#1

In this episode from today, Ralph DeFronzo says the following about Pioglitazone:

  1. it is the best drug for treating NASH.
  2. it improves mitochondrial dysfunction, potentially even more than aerobic training
  3. redistributes fat from muscles and beta cells to subcutaneous fat
  4. is the only drug that increases insulin sensitivity
  5. improves cardiac blood flow, helps with NO production
  6. Causes a small amount weight gain but can be used with GLP-1 agonists where this is counteracted

If I heard right, there was a report of someoneā€™s HbA1c going down from 12-ish to 6-ish after using their combo that included Pioglitazone.

Does anyone have any experience with this at all?

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#2

Good episode. First time hearing about this drug. I didnā€™t love the slight weight gain side effect that was mentioned though.

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#3

Very interesting episode indeed. Havenā€™t heard about Pioglitazone either.

IIRC he did say that this side effect (and others) goes away if you take it along a GLP-RA which is why his trifecta of meds is GLP1-RA, Pioglitazone and SGLT2i.
He also mentioned that Pioglitazone increased the ejection fraction.

BTW if somebody has access to ChatGPT deep research, it could be useful to gather more information on Pioglitazone.

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#4

True. Iā€™d take it if I had T2D but donā€™t think Iā€™d play around with it as a preventative thing when Iā€™m also doing low doses of SGLT2, Acarbose, and GLP1

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#5

I ordered from India, at least a yearā€™s worth and started taking it because of Sandra Kaufmannā€™s talk. Pioglit 15mg once a day. My doctor warned I would gain weight, but supported the idea and believed in the drug. Itā€™s an old drug and heā€™s an old Dr. with experience. It did absolutely nothing that I could tell after several months I heard some negative stuff about it and decided it wasnā€™t a longevity drug so I quit. Never noticed anything from quitting either.

I think what i heard came from something like ITP, or the million molecule challenge. Canā€™t recall. Maybe I should finish the box anyway. Thanks,

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#6

There you goā€¦

Pioglitazone is a thiazolidinedione (TZD) medication primarily used to improve insulin sensitivity in patients with type 2 diabetes mellitus and insulin resistance. Hereā€™s a structured overview of its role and considerations:

Mechanism of Action

  • PPAR-Ī³ Activation: Binds to peroxisome proliferator-activated receptor gamma (PPAR-Ī³) in adipose tissue, muscle, and liver, enhancing insulin sensitivity.
  • Adiponectin Increase: Promotes secretion of adiponectin, a hormone that improves insulin signaling and glucose uptake.
  • Fat Redistribution: Shifts fat storage from visceral to subcutaneous depots, reducing harmful lipid metabolites and inflammation linked to insulin resistance.

Indications**

  • Type 2 Diabetes: Often combined with metformin, sulfonylureas, or insulin.
  • Insulin Resistance Syndromes: Off-label use in conditions like PCOS or prediabetes, though evidence varies.

Efficacy**

  • Glycemic Control: Lowers HbA1c by ~1ā€“1.5% and improves lipid profiles (reduces triglycerides, increases HDL).
  • Cardiovascular Effects: Neutral or possible benefits (e.g., reduced stroke risk), unlike rosiglitazone (associated with ischemic risks).

Side Effects & Risks**

  • Weight Gain: Due to fat redistribution and fluid retention.
  • Edema/Heart Failure: Contraindicated in NYHA Class III/IV heart failure; caution in predisposed patients.
  • Bone Fractures: Increased risk in postmenopausal women (long-term use).
  • Bladder Cancer: Mixed evidence; avoid in active bladder cancer or history of hematuria.
  • Hepatotoxicity: Rare but requires baseline and periodic liver enzyme monitoring.

Dosing & Monitoring**

  • Dose: Initiated at 15ā€“30 mg once daily, max 45 mg/day. Effects manifest over weeks.
  • Monitoring: Regular checks for weight, edema, liver enzymes, and HbA1c.

Contraindications**

  • Heart failure (NYHA Class III/IV), active bladder cancer, severe hepatic impairment.

Clinical Considerations**

  • Risk-Benefit Assessment: Reserved for patients unresponsive to first-line agents (e.g., metformin) or specific insulin-resistant phenotypes.
  • Alternatives: Consider GLP-1 agonists or SGLT2 inhibitors in patients with cardiovascular comorbidities.

Conclusion**
Pioglitazone effectively improves insulin resistance but requires careful patient selection and monitoring due to its side effect profile. It remains a valuable option in tailored diabetes management, particularly where metabolic benefits outweigh risks.

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#7

By nothing, do you mean that it didnā€™t lower your A1c?

#8

It might be worth using Actos intermittently to get rid of any visceral fat. The only downside I have found is a possible risk of bladder cancer. Apparently, Actos was banned in India. I would imagine that using this medication for a couple of weeks once or twice a year would be very low risk. The appetite increase would be welcome for people on a strength training program. This drug is super interesting. I hope the ITP tests it soon.

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#9

I mean I never noticed it was there. I check A1c once yearly, lipids and CBC every 3 months and check all the things on Levine. I just didnā€™t notice any big changes.

Iā€™m thinking about throwing it back in to finish the box. No weight gain for me.

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#10

I got stuck on a 4 hour drive today and listened to the whole thing. He mentioned 15,30 or 45mg rates didnā€™t he? Maybe I should try taking 2 of these a day.

#11

He also said metformin doesnā€™t get into muscles. Only liver, kidneys and bladder. Up to 2g / day should not be negative for adaptation to exercise. It lowers blood sugar by reducing liver production of glucose. It does not improve insulin sensitivity.

It was a very interesting discussion about glucagon. Since Iā€™m not overweight, t2d or pre, I think my higher than ideal A1C (5.5) is a stress reaction driving high glucagon and then higher blood glucose.

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#12

I know weā€™ve shed gallons of ink on acarbose, metformin, and SGLT-2 inhibitors, but it would be nice to have an algorithm that linked a little lifestyle data and lab results to a proper treatment plan. E.g. if you are taking rapamycin once per week and regularly have high normal fasting blood glucose, should you treat that? If your a1c is around 5.5 is that worth treating? How would you decide which drug to try for a marginal case where monotherapy might get you the distance you want from the top of the normal reference range?

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#13

Letā€™s take this a big step further. As one of the few medications to directly improve mitochondrial dysfunction with negligible side effects (zero side effects if taken with either glp1a and/or sglt2i), this needs to be put through an ITP trial.
This also appears to be one of the only medications to reverse atherosclerotic changes and be directly cardio protective, and is basically free.

And there are cancer treatments to be considered. RCT trials have shown no increased risk of cancer but there have been some data mostly from observational studies that have shown a slight increased risk in bladder cancer in smokers.

https://pubs.acs.org/doi/10.1021/acs.nanolett.3c04706#:~:text=Herein%2C%20we%20report%20the%20repurposed,prepared%20using%20the%20reported%20protocols.%20

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#14

Also considering Matt Kaeberleinā€™s latest podcast involving thymic rejuvenation with growth hormone (or HGH secretagogues), maybe pioglitazone is the right medication to prevent the insulin resistance that comes along with exogenous HGH since it directly targets the pathway? My main concern would be that since both HGH and pio can cause fluid retention, would this increase the risk of heart failure? Something like tesamorelin and pio would seem like a 1-2 knockout punch for visceral fat.

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#15

Which brings to me a question : has pioglitazone been used in the body building community? I imagine it could be quite useful on a bulk, when used with GH: providing adipose tissue, while controlling blood sugar .

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#16

I would expect the opposite. Some insulin resistance (hepatic insulin resistance and probably even in the muscle) is quite benefical for muscle growth. I have seen a lot of bodybuilders who need to be insulin resistance to grow muscle. The usual way is to achieve this is to overeat (mass phase) for a longer period of time (6-9 months).

#17

The bone fracture risk is a concern for me.
This has been shown even for non-diabetics,
Hazard ratios are quite high for men and women.
In the study below the risk was even higher for men.
Also, the low dose of 15 mg seems to have a negative effect on bone mass.
Maybe this could be amoleriated by strength training, but maybe not.

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#18

Pioglitazone was on my radar from my Pubmed rabbit hole adventures relating to Alzheimerā€™s.

https://www.kisupplements.org/article/S2157-1716(15)31196-5/fulltext

Importantly, we found that pioglitazone treatment in aging also increased renal klotho expression by more than 60%, another possible contributor to its effects on senescence and reactive oxygen species.

Klotho being so important for Alzheimerā€™s preventionā€”halting or reversing kidney aging is a bonus.

https://www.sciencedirect.com/science/article/abs/pii/S1056872716306754

See above for signal re: dementia (I didnā€™t think the paper splits up dementias into individual diseases).

Mitochondrial biogenesisā€¦another possible mechanism of action is helping with dementia prevention.

Then again the data looked less promising when honing in on Alzheimerā€™s alone, so I stopped looking at that point. Potentially messing with bone density is the biggest consideration holding me back.

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#19

Also curious as I havenā€™t listened to the interview and likely wonā€™t have time to ā€” those of you who have, can you tell me if the guest makes any reference to sex specific effects? From what I can see itā€™s only men who benefit:

The Effect of Pioglitazone and Resistance Training on Body Composition in Older Men and Women Undergoing Hypocaloric Weight Loss - PMC.

Men receiving pioglitazone lost more abdominal visceral fat compared to men who were not given pioglitazone and men who resistance-trained lost less appendicular lean mass compared to men who did not (Figure 2). Men who were given pioglitazone lost more thigh muscle volume, compared to men who were not given pioglitazone (āˆ’82 vs. āˆ’47 cm3; P = 0.026). Among women, there was no significant effect of pioglitazone on change in abdominal VAT (P = 0.223) and no effect of resistance training on change in appendicular lean mass (P = 0.829). Women receiving pioglitazone lost less thigh subcutaneous fat compared to women who were not given pioglitazone (āˆ’104 vs. āˆ’298 cm3; P = 0.002). However, there was no effect of pioglitazone on any other measure of body composition in women.

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#20

As I recall they never mentioned sex in this episode. The focus was on the ominous octet and the various manifestations of IR and T2D.

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