Medichealthy Pioglitazone and Bladder Cancer Risk - Medichealthy Pioglitazone and Bladder Cancer Risk

Pioglitazone and Bladder Cancer Risk

In 2016, the Food and Drug Administration issued a recent warning relating to the use of pioglitazone. Pioglitazone was associated with an increased risk of bladder cancer.

Pioglitazone and Bladder Cancer Risk
Pioglitazone tab
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Pioglitazone is a glucose-lowering drug or an antidiabetic agent that works by increasing the target cell's response to insulin and decreasing hepatic gluconeogenesis. Pioglitazone is a thiazolidinedione (TZD) drug that increases insulin sensitivity. The TZD drugs are agonists of the Gamma Peroxisome Proliferator-Activated Receptor (PPAR-gamma). PPAR-gamma is a nuclear transcription factor that is generally expressed in the urothelium. In the condition of gallbladder cancer, excessive PPAR-gamma expression occurs.

Pioglitazone effectively reduces HbA1c levels. Pioglitazone also increases insulin sensitivity, maintains pancreatic beta-cell function in diabetic patients, and has a good effect on the balance of lipid profiles. The side effects reported on the use of pioglitazone are weight gain and peripheral edema as a result of coronary and peripheral vasodilation.

At present, many studies have tried to find an association of using pioglitazone with an increased risk of bladder cancer. Bladder cancer is one of the most common types of cancer, ranking fourth in men and eleventh in women in developed countries. Diabetes is one of the risk factors for cancer, including bladder cancer. There is an increased risk of 40% in people with diabetes to suffer from bladder cancer compared to non-sufferers. Other risk factors for bladder cancer are age, male sex, smoking, occupational and environmental factors, and urinary tract disease.

Research supporting the relationship between Pioglitazone and Bladder Cancer

A case-control study was carried out in the UK to find out the association of bladder cancer in the use of pioglitazone. This study involved 376 cases of bladder cancer patients with 6,699 controls. This study found that there was an association between the use of pioglitazone with an increased risk of bladder cancer by 83%. The study also found that there was a related pioglitazone dosage used by patients with bladder cancer. Patients who received pioglitazone for more than 24 months had the highest risk of developing bladder cancer. Patients who received a cumulative dose of pioglitazone of 28,000 mg showed a higher incidence of bladder cancer.


Researches Opposing the Relationship of Pioglitazone and Bladder Cancer

Another study conducted in the United States involved 464 patients with bladder cancer and control with the same number. This study found that there was no relationship between bladder cancer with the use of pioglitazone or other antidiabetic drugs. Also found no association between duration of therapy or cumulative dose of pioglitazone with the risk of Bladder Cancer. Other studies conducted in the UK in 2010 support this finding. The study also concluded that there was no correlation between the incidence of bladder cancer in the use of pioglitazone.

A randomized controlled trial (RCT) was carried out by administering pioglitazone from a dose of 15 to 45 mg in 2605 patients and a placebo in the other group. This study aimed to find out whether the use of pioglitazone can reduce macrovascular morbidity and mortality in high-risk diabetic patients. In this study, there were more patients with bladder cancer in the group receiving pioglitazone than in the control group but did not reach statistical significance.

Meta-Analysis Against the Association of Pioglitazone and Bladder Cancer

A meta-analysis was conducted to look for the relationship between the incidence of bladder cancer in the use of pioglitazone. The study involved 26 studies that were analyzed in depth. This meta-analysis concluded that there was no increased risk of bladder cancer in the use of pioglitazone. It is contrary to the findings in many studies. The study also concluded that no association was found between long-term use of pioglitazone and bladder cancer. This meta-analysis states that bladder cancer that occurs in people with diabetes occurs due to other factors, so it is not advisable to replace pioglitazone in diabetic patients who need pioglitazone.

In that meta-analysis, an analysis was carried out on 14 studies that calculated the relative risk of bladder cancer incidence in the use of pioglitazone by involving cohort studies, case-control, observational studies, and an RCT study. Nine of the studies said there was no increased risk of bladder cancer in the use of pioglitazone, while five other studies mentioned an increased risk. There was no significant increase. However, these results could not conclude whether long-term use of pioglitazone can increase the potential for bladder cancer or not.

The meta-analyses that Support the Association of Pioglitazone and Bladder Cancer

Another meta-analysis conducted in 2012 showed different results. The meta-analysis included 5 studies that assessed the relationship of increased bladder cancer to the use of pioglitazone. Researchers found that the use of pioglitazone increases the risk of bladder cancer in diabetic patients. This meta-analysis also stated that the use of pioglitazone for less than 1 year was not associated with an increased risk of bladder cancer compared to a group of patients who had never received pioglitazone. However, it found the highest risk in pioglitazone users for more than 24 months. This meta-analysis did not find the association between the incidence of bladder cancer with an accumulative dose of pioglitazone.

In 2017, by using a meta-analysis with the subject of 15 articles, researchers found that the use of pioglitazone was significantly associated with the occurrence of bladder cancer. Besides, the use of pioglitazone with cumulative doses above 10,500 mg showed a significant association with the occurrence of bladder cancer. The study also found that the duration of using pioglitazone also affected the occurrence of bladder cancer. The use of pioglitazone for more than 1 year showed a significant relationship while using pioglitazone for less than 1 year did not show a significant relationship with the incidence of bladder cancer.

Factors Cause Inconsistency of Results

Many studies did not found results consistently that an association between the use of pioglitazone and an increase in bladder cancer. This happened due to several factors. One decisive factor was the imbalance of confounding factors in the two groups.  The study comparison between groups of pioglitazone users who did not use pioglitazone found that the use of thiazolidinedione, including pioglitazone, had a risk of becoming fatter, smoking more and having uncontrolled diabetes than those who had never used it. These were the confounding factors that can obscure the results of the research.

Another confounding factor is the antidiabetic agent consumed by the patient. Patients who receive pioglitazone are those who have failed with other antidiabetic medications. Several other studies found that other antidiabetic agents increase the risk of cancer. For example, insulin analogs that can increase the occurrence of cancer. Other drugs that can increase the risk of cancer are rosiglitazone and sulfonylureas, such as glimepiride and glibenclamide. Diabetes is also a risk factor for cancer. A history of diabetes is associated with an increased risk of bladder cancer. Studies found that the risk of bladder cancer increases with the length of time a person has diabetes. Besides diabetes, other metabolic disorders characterized by an increase in body mass index, obesity, and insulin resistance also increased the risk of developing diabetes mellitus.

Until now, no mechanism can clearly explain the increased risk of bladder cancer in the use of pioglitazone. One thing that was hypothesized is the gamma peroxisome proliferator-activated receptor ligand (PPAR-γ). In animal studies, bladder cancer can occur after PPAR-aj exposure. It is supported by the finding of increased expression of PPAR-γ in bladder cancer cells.

Conclusion

Pioglitazone is used as one of the modalities of antidiabetic therapy. Several studies had shown an association between using pioglitazone with an increased risk of bladder cancer. Even so, the results shown by the studies are still not consistent. Existing research is also still limited to observational research. However, doctors need to increase the awareness of bladder cancer in diabetic patients, especially patients who get pioglitazone. Some studies also find that the cumulative dose and duration of use of pioglitazone are also associated with the occurrence of bladder cancer, although it is still controversial, so this needs to be a doctor's concern.

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