#21

https://www.sciencedirect.com/science/article/pii/S0085253815533875#:~:text=The%20results%20showed%20that%20rosiglitazone,**P<0.01%20vs%20control.

Great find @medaura! To have a medication that substantially increases klotho is definitely going to go on my stack of meds.

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#22

Telmisartan is also a PPAR-Ī³ agonist and helps with Klotho too:
New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms

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#23

Well I hate to play this card but itā€™s true that in medical discussions human beings are assumed to be male by default and that sucks. I see zero proof that it can help with visceral fat, or anything at all, in non diabetic women.

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#24

As posted countless time;

ā€œIf you wait until you are ready, it is almost certainly too late.ā€ ~Seth Godin

15mg x 90 tablets of Pioglitazone{Generic Actos]cost less than $20.00 with GoodRX code

In my opinion and view this is ā€œCheap Insuranceā€.

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#25

Might be worth giving this a spin, but in a time limited way, just to accomplish fat redistribution away from visceral, and any possible insulin sensitizing along the way as a bonus. Then see if the benefits persist after stopping, and if so, for how long. I wouldnā€™t necessarily want to be on this long term. Occasional treatment, as visceral fat builds back. Theoretically you can exercise visceral fat away, but this can presumably really push that low, plus getting any possible fat out of muscles and organs such as liver and kidney. For me, I donā€™t think I have much if any fat in my muscles or organs, but some visceral. Also, this drug is interesting to me because Iā€™m always in the hunt for what can lower my A1c and FBS from my current pre-diabetic range - this might be another option.

Iā€™ll keep taking empagliflozin, maybe escalate to 25mg/day, and keep monitoring my blood sugar. Pioglitazone is another thing for me to consider.

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#26

That is crazy fascinating. Do you know what that is?

#27

Yes that would be my MO if I were a man.

#28

PPAR agonists have been on my radar relating to Alzheimerā€™s too. I highly recommend listening to the full podcast as DeFronzo discusses Pioglitazone safety, potential for AD treatment, as well as vascular disease treatment (via NOS) which often comes with AD eventually, at least in the brain.

Animal models and human clinical trials have shown PPAR agonist potential as a strategy for AD prevention by modulating inflammation, reducing amyloid plaque deposits and improving cognitive function:
https://www.sciencedirect.com/science/article/pii/S1878747923004919

I may eventually try an n=1 with Pioglitazone as I have elevated amyloid plaque so I can test in my blood work. No cognitive symptoms as of yet and Rapamycin appears to lower my amyloid levels.

So happy to hear about the potential impact on Klotho! I have the Klotho longevity mutation so all is not lost. Iā€™m extremely insulin sensitive in the periphery but who knows in the brain. Good stuff here.

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#29

Impact of Empagliflozin in Patients with Diabetes and Heart Failure

ā€œAt 6 weeks post-randomization, there was no increase in the frequency of edema or HF in patients receiving empagliflozin and pioglitazone compared with placeboā€

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#30

Effect of pioglitazone on the abrogated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart

ā€œPerfusion of wortmannin or rapamycin alone significantly and in combination almost completely abolished the pioglitazone-induced restored cardioprotectionā€

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#31

Thank you so much for this! I had been worried about the HF side effects of pioglitazone for my mother, but it appears that empagliflozin removes it!

This is wonderful news. Thank you! :blush:

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#32

You are more than welcome. As I am considering taking pioglitazone down the line for visceral fat elimination and insulin sensitivization (Iā€™m prediabetic), I am doing what I always do for any drug - massive research, especially the interactions with other drugs Iā€™m taking (polypharmacy). It takes months as I try to address all the possible risks. Edema, HF, bone fractures and so forth.

It is already clear to me that I cannot take pioglitazone long term. Most likely, three months or so, and then repeated as needed. That minimizes bone fracture risk, as the risk is cumulative and starts going up after four months or so according to the graphs Iā€™ve seen - the risk is primarily in the elderly, diabetic and osteoporotic.

Importantly, it is looking more and more like pioglitazone and rapamycin donā€™t play nice together. I would therefore have to take a rapa holiday during the pioglitazone intervention, another reason to keep the pioglitazone intervention as brief as possible, rapamycin being a high priority in my pharma stack.

The research continues. I will likely not go for pioglitazone this year, as I dial in my other drugs and interventions before making the final decision and seeing clearly how it fits into my overall health plan.

As I continue researching pioglitazone, I will keep posting anything interesting that I come across - stay tunedšŸ¤“ā€¦

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#33

And here is another study, not so heartening for those of us concerned with Alzheimerā€™s: Pioglitazone use increases risk of Alzheimerā€™s disease in patients with type 2 diabetes receiving insulin - PMC

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#34

I used it with Rapa because I didnā€™t know anything about the conflict. Since I go 2 weeks between doses, what do you think about doing the Pio during the second week? What was the conflict? I never noticed a thing with Pio before, so thought Iā€™d double the dose and go every other week.

Donā€™t go to too much trouble for me, I seldom follow advice anyway. Thanks!

#35

I posted the study above, where rapa worked at cross-purposes to pio when it came to heart health benefits within the context of morbidity. We donā€™t have outcome studies of rapa-pio administration in healthy individuals for life extension purposes, but there are mechanistic reasons for suspecting unfavorable interactions. Obviously, we donā€™t have any kind of solid proof.

Re: weekly alternating - I canā€™t see anything positive healthwise, because you need some time for pio to take effect. Interrupting exposure every other week strikes me as non-productive. Of course Iā€™m entirely speculating, soā€¦

It seems to me much better to take pio as indicated for a sustained period of time, like months, where we know effects do occur (we donā€™t know if they do on the bi-weekly schedule ), and not take rapamycin during that limited period so as to avoid any potential negative interactions. Once pio has done its job, one can go back to rapa, until (or if) it is needed again and one can repeat the process. Again, this is speculation on my part. YMMV.

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#36

It does make me wonder if any other medications or supplements are working at cross purposes to Rapamycin. Is anyone aware of any off the top of their head?

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#37

Thatā€™s what I alluded to earlier. It looked good for dementia in general but bad for Alzheimerā€™s in particular.

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#38

I only examined rapa interactions with drugs that I take currently or might take in the future. And so, in researching DDI, I saw no red flags for rapa and pitavastatin, empagliflozin, bempedoic acid, ezetemibe, telmisartan, acarbose. And I saw no DDI for any combination of these drugs.

As to supplements, thereā€™s the caution wrt. turmeric and astaxanthin. Some folks are cautious with taurine. My approach is based on general caution, where I avoid some supps on the day of, and the following day of rapa intake. Again, I only looked at my supplements, and did not research others. So on those two days, I do not take astaxanthin, lutein, meso-zeaxanthin, zeaxanthin, taurine, garlic powder, glucosamine, TMG. Except for astaxanthin, I have no evidence that rapa interacts with any of these supplements listed above, but I avoid them based on purely an abundance of caution, plus some highly speculative mechanistic reasoning. I also figure that not taking these supps on just those two days really should not represent any significant loss of benefits of these for my overall health, but gives a more clear and unobstructed path for rapamycin to do its magic. YMMV.

#39

Why do you believe there is a conflict with rapamycin? Is it just the study you posted above? Iā€™m not sure why thatā€™s relevant - the study was very narrowly looking at heart issues in hyperlipidemia and noted that Pioglitazone restored the benefits of ā€œischemic preconditioningā€ in rat hearts with hyperlipidemia, and that Rapamycin cancelled out this effect. Basically this was a mechanistic study showing that the beneficial effects in a narrow case are due to mTOR activation. Unless you have a heart suffering from ischemia preconditioning and/or ischemia with hyperlipidemia, this study does not show a conflict.

I suppose one could argue that because some of the cardio protective benefits are likely due to mTOR activation, taking Rapamycin might cancel them out. I suspect that Rapamycinā€™s mTOR inhibition overpowers the mTOR activation based on the study, so youā€™d probably be fine just taking Pioglitazone daily and Rapamycin intermittently to get the best of both worlds (mTOR activation/inhibition cycles). And youā€™d still get all of the other benefits of Pioglitazone daily administration.

Some quotes

Hyperlipidemia (HL) is a well-known risk for the cardiovascular complications including coronary artery disease.[1] It has been reported that ischemic preconditioning (IPC), i.e., short intermittent cycles of sublethal ischemia followed by reperfusion before the subsequent prolonged ischemic insult, produces cardioprotection against ischemia-reperfusion (I/R) induced injury.[2,3] The absence of the cardioprotective effect of IPC during the HL is reported.[4] Also, the decrease of the insulin sensitivity is a major risk of HL.[5]

Therefore, the present study is designed to investigate whether or not pioglitazone, an insulin sensitizer, restores the attenuated cardioprotective effect of IPC in hyperlipidemic rat heart and to determine the possible signaling pathway involved in this effect.

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#40

Yes, it is a study in rats. Unless we dismiss all studies in rodents, including the ITC and rapamycin, as having any relevance to humans, oftentimes thatā€™s all we have. And when looking for potential DDI conflicts it is standard to look to animal models to alert us to possible interactions in humans. Thatā€™s how scientists look for safety data in drugs, LD50 in rats is as standard as it gets. Depriving yourself of this resource leaves you with nothing, absent human studies, which we donā€™t have. Surely I donā€™t have to explain this to you? This ā€œratsā€ objection is not worth spending any time on, as we all understand the advantages and limitations of animal models.

ā€œHyperlipidemia (HL) is a well-known risk for the cardiovascular complications including coronary artery disease.ā€

Yes, and rapamycin can induce hyperlipidemia in humans. As someone who is already hyperlipidemic, it is of interest to me that this is an effect that rapamycin can cause in humans, because in taking pioglitazone I would be interested in any benefits that might give me, a person with hyperlipidemia. Do you see how that might be of interest to me to learn if rapamycin abolishes that benefit?

ā€œAlso, the decrease of the insulin sensitivity is a major risk of HLā€

Yes, and rapamycin can induce insulin insensitivity and raise glucose levels in humans. As someone who is already suffering from insulin resistance with elevated blood glucose, it is of interest to me that this is an effect that rapamycin can cause in humans, because as I wrote in many posts above, that is the whole point of why I am interested in possibly taking pioglitazone in the first place, for the primary benefit that pioglitazone can give me in increasing insulin sensitivity as that is the indication for pioglitazone in humans. Do you see how that might be of interest to me to learn that rapamycin abolishes that benefit? Especially that ā€œthe decrease of insulin sensitivity [an effect of rapamycin in humans] is a major risk of HL - hyperlipidemia - [in humans, and also HL effect of rapamycin in humans]ā€ for me, someone who is already hyperlipdemic. I donā€™t want to stack the risk factor of further rapamycin induced insulin resistance on top of the hyperlipidemia risk factor further increased by rapamycin. I would be looking to pioglitazone to ameliorate both of these rapamycin side effects, and it is of great concern to me if rapamycin abolishes those benefits of pioglitazone.

ā€œIt has been reported that ischemic preconditioning (IPC), i.e., short intermittent cycles of sublethal ischemia followed by reperfusion before the subsequent prolonged ischemic insult, produces cardioprotection against ischemia-reperfusion (I/R) induced injury.ā€

Do you know what the most common use of noninvasive ischemic preconditioning in humans is? Thatā€™s exercise. As a person who is already exercising for health in general and cardiovascular health in particular (additionally driven by concern over my hyperlipidemia and insulin resistance), I am highly interested in enhancing those exercise benefits by utilizing ischemic preconditioning. Many people also use bands and other means of blood flow restriction and reperfusion in exercise (Peter Attia is a prominent advocate). If you are unaware of the applicability of this intervention you are welcome to aquaint yourself with the literature, that way you can grasp why this is highly relevant - hereā€™s a start:

An overview of ischemic preconditioning in exercise performance: A systematic review

https://www.sciencedirect.com/science/article/pii/S2095254619300080

ā€œThis intervention was initially developed to decrease the damage caused to internal organs by ischemia and reperfusion.2 However, it has been speculated that IPC also has an effect on exercise performance, notably by improving muscle oxygenation, vasculature, and blood flow delivery to active tissues and organs.3

The mechanisms involved in these athletic improvements are likely related to both metabolic and vascular pathways.4 As a matter of fact, it is thought that IPC can act through 3 main pathways (i.e., neuronal, humoral, and systemic response)ā€

I am a hyperlipidemic insulin resistant exerciser who is interested in using IPC for cardiovascular protection. Can you see why I would be interested to learn if rapamycin abolishes the protective effects of pioglitazone in this context?

All of these effects are found in humans - RAPAMYCIN inducing both hyperlipidemia and insulin resistance. IPC is an effect present in humans and a readily available intervention for any exercising human. PIOGLITAZONE is a insulin sensitizer with cardioprotective effects in humans.
None of this is ā€œmechanistic speculationā€ - if you ā€œare not sure why thatā€™s relevantā€, I fear to ask when youā€™d deem something relevant.

I for one think it extraordinarily relevant (particularly to people in my situation!) to learn that rapamycin might abolish those benefits of pioglitazone in humans, because it certainly does that in animal models - something that medical science has used as standard to alert us to possible effects in humans. Indeed, why do you think this study was performed in the first place? For the benefit of rats or as part of standard research methodology in medical science in humans? But thatā€™s me, you do you.

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