Pioglitazone Added to Metformin, Dapagliflozin Lowers Glucose for Patients With Diabetes

Adding pioglitazone (Actos) to treatment of dapagliflozin (Farxiga) and metformin effectively lowered glucose for patients with type 2 diabetes who did not reach the targeted hemoglobin A_1c (HbA_1c) of 7% or less. In the study published in Diabetes and Metabolic Journal, investigators noted that the regimen did not contribute to significant hypoglycemia and had good tolerability with a low prevalence of edema despite weight gain.¹

“Beyond glycemic endpoints, treatment with pioglitazone led to significant enhancements in insulin sensitivity, as evidenced by reductions in HOMA-IR and fasting insulin levels,” the study authors said.¹ “These findings are consistent with pioglitazone’s established mechanism as a PPARγ agonist.”

Pioglitazone is used to treat high HbA_1c in addition to proper diet and exercise. It works by helping the body use insulin more efficiently, but it is not indicated for patients who have type 1 diabetes or who are insulin dependent. According to Mayo Clinic, it can be used alone or with other medications such as insulin, metformin, or sulfonylurea agents. Common adverse events include chest pain, decreased urine output, dilated neck veins, extreme fatigue, irregular breathing or heartbeat, swelling of the face, fingers, feet, or lower legs, and weight gain.²

In the study (NCT05296044), investigators conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of high-dose pioglitazone at 30 mg as an add-on therapy to metformin and dapagliflozin. Investigators included 34 sites in Korea between March 2022 and March 2023. Patients included were 19 years and older with type 2 diabetes, an HbA_1c of 7% to 11%, and a body mass index of 45 kg/m². The primary end point was changes in HbA_1c from baseline to week 24.^1,3

Investigators included 246 individuals in the study, with 124 being assigned pioglitazone and 122 being assigned the placebo. A total of 105 patients in each group finished the primary outcome period of 24 weeks. After the primary study finished, patients could choose to enter the open-label extension study, which took place between September 2022 and September 2023 and lasted an additional 24 weeks. There were 213 patients who agreed to the extension study, with 97 in the pioglitazone group and 101 in the placebo-to-pioglitazone group finishing the 48 weeks.¹

The changes of HbA_1c reduced from 7.8% to 7% with pioglitazone 30 mg compared with 7.8% to 7.7% with the placebo at 24 weeks. Additionally, pioglitazone reduced HbA_1c and fasting plasma glucose in the extension period, and switching to pioglitazone showed similar reductions compared with those receiving pioglitazone from the beginning of the study. Insulin resistance also improved and lowered serum insulin levels. However, the investigators noted that the β-cell function of HOMA-β had no significant differences at 24 weeks. Furthermore, approximately 51.61% of patients achieved an HbA_1c of less than 7% at 24 weeks in the pioglitazone group compared with 22.95% in the placebo group. Approximately 21.77% and 2.46%, respectively, achieved a less than 6.5% HbA_1c.¹

As for safety, the investigators reported that there were no significant adverse events in the pioglitazone group for both the primary and extension periods.¹

“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 [high-density lipoprotein cholesterol],” the study authors said.¹ “Therefore, pioglitazone 30 mg/day added to dapagliflozin and metformin is effective and tolerable regimen as a triple combination therapy to T2DM [type 2 diabetes mellitus].”

READ MORE: Diabetes Resource Center

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REFERENCES

1. Hong JH, Han KA, Hwang YC, et al. 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. Published online October 28, 2025. doi:10.4093/dmj.2024.0696

2. Mayo Clinic. Actos. Updated October 1, 2025. Accessed October 29, 2025. https://www.mayoclinic.org/drugs-supplements/pioglitazone-oral-route/description/drg-20065503

3. To evaluate the efficacy and safety of JT-003 add-on in patients with type 2 diabetes mellitus inadequately controlled with metformin and dapagliflozin. ClinicalTrials.gov identification: NCT05296044. Updated March 25, 2022. Accessed October 30, 2025. https://clinicaltrials.gov/study/NCT05296044