Started pioglitazone today

[tetris]

Why: We know that leriglitazone/MIN-102 is effective at slowing the progression of AMN and greatly reducing the risk of cerebral involvement, but unless I'm missing something, it's not available to me here in the US currently. But its prodrug, pioglitazone, is, and given that leriglitazone is one of the 2 major metabolites of pioglitazone, I'm willing to give it a try.

How: It's a diabetes medication, and diabetes is the most common condition for endocrinologists to treat. Last night, I emailed my endocrine doctor a request to prescribe it, along with AMN-related reasons and what I plan to do to reduce its risk, he's willing to try pioglitazone, and I picked up a starting dose of 15 mg/day from the pharmacy today.

Risks:

- Like leriglitazone, pioglitazone causes edema, and can cause heart problems. I walk on my treadmill everyday (using the handlebars to regain my balance every few steps) and wear compression socks, but I wasn't a part of the MIN-102 AMN trial, so I have no firsthand experience to know what I can do about the level of edema that it will cause.

- Like leriglitazone, pioglitazone can cause weight gain beyond the water weight from edema. For 3 months now, I have been taking the diabetes medication metformin, in case its upregulation of ABCD2 ends up being helpful for AMN (and for its other benefits, like decreasing long COVID risk, decreasing cancer risk, and slowing aging). But metformin is also effective for weight loss (and is frequently coupled with pioglitazone in diabetic patients anyway), so maybe it offers some degree of protection against weight gain, too

- Pioglitazone increases risk of bladder cancer, there was a $2.4 billion settlement over it in 2015. But most people who take pioglitazone have type 2 diabetes, which significantly increases risk of bladder cancer, and because I don't have diabetes, my starting risk of bladder cancer is lower than the average pioglitazone patient. I'm eating 2 lemons a day and will starting drinking more water and eating broccoli, all things that reduce bladder cancer risk.

- Pioglitazone can cause hepatotoxicity/liver toxicity, and in some cases, liver failure. I take 1000 mg NAC, 300 mg alpha-lipoic acid ER, and 100 IU Vitamin E 3 times per day, all of which can have a positive impact on liver health (especially NAC, which is a treatment for hepatotoxicity). I also don't drink alcohol, a major risk factor for hepatotoxicity, so hopefully liver problems don't happen.

The primary marker I'll be looking at to know if it's doing anything is my serum neurofilament light chain levels (nature.com/articles/s41467-... ), which measures rate of neuroaxonal damage, and it goes up as AMN or ALD patients age (and goes way up with cerebral involvement). I'm 34/7 years from AMN onset and my sNfL is already at 22.6 pg/mL, but maybe pioglitazone will slow down its increase a little.

So, I've started taking pioglitazone. Given that virtually all of us have endocrine doctors, maybe pioglitazone is accessible to any of us who don't have existing contraindications like heart problems, liver problems, or bladder problems. I'm especially curious how any former leriglitazone patients, who Minoryx has cut off, fare on pioglitazone.

Needless to say, once leriglitazone becomes FDA-approved, I manage to get in vivo gene therapy, or I end up with cerebral involvement and get HPSCT, I won't be taking pioglitazone anymore.

If it turns out I tolerate 15 mg pioglitazone well, I might go up to 30 mg in a month or two.

[cfox]

I asked my doctor about these issues in the past, but she was not willing to prescribe pioglitazone to me. But I agree with you that at some level pioglitazone might be considered a poor-man's leriglitazone, since most of a dose of pioglitazone is converted into leriglitazone inside the body. One thing to keep in mind is that you're taking a much smaller dose compared to the Minoryx studies. I believe those study participants are taking somewhere in the range of 100-150 mg of leriglitazone per day. Pioglitazone is only approved for up to 45 mg per day, so you will be getting the a much smaller dose that what they are studying in the Minoryx clinical trials.

[tetris in reply to cfox]

> I asked my doctor about these issues in the past, but she was not willing to prescribe pioglitazone to me.

I was careful to acknowledge the bladder/liver/edema risks and include the precautions I planned to take, but yeah your mileage may vary depending on your endocrinologist. I briefly had a different endo before this one who, while having good intentions, micromanaged my medications (refusing to prescribe 100mg emergency solu-cortef because they thought that was too high of an amount) and tried to mastermind my treatment without leaving the decisions to me. That prompted me to switch to my current endo, who offers advice when I ask, but also takes a step back and let me guide my own treatment (within reason of course: he obviously won't agree to anything that would cause harm to me). I'm probably very fortunate to have an endo who is willing to go along with my shenanigans (when prescribing metformin, he said "I doubt this will help in the way you're hoping it will. Anyway, I sent a prescription to your pharmacy").

> But I agree with you that at some level pioglitazone might be considered a poor-man's leriglitazone, since most of a dose of pioglitazone is converted into leriglitazone inside the body.

Pretty much: If I'm reading Eckland and Danhof's "Clinical pharmacokinetics of pioglitazone" correctly (find it on LibGen or DM me), virtually the only pharmacologically-active metabolites of pioglitazone is leriglitazone (which the literature refers to as metabolite "M-IV"), but M-IV only accounts for about 40% (based on Table 1) of the metabolites of pioglitazone. So 45 mg pioglitazone only gets you about 18 mg leriglitazone.

Pioglitazone's only other main pharmacologically-active metabolite, M-III, is metabolized from M-IV (same as MIN-102/leriglitazone) and not directly from pioglitazone, so you're not getting some other pharmacologically-active drug that you wouldn't be getting anyway by taking leriglitazone directly. From "Clinical pharmacokinetics of pioglitazone":

> Pioglitazone is rapidly absorbed after oral administration (81%-94%) and reaches peak concentration in approximately 2.5 hours in patients with type 2 diabetes.It is extensively metabolised in the liver, and most is excreted as inactive metabolites in the faeces. Although the parent compound, pioglitazone, has a half-life of approximately 9 hours, its chief active metabolites, M-III and M-IV, have half-lives of approximately 26-30 hours.

M-II is also technically pharmacologically active, but its total effect is not significant:

> M-II is found in relatively low concentrations in man (about 10% of M-III metabolite) and does not significantly contribute to total active compounds.

> One thing to keep in mind is that you're taking a much smaller dose compared to the Minoryx studies. I believe those study participants are taking somewhere in the range of 100-150 mg of leriglitazone per day. Pioglitazone is only approved for up to 45 mg per day, so you will be getting the a much smaller dose that what they are studying in the Minoryx clinical trials.

Based on the above, one could theoretically just take enough pioglitazone to achieve the same effect as 100 mg-150 mg leriglitazone, without side effects that would not be experienced anyway under leriglitazone. But since pioglitazone is only 40% efficiency for getting leriglitazone, I'd need to take 250 mg pioglitazone to achieve the same effect as 100 mg leriglitazone. So, not very efficient (and no one's getting a 250 mg per day prescription of pioglitazone).

But maybe 45 mg pioglitazone will be helpful anyway, assuming I progressively increase that far without my labs looking abnormal.