#64

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

https://diabetesjournals.org/diabetes/article/57/1/24/40558/Comparison-of-the-Effects-of-Pioglitazone-and

(1) “Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 ± 3 vs. 24 ± 2 μmol · kg−1 · min−1) or metformin (22 ± 2 vs. 24 ± 3 μmol · kg−1 · min−1). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 ± 1.0 vs. 0.2 ± 1.6 μmol · kg−1 · min−1) and gluconeogenesis (n= 11; 4.5 ± 0.9 vs. 0.8 ± 1.2 μmol · kg−1 · min−1). Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 μmol · kg−1 · min−1) or gluconeogenesis (n = 9; 3.7 ± 0.8 vs. 2.6 ± 0.7 μmol · kg−1 · min−1). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 ± 0.03 vs. 0.06 ± 0.01 mmol/l) but unchanged with metformin (0.12 ± 0.03 vs. 0.15 ± 0.07 mmol/l).

CONCLUSIONS - Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake.”

(2) “We report that, whereas pioglitazone and metformin have comparable effects on insulin-induced stimulation of glucose uptake, pioglitazone improved hepatic insulin action at least in part by enhancing insulin-induced suppression of gluconeogenesis.”

(3) “Treatment with pioglitazone resulted in an marked increase (P < 0.01) in both total and high molecular weight (HMW) plasma adiponectin concentrations (Fig. 6). In contrast, neither total nor HMW plasma adiponectin concentrations changed after treatment with metformin.”

(4) “Taken together, these data suggest that in the presence of low physiological insulin concentrations, the effects of pioglitazone on hepatic insulin action is likely as important, if not more important, than the effects of pioglitazone on extra-hepatic insulin action in the regulation of glucose metabolism.”

(5) “Thus, the common belief that pioglitazone improves glycemic control in people with type 2 diabetes primarily by increasing glucose uptake whereas metformin does so by suppressing glucose production needs to be reexamined.”

Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients

“These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.”

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#65

I think the bone fracture risk was largely in women.

It’s hard to get away from the bladder cancer risk. Here is a 2018 meta-analysis that compute an OR of 1.84 in RCT’s and show evidence of both time and dose dependence. I was thinking of trying it to but given surveillance for bladder cancer is not great I don’t think I’ll go there. Bummer because I like that it significantly up-regulates Klotho as well.

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Pioglitazone and bladder cancer risk: a systematic review and meta‐analysis - PMC

#66

Looks like the 1.84 OR was not significant. Am I missing something?

#67

95% CI was 0.99 to 3.42. So meta was pretty much significant. Both individual studies didn’t quite reach significance. Significance isn’t really binary anyway since even a 95% confidence leaves a 5% risk of being random. So call it significant with a 94.9% CI. The data showing correlation with dose and time is further support of cause → effect. Like I said given surveillance is insensitive or expensive it just doesn’t seem like a chance I would take unless there were more definitive studies.

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#68

There’s conflicting data on that. Earlier in this thread a study was posted showing the opposite, substantially higher risk for men, especially serious events.

Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial

“Risk for serious fracture in the pioglitazone group compared with placebo was significantly elevated in men (5.4% vs 2.2%; HR, 2.34; 95% CI, 1.45 to 3.76) but not women (7.8% vs 6.4%; HR, 1.18; 95% CI, 0.76 to 1.83) (Supplemental Table 2 (283.1KB, docx) ). When serious fractures were restricted to low-energy, nonpathologic events, the risk remained elevated in men (3.8% vs 1.4%; HR, 2.64; 95% CI, 1.46 to 4.77) and was further reduced in women (6.6% vs 6.2%; HR, 1.03; 95% CI, 0.65 to 1.63). For both any serious fractures and low-energy, nonpathologic serious fractures, HRs for men were significantly higher than for women (P for interaction of treatment with sex = 0.04 and 0.01, respectively).”

Re: bladder cancer - both dose and duration were positively associated with increased incidence in pioglitazone users.

For me both fractures and bladder cancer are a concern. I will still go ahead and use this drug, but at a very low dose 7.5mg/day (see other posts in this thread regarding dosage), if empagliflozin and other measures don’t bring my A1c below the prediabetic range. The other thing, is I will try to limit the duration of exposure to get my A1c to 5.6 or below, and hopefully shift any visceral adipose tissue to less deleterious location, which will hopefully result in better insulin sensitivity. Then stop. If the glucose issues come back, I’ll do another spell of pio to get to target again. My hope would be that if I can limit exposure to, say, three months once a year, I can limit the corresponding risks. But of course plans are one thing, it will all have to be tested in practice. I intend to possibly go on pio 7.5mg October at the earliest.

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#69

I think this sounds like a reasonable plan. Given the bladder cancer and fracture risk I’ve put it on the back burner, but I think it’s still a good option for folks that are pre diabetic/diabetic that can’t resolve with SGLT2-inhibitors or other diabetic medications (or lifestyle).

I do wonder if the bone fracture and bladder cancer risk is due to PPAR-gamma activation or something else. Presumably you would have similar risks with Telmisartan and other partial agonists?

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#70

From the meta study:

“Pioglitazone exerts its anti‐hyperglycemic effects through activation of PPAR γ 1, which is highly expressed not only in adipocytes but also in several other tissues (e.g., urinary bladder) 47. Furthermore, PPAR γ is also expressed on cancer cells 48. It has been reported that activation of PPAR γ may alter tumor growth and progression in nonadipose cells 49. Preclinical research in rats showed that high doses of pioglitazone for 2 years increased risk of bladder tumors among male rats but not among female rats 50. Recently, one study performed on 120 mice showed that prolonged use of pioglitazone might induce significant abnormalities in several biomarkers and hematological indices associated with histopathological changes in the bladder, depending on dose 51. In accordance with the findings from animal studies, our meta‐analysis indicated that greater dose or longer duration of pioglitazone was associated with higher risk of bladder cancer, which supported the notion that pioglitazone’s risk of bladder cancer is dose‐dependent, in terms of cumulative dose or cumulative duration.”

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#71

I realize its a different mechanism but it seems metformin is a safe effective way to reduce glucose levels caused by overly active gluconeogenesis. Unless you’ve already tried that I think that might be a better option. Having a similar problem (fasting glucose usually ~100) I think I’ll first try metformin. I’ll admit pio is attractive for other reasons. I’m not suggesting you can’t reduce risk by using lower dose and time limitation but also you are unlikely to achieve your goal with a lower dose and what is the point if you can’t continue taking it?

#72

I tried metformin for a year - did absolutely nothing for me. However, I used a 500mg/day dose, never higher. No side effects that I could tell, just no effect positive or negative. My FBS is usually around 108 mg/dL these days (until a few years ago, was in the 99-102 range), and A1c 5.8% (ranges from 5.7-5.9). Nothing moves it.

Regarding pioglitazone vs metformin for gluconeogenesis, it appears pioglitazone suppresses the production of glucose by the liver, but metformin does not. This was shown in the study I posted a few posts above:

As to the low dose pioglitazone 7.5mg/day, there appear to be studies showing it effective in lowering A1c and being a valid therapeutic dose for intended purposes. I posted a paper to that effect earlier in the thread:

It’s well worth reading, because it concludes that there’s almost no difference in measured benefits of the 7.5mg dose vs higher doses, but having much lower adverse effects. Of course, a giant caveat here - we all react differently to drugs. I may try the 7.5mg dose and it may do absolutely nothing for me, or I might have a bad reaction to pioglitazone. So this absolutely has to be verified in the real world with a given patient.

I’m interested in pioglitazone precisely because it suppresses gluconeogenesis (which metformin does not!), which I suspect is my problem. It also increases insulin sensitivity. That’s my interest. Other things like cardio protection is a bonus, but not something that’s a deciding factor for me, and futhermore, I believe odds are rapamycin will abolish the cardio benefits of pioglitazone (unless I take a rapa holiday for the three months or so of pio exposure). Again, all this is theory. How it will work in practice I’ll find out, should I move forward with pio.

FWIW, I’m trying to investigate whether low dose bisphosphonate concurrently with pioglitazone might not ameliorate at least some of the bone fracture risk - this is something that I’m doing a deep dive on currently. There is also a somewhat intriguing possible signal of bisphosphonates being mildly geroprotective, though obviously it’s a very thin ledge to go out on, as there are distinct risks too.

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#73

@CronosTempi Fair enough, I’m equally intrigued by Pioglitazone, just a little more worried about the bladder cancer risk. I still think if I were you I might try a higher dose of Metformin first, it should reduce fasting blood glucose even though I agree with you the data suggests it is not through an increase in insulin sensitivity.

I’ll have to read more of the paper you linked above, thanks for that link. Have you looked at bladder cancer risk (perhaps meta analysis) for patients on the 7.5 mg dose? That might help both of us feel better. I’ll keep a look out. Pioglitazone is an older drug so I’m guessing large studies using it are getting less common since the patent protection is done.

I’m going to re-listen to Attia’s podcast interview with Ralph DeFronzo (#337) but I think he recommends hitting the problem with pio, sglt2i, and glp1a. He’s pretty convincing and perhaps you are more likely to achieve success with adding sglt2i and glp1a as well? If you haven’t heard that interview I recommend it. Sorry if I haven’t thoroughly reviewed all the comments in this thread.

#74

Thanks. Yes, that’s a great Ralph DeFronzo interview, that’s when I became interested in pioglitazone. I have not seen any data on the 7.5mg dose and bladder cancer, but note that this is lower than the lowest dose (15mg) used in the West, so there wouldn’t be much data. The 7.5mg dose is used in India as far as I know - I have even bought pioglitazone from India in the 7.5mg dose tablets. However, keeping in mind that both length of exposure and cumulative dose increase blader cancer, it would make sense for a lower dose to represent less risk. From the data it appears that the danger of bladder cancer climbs around 28,000mg cumulative dose - if you’re on 7.5/day that’s over 10 years :slight_smile: - of course, length of time is a factor all by itself.

And yes, I’m already on 25mg empagliflozin, so SGLT2i is covered. I’m staying away from GLP-1 drugs for now.

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#75

Dr DeFronzo comments on side effects of pioglitazone (40 min).
Bladder cancer is a “misconception” and osteoporosis is only a risk for post menopausal women.
Not sure if he’s right.

Pio discussion starts at 40 min:

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#76

2 year lifespan studies in rats for pioglitazone?

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(source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/021073A_Actos_phrmr_P7.pdf)

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(source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/021073A_Actos_phrmr_P8.pdf)

#77

I respect the heck out of Ralph DeFronzo, but he’s clearly wrong here. Bladder cancer is very real with increasing time and cumulative dose (28,000mg). And so is bone fracture risk, in fact esoecially among men. I posted the studies, solid RCT. No way around it. He might be operating on old information.

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#78

Again dose is important. However, the differences are not substantial, so hard to make definitive conclusions. Low/medium doses appear best, depending on sex. But one has to be particularly careful in using cancer mortality in rats/mice as the determinant, because cancer very frequently is triggered differently in humans and rodents - a good example was the thyroid cancer in rats on GLP-1RA, humans don’t have the type of cells in the thyroid that cause cancer in rats.

Bottom line, unfortunately, this doesn’t tell us much of anything about pioglitazone in humans long term.

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#79
#80

This is a study in rats, but if the same effect obtains in humans, we might have a way of avoiding one of the undesirable effects of pioglitazone: weight gain through increase in adipose tissue. Combining pioglitazone with telmisartan in rats prevents increase in adipose tissue. This is another case of polypharmacy use where negative effects of one drug are offset by another. We already saw how an SGLT2i like empagliflozin can ameliorate edema and associated heart failure with pioglitazone use. Separately, below is a study I posted to the telmisartan thread and linked at the end of this post, showing that telmisartan might be useful in lowering the risk of bladder cancer, and as we know, pioglitazone has been associated with a higher risk. It’s looking more and more as if you almost should always be taking pioglitazone with telmisartan - of course, if you don’t need BP lowering that becomes impractical, but if you have some BP issues, and are taking pioglitazone, this seems like potentially a very good combo. In particular that the combination of pioglitazone and telmisartan has not been shown to have any toxicity (at least in rats), nor does telmisartan appear to additionally (to pioglitazone) increase bone fracture risk by itself, per the study I linked to from the telmisartan thread.

Telmisartan prevents the glitazone-induced weight gain without interfering with its insulin-sensitizing properties

https://journals.physiology.org/doi/full/10.1152/ajpendo.00024.2007

Meanwhile, it is good to note that at any given dosage there is no toxicity from telmisartan and pioglitazone combination - though again, this is a study in rats.

Safety profiling of pioglitazone and telmisartan combination by sub-chronic toxicity study in rat

https://www.sciencedirect.com/science/article/abs/pii/S0273230016302306

"Highlights

  • •

Subchronic toxicity study of combination of Pioglitazone and Telmisartan performed.

  • •

No significant effect on the rat hematology was evidenced.

  • •

Beneficial effect in terms of alteration of the biochemical parameters observed.

  • •

No treatment related histopathological changes were observed."

Finally a really interesting paper on the differential effects of pioglitazone and telmisartan on mTORC2 in cell proliferation and migration.

Differential expression of PPARγ by pioglitazone and telmisartan causes effect of disparity on mTORC2-mediated cell proliferation and migration

https://www.nature.com/articles/s41598-025-93320-x

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Telmisartan -- 40 or 80 mg
#81

[This post is a bit of a grab bag of disparate studies with pioglitazone, simply a way around posting limits od separate posts, so I just keep amending this post to add further studies without bumping up against the limit - apologies for the scattershot effect.]

Empagliflozin and pioglitazone do not appear to have adverse DDI (drug drug interactions), at least short term. Why is this important - because this was in healthy people.

Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers

Regarding bladder cancer and lack of treatment options - progress is being made:

New treatment eliminates bladder cancer in 82% of patients

CV health and pioglitazone:

Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials

Association of Pioglitazone With Major Adverse Cardiovascular Events, All-Cause Mortality, and Heart Failure Hospitalizations: A Systematic Review

This is an interesting paper on genetic variability affecting pioglitazone:

Current clinical evidence on pioglitazone pharmacogenomics

More on AD and pioglitazone - it’s complicated!

Reassessment of Pioglitazone for Alzheimer’s Disease

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MSDC-0160 - ITP 9% Increase in Mouse Lifespan (Males)
Canagliflozin - Another Top Longevity Drug
#82

Here was the largest interventions minimum 1000 people while using the search term “pioglitazone” on clinicaltrials.gov:

Study Title Study URL Enrollment
Action to Control Cardiovascular Risk in Diabetes (ACCORD) ClinicalTrials.gov 10251
Efficacy of Pioglitazone on Macrovascular Outcome in Patients With Type 2 Diabetes ClinicalTrials.gov 4373
Insulin Resistance Intervention After Stroke Trial ClinicalTrials.gov 3876
Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer’s Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset ClinicalTrials.gov 3494
Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial ClinicalTrials.gov 3371
Safety and Efficacy of Empagliflozin (BI 10773) and Sitagliptin Versus Placebo Over 76 Weeks in Patients With Type 2 Diabetes ClinicalTrials.gov 2705
Safety and Efficacy of Vildagliptin vs. Thiazolidinedione as add-on Therapy to Metformin in Patients With Type 2 Diabetes Not Controlled With Metformin Alone ClinicalTrials.gov 2665
Safety and Efficacy of Linagliptin (BI 1356) as Monotherapy or in Combination in Type 2 DM ClinicalTrials.gov 2122
Safety Study of Pioglitazone Compared To Glyburide on Liver Function ClinicalTrials.gov 2120
Study of Rivoglitazone in Type 2 Diabetes Mellitus ClinicalTrials.gov 1912
MK0431 and Pioglitazone Co-Administration Factorial Study in Patients With Type 2 Diabetes Mellitus (0431-102 AM2) ClinicalTrials.gov 1615
Efficacy and Safety of Alogliptin Combined With Pioglitazone in Treating Subjects With Type 2 Diabetes Mellitus. ClinicalTrials.gov 1554
Effect of Pioglitazone on T2DM Patients With COVID-19 ClinicalTrials.gov 1506
A Phase III Study of BMS-512148 (Dapagliflozin) in Asian Patients With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone ClinicalTrials.gov 1484
Study Assessing Saxagliptin Treatment In Type 2 Diabetic Subjects Who Are Not Controlled With Metformin Alone ClinicalTrials.gov 1462
GALLANT 6 Tesaglitazar vs. Pioglitazone ClinicalTrials.gov 1450
Study of Muraglitazar Versus Pioglitazone in Type 2 Diabetes ClinicalTrials.gov 1440
Thiazolidinedione Intervention With Vitamin D Evaluation ClinicalTrials.gov 1332
A Phase 3 Study of BMS-477118 in Combination With Metformin in Subjects With Type 2 Diabetes Who Are Not Controlled With Diet and Exercise ClinicalTrials.gov 1306
A Study to Evaluate Combining Metformin With Muraglitazar or Pioglitazone in Type 2 Diabetics ClinicalTrials.gov 1159
GALLEX 6: Study to Evaluate the Safety and Tolerability of Tesaglitazar in Patients With Type 2 Diabetes Mellitus ClinicalTrials.gov 1100
Comparison of NN1250 With Insulin Glargine Plus Insulin Aspart With/Without Metformin and With/Without Pioglitazone in Type 2 Diabetes ClinicalTrials.gov 1006
Study on MAFLD-related Cirrhosis Prevention and Treatment Strategies ClinicalTrials.gov 1000
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#83

Old, but nice DeFronzo paper.

Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

https://www.nejm.org/doi/full/10.1056/NEJMoa1010949

“Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima–media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).”

Cold water poured on the study:

Pioglitazone for Diabetes Prevention

https://www.nejm.org/doi/full/10.1056/NEJMc1104572

“DeFronzo and colleagues (March 24 issue)1 reported that pioglitazone reduced the conversion from a condition of impaired glucose tolerance to type 2 diabetes. However, the results showed only that pioglitazone reduced patients’ blood glucose levels during a glucose-tolerance test while they were taking the active drug. The cost of pioglitazone treatment was substantial weight gain and fluid retention. The potential disease-modifying effects of insulin-sensitizing agents have been investigated previously in studies involving metformin2 and troglitazone.3,4Prevention of diabetes with these drugs can be attributed largely to their short-term pharmacologic effects, with progression to diabetes occurring in a large percentage of the study participants after the drug has been discontinued. In the study by DeFronzo et al., the critical question is whether pioglitazone might have a disease-modifying effect: as part of the primary analysis, the rate at which diabetes developed after the drug washout period should have been determined. The parallel rise in HbA1clevels in both the placebo and the pioglitazone groups that followed the initial decline in these levels in the pioglitazone group suggests that this drug has only a short-term pharmacologic effect. If so, an end point that is more relevant than the effect of pioglitazone on glucose levels should be pursued.”

But the authors reply:

https://www.nejm.org/doi/pdf/10.1056/NEJMc1104572?download=true

More DeFronzo:

Prevention of Diabetes With Pioglitazone in ACT NOW: Physiologic Correlates

https://diabetesjournals.org/diabetes/article/62/11/3920/33911/Prevention-of-Diabetes-With-Pioglitazone-in-ACT

Some commentary:

How Does Pioglitazone Prevent Progression of Impaired Glucose Tolerance to Diabetes?

https://diabetesjournals.org/diabetes/article/62/11/3663/33923/How-Does-Pioglitazone-Prevent-Progression-of

Newer paper from the Cochrane Library.

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus

Age is not a factor.

Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance

Solid med.

Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease

https://diabetesjournals.org/care/article/39/10/1684/158/Pioglitazone-Prevents-Diabetes-in-Patients-With

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