GRAPHICAL ABSTRACT

Highlights

• Pioglitazone 30 mg was added for T2D patients uncontrolled on metformin/dapagliflozin.

• Add-on therapy improved glycemic control and significantly reduced HbA1c levels.

• It was well tolerated with low risk of hypoglycemia and edema despite weight gain.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by hyperglycemia resulting from insulin resistance and declining β-cell function. In recent years, the paradigm of pharmacologic approaches to glycemic treatment of T2DM has shifted from a glucose-centric approach to a more comprehensive, patient-centered approach for managing T2DM and its complications [1].

Sodium glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of oral antidiabetic agents that improve glycemic control by inhibiting renal glucose reabsorption in the proximal tubule and increasing urinary glucose excretion [2]. Beyond glucose lowering, SGLT2 inhibitors were also shown to have other clinical benefits, including cardiovascular and renal protective effects [3]. These pleiotropic effects have positioned SGLT2 inhibitors as a key component in the management of T2DM, particularly in patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease [1].

Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPARγ) agonists, enhance insulin sensitivity in adipose tissue, muscle, and the liver. They also showed durable glycemic efficacy and may improve β-cell function. However, their use has been limited by concerns over weight gain, fluid retention, and a potential risk of heart failure [4].

Combining SGLT2 inhibitors and TZDs may offer a complementary therapeutic approach in T2DM. The two drug classes also have complementary mechanisms—TZDs primarily target insulin resistance via PPARγ activation [5], whereas SGLT2 inhibitors act independently of insulin to promote urinary glucose excretion and modulate cardiorenal function. Moreover, TZD-associated fluid retention may be attenuated by the natriuretic properties of SGLT2 inhibitors, potentially mitigating one of the significant adverse effects of TZD [6]. Meta-analysis of the combination of pioglitazone with SGLT2 inhibitors showed that combination treatment reduced glycosylated hemoglobin (HbA1c), weight, and systolic blood pressure to a greater extent than the control treatment and reduced the risk of heart failure [5]. However most of the studies have focused on adding SGLT2 inhibitors to pioglitazone-based regimens, studies evaluating the reverse sequence—adding pioglitazone to ongoing SGLT2 inhibitor therapy—are relatively recent and remain limited in number [7-9].

In this study, we conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of high-dose (30 mg) pioglitazone as an add-on therapy in patients with T2DM inadequately controlled with metformin and dapagliflozin.

METHODS

Study design and study participants

This multicenter, randomized, double-blind, placebo-controlled phase 3 study was conducted at 34 sites in Korea between March 2022 and March 2023 (ClinicalTrials.gov identifier: NCT05296044). The main study design consisted of an 8-week single-blind treatment period, a 2-week run-in period before randomization, and a 24-week double-blind treatment period with treatment of pioglitazone 30 mg/day or placebo. After finish of primary study period, patients who agreed to participate open label extension period subsequently enrolled in extension study (between September 2022 and September 2023). During the extension study period, pioglitazone 30 mg/day was administered to both experiment and placebo groups by open label manner from 24 to 48 weeks. Planned efficacy and safety evaluations were conducted at 36 and 48 weeks after administration of three drugs. A total of 209 participants were included in the full analysis set (FAS) and 198 in the per-protocol set (PPS). The participants of this study were T2DM patients over age 19 years old and body mass index (BMI) below 45 kg/m2. The details of inclusion and exclusion criteria are summarized in Supplementary Table 1.

Participants who met inclusion criteria had been explained all the study procedures by investigator, and written informed consent was obtained from all participants.

After a stabilization period (≥1,000 mg/day titrated metformin plus 10 mg/day dapagliflozin for 8 weeks), patients with T2DM with HbA1c 7.0% to 11.0% were randomized to pioglitazone 30mg/day (JT-003, Jeil Pharmaceutical Co. Ltd., Seoul, Korea) add-on group and placebo group in a 1:1 ratio. During the main study period, the doses of metformin (≥1,000 mg/day) and dapagliflozin (10 mg/day) were maintained without change, accompanying concomitant diet and exercise routines. Follow-up assessments were made at 12- and 24-week after randomization. Stratified randomization was executed at each site using SAS software version 9.4 (SAS Institute, Cary, NC, USA) within the framework of a double-blind study protocol. The stratification variables were numbers of oral hypoglycemic agents (no more than two or three) before randomization and HbA1c level at randomization (<8% or ≥8%).

While study period, rescue therapy was permitted for patients with fasting plasma glucose (FPG) >270 mg/dL during first 6 weeks, or FPG >240 mg/dL between 6 and 12 weeks, FPG >200 mg/dL or HbA1c >8% between 12 and 24 weeks. Sulfonylurea except for SGLT2 inhibitor and TZD is permitted to use to aforementioned participants with decision of necessity evaluation by investigator.

This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The clinical trial protocols were approved by the Institutional Review Board of Seoul National University Hospital (IRB approval No. H-2112-149-1286) in Korea.

Outcome assessment

The primary outcome was the mean change of HbA1c from baseline to 24 weeks treatment of high-dose pioglitazone 30 mg/day or placebo add-on to dapagliflozin 10 mg/day and metformin (≥1,000 mg/day). Secondary outcomes were (1) the proportions of patients achieving HbA1c less than 7.0% or 6.5% at 24 weeks; (2) the mean changes of HbA1c from baseline to 12, 24, 36, 48 weeks treatment points including extension period; (3) the mean changes of FPG from baseline to 12, 24, 36, 48 weeks treatment points including extension period; (4) the mean changes of fasting insulin value from baseline to 12 and 24 weeks; (5) the mean changes of insulin resistance by homeostatic model assessment for insulin resistance (HOMAIR) from baseline to 12 and 24 weeks; (6) the mean changes of homeostatic model assessment of β-cell function (HOMA-β) from baseline to 12 and 24 weeks; and (7) other metabolic parameters including blood pressure, lipid profile (total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein), liver enzyme, and renal function also compared from baseline to 24 weeks.

Safety assessment

Investigator checked and reported any adverse events at every visit and measured blood pressure and body weight. Treatment emergent adverse events (TEAEs) and any other adverse events were monitored throughout the trial including primary study period (24 weeks) and extension study period (48 weeks).

Statistical analysis

This study used a statistical superiority design to verify the superiority of 30 mg/day of pioglitazone over the placebo on HbA1c reduction. Assuming a mean HbA1c reduction relative to placebo at week 24 of 0.43% with a standard deviation of 1.09%, based on previous clinical trials, a sample size of 102 per group was calculated to provide a statistical power of 80% at a significance level of 5%. Assuming a dropout rate of 20%, we planned to recruit 128 participants per group. The FAS consisted of patients who were exposed to at least one dose of the study drug and had at least one HbA1c result after randomization. The PPS consisted of patients who completed the 24-week treatment period without major protocol deviations among those included in the FAS. Although the main analysis set for efficacy evaluation was the FAS, efficacy analyses were repeated in the PPS. The safety analysis set included patients who received at least one dose of the study drug after randomization and had post-randomization safety follow-up data.

Continuous variables were presented as descriptive statistics at each time point, and the significance of the changes from baseline within a group was tested using paired t-test or Wilcoxon signed-rank test. Between-group differences in continuous variables were tested using analysis of covariance (ANCOVA) with baseline values and randomization stratification factors as covariates. Changes from baseline for these endpoints are presented as adjusted mean changes and between-group differences with least square mean differences in changes were tested by ANCOVA. Categorical variables were summed as frequency (%) and tested for between-group differences using chi-square or Fisher’s exact tests. The between-group differences in the percentages of patients achieving various glycemic responses were evaluated based on the odds ratios and 95% confidence interval (CI), calculated using logistic regression analysis. In subgroup analysis, multivariate logistic regression analysis was performed for age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), BMI, HOMA-IR, and estimated glomerular filtration rate (eGFR). Mean changes of HbA1c (%) at 24 weeks by sub-groups were analyzed by paired t-test. All statistical analyses were performed using SAS version 9.4 or higher. Statistical significance was set at P<0.05.

RESULTS

Baseline characteristics of the study participants

Among 326 screened patients, total 246 participants were enrolled in this trial who met inclusion criteria and randomized to high-dose pioglitazone add-on group (n=124) and placebo (n=122). Total 210 participants (pioglitazone n=105, placebo n=105) finished the primary outcome period, 24 weeks. Of whom agreed to extend to 48 weeks were 213 participants (pioglitazone n=107, placebo to pioglitazone n=106), then finally 198 participants (pioglitazone n=97, placebo to pioglitazone n=101) finished the extension period, 48 weeks successfully. Baseline characteristics are summarized in Table 1 (FAS). Both groups were well balanced in anthropometric data and diabetes state with HbA1c, FPG, diabetes mellitus duration. Before screening, there was no patient who taking metformin alone. Over 90% of screened participants had been taking dapagliflozin and metformin (1,000 mg/day) or 2 oral hypoglycemic agents over 8 weeks.

Primary outcome

The changes of HbA1c, FPG, and metabolic parameters after 24 weeks treatment of high-dose pioglitazone 30 mg/day or placebo were described in Table 2. Pioglitazone add-on resulted in a significant reduction in HbA1c level (7.8%±0.8% to 7.0%±0.6%) compared with placebo (7.8%±0.8% to 7.7%± 0.9%) after 24 weeks treatment (adjusted mean differences, –0.65%; 95% CI, –0.80 to –0.49; P<0.0001). The difference of HbA1c after treatment was already prevalent in 12 weeks (–0.57%±0.06% in pioglitazone group, –0.10%±0.06% in placebo group), and more prevalent in 24 weeks (–0.72%±0.06% in pioglitazone group, –0.07%±0.06% in placebo group), depicted in Fig. 1A.

Secondary outcome

The mean change of HbA1c and FPG from baseline to 12, 24, 36, 48 weeks were described in Fig. 1B and C. Pioglitazone 30 mg/day added to metformin and dapagliflozin 10 mg/day constantly reduced HbA1c and FPG in extension period till 48 weeks. Switching from placebo to pioglitazone 30 mg/day also reached to similar HbA1c (mean difference –0.80%±0.86%) and FPG (mean difference –18.05±27.96 mg/dL) to continued pioglitazone add-on group. The changes of FPG after 24 weeks treatment of high-dose pioglitazone 30 mg/day or placebo were described in Fig. 2A. Insulin resistance was also significantly improved by treatment of pioglitazone add-on therapy with lowering serum insulin level; however, β-cell function of HOMA-β didn’t present significant difference at 24 weeks, in Fig. 2B-D. 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) in Fig. 3A. Besides of glucose lowering efficacy with pioglitazone add-on to dapagliflozin and metformin, there was no adverse event of hypoglycemia.

Safety outcome

Total TEAE during study period are summarized in Table 3. There were no significant adverse events with treatment of pioglitazone 30 mg in primary and extension period. Especially no event of hospitalization of heart failure or dyspnea was reported in spite of mild weight gain. Body weight gain was 2 kg at 24 weeks with pioglitazone 30 mg/day and –0.6 kg at 24 weeks with placebo, as shown in Fig. 3B. One patient presented generalized edema and other one patient presented facial edema with treatment with pioglitazone 30 mg/day; however, there was no need to discontinue the medication with improvement within primary study period.

DISCUSSION

This multicenter, double-blind, randomized, placebo-controlled phase 3 trial evaluated the efficacy and safety of high-dose pioglitazone (30 mg/day) added to dapagliflozin and metformin in patients with inadequately controlled T2DM. A total of 246 participants were enrolled and followed for 24 weeks in the primary phase, with 213 extending to 48 weeks. The study demonstrated that pioglitazone add-on in patients with T2DM inadequately controlled with dapagliflozin and metformin significantly improved glycemic control compared to placebo, with favorable tolerability despite modest weight gain.

After 24 weeks, HbA1c decreased significantly in the pioglitazone add-on group compared to the placebo group. The adjusted mean difference of HbA1c relative to placebo group was –0.65% (95% CI, –0.80 to –0.49), P<0.0001. There are several studies investigating the efficacy of pioglitazone add-on to T2DM patients inadequately controlled with dapagliflozin and metformin. Pioglitazone 15 mg/day add-on showed the adjusted mean difference of HbA1c relative to placebo –0.38% to –0.53% [7-9] while pioglitazone 30 mg/day add-on showed –0.83% [9]. Taken these data together, changes in HbA1c with 30 mg/day pioglitazone add-on showed greater reduction in HbA1c compared to 15 mg/day pioglitazone add-on to T2DM patients inadequately controlled with dapagliflozin and metformin.

Since pioglitazone improves glycemic control by reducing insulin resistance in target tissue [5], we performed exploratory subgroup analyses to identify potential predictors of treatment response to pioglitazone add-on. However, no subgroup differences were observed across age, sex, AST, ALT, BMI, HOMA-IR, or eGFR (Supplementary Table 2, Supplementary Fig. 1). Age category of participants showed statistical difference, because of not included in stratification variable when randomization at inclusion. However, there was no difference of glucose lowering effect by age and subgroup with below and over 40 and 60 years.

Data from the extension phase up to 48 weeks suggest sustained glycemic improvement in patients continuing pioglitazone, suggesting good durability of glycemic control. However, the follow-up duration of this study may be insufficient to evaluate the long-term glycemic durability of pioglitazone addon therapy.

Beyond glycemic endpoints, treatment with pioglitazone led to significant enhancements in insulin sensitivity, as evidenced by reductions in HOMA-IR and fasting insulin levels. These findings are consistent with pioglitazone’s established mechanism as a PPARγ agonist [5]. In addition, favorable changes were observed in lipid profiles, including increased high-density lipoprotein cholesterol (HDL-C) and a marked reduction in triglycerides. Cho et al. [9] showed that improvements in HOMA-IR and lipid parameters—particularly triglyceride reduction and HDL-C elevation—were more pronounced at the higher dose.

The observed improvements in lipid profiles and insulin sensitivity may have broader implications beyond glycemic control. Pioglitazone has been shown to exert beneficial cardiovascular effects [10,11], and when combined with the natriuretic and cardiorenal protective properties of SGLT2 inhibitors, the dual therapy may offer a complementary strategy to reduce overall cardiometabolic risk. Additionally, the reductions in hepatic enzymes such as ALT and gamma glutamyl transfererase observed in this study are consistent with prior evidence suggesting a potential role of pioglitazone in ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD) [12].

High-dose pioglitazone (30 mg/day) was well tolerated in this study. No increase in hypoglycemic events was observed, and the overall safety profile was acceptable. Although the addition of 30 mg/day pioglitazone for 24 weeks resulted in greater weight gain of approximately 2 kg in our study and other study [9] compared to those observed 15 mg/day pioglitazone in previous studies [7-9], the magnitude of weight gain was considerably lower than what has been reported with pioglitazone therapy [13]. Moreover, the incidence of peripheral edema was low and did not result in treatment discontinuation. Notably, no cases of hospitalization for heart failure occurred during the study period, suggesting that co-administration of dapagliflozin may attenuate fluid retention and weight gain associated with TZDs.

Several limitations were considered in interpreting our study. First, This study was conducted by the sequential addition of pioglitazone to metformin and dapagliflozin. Therefore, the findings should not be generalized to the efficacy and safety of combination therapy with dapagliflozin and pioglitazone in patients who were already receiving pioglitazone or in cases where the two agents are initiated simultaneously [6]. Second, since body composition analysis was not performed in this study, we were unable to determine the extent to which the observed weight gain in the pioglitazone add-on group, compared to the placebo group, was attributable to changes in body water or body fat. Third, as this study evaluated only the high-dose (30 mg/day) pioglitazone add-on therapy, a direct comparison of the efficacy and safety between high-dose and low-dose (15 mg/day) pioglitazone was not possible. Recently several clinical trials evaluating low-dose (15 mg/day) or high-dose (30 mg/day) pioglitazone add-on to dapagliflozin and metformin have been conducted in Korea [7-9]. Given that the number of participants in each individual study was relatively small, combining the results from the previously published trials with our current findings could provide more definitive evidence regarding the efficacy and safety of pioglitazone add-on therapy in Korean patients with T2DM treated with dapagliflozin and metformin.

In conclusion, this study indicated that 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. Especially, higher dose of pioglitazone 30 mg/day presented more glucose lowering effect and improvement of atherogenic dyslipidemia with lowering triglyceride and elevation of HDL-C. Therefore, pioglitazone 30 mg/day added to dapagliflozin and metformin is effective and tolerable regimen as a triple combination therapy to T2DM. Further researches are expected to verifying the long-term glycemic durability and beneficial effects to cardiovascular and renal complications as well as MASLD.

SUPPLEMENTARY MATERIALS

NOTES

CONFLICTS OF INTEREST

Kyong Soo Park has been a honorary editor of the Diabetes & Metabolism Journal since 2020. He was not involved in the review process of this article. Otherwise, there was no conflict of interest.

AUTHOR CONTRIBUTIONS

Conception or design: all authors.

Acquisition, analysis, or interpretation of data: all authors.

Drafting the work or revising: J.H.H., K.A.H., Y.C.H., E.G.H., H.J.K., C.B.L., H.C.C., J.C.W., H.S.K., K.S.P.

Final approval of the manuscript: all authors.

FUNDING

This study was sponsored by Jeil Pharmaceutical Co. Ltd., Seoul, South Korea. The sponsor participated in the study design, data management, and analysis.

ACKNOWLEDGMENTS

The authors appreciate and acknowledge Dr. Jae Myung Yu from Hallym University College of Medicine (Seoul, Korea), Dr. Eon Ju Jeon from School of Medicine, Catholic University of Daegu (Daegu, Korea), Dr. Chul Sik Kim from Yongin Severance Hospital, Yonsei University College of Medicine (Yongin, Korea), Dr. Hyeong-Kyu Park from Soonchunhyang University College of Medicine (Seoul, Korea), Dr. Ohk-Hyun Ryu from Hallym University College of Medicine (Chuncheon, Korea), Dr. Hyuk-Sang Kwon from Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea (Seoul, Korea), Dr. Sun Hee Beom from Seoul Medical Center (Seoul, Korea), Dr. Jae-Seung Yun from St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea (Seoul, Korea), Dr. Kyung Mook Choi from Korea University College of Medicine (Seoul, Korea), Dr. Chong Hwa Kim from Bucheon Sejong Hospital (Bucheon, Korea), Dr. Min Kyong Moon from Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine (Seoul, Korea), Dr. Doo-Man Kim from Hallym University College of Medicine (Seoul, Korea), Dr. Su Kyoung Kwon from Kosin University College of Medicine (Busan, Korea), Dr. Jae-Han Jeon from Kyungpook National University, Kyungpook National University Hospital (Daegu, Korea), Dr. Dong-Lim Kim from Konkuk University School of Medicine (Seoul, Korea), Dr. Jang Won Son from Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea (Bucheon, Korea), Dr. Dong-Joon Kim from Inje University College of Medicine (Goyang, Korea), Dr. Jung Hwan Park from Hanyang University College of Medicine (Seoul, Korea), Dr. Han Seok Choi from Dongguk University Ilsan Hospital (Ilsan, Korea), Dr. Sung Hee Choi from Seoul National University College of Medicine (Seongnam, Korea), Dr. Jae Hyuk Lee from Myongji Hospital (Goyang, Korea), Dr. Eun Sook Kim from Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea (Incheon, Korea), Su Young Lee from Jeil Pharmaceutical Co. Ltd. (Seoul, Korea) for their great efforts in recruiting patients and collecting study data.

Fig. 1.

Primary outcome: Least square (LS) mean change of glycosylated hemoglobin (HbA1c) from baseline to 24 weeks treatment (A). Changes of HbA1c in primary and extension period (B) and changes in fasting plasma glucose (FPG) in primary and extension period (C) for 24 weeks after additional of pioglitazone 30 mg/day to patients with uncontrolled type 2 diabetes mellitus treated with dapagliflozin and metformin. Data are mean±standard error of mean. SE, standard error. Significant change from the baseline ^aP<0.001, ^bP<0.0001; Significant difference between the groups ^cP<0.0001.

Fig. 2.

Least square (LS) mean change in (A) fasting plasma glucose (FPG), (B) fasting insulin, and (C) homeostatic model assessment for insulin resistance (HOMA-IR), and (D) homeostatic model assessment of β-cell function (HOMA-β) from baseline to 24 weeks treatment. SE, standard error. Significant change from the baseline ^aP<0.0001; Significant difference between the groups ^bP<0.05, ^cP<0.001, ^dP<0.0001.

Fig. 3.

(A) Participants who achieved target glycosylated hemoglobin (HbA1c) below 7.0% and 6.5% after treatment of add-on pioglitazone 30 mg/day or placebo to patients with uncontrolled type 2 diabetes mellitus treated with dapagliflozin and metformin at 24 weeks. (B) Changes of body weight at 12, 24 weeks after treatment of pioglitazone 30 mg/day add-on or placebo to patients with uncontrolled type 2 diabetes mellitus treated with dapagliflozin and metformin. SE, standard error. Significant change from the baseline ^aP<0.05, ^bP<0.0001; Significant difference between the groups ^cP<0.0001.

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Hong JH, Han KA, Hwang YC, Hong EG, Kim HJ, Lee CB, Cho HC, Won JC, Kim HS, Kim EH, Koh G, Ahn KH, Park KS. 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. Diabetes Metab J. 2026;50(2):320-330.

Received: Nov 14, 2024; Accepted: May 29, 2025

DOI: https://doi.org/10.4093/dmj.2024.0696.

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