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Prescribing Trend of Pioglitazone After Safety Warning Release in Korea
Han Eol Jeong, MPH; Sung-Il Cho, MD, ScD; In-Sun Oh, BA; Yeon-Hee Baek, BA; and Ju-Young Shin, PhD

Prescribing Trend of Pioglitazone After Safety Warning Release in Korea

Han Eol Jeong, MPH; Sung-Il Cho, MD, ScD; In-Sun Oh, BA; Yeon-Hee Baek, BA; and Ju-Young Shin, PhD
The pioglitazone safety warning issued in South Korea, which recommended prescribing with careful attention among those with high risk of bladder cancer, led to a moderate decrease in pioglitazone users.
Following the intervention, the MFDS updated pioglitazone’s label to contain information on its increased risk of bladder cancer in November 2011. Since the intervention, there has been a continuous decrease in the proportions of both prevalent and incident pioglitazone users. However in January 2013, following positive results of the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) clinical trial, which reported the benefits of pioglitazone for patients with diabetes with a history of CV disease,24 insurance reimbursement was extended to include 30-mg pioglitazone on top of the previously reimbursed 15-mg pioglitazone to lessen the burden of patients with diabetes showing no improvement in blood glucose levels with 15-mg pioglitazone.2 This resulted in an increase in the proportions of both prevalent and incident pioglitazone users. In addition, in November 2013, health insurance benefit coverage criteria to third-line antidiabetic drugs were extended and a pioglitazone complex was released to the market in the following month.25,26 The aforementioned events resulted in an increase in pioglitazone users.

Despite the intervention, pioglitazone still accounted for 11.73% of all antidiabetic drugs used in the period after the intervention (July 2011 to December 2015), showing only a minor absolute reduction of 1.04 percentage points. A study in France showed trends between 2006 and 2013 of pioglitazone and other antidiabetic drug use similar to those shown in our study, with decreased incidence of first-line noninsulin glucose-lowering drugs (especially TZDs), but DPP-4 inhibitors and metformin showing opposite trends to those found in our study.20 We found no discrepancies regarding the trend of antidiabetic drug use, and the decrease in the proportion of pioglitazone users in Korea was considered a result of the intervention.

Our study showed a significant short-term reduction in the proportion of pioglitazone users after the intervention. Without it, high-risk patients, such as those 65 years or older, men, and those with additional risk factors like having been exposed to aromatic chemicals or smoking, would have been vulnerable to bladder cancer with the use of pioglitazone.27 However, the intervention prevented such vulnerability implicated with the drug from occurring within this high-risk population, thereby minimizing health risks of these patients. Our study showed that the MFDS safety warning for pioglitazone effectively decreased the proportion of pioglitazone users. This finding was also observed in several past studies evaluating the effectiveness of similar interventions.5,22,28,29 However, the observed effect is not universal because others have found contrasting results.8 Nonetheless, in Korea, safety warnings along with the pop-up alert system of drug utilization review have been shown to affect prescribing, thereby reducing the proportion of users of the flagged drugs.30,31 Thus, further studies are needed to validate the true effectiveness of safety warnings.

Strengths and Limitations

The strengths of our study are that, to the best of our knowledge, this is the first population-based study conducted in Korea to examine the temporal trends in the prevalence of pioglitazone users before and after the safety warning issued in June 2011. In addition, we used the nationally representative NHIS-NSC database, which provided a valuable opportunity to investigate and explore the extent of pioglitazone use and its changes over time in Korea. Notably, the NHIS-NSC database underwent strict systematic stratified random sampling with proportional allocation within each stratum by using the individual’s total annual medical expenses as a target variable for sampling, resulting in robust representation of the Korean population.9

Despite the strengths of this study, the results should be interpreted with caution considering the following limitations. First, the disease codes listed in the NHIS-NSC database may not represent the participant’s true disease status, as the codes were created for health insurance claims. Moreover, as this was an ITS study, other interventions besides the intervention of interest may have influenced the number of pioglitazone users. It is therefore difficult to ascertain whether the steady decline in the number of pioglitazone users was either accelerated or slowed by factors other than the intervention of interest (eg, by the release of a new and more effective antidiabetic drug).


Regulatory actions, such as the pioglitazone safety warning released by the MFDS, have been shown to reduce the likelihood of prescribing the relevant drug. This population-based study demonstrated decreases in the proportion of pioglitazone users compared with the proportions of those using other antidiabetic drugs over time. However, this decreasing trend appeared to have started before the intervention. Those with high potential risk of bladder cancer should be prescribed pioglitazone with caution or should consider alternative treatments.

The results of our study are relevant to ongoing research investigating and evaluating the effectiveness of regulatory actions taken by national regulatory bodies. Importantly, future studies should assess regulatory actions using various study designs, and comparison of their results would allow for conclusions to be drawn regarding the true effectiveness and impact of a regulatory action.

Author Affiliations: School of Pharmacy, Sungkyunkwan University (HEJ, ISO, YHB, JYS), Suwon, Gyeonggi-do, South Korea; Department of Public Health Science, Graduate School of Public Health, and Institute of Health and Environment, Seoul National University (SIC), Seoul, South Korea.

Source of Funding: The authors gratefully acknowledge funding from the Basic Science Research Program through the National Research Foundation, South Korea, by the South Korean government (Ministry of Science and ICT, grant No. 2017K1A3A1A12073341); this study was conducted independently of the funder.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (HEJ, SIC, JYS); acquisition of data (HEJ, ISO, YHB); analysis and interpretation of data (HEJ, SIC, ISO, JYS); drafting of the manuscript (HEJ, JYS); critical revision of the manuscript for important intellectual content (HEJ, SIC, JYS); statistical analysis (HEJ, ISO, YHB); and administrative, technical, or logistic support (YHB).

Address Correspondence to: Ju-Young Shin, PhD, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, South Korea. Email:

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