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 MakhdoomObjective:
To evaluate the efficacy and safety of adding pioglitazone as a third-line agent in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sodium-glucose cotransporter-2 inhibitors.
Data Sources:
A systematic search of PubMed, Scopus, the Cochrane Library, and Google Scholar was conducted through February 2026 for randomized controlled trials (RCTs).
Study Selection and Data Extraction:
Eligible RCTs reported outcomes on glycemic control and cardiometabolic parameters. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane Risk-of-Bias tool 2, with certainty of evidence evaluated using the Grading of Recommendations Assessment, Development, and Evaluation tool.
Data Synthesis:
Four RCTs (n = 1213) were included. Using a random-effects model, pioglitazone significantly reduced glycated hemoglobin (HbA1c) (mean difference [MD]: −0.56%; 95% confidence interval −0.74 to −0.38;
Relevance to Patient Care and Clinical Practice:
These findings suggest that pioglitazone is an effective add-on therapy for patients with T2DM who remain uncontrolled on metformin and SGLT2 inhibitors, particularly in those with significant insulin resistance. However, its use should be individualized, with careful consideration of predictable adverse effects such as weight gain and tolerability, rather than routine escalation for all patients.
Conclusions:
Adding pioglitazone to metformin and SGLT2 inhibitors significantly improves glycemic control and metabolic parameters. While the 30 mg dose offers greater efficacy, clinicians must balance these benefits against predictable side effects like weight gain.