Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are a class of drugs used to manage type 2 diabetes by enhancing insulin sensitivity and regulating lipid metabolism.
Among these, pioglitazone is a well-known example, widely prescribed for its effectiveness in controlling blood glucose levels and providing cardiovascular benefits.
And now, we even have additional information that PPAR-GAMMA receptor agonists drugs like pioglitazone may be useful in dermatological conditions that concern poor lipid metabolism: here we set our focus on Lichen Planopolaris.
But, the use of pioglitazone, like other PPAR-gamma agonists, is not without potential risks.
Pioglitazone is generally safe and effective but it is associated with several side effects, including weight gain, fluid retention, and an increased risk of heart failure—side effects that are typically manageable under medical supervision.
PPAR-GAMMA receptor agonists are commonly prescribed to older patients with type-2 diabetes. As a result, some of the reported side effects might actually be amplifications of pre-existing conditions or simply associations with the underlying health issues that these patients already have.
The most serious concern, however, has been the potential link between pioglitazone and cancer, particularly bladder cancer.
This concern was first raised by Sciarra et al. in a study where an increased incidence of bladder tumors was observed in male rats treated with pioglitazone.
Although subsequent studies in humans have produced mixed results, with some suggesting a potential increased risk of bladder cancer and others finding no significant association, the possibility of a cancer risk has remained a significant consideration in the drug’s risk profile.
In light of these concerns, I’ll be making pioglitazone as a reference point for evaluating the broader safety implications of PPAR-gamma agonists, particularly in the context of long-term treatment.
According to the paper titled, “Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis”, by Filipova et al., the authors conducted a meta-analysis to evaluate the potential link between pioglitazone use and the risk of bladder cancer in patients with type 2 diabetes.
Concerns about this link initially arose from preclinical studies, particularly in male rats, where pioglitazone treatment was associated with an increased incidence of urothelial hyperplasia and malignant tumors in the urinary bladder.
Further concerns were raised by the PROactive study, which observed more cases of bladder neoplasm in the pioglitazone group compared to the placebo group (14 cases vs. 6 cases).
Although this finding was not statistically significant (p = 0.069), it contributed to the apprehension regarding pioglitazone’s safety.
Additionally, several observational studies in humans, such as those by Azoulay et al., reported an increased risk of bladder cancer associated with pioglitazone use, especially in long-term users.
These studies were mostly epidemiological and observational, meaning they identified correlations but could not definitively establish causality.
So, Filipova et al. performed a comprehensive meta-analysis, incorporating data from 14 studies using risk ratio (RR) and 12 studies using hazard ratio (HR).
The analysis included both retrospective and prospective cohort studies, case-control studies, and randomized controlled trials, all conducted in human populations.
The overall RR was found to be 1.13 with a 95% confidence interval (CI) of 0.96–1.33, and the summary HR was 1.07 (95% CI: 0.96–1.18), indicating no significant connection between pioglitazone use and an increased risk of bladder malignancy.
The meta-analysis showed no substantial evidence linking pioglitazone to bladder cancer in humans.
Also, concerns about PPAR-GAMMA upregulation, which pioglitazone targets, and its potential link to cancer were addressed.
The authors emphasized that these fears might be overstated, as the evidence did not support a significant cancer risk.
They suggested that the increase in bladder cancer cases observed in some studies might be due to other factors, such as the characteristics of the diabetic population or the use of other medications, rather than pioglitazone itself.
Some other studies to consider…
https://www.sciencedirect.com/science/article/abs/pii/S187140210700094X
https://www.sciencedirect.com/science/article/abs/pii/S1056872716301039