Diabetes Metab J.  2024 Sep;48(5):937-948. 10.4093/dmj.2023.0314.

Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial

• Heo JH
• Han KA
• Hong JH
• Seo HA
• Hong EG
• Yu JM
• Jung HS
• Cha BS

• KMID: 2559003
• DOI: http://doi.org/10.4093/dmj.2023.0314

Abstract

Background
This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin.
Methods
In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135).
Results
At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (–0.47%; 95% confidence interval, –0.61 to –0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%).
Conclusion
Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

Keyword

Cardiovascular diseases; Diabetes mellitus, type 2; Insulin resistance; Sodium-glucose transporter 2 inhibitors; Thiazolidinediones

Figure

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  Fig. 1. Patient disposition.

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  Fig. 2. Least square (LS) mean changes from baseline in major efficacy endpoints throughout 24 weeks. (A) Glycosylated hemoglobin (HbA1c). (B) Fasting plasma glucose (FPG). Error bars are standard errors (SEs) of the mean. Significant change from the baseline (aP<0.05, bP<0.0001), cSignificant difference between the groups (P<0.0001).

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  Fig. 3. Proportions of patients achieving glycosylated hemoglobin (HbA1c) less than 7.0% or 6.5% at week 24.

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