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

Abstract

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta‐analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least‐squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever‐users of pioglitazone versus never‐users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time‐ (P = 0.003) and dose‐dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose‐ and time‐dependent manner. Patients with long‐term and high‐dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.

PPARγ-Independent Side Effects of Thiazolidinediones on Mitochondrial Redox State in Rat Isolated Hearts

“…As a result rosiglitazone was taken off the market in Europe and had been put under sales restriction in the USA for several years [20,21]. Pioglitazone, another popular TZD, has a better cardiovascular safety profile [22], but was subsequently taken off the market in several countries after reports of an increased incidence of bladder cancer [23][24][25]. Although rosiglitazone was subsequently not found to be associated with increased ischemic events [26] and the sales restrictions were lifted in the USA, both drugs remain contra-indicated in patients with heart failure [27,28].…”

Effect of switching from pioglitazone to the sodium glucose co‐transporter‐2 inhibitor dapagliflozin on body weight and metabolism‐related factors in patients with type 2 diabetes mellitus: An open‐label, prospective, randomized, parallel‐group comparison trial

“…PIO use has decreased because of an association with increased risk of bladder cancer, as identified from animal studies and a cumulative meta‐analysis of observational studies . Almost all patients currently receiving PIO are therefore good responders in terms of glucose‐lowering effects, and are at risk of worsening glycaemic control if switched to other hypoglycaemic agents.…”

Pioglitazone: An Ongoing Misery in the Developing Countries to Which I can’t be Pragmatic!

“…We've sent dear dr letters to raise the awareness of the prescribing doctors" and even though every single doctor I've asked denied receiving any message regarding this highly important topic, the message remains the same: "Be pragmatic" I'm really sorry that I can't be pragmatic especially when reading more and more evidence linking pioglitazone to bladder cancer; Garry et al in 2018 have concluded: "Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing" Tang et al [2] after confirming that current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose-and time-dependent manner have also pointed to the miserable fact that this association differs with the source of funding (sponsored by industry or not) [3] Another met analysis confirmed that pioglitazone increased the risk for bladder cancer could be found in European population, especially in patients who undergo treatment with pioglitazone for longer durations (>12 months) or are administrated a larger cumulative dose (>28,000 mg) and tried to investigate the causes for conflicting results [4]. I'm really sorry that I can't be pragmatic accepting that there's no conflict of interest when an author calls for a "resurrection" in the usage of pioglitazone and we notice at the end of his article that he was an expert witness for Takeda pharmacetuicals!…”