Interesting review. Figure 1 indicates that the cardioprotective effects are only significant in secondary prevention of MACE, non-fatal MI and non-fatal stroke. My takeaway is that pioglitazone at one time was thought to possibly worsen cardiovascular issues due to fluid retention, but is now seen as neutral to positive for cardioprotection. I probably wouldn’t reach for pioglitazone if cardioprotection was my primary concern, I think the other benefits of PPAR-gamma activation are a more compelling reason to take it.
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Yes, figure 1 is scary to me and verifies why I quit taking it. Also I never knew about Rapa interaction. Having said that it looks like for healthy people the heart failure thing does not apply. ACM for healthy people is probably lower than what they show there, because their hearts are not drowning.
I can think of better drugs to spend my money on, but I bet this one is a positive for me.
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In rats:
Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination
https://www.sciencedirect.com/science/article/abs/pii/S0273230017303446?via%3Dihub
"Highlights
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Pharmacokinetics of pioglitazone and telmisartan combination was evaluated in rat.
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No significant changes in pharmacokinetics was evidenced.
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Acute toxicity study of the combination with high dose was performed.
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Histopathological or any other abnormal changes were not observed."
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Pioglitazone is looking good here, compared to many other drugs in a monotherapy setting in DMT2.
Efficacy and Safety of Pioglitazone Monotherapy in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
More color on pioglitazone and the heart.
Cardioprotective Effects of Pioglitazone in Type 2 Diabetes
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Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial
"Results: Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).
Limitation: Single-center study.
Conclusion: Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH."
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The Low-Dose (7.5 mg/day) Pioglitazone Therapy
“The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism, fatty liver, insulin resistance, and adiponectin as the standard- and high-dose pioglitazone therapy. Furthermore, the low-dose pioglitazone therapy may also show less adverse effects on weight gain, edema and heart failure as compared with the standard- and high-dose pioglitazone therapy.”
Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging
“Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling.”
Pioglitazone improves whole‐body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome
“Pioglitazone significantly improved the MetS patients’ whole‐body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole‐body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.”
Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial
“Pioglitazone treatment resulted in a decrease in hemoglobin A(1c) level by 0.96 +/- 1.1% vs 0.11 +/- 0.8% in the placebo group (P < .005). Body weight and fat increased steadily in the patients treated with pioglitazone during the 6 months of the study (+3.9 +/- 3.1 kg at 6 months in pioglitazone-treated patients vs -0.8 +/- 3.4 kg in the placebo-treated patients). Subcutaneous fat in the trunk, arms, and legs were all increased in the pioglitazone-treated group. Visceral fat did not change significantly in either group. Neither resting metabolic rate nor the thermogenic responses to a meal were altered by pioglitazone. Subjective measures of hunger (visual analog scale) did not change with pioglitazone treatment. Triglycerides fell in the pioglitazone-treated group (-58.5 +/- 124 mg/dL, P < .003). Neither the prior use of sulfonylureas nor the level of insulinemia before treatment was a predictor of weight or fat change.”
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Pioglitazone, SGLT2 inhibitors and their combination for primary prevention of cardiovascular disease and heart failure in type 2 diabetes: Real-world evidence from a nationwide cohort database
"After propensity-matching, each group included 15,601 patients. Compared with the reference group, the pioglitazone/SGLT2i combination group had a significantly lower risk for MACE (aHR 0.76, 95 % CI 0.66-0.88) and heart failure (aHR 0.67, 95 % CI 0.55-0.82). Pioglitazone was associated with a lower risk of MACE (aHR 0.82, 95 % CI 0.71-0.94) and there was no difference in risk of heart failure compared with the reference group. The incidence of heart failure was significantly decreased in the SGLT2i group (aHR 0.7, 95 % CI 0.58-0.86).
Conclusion: Combination therapy with pioglitazone and SGLT2is is an effective treatment in the primary prevention of MACE and heart failure in patients with type 2 diabetes."
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Effects of Pioglitazone Versus Diet and Exercise on Metabolic Health and Fat Distribution in Upper Body Obesity
“Diet and exercise resulted in an 11.8 ± 1.1 kg weight loss. Both diet and exercise and pioglitazone improved insulin sensitivity, but only the former was associated with loss of intra-abdominal fat. Pioglitazone increased total body fat, which preferentially accumulated in the lower body depot in both men and women. WHRs decreased in both groups. Abdominal fat cell size decreased (P = 0.06) after diet and exercise. No statistically significant changes in fat cell size were observed in pioglitazone-treated volunteers.”
“In nondiabetic upper body obese subjects, increasing insulin sensitivity via diet and exercise accompanies reductions in visceral fat. Pioglitazone treatment also improves insulin sensitivity and lowers WHR, but this is due to a selective increase in lower body fat. This confirms a site-specific responsiveness of adipose tissue to TZD and suggests that improvements in insulin sensitivity by pioglitazone are achieved independent of changes in intra-abdominal fat.”
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Not surprising when used alone. It really needs to be combined with a GLP mimetic (and ideally an SGLT2i ) for optimal efficacy.
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Pioglitazone and ceramides.
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Pioglitazone reduces cardiovascular events and dementia but increases bone fracture in elderly patients with type 2 diabetes mellitus: a national cohort study
“In results, the pioglitazone group (n = 17,388) exhibited a lower rate (per person-years) of major advanced cardiovascular events MACCE (2.76% vs. 3.03%, hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.87–0.95), new- diagnosis dementia (1.32% vs. 1.46%, HR: 0.91, 95% CI: 0.84–0.98) but a higher rate of new-diagnosis bone fractures (5.37% vs. 4.47%, HR: 1.24, 95% CI: 1.19–1.28) than the non-pioglitazone group (n = 174,549). In conclusion, using pioglitazone may reduce the risks of MACCE and dementia but increases the probability of bone fractures in the elderly DM population.”
This study was mentioned further up in this thread:
Pioglitazone use increases risk of Alzheimer’s disease in patients with type 2 diabetes receiving insulin
Note, these are insulin dependent diabetics.
What if insulin was removed from the equation:
Effect of pioglitazone medication on the incidence of dementia
"Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR = 0.53, p = 0.029). If diabetes patients used pioglitazone <8 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.16, p = 0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR = 1.23, p < 0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity.
Interpretation: These findings indicate that pioglitazone treatment is associated with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population."
Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study
Effects of pioglitazone on the incidence of dementia in patients with diabetes
“Pioglitazone is a time- and dose-dependent protective factor against dementia in patients with diabetes. The risk of dementia is lower in long-term and high-dose pioglitazone users than in never users of pioglitazone.”
Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke
“Pioglitazone use was associated with a reduced risk of dementia, compared with nonuse (adjusted hazard ratio [aHR] = 0.84, 95% CI 0.75–0.95); the risk reduction in dementia was greater among patients with a history of ischemic heart disease or stroke before DM onset (aHR = 0.46, 95% CI 0.24–0.90; aHR = 0.57, 95% CI 0.38–0.86, respectively). The incidence of stroke was also reduced by pioglitazone use (aHR = 0.81, 95% CI 0.66–1.00). However, when the stroke developed during the observation period of pioglitazone use, such lowered risk of dementia was not observed (aHR = 1.27, 95% CI 0.80–2.04).”
Ralph DeFronzo Banting Hall lecture from some years ago, getting into the details of insulin resistance in the context of atherosclerosis. There is a lot of cellular and molecular information which I think gives us a good picture of the processes involved. There is also light thrown on pioglitazone, as he says “the only true insulin sensitizer”:
Banting Hall - Dr. Ralph A. DeFronzo (via Diavcon 2020)
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This is very interesting. However we must look at it in a nuanced way. Pioglitazone is definitely associated with greater rates of bladder cancer (cumulative dosage and time dependent), so it would be a big mistake to see pioglitazone as anti-cancer in general. That said, in limited circumstances, for PPAR-gamma mediated cancers like PC, it may have some use. Given the relative incidence of PC vs bladder cancer, this might be an interesting drug.
The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer
“Our findings suggest that using metabolic drugs such as PPARγ agonists could improve PCa treatment outcomes by reducing tumor growth, reprogramming metabolic pathways, and promoting a more benign epithelial phenotype.”
Note, we are talking extant PC, which is distinct from primary prevention.
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If I remember well that is the reason why it has be removed from the market in France and in a lot of EU countries.
Yes. That was the reason. There was some controversy about the exact risk numbers, but longer term use can elevate relative risk to 1.75 times. In absolute numbers over the span of years it may be a risk worth taking compared to benefits. That said, pioglitazone is definitely contraindicated in those who have previously had bladder cancer or strong risk factors for it. This is the next biggest risk after the risk of bone fractures. It’s a drug that needs careful consideration and close monitoring. That’s why I’m still researching it and not just jumping in. Preliminarily my plan is to try it at a low dose of 7.5mg/day later this year and evaluate it along the way for effectiveness vs A1c and fasting blood sugar.
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Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes
(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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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.
Pioglitazone and bladder cancer risk: a systematic review and meta‐analysis - PMC
Looks like the 1.84 OR was not significant. Am I missing something?
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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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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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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