adssx
#242
I understand that it’s looking at genes associated with high IL-6 only. Not necessarily with high SASP. And high IL-6 only (independently from everything else) is causally associated with a higher risk of PD. Did I misunderstand something?
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How is high IL-6 causally associated with a higher risk of PD?
AnUser
#244
It’s quoted:
In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = −2.364, 95% confidence interval (CI) = −4.789–0.060; years difference per 1 log-unit increase = −2.011, 95% CI = −3.706 to −0.317; years difference per 1 log-unit increase = −1.569, 95% CI = −2.891 to −0.247].
Have you missed mendelian randomization studies (and part of the evidence why LDL is causal)?
I have not seen any evidence why LDL is causal of parkinsons.
AnUser
#246
I meant the mendelian randomization studies as a method have shown partly why LDL is causal in ASCAD. The same reason why IL-6 is for earlier onset for PD, the method can discover causality.
Why is that relevant in a topic relating to Parkinsons.
AnUser
#248
It was pertaining to your question how it is causal with early onset PD, because the MR data shows it.
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adssx
#249
The paper concludes:
We found evidence for a causal association between the onset of Parkinson’s disease and interleukin-6.
In the present study, we explored a possible causal relationship between inflammatory processes and Parkinson’s disease using an MR design, which is a statistical framework that provides valid causal inference on the effect of exposures on outcomes by leveraging genetic information. Connections between inflammation and Parkinson’s disease through that design have been explored by previous studies. We extended this evaluation by considering multiple well-established markers of inflammation. Moreover, we studied the causal effect of the exposures on datasets from different data sources to assess the consistency of the results. Based on the present findings, we did not observe any strong evidence for causality between inflammatory biomarkers and Parkinson’s disease except for IL-6 and AAO.
Of course, there are still many potential limitations.
1 Like
adssx
#250
Risk of Parkinson’s disease divided by 7 among SGLT2 users vs metformin users: Anti-Diabetic Drug Use and Reduced Risk of Parkinson’s Disease: A Community-Based Cohort Study 2024
The study population comprised 86,229 T2DM patients, with 53.9% males. The mean age at the first anti-diabetic drug purchase was 59.0±11.0 and 62.0±11.0 years for men and women respectively. Compared to metformin, several drug types were associated with a significantly lower PD risk: thiazolidinediones (HR=0.91, 95% CI:0.074-1.14); DPP4 inhibitors (HR=0.60, 95% CI:0.53-0.67); meglitinides (HR=0.63, 95% CI:0.53-0.74); GLP-1 agonists (HR=0.54, 95% CI:0.39-0.73); and SGLT2 inhibitors (HR=0.15, 95% CI:0.10-0.21).
Particularly significant in our study is the finding that SGLT2 inhibitors are associated with the most substantial and statistically significant reduction in PD risk.
(I don’t understand why it shows 20 years even though SGLT2i and GLP-1RAs arrive on the market later…)
This confirms that metformin isn’t great for PD (at least at high doses?) and that SGLT2i might be even more neuroprotective than GLP1-RA.
Of note: it seems that only dapagliflozin and empagliflozin are used in Israel as I cannot find canagliflozin here: https://israeldrugs.health.gov.il/#!/byDrug. This paper also says: “any of the available SGLT2is in Israel (empagliflozin or dapagliflozin)”.
Can we find which one is most prescribed in Israel?
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What do you think about taking both Metformin and SGLT2I? Would it have a better effect at preventing PD vs SGLT2I alone?
adssx
#252
Metformin is a dirty drug that is generally associated with a higher risk of PD, especially at high doses. I would like to see trials replacing “old” gluclose-lowering drugs like metformin with SGLT2i and/or GLP-1RAs. I guess the results would be amazing.
2 Likes
It sounds plausible though.
tananth
#255
What about the anti-cancer benefit of Metformin that is missing from SGLT2i’s (other than Canagliflozin which has an anti-cancer benefit independent of Metformin) ?
I take 500mg Metformin 2x/day in addition to Empagliflozin and would not want to drop Metformin unless there is actual evidence that the risk of PD for SGLT2i + Metformin is significantly higher than just SGLT2i.
1 Like
adssx
#256
Cancer risk: I don’t know much. But I think the majority of mice die from cancer. And yet metformin doesn’t increase lifespan in mice. While canagliflozin (and probably empagliflozin and maybe other SGLT2) do. So the case for metformin seems weak to me. I don’t understand why people in the “longevity” field still use this dirty drug when there are so many alternatives with proven life extension properties (acarbose and SGLT2) and/or other benefits (such as cardioprotection, nephroprotection and maybe neuroprotection for GLP-1 and SGLT2).
If metformin is associated with a higher PD risk then you can reasonably assume that anything + metformin is worse than anything alone.
2 Likes
tananth
#257
Metformin does increase lifespan in mice around 5% : Metformin improves healthspan and lifespan in mice
Also only Canagliflozin (but no other SGLT2i’s) has an anti-cancer effect, so we cannot assume that life extension for Canagliflozin in mice generalizes to other SGLT2i’s, precisely because cancer is the leading cause of mortality in mice. However, I suspect it is likely that the other (non-cancer related) benefits of SGLT2i’s are sufficient to result in a life-extension effect.
adssx
#258
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tananth
#259
Regarding the anti-cancer effect of Canagliflozin, it looks like I oversimplified and that Canagliflozin has a stronger anti-cancer effect than other SGLT2i’s because it is also a SGLT1i and GLUT1 inhibitor, as well as a mitochondria inhibitor (like Metformin), as discussed in this article Glucose absorption inhibitors to Inhibit Cancer
adssx
#260
This 2017 blog post (isn’t there a better and more recent source?) says:
Even more, Dapagliflozin (next to gemcitabine) cause the necrosis in the tumors that were larger, i.e. the higher the tumor, the more necrotic area (Ref.) which I would expect since it does not have impact on GLUT1 as Canagliflozin does, but is very specific to SGLT2 which will only start to be over-expressed when there is no glucose which should be the case even more at the center of large tumors.
Based on the above you could argue that we should chose between e.g. Dapagliflozin and Canagliflozin depending on the tumor size and glucose status in the body.
Therefore, Dapagliflozin may be more relevant for the very large tumors, while Canagliflozin may be more relevant for smaller tumors in people with high blood glucose levels (e.g. who do not follow a low-sugar diet and do not use other glucose lowering medication).
Conclusion:
When having to deal with cancer, I would strongly consider the IV treatment with Phlorizin or the oral drugs such as Canagliflozin and Dapagliflozin. They could be used:
- together with chemotherapy or radiotherapy to increase treatment effectiveness
- together with new treatments such as 3BP, Salinomycin to increase treatment effectiveness
- together with mitochondria inhibitors such as Metformin
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@adssx I believe that the reason people stick with Metformin is due to the ITP results when Rapamycin was paired with Metformin and Acarbose. They both enhanced the lifespan of mice over and above what Rapamycin could do alone.
So, Metformin by itself is not great unless you are diabetic. However, if you are taking Rapamycin, you should consider also taking Metformin or Acarbose.
There was an excellent video by LSN
which showed studies on how Metformin overcame the detriments of Rapamycin to make the pair far superior to Rapamycin alone.
As for the PD risks, I would not take more than 1 g of Metformin daily.
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