Pioglitazone

a brief overview of the risks and potential benefits of the use of piglitazone for transfems

by Sage on 2023-12-23 23:38

TLDR: Drug that makes it so when you gain weight, the majority of it goes to your lower body and none ends up as visceral fat. It can also mess you up if you aren’t careful. If you do take it, dose it at 30mg/day and only use it while intentionally gaining weight. Do not take it if you are at risk for edema, CHF, bladder cancer, or have bone density issues. If you see any signs of edema or bladder cancer, discontinue use immediately.

DISCLAIMER: I am not not a medical professional, I have no qualifications that would allow me to prescribe drugs, and anything I say should probably be taken with a grain of salt. All I am is some girl with an internet connection who can read studies that are available for free on the internet. This document is not meant to be a complete guide and is not enough information to base a decision of whether or not to take pioglitazone on, it’s just a brief overview of the benefits and risks. Always do your own research ESPECIALLY about any unique risk factors you may have.

Section 1 - Background

1.1 - What is pioglitazone

Pioglitazone (pio) is an anti diabetic medication commonly used to treat type 2 diabetes with millions of prescriptions filled every year [1][2]. It is approved in the US, however controversies surrounding the risk of bladder cancer have led to it being withdrawn in France and Germany[3]. It has seen a rise in unsanctioned use in trans women trying to achieve a more favorable body fat distribution and improved waist-hip ratio (WHR).

1.2 - How does it work?

According to StatPearls[4]:

The mechanism through which TZDs exert their anti-diabetic effect is augmenting insulin sensitivity by acting on muscle, adipose, and liver tissue. TZDs increase peripheral tissue glucose utilization and, to some extent, decrease glucose production in the liver. This action involves activating a nuclear receptor, the gamma isoform of peroxisome proliferator-activated receptor (PPAR-gamma). The activation of this nuclear receptor, in turn, alters the gene transcription of several genes involved in glucose and lipid metabolism, along with energy balance.

Basically, it’s all really complicated but pioglitazone changes the way your body uses energy. This leads to some interesting effects, namely how fat is stored on the body.

1.3 - Why take it

There is a popular idea in online DIY trans spaces that “weight cycling” (the process of cyclically losing weight then regaining it) may speed up fat redistribution. However, it was shown in a study on anorexic women that while anorexic vs non-anorexic women do not have a statistically significant difference in the ratio of trunk fat to extremity fat, upon gaining weight the anorexic women tend to disproportionately gain weight on the trunk region[5]. This is obviously not what is the goal for weight cycling, therefore something must be done to promote weight gain in the proper regions while gaining weight. This is where pioglitazone comes in. While taking pio, fat gain is redirected almost exclusively towards the lower body, and studies consistently fail to show any significant increase in visceral fat tissue accumulation while gaining weight on pioglitazone.

1.4 - Evidence for improved WHR

In one study on non-diabetic upper body obese women, pioglitazone showed a decrease in WHR from 0.94 (±0.01) to 0.90 (±0.01) with a 1.3kg gain in total body fat leading to 1kg of leg fat gained (\~75% of fat gained went to legs)[6]. That study also showed that pioglitazone led to no statistically significant change in visceral fat area, however this was accompanied by a non-significant decrease in the ratio of visceral fat to subcutaneous fat (more subq fat compared to visceral). This claim was repeated, this time with statistical significance, in another study[7]. It was also shown in this study that the proportion of new adipocytes (fat cells that have just been created), was only shown to significantly increase in the gluteal and femoral (buttocks and thighs) fat deposits. Essentially, pioglitazone works by creating new fat cells at a disproportionately increased rate in your lower body.

Section 2 - Usage

2.1 - When to use it and how long to use it

Given that pio works by creating new fat cells it is not recommended to use while losing it seems it would only be maximally effective during periods of weight gain. It also can lead to some negative long term side effects (discussed in section 3), so it is advised to not go past a year of continuous use and to keep lifetime exposure minimal. Therefore, I’d only recommend using it while intentionally gaining weight, and only for a maximum of 6 months to a year at a time.

2.2 - Dosing

Both of the studies mentioned in section 1.4 involved patients taking 30mg once per day, a dose commonly prescribed for treating type 2 diabetes. Earlier guides and some second hand information have led to recommendations as low as 7.5mg, however given the relative safety and proven efficacy of 30mg a day it seems advisable.

2.3 - Contraindications

Do not take pioglitazone if:

You have a family history of bladder cancer
You have bone density issues
You have a history of and/or are at risk for edema and/or congestive heart failure

Discontinue use immediately if:

You notice any signs of edema
- Swelling or puffiness of the tissue right under the skin (especially in legs or arms), skin that holds a dimple (also known as pitting) after it's been pressed for a few seconds, etc.
You develop bladder cancer (extremely unlikely)

Section 3 - Risks

3.1 Edema/CHF

Pioglitazone is known to cause peripheral edema. One meta analysis suggests a 2.42 odds ratio for pioglitazone induced edema, affecting 4.8 – 7.2% of patients treated with pioglitazone alone[8]. It should be noted that those with type 2 diabetes tend to have generally worse health markers and diabetes itself increases risk of edema, therefore the incidence rate for edema may be exaggerated compared to young and healthy people.

This is not to say it should be disregarded however as the only cases i’ve ever heard of people stopping pioglitazone due to side effects involved peripheral edema. If you are predisposed to it (through diet, lifestyle, genetics, etc), I would strongly caution against pioglitazone, and as I mentioned in section 2.3, discontinue use immediately if you notice any signs of edema developing.

In rare cases, pioglitazone is also associated with congestive heart failure in patients with underlying heart conditions and therefore should be avoided by those at risk.

Overall, I would say the risk is low but it is still something to be concerned about. It should also be noted that spironolactone (a commonly used anti androgen), may work to lower the risk of edema by decreasing renal sodium reabsorption, one of the causes of edema caused by pioglitazone[8]

3.2 Bone density issues

Pioglitazone has been shown to decrease bone density by way of reduction in bone formation and an increase in bone resorption. This has the effects of increased long term fracture risk, however the difference in fracture rate only became significant in women after one year[10]. These changes are likely reversible upon cessation of use.

3.3 Bladder cancer

Pioglitazone has had dozens of studies examining its likelihood to cause bladder cancer and the results have been varied. Bladder cancer concerns caused it to be removed from French and German markets, but according to the FDA, risks only start to become statistically significant after 2 years of use[11]. It is however recommended to avoid if at risk for bladder cancer and to stop use immediately if bladder cancer develops.

3.4 Negative impacts on breast growth

This blog post does a better job of explaining the concerns of the negative impacts of pio than I could so give it a read. Essentially, a drug of the same class (TZDs) has been shown to have anti proliferative effects on human mammary epithelial cells, which may have negative impacts on breast growth. However it may also increase fat deposition in the breasts. Honestly, nobody has ever studied or observed this in live humans so I’m of the opinion that it’s not something that will have a huge effect on breast size.

Section 4 - My thoughts

DO NOT TAKE THIS AS MEDICAL ADVICE OR CITE IS AS A SOURCE, IT IS AN OPINION PIECE

This is my third writeup on pioglitazone and since then (and I wouldn't credit myself for this), I've seen at least a dozen people get on it. The results are generally what you’d expect from this writeup, that their WHR improved, that their thighs are more jiggly, that their ass is fatter. Honestly, it seems like a great drug and I plan on doing it myself. At the time of writing this, I’ve got 6 months worth of pio on hand and my plan at the moment is to do a quick (\~3 months) bulk and gain 10-15lbs then slowly lose it with the intent to atrophy upper body muscles while maintaining what I can on my lower body.

As for safety, it’s not really something that carries a huge risk in my opinion. The only cases I’ve heard of involving edema were in people who were predisposed to it (one through an extreme diet, and the other with a severe history of fluid retention issues who really shouldn’t have touched it).

Also fun fact, I suspect talking about pio is what got me banned from the transDIY discord server (they never told me the official reason), so don’t bring this up there. Or do. It would be fun to have them try to point holes in this, I’m sure the people there would be good at finding mistakes I’ve made.

Hypoglycemia, while not commonly cited as a risk of pioglitazone, is something that is a concern with extreme diets. Intermittent fasting/OMAD, keto diet, and anything else meant to lower blood glucose levels are probably a bad idea.

It should also be noted (although I can’t find the studies atm so I’m not 100% sure this is true) that the fat redistribution effects of pioglitazone are only maximally effective on an estrogen dominant endocrine system, so you need to be on hrt if you’re going to do it. I’m also reasonably confident that effects are permanent (or sustainable assuming proper diet and lifestyle), but this part I’m not the surest on so someone correct me if I’m wrong.

I’d also like to thank Jade, Estradiolnihil, and Krystal, for compiling many of the sources I’ve drawn from.

You can download this post in pdf form here

Citations