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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.

We identified a total of 80,724 patients with diabetes between 2009 and 2015. Among these, 12,249 (15.17%) were pioglitazone users, with men representing a higher proportion of both patients with diabetes and pioglitazone users. There were no statistically significant differences in age before or after the intervention for both groups (aSD >0.1), whereas there were statistically significant differences in medical institutions for only patients with diabetes and in comorbidities for both groups (aSD < 0.1) (Table 1). Proportions of women, patients aged 50 to 59 years, patients aged 70 to 79 years, and visitors to primary care clinics who used pioglitazone decreased after the intervention, with relative changes of –3.74%, –7.13%, –37.85%, and –7.91%, respectively (eAppendix B).

In the preintervention period, the proportion of pioglitazone users was 12.77%, and this decreased to 11.73% after the intervention, resulting in relative and absolute changes of –8.13% and –1.04 percentage points, respectively. However, proportions of patients using sulfonylurea and metformin, DPP-4 inhibitors and GLP-1 analogues, and insulin analogues all showed an increase after the intervention, with use of DPP-4 inhibitors and GLP-1 analogues increasing the most (relative change, 209.03%) (Table 2).

The estimates for “intervention” and “time after intervention” are the main coefficients of interest from the segmented regression analysis. As observed from the “time” estimates, use of all antidiabetic drugs except rosiglitazone showed an increasing trend over the entire study period. The “time after intervention” coefficient showed a decreasing trend for use of pioglitazone, sulfonylurea and metformin, and insulin analogues, although the trend for pioglitazone was not statistically significant. Finally, the coefficient for “intervention” was statistically significant only for pioglitazone, sulfonylurea and metformin, and insulin analogues (P <.05) (Table 3). The intervention was associated with an immediate decrease in pioglitazone users of 177 per 1000 patients with diabetes (P <.05), whereas there was a decrease of 448 for DPP-4 inhibitors and GLP-1 analogues.

From 2009 to 2015, proportions of pioglitazone and insulin analogue users showed a decreasing trend (Figure 1), although this trend was not as steep as that of rosiglitazone. Without the intervention, the predicted proportion of pioglitazone users was 90 per 1000 patients with diabetes, whereas the actually observed proportion was 60 per 1000 patients with diabetes (Figure 2). Likewise, by applying a 3-month lag both before and after the intervention, similar results were observed, indicating robustness in results (eAppendix C). The numbers of prevalent and incident pioglitazone users are shown, with the general trend of prevalent users increasing and that of incident users decreasing (eAppendix D).


The prevalence of diabetes shown in our study is in agreement with the 8.0% reported by the Diabetes Fact Sheet in Korea in 2016.16 Pioglitazone accounted for 15.2% of all antidiabetic drugs used in Korea in this study. All antidiabetic drugs except rosiglitazone and pioglitazone showed an overall increasing trend of use from 2009 to 2015. After the intervention, the relative change in the proportion of pioglitazone users was –8.13%, with the intervention being associated with an immediate decrease of 177 pioglitazone users per 1000 patients with diabetes. Thus, it can be deduced that safety warnings are effective in decreasing the number of patients using the flagged drug.

Upon release of the pioglitazone safety warning by the MFDS, a moderate decrease in the proportion of pioglitazone users was observed. The proportion of pioglitazone users actually began to decrease a few months prior to the intervention, possibly due to healthcare provider awareness arising from various study results reporting an increased risk of bladder cancer associated with pioglitazone use and precautionary actions prior to the national regulatory body announcement.2,17 A study conducted in Korea examining the trends of antidiabetic drug use in adult patients with diabetes from 2002 to 2013 showed a trend similar to that reported in our study, with the use of TZDs decreasing steadily from a peak of 13.0% in 2009 to 6.5% in 2013, which was lower than the use in 2002 (7.3%).18

Key events associated with pioglitazone between 2009 and 2015 had either a positive or negative influence on its use. Before the intervention, in July 2010, a study reported an increased risk of cardiovascular (CV) disease with rosiglitazone use, leading to the withdrawal of the drug in September 2010.19 This resulted in a sharp increase in the number of pioglitazone users, as results of previous studies suggested that safety warnings lead to a decrease in the respective drug’s use while concurrently prompting an increase in the use of drugs with similar mechanisms.6,20 This particular trend was observed worldwide, including in Australia, Denmark, France, Germany, the Netherlands, Taiwan, and the United States.7,20-23 However, around the time of rosiglitazone withdrawal, in August 2010 and April 2011, respectively, 2 studies reported a risk of fracture and bladder cancer associated with the use of pioglitazone, leading to a decrease in pioglitazone use.2,17

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