Pioglitazone, Ozempic, and Weight Cycling

Content info: I am going to discuss gender dysphoria, disordered eating, body dysmorphia, and weight loss in the context of intentional body changes (both to affect where fat is stored on the body and overall weight loss) and tools such as pioglitazone, Ozempic, and weight cycling. This blog was written by Dr. Crystal Beal.

Body Acknowledgements

I want to start out by acknowledging that all bodies are great bodies, and that idealized standards of beauty are oppressive tools of colonialism and misogyny. I also want to recognize that racism, colonialism, misogyny, and ableism tell us that a person’s moral and ethical “goodness” can be determined by how closely their body matches arbitrary and changing beauty standards. Despite centuries of folklore, religion, and law, “pretty” doesn’t actually match up to any scale of human worth or ability. Bodies come in a wonderfully broad range of shapes and sizes, and I am so grateful to experience and celebrate that diversity.

I also want to acknowledge that I have lived my life with thin privilege and have not had significant dysphoria around my body shape. I did experience abusive body shaming from a domestic partner for 8 years, and I have a history of body dysmorphia and bulimia. I want to be transparent here:

While I find every body a unique and special body as it is, I work and live in a community full of humans who:

• Want and need to change their bodies
• Whose bodies are oppressed by our society,
• Who are often denied bodily autonomy,
• and who the medical community frequently harms and traumatizes.

And I am one of the people they rely on to help with that.

It is my honor to witness and uphold their right to bodily autonomy and bodily change within the bounds of my role as a physician (and, outside of work, as a friend, partner, lover, and fellow human.)

This is Your Body

I believe in bodily autonomy so strongly. I often tell my patients:
this is your body and your decision.

It is not infrequent for me to say:
you are going to make whatever choices you make with the medications I prescribe, I would just love to be informed if you feel safe doing so, so I can help support you with the most pertinent lab work and educational information.

No one gets to tell you what your gender identity or gender expression is. For me those two things seemingly coincide: I identify as femme and I present as high femme.

Ultimately, at QueerDoc, we just want to support you in finding and feeling your gender euphoria as you define it.

Pioglitazone

A few patients have asked us about pioglitazone recently, probably in relation to this Reddit post. In accordance with many of the Redditors, I agree that there seems to be no research on pioglitazone in transgender patients. The referenced article (2) does indicate an upregulation of SHBG in a sample size of 40 people with PCOS. SHBG does preferentially bind testosterone over estrogen (3), but there is still debate as to whether the free testosterone theory is physiologically meaningful (4). While the people with PCOS seem to have some improved estrogen effects (ovulation), there is such a complex interplay between insulin, ILGF, SHBG, and sex steroid hormones, I don’t think we can confidently say the pioglitazone drove the increased estrogen effects. It may have been pioglitazone’s effects on insulin in people with insulin resistance that drove seemingly increased estrogen effects.

What we do have published research on is the risks associated with pioglitazone.

Pioglitazone may increase the risk of bladder cancer. This was pretty well supported by a decent study (5). Older data suggest the risk may be as high as 40% if you take pioglitazone for more than 2 years and take more than a total of 28,000 mg over time (6). Pioglitazone has been with associated with an increased risk of heart failure and dose-dependent edema(7). It also has been associated with liver failure (8,9,) so it is very important: DO NOT MIX pioglitazone with bicalutamide.

According to Up To Date (a clinical decision-making resource site,) other common side effects include:

Cardiovascular: Edema (3% to 27%; including exacerbation of edema), Cardiac failure (8%; including worsening of heart failure)
Endocrine and metabolic: Hypoglycemia (27%), Decreased serum triglycerides, increased HDL cholesterol, weight gain
Respiratory: Upper respiratory tract infection (13%), Pharyngitis (5%), sinusitis (6%)
Nervous system: Headache (9%)
Neuromuscular & skeletal: Back pain (6%), bone fracture (females: 5%; males: 2%) (table 3), myalgia (5%), Increased creatine phosphokinase in blood specimen

Bladder cancer seems like a pretty bad possibility. When I think about the risk and benefits here, this one doesn’t seem worth it to me unless you have some other health condition for which pioglitazone is indicated. I am a physician willing to try many “non-evidence based” treatments. But we always have to weigh the potential risk versus the potential benefits for each individual accounting for their pre-existing health and their care goals.

For most patients, the risks in using pioglitazone seem far too high. That said, if you were planning a short-term treatment course of pioglitazone as an experiment, the risk benefit ratio may shift. For example, if someone wanted to do a short-term (3-month) trial at a low dose (15mg daily), I might consider that in an otherwise healthy patient who could understand the inherent risks and lack of data. I wouldn’t recommend it, but I wouldn’t necessarily say no, “I won’t prescribe that.” I think the questions we really can’t answer are:

• Does pioglitazone make a difference in fat redistribution? If it does,
• Is fat redistribution faster on pioglitazone?
• Is fat distribution improved on pioglitazone?
• Or other (or neither?)

Ozempic (and other GLP1 inhibitors)

Pioglitazone may or may not contribute to improved fat redistribution, so what about GLP1 inhibitors, like Ozempic or Wegovy? GLP1 inhibitors don’t have research in trans populations either. But when we look at the literature in patients with PCOS we see an interesting story, serum testosterone seems to decrease when GLP1 inhibitors are taken alone (10) and when they are taken with metformin there is an increase in SHBG (11,12.) This seems to me to again point to how complex the endocrine system is: we don’t fully understand the interplay between insulin, sex steroid hormones, and SHBG. We do know that GLP1’s cause more weight loss than pioglitazone.

While we also know some information about GLP1 side effects, they are relatively new drugs. They first gained FDA approval in 2005 compared to pioglitazone’s approval in 1999. We often learn about new safety concerns for new medications in the initial few years after they are first approved as more people use them for longer than in their drug trials. What we currently know, however, is that more serious potential side effects include

• acute kidney injury requiring dialysis,
• diabetic retinopathy,
• gallbladder disease,
• anaphylaxis,
• thyroid cancer, and
• pancreatitis.

Other common side effects include:

Gastrointestinal: Abdominal pain (adolescents and adults: 6% to 20%), constipation (oral: 5% to 6%; SUBQ: Adolescents: 6%; adults: 3% to 24%), diarrhea (oral: 9% to 10%; SUBQ: Adolescents and adults: 9% to 30%), nausea (oral: 11% to 20%; SUBQ: Adolescents and adults: 16% to 44%), vomiting (oral: 6% to 8%; SUBQ: Adolescents: 36%, adults: 5% to 24%), Abdominal distension (2% to 7%), cholelithiasis (Adolescents and adults: 0% to 4%), decreased appetite (oral: 6% to 9%)), dyspepsia (oral: 0.6% to 3%; SUBQ: 3% to 9%), eructation (adolescents and adults: ≤7%), flatulence (1% to 6%), gastritis (2% to 4%), gastroenteritis (SUBQ: Adolescents and adults: 6% to 7%), gastroesophageal reflux disease (adolescents and adults: 2% to 5%), viral gastroenteritis (SUBQ: 4%)
Nervous system: Fatigue (SUBQ: 11%), headache (SUBQ: Adolescents and adults: 14% to 17%), Anxiety (SUBQ: Adolescents: 4%), dizziness (SUBQ: Adolescents and adults: 8%)
Respiratory: Nasopharyngitis (SUBQ: Adolescents: 12%), Sinusitis (SUBQ: Adolescents: 4%)
Cardiovascular: Hypotension (SUBQ: Adolescents and adults: 1% to 2%; including orthostatic hypotension)
Dermatologic: Alopecia (SUBQ: Adolescents and adults: 3% to 4%), skin rash (SUBQ: Adolescents: 3%), urticaria (SUBQ: Adolescents: 3%)
Endocrine & metabolic: Diabetic retinopathy (complications: 3% to 7%; vitreous hemorrhage: 1%; blindness: <1%) (Marso 2016a), hypoglycemia (SUBQ: 2% to 6%), severe hypoglycemia (≤1%)
Hepatic: Increased serum alanine aminotransferase (SUBQ: Adolescents: 3%)
Immunologic: Antibody development (≤3%)
Infection: Influenza (SUBQ: Adolescents: 3%)
Neuromuscular & skeletal: Sprain (ligament: SUBQ: Adolescents: 4%)

Oof. That’s a long list!

I, for one, don’t love that this is being used in adolescents. I mean, seriously, puberty blockers which have been used since the 1980s are being called “unsafe” and “experimental” and people are over here giving this mucher new medication to adolescents when we have a lot of data saying that weight loss is rarely maintained over time (13.) And that the chronic dieting/weight gain cycle increases rates of many health complications (14,15.)

I digress.

However, we again are left with the question: do GLP1 inhibitors increase the fat redistribution you would already see on estrogen based therapies, simply speed it up, or have no significant benefit?

I really lean into these medications having risks that outweigh the benefits for most patients who don’t have an indication to take them for other health conditions.

I have used them, however, in my trans patients seeking gender affirming surgeries with BMIs that make accessing surgery incredibly challenging or impossible.

First, let’s point out that BMI is racist and not actually a health statistic – the Maintenance Phase podcast breaks it down really well. We also wrote a blog about BMI and surgery recently. I don’t include BMI on my surgery referral letters because I am not interested in perpetuating systems of oppression. That said, we live in an oppressive society with a broken healthcare system and some of my patients decide temporary weight loss to access surgery is the better fit for them than no surgery or fighting for surgery. I’m okay with that.

Weight Cycling

Okay some of the theory behind using pioglitazone and GLP1s to aid in fat redistribution may rest on the concept of weight cycling, which is the idea that repetitively gaining and losing weight in a cyclic pattern may benefit fat redistribution. Again, we have no significant evidence-based medicine or published research here.

It is a theory that seems to make moderate physiological sense in that weight put on under the influence of estrogen tends to be distributed more in a gynecoid pattern and weight put on under the influence of testosterone tends to be distributed in a more android pattern.

The major caveats are that:

1. We don’t know if this speeds up or “improves” fat redistribution that would happen anyways.
2. Weight cycling has some known risks: increased rates of non-fatal myocardial infarction, non-fatal stroke, peripheral arterial disease, peripheral vascular angioplasty, hospitalization for heart failure, foot ulcer, and all-cause mortality.

After learning about the lack of data on whether or not it works and the risks of weight cycling,

if you are going to try weight cycling

I would recommend limiting the amount of weight and duration of the intervention.

Also, consider your individual risks for heart disease. Do you already have risk factors for heart disease? Maybe this isn’t the best intervention for you.

I usually tell my patients if they are going to weight cycle to:

• cycle gaining and losing five pounds
• every 2 to 3 months
• for no longer than a year.

Weight cycling also means you should use the same scale at the same time of day when you are measuring weight, and I recommend a fabric measuring tape to check body dimensions. It is notoriously hard to get consistent body measurements, so I also recommend having a test piece of clothing that doesn’t stretch. You can feel and take photos of how you fit into it every few months. Again, this isn’t an intervention I would recommend, but I believe everyone gets to choose what they do with their body.

Fat Redistribution Anyways

The big question we really haven’t answered is would fat redistribution happen without interventions anyway? We know that fat and muscles change distribution, shape, and size under the influence of estrogen and testosterone. We don’t know conclusively that any of the above interventions make that redistribution more effective or more efficient. We do know that your pre-existing genetics, the timing of gender care initiation, and duration of hormonal therapy have a large impact on fat redistribution. We also know supporting your heart, muscles, and bones with regular cardiovascular and weight-bearing exercises is a great addition to your overall health no matter your shape or size. Further, we know targeted training can help amplify redistribution into shapes you want. If targeted training interests you, consider working with a trans personal trainer like Shawn Stinson (he/him) or Non Gendered Fitness. Or even better, challenge colonialism and white supremacy with Ilya Parker (they/them). And know that there is no one way and no right way to be trans.

Also, check out our guest blogs by Jessie Rard of Twisted Fox Training:

• Building a Broader Physique: Exercises for Angles
• Gettin’ Curvy: Workouts for Flexibility, Strength, and BOOTY

Stay checked in with QueerDoc:

Citations

1. Reddit post- https://www.reddit.com/r/DrWillPowers/comments/tieh1o/has_there_been_any_progress_on_investigating/?utm_source=share&utm_medium=android_app&utm_name=androidcss&utm_term=1&utm_content=share_button
2. Brettenthaler, Nora & De Geyter, Christian & Huber, Peter & Keller, Ulrich. (2004). Effect of the Insulin Sensitizer Pioglitazone on Insulin Resistance, Hyperandrogenism, and Ovulatory Dysfunction in Women with Polycystic Ovary Syndrome. The Journal of clinical endocrinology and metabolism. 89. 3835-40. 10.1210/jc.2003-031737.
3. Knochenhauer ES, Boots LR, Potter HD, Azziz R. Differential binding of estradiol and testosterone to SHBG. Relation to circulating estradiol levels. J Reprod Med. 1998 Aug;43(8):665-70. PMID: 9749416.
4. David J Handelsman, Free Testosterone: Pumping up the Tires or Ending the Free Ride?, Endocrine Reviews, Volume 38, Issue 4, 1 August 2017, Pages 297–301, https://doi.org/10.1210/er.2017-00171
5. Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7(4):1070-1080. doi:10.1002/cam4.1354 [PubMed 29476615]
6. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645. doi:10.1136/bmj.e3645 [PubMed 22653981]
7. de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol. 2017;16(1):134. doi:10.1186/s12933-017-0617-4
8. Floyd JS, Barbehenn E, Lurie P, Wolfe SM. Case series of liver failure associated with rosiglitazone and pioglitazone. Pharmacoepidemiol Drug Saf. 2009;18(12):1238-1243. doi:10.1002/pds.1804 [PubMed 19623674]
9. May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002;136(6):449-452. doi:10.7326/0003-4819-136-6-200203190-00008 [PubMed 11900497]
10. Niafar M, Pourafkari L, Porhomayon J, Nader N. A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries. Arch Gynecol Obstet. 2016 Mar;293(3):509-15. doi: 10.1007/s00404-015-3976-7. Epub 2015 Dec 10. PMID: 26660657.
11. Xing C, Li C, He B. Insulin Sensitizers for Improving the Endocrine and Metabolic Profile in Overweight Women With PCOS. J Clin Endocrinol Metab. 2020 Sep 1;105(9):2950–63. doi: 10.1210/clinem/dgaa337. PMID: 32490533; PMCID: PMC7365687.
12. Yang S, Zhao L, He W, Mi Y. The Effect of Oral Antidiabetic Drugs on Improving the Endocrine and Metabolic States in Women with Polycystic Ovary Syndrome: A Systematic Review and Network Meta-analysis. Drugs. 2022 Sep;82(14):1469-1480. doi: 10.1007/s40265-022-01779-z. Epub 2022 Sep 21. PMID: 36129662.
13. Mann, Traci, Tomiyama, A. Janet, Westling, Erika, Lew, Ann-Marie, Samuels, Barbra, & Chatman, Jason. (2007). Medicare’s Search for Effective Obesity Treatments: Diets Are Not the Answer. American Psychologist, 62(3), 220-233.
14. Ceriello A, Lucisano G, Prattichizzo F, Eliasson B, Franzén S, Svensson AM, Nicolucci A. Variability in body weight and the risk of cardiovascular complications in type 2 diabetes: results from the Swedish National Diabetes Register. Cardiovasc Diabetol. 2021 Aug 26;20(1):173. doi: 10.1186/s12933-021-01360-0. PMID: 34446018; PMCID: PMC8394543.
15. Petria I, Albuquerque S, Varoquaux G, Vie JJ, Venteclef N, Mohammedi K, Roussel R, Camoin M, Perseghin G, Velho G, Potier L. Body-weight variability and risk of cardiovascular outcomes in patients with type 1 diabetes: a retrospective observational analysis of data from the DCCT/EDIC population. Cardiovasc Diabetol. 2022 Nov 17;21(1):247. doi: 10.1186/s12933-022-01689-0. PMID: 36397092; PMCID: PMC9670666.