Diabetes & Metabolism Journal

Original Article

Pharmacotherapy
Efficacy and Safety of High-Dose Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial: Jun Hwa Hong, Kyung Ah Han, You-Cheol Hwang, Eun-Gyoung Hong, Hae Jin Kim, Chang Beom Lee, Ho Chan Cho, Jong Chul Won, Hun-Sung Kim, Eui-Hyun Kim, Gwanpyo Koh, Kwang Hyun Ahn, Kyong Soo Park; Diabetes Metab J. 2026;50(2):320-330. Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0696

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Background
This study investigated the efficacy and safety of pioglitazone 30 mg/day add-on to inadequately controlled type 2 diabetes mellitus (T2DM) patients with treatment of dapagliflozin and metformin.
Methods
In this multicenter (34 sites), double-blind, randomized, phase 3 study, patients with T2DM with an inadequately controlled glycosylated hemoglobin (HbA1c) over 7.0% to treatment with dapagliflozin (10 mg/day) and metformin (≥1,000 mg/day) were randomized to receive additional pioglitazone 30 mg/day (n=124) or placebo (n=122) for 24 weeks. The primary outcome was the mean change of HbA1c from baseline to 24 weeks treatment. The efficacy and safety were evaluated with open label extension period, switching placebo to pioglitazone 30 mg/day at 48 weeks (ClinicalTrials.gov identifier: NCT05296044).
Results
The HbA1c after 24 weeks treatment reduced from 7.8%±0.8% to 7.0%±0.6% (P<0.0001). The proportions of patients who achieved HbA1c less than 7.0% at 24 weeks were significantly higher in pioglitazone add-on group (51.61% in pioglitazone vs. 22.95% in placebo, P<0.0001), or less than 6.5% at 24 weeks (21.77% in pioglitazone vs. 2.46% in placebo, P<0.0001). Body weight gain was 2.0 kg at 24 weeks with pioglitazone 30 mg/day and –0.6 kg at 24 weeks with placebo.
Conclusion
Addition of pioglitazone 30 mg/day to T2DM patients who did not reach the target HbA1c (≤7%) with treatment of dapagliflozin 10 mg/day and metformin over 1,000 mg/day showed effective glucose lowering efficacy without significant hypoglycemia and good tolerability with low prevalence of edema in spite of modest weight gain.

Citations

Citations to this article as recorded by

Efficacy and Safety of Pioglitazone Added to Metformin and SGLT2 Inhibitors in Type 2 Diabetes: An Updated Systematic Review and Meta-analysis
Syed Ibad Hussain, Amna Amir Jalal, Zahabia Adnan, Shanza Shakir, Devya Khaim Chandani, Muhammad Ali Makhdoom
Annals of Pharmacotherapy.2026;[Epub] CrossRef
Bioequivalence of Fixed-Dose Dapagliflozin-Pioglitazone in Healthy Indian Adults: Results From the Randomized Crossover PRO-4 Study
J. Hari Prasath, Umesh Garg, Kalyan Kurapati, Abhamoni Baro Agarwal, Parul Singhal, Thamburaj Anthuvan, Smriti Gadia, Amit Gupta, Sridhar S B.
Cureus.2026;[Epub] CrossRef

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