Summary: I started taking 4 mg saroglitazar before breakfast, I'm optimistic about its efficacy for AMN, and I'm still taking pioglitazone in the evening, because combining saroglitazar and pioglitazone probably has a synergistic, stronger overall effect.
What saroglitazar is: It's a strong PPARα agonist (slightly weaker than fenofibrate, see pmc.ncbi.nlm.nih.gov/articl... ), with a small amount of PPARγ agonist activity, that has 4.8 times the blood-brain barrier permeability of leriglitazone (MIN-102).
The math: A study was published back in 2020 (Westlund and Zhang, Molecules 2020) that lists the BBB permeability of various PPARγ agonists. See Table 1: pmc.ncbi.nlm.nih.gov/articl...
The logBB of saroglitazar is -0.03, and the logBB of leriglitazone is -0.714. 10 ^ (-0.03 - -0.714) is about 4.83, meaning that saroglitazar is 4.8 times more BBB-permeable than leriglitazone.
How other PPARα agonists do for AMN: Historically, the best-known PPARα agonists are fibrates. The most BBB-permeable fibrate is bezafibrate, which monkeybus previously mentioned (healthunlocked.com/amneasie... ). In general, PPARα agonists like fibrates make your peroxisomes more active in a way that decreases triglycerides and bad cholesterol (LDL) and increases good cholesterol (HDL). But fibrates cross the BBB very slowly, and bezafibrate is no exception. So even though bezafibrate seemed promising for ALD in fibroblasts (pmc.ncbi.nlm.nih.gov/articl... ), it was ineffective in actual ALD patients. This means that a PPARα agonist that crosses the BBB more efficiently could be really promising for AMN and ALD.
Glitazars: In terms of PPAR agonists (en.wikipedia.org/wiki/PPAR_... ), there are "glitazones" (PPARγ agonists), which make your peroxisomes more active in a way that increases insulin sensitivity, and glitazars, which combine PPARα agonist and PPARγ agonist activity. There have been several glitazars developed over the years, but they kept getting cancelled. Aleglitazar failed trials due to side effects to the kidney and heart, muraglitazar failed trials due to higher incidence of edema and heart failure than pioglitazone, and tesaglitazar was scrapped due to cardiac toxicity related to mitochondrial toxicity. For years, glitazars seemed like they could have promise, but the awful side effects of these specific glitazars made them unsafe.
Enter saroglitazar. In India, where it was developed by Zydus, it was approved in 2013 for "diabetic dyslipidemia and hypertriglyceridemia in patients with type-2 diabetes not controlled by statins alone". In 2020, it was approved in India to treat type-2 diabetes, NAFLD, and NASH (economictimes.indiatimes.co... ). Saroglitazar is undergoing clinical trials in the US and in the EU (the FDA and EMA have both granted it orphan drug status to treat PBC), and as of their February 2025 earnings call (transcript: web.archive.org/web/2025021... ), Zydus hopes to file for FDA approval in Q3 of the 2025 calendar year.
But saroglitazar could be useful for neurological diseases, too. As one might expect of a PPARα agonist that crosses the blood-brain barrier efficiently, saroglitazar was found to be neuroprotective, protected against Alzheimer's in rats (pubmed.ncbi.nlm.nih.gov/376... ), and it is hypothesized that it could be efficacious for treating Parkinson's (pubmed.ncbi.nlm.nih.gov/393... ). Additionally, saroglitazar enhances learning and memory, and based on another rat study, it is promising as a Huntington's treatment (pubmed.ncbi.nlm.nih.gov/392... ):
> Studies have shown that both PPAR α & γ individually modulate various pathophysiological events like neuroinflammation and insulin resistance, which are known to variedly affect neurogenesis. [...] We have found that SGZR at the dose of 4 mg/kg per oral showed significant improvement in learning and memory compared to ICV STZ-treated rats. [...] In conclusion, treatment with Saroglitazar attenuated Huntington's disease-like symptoms in rats which are induced by 3-NP via activation of PPAR α/γ pathway.
I think a lot of saroglitazar's efficacy for AMN comes down to how different cell types in the brain express PPARα. This is a complex topic with many variables, because
- To date, saroglitazar's potential to treat adrenomyeloneuropathy and adrenoleukodystrophy has not been investigated at all, as far as I can tell. Until it is investigated, or until I or another AMN community member has reported positive results from saroglitazar, it remains theoretical.
- One of the most notable effects of fibrates that is supposed to be useful for treating AMN is their upregulation of ABCD2 (pmc.ncbi.nlm.nih.gov/articl... ). Presumably, saroglitazar upregulates ABCD2, as well. Although PPARα is expressed throughout the brain, if cell types throughout the brain that are high in ABCD1 (see figure 4 of onlinelibrary.wiley.com/doi... ) are not also high in ABCD2, I don't know if PPARα agonism is nearly as effective. I asked my ALD expert doctor about this over 2 weeks ago and he has yet to respond.
- Almost none of the literature out there about PPARα agonists use saroglitazar specifically. So although some things sound promising (like pmc.ncbi.nlm.nih.gov/articl... saying that PPARα is more highly expressed throughout the brain than PPARγ), saroglitazar in particular needs to be studied.
Even with these unknowns about saroglitazar, relating to AMN, saroglitazar seems relatively safe, and considering how promising it could be for AMN, it is probably worth a try.
I'm not taking saroglitazar by itself, I am continuing to take 45mg pioglitazone every day (see healthunlocked.com/amneasie... ). By several metrics, combining a PPARα agonist and a PPARγ agonist makes both of them more effective. From sciencedirect.com/science/a... (FAO means "fatty acid oxidation"):
> A decrease in triglycerides content associated with an increase in FAO-related gene expression and activity was observed with all agonists after 14-day repeat exposure. The strongest effects were obtained after treatment with the dual PPARα/γ agonist muraglitazar.
And from pubmed.ncbi.nlm.nih.gov/268... :
> The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin.
These are about other diseases, though. I haven't found anything about the efficacy of combining a PPARα agonist and a PPARγ agonist to treat AMN. Again, I asked my ALD expert doctor over 2 weeks ago and he hasn't responded. I will probably ask him again soon, since I have now started taking saroglitazar.
Now that we've speculated a bit about efficacy, let's talk about safety.
Saroglitazar increases the creatinine of patients in studies by an average of 0.12 mg/dL (pubmed.ncbi.nlm.nih.gov/329... ). These are all diabetic patients, and non-diabetic patients won't have the same risk factors, but if your creatinine is already high, or if you have kidney problems or any kidney disease, taking saroglitazar is probably a bad idea.
I haven't found any study at all where patients take saroglitazar and pioglitazone at the same time. Typically, if a type-2 diabetes patient was previously taking pioglitazone and they start saroglitazar, they'll stop pioglitazone, as saroglitazar gives the patient almost-as-good insulin sensitivity as when they were taking pioglitazone. In theory, taking saroglitazar and pioglitazone at the same time will not cause problems, but it hasn't been studied. Because there's plenty of studies on taking pioglitazone and another PPARα agonist, fenofibrate, together, I'm not particularly worried, but I'm asking my endocrinologist about this.
Drug interactions: Don't bother searching for specific medicine names. Because saroglitazar is a medication that is only approved in India so far, the specific medications it interacts with will probably not be listed, saroglitazar is not listed on popular sites for patients like WebMD, and its DrugBank page is very, very incomplete. But we can still check the interactions, by just knowing that saroglitazar is metabolized by CYP2C8 and CYP3A4 (carehospitals.com/medicine-... ):
> Saroglitazar is metabolised by the cytochrome P450 (CYP) enzyme system, specifically CYP2C8 and CYP3A4.
This means that saroglitazar is metabolized in the liver. For one example of an interaction, Paxlovid works by inhibiting the whole CYP3A enzyme family (labeling.pfizer.com/ShowLab... ):
> PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications
I got COVID last week. For 8 days, with this last Sunday being the last day, I was taking Paxlovid, and I had to wait until the Paxlovid cleared out before starting saroglitazar. As a side note, pioglitazone (and probably leriglitazone) increases your risk of going to the ICU from COVID three-fold (pmc.ncbi.nlm.nih.gov/articl... ), but because a key component of long COVID is mitochondrial and peroxisomal disregulation, pioglitazone is good for long COVID, and saroglitazar should be, too.
In 6 months, if my neurofilament light chain (NfL) levels stop going up, or go down, I'll know that it's working.
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