL-lowering therapy compared to existing non-statin treatments.
Furthermore, we believe that obicetrapib’s oral delivery, demonstrated activity in low doses, chemical
properties and tolerability make it well-suited for combination approaches. We are developing a fixed
dose combination of obicetrapib 10 mg and ezetimibe 10 mg, which we believe will demonstrate even
greater potency

We believe that CETP inhibition may also play a role in other indications by potentially mitigating
the risk of developing diseases such as Alzheimer’s disease or diabetes. Evidence suggests that
cholesterol accumulation in the brain is a precursor to Alzheimer’s disease. For example, rodents lack
the CETP gene and are resistant to Alzheimer’s disease. In early preclinical studies, when the human
CETP gene is knocked into a mouse, the cholesterol content of the mouse brain was observed to increase
by 25% and when combined with the gene for the amyloid precursor protein, hypothesized to be a driver
of Alzheimer’s disease, the risk of developing Alzheimer’s disease may greatly increase. In a preclinical
study, we observed that CETP inhibition promoted cholesterol removal from the brain and improved
cognition. We commenced a Phase 2a trial in early 2022 in patients with early Alzheimer’s disease and
the apolipoprotein E4 (“ApoE4”) mutation to evaluate the pharmacodynamic and pharmacokinetic
effects, safety and tolerability of obicetrapib. Clinically demonstrated anti-diabetic benefits have been
observed with CETP inhibition in Phase 3 CVOTs that, if seen in obicetrapib, would differentiate it from
current treatment alternatives, especially statins. We are planning preclinical studies to examine the
potential of obicetrapib for patients suffering from diabetes and have included the onset of diabetes as
an endpoint in our PREVAIL CVOT, as measured by AEs indicating Type 2 diabetes, initiation of anti-
diabetes medication after confirmed diabetes diagnosis or high levels of hemoglobin A1c and fasting
plasma glucose.

https://ir.newamsterdampharma.com/static-files/91cc75c7-08db-4696-9bd6-c05bb01762ed

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Obicetrapib (CETP inhibitor for dyslipidemia)
#3068

Super interesting. This preprint MR confirms the potential for dementia prevention: https://www.medrxiv.org/content/10.1101/2023.11.03.23298058v2

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#3069

Hopefully we can see their 2023 annual report soon?

Also promising Lp(a) it seems (even if I know there are other meds for that also reading out soon that look promising).

Obicetrapib 5 mg reduced ApoB by 24.4%, non-HDL by 38.9% and Lp(a) by 33.8%, whereas obicetrapib 10 mg reduced ApoB by 29.8%, non-HDL by 44.4% and Lp(a) by 56.5% (P for all < .0001), Davidson and colleagues found.

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And also beyond Lp(a) and Apo B effects - increase in HDL (that they are not focusing communication on as people are skeptical about past attempts to HDL up…)

https://www.nature.com/articles/s41591-022-01936-7

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Seeking Advice on High LP(a) Levels: Any Insights or Personal Experiences?
#3070

I would be surprised if that didn’t publish and pass peer review. It is after all the scientists at NewAmsterdam Pharma like Kastelein.

I don’t understand why they didn’t look at other dementia like for Alzheimer’s, instead specifically PD dementia and LBD. The effect on PD dementia was nice though.

#3071

Yes great team so can’t wait to see it published. For AD they write: “Given the observed APOE4 interaction with CETP, and the absence of APOE4 stratified GWAS we did not explore associations with AD.”

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#3072

Great, I was worried for a second. So far this drug seems very promising. CETP target also have a bunch of old papers from longevity researchers like Barzilai.

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#3073

What’s the gist of the longevity impact (outside of cardiovascular)?

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#3074

Dunno I didn’t bother reading them as they are probably using outdated methodologies.
I could take a look at a later time and compile a lot of evidence for the Obicetrapib fanclub.
It has potential to be a longevity blockbuster drug.

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#3075

Hello Lara, old post but may I suggest Intermittent Fasting. Please view YouTube videos by Pradeep Jamnadas. My blood results improved after 6 months or so of IF. It was well worth it, please persevere.

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#3076

I agree about IF and usually follow it naturally for as long as I remember myself. I stop eating not later than 7 pm and have my firsts meal around 9-10 am. My lipids improved much after I consistently took rosuvastatin, 5 mg, and ezetimibe.

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#3077

FWIW

You do not like Calley Means message/comments.

As he tell’s the truth.

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#3078
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#3079

From a few days ago: Taming cardiovascular risk: the promise of LDL cholesterol lowering therapeutics

We also showed that in combining obicetrapib with ezetimibe, we got 63 percent LDL lowering. So we are proceeding with developing a fixed dose combination of obicetrapib and ezetimibe, which would be a single pill that could be one of the most effective LDL lowering therapies, especially as an oral therapy to reduce cardiovascular risk.
What are the benefits for patients taking fixed dose combinations in one pill to reduce LDL cholesterol?
Most importantly, it provides greater efficacy. Obicetrapib alone is in the 40 percent range. Ezetimibe traditionally is in the 15 to 20 percent range. If you put the two together, you actually get synergy more than expected. That is what we showed in our ROSE II trial. Almost all participants achieved the goal using this combination regime.

By the way, given when phase 3 trials are expected to end, I think an approval next year is more realistic.

The market seems optimistic:

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#3080

I don’t believe LDL and HDL levels are the sole determinants for heart disease. There are studies where both high and low are causes heart disease. For myself my cholesterol level is always low regardless what I eat. But sadly that does not make me immune to obesity.

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#3081

Yeah so you choose to have a low cholesterol rather than an ultra low cholesterol despite the fact that you know the disease develops at your cholesterol level?

You can disprove the ‘crush apoB’ hypothesis by showing a single case of total abetalipoproteinemia (LDL = 0) where plaque has built up in the aterial wall or led to a MI after a plaque rupture.

Your studies you talk about are probably flawed in the way of not measuring LDL throughout life instead at a few points at most.

What does obesity have to do with LDL?

#3082

@adssx This looks very promising. I hope there are no long-term side effects!

However, it states it is an adjunct to statins? Therefore you need to take a statin and ezetimibe as well to get 50-60%? So, it just adds an extra 10%?

In July 2021, we reported positive results from a Phase 2 study of oral obicetrapib demonstrating more than 50% LDL-lowering as an adjunct to high-intensity statins showing an oral dose of obicetrapib could potentially address the substantial unmet need for patients whose LDL-C levels and cardiovascular risk remain too high despite being treated.

#3083

Suboptimal apoB has known long-term side effects.
Pharmaceuticals, unknown.

No it adds 50%.

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