Efficacy and Safety of Pioglitazone Added to Metformin and SGLT2 Inhibitors in Type 2 Diabetes: An Updated Systematic...

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.

A systematic search of PubMed, Scopus, the Cochrane Library, and Google Scholar was conducted through February 2026 for randomized controlled trials (RCTs).

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.

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; P < 0.00001) and increased the likelihood of achieving HbA1c <7% (risk ratio: 2.37; 95% CI 1.87-3.01). Subgroup analysis demonstrated a dose-dependent effect, with 30 mg providing greater glycemic reduction than 15 mg. Significant improvements were also observed in fasting plasma glucose, homeostasis model assessment of insulin resistance, triglycerides, high-density lipoprotein cholesterol, and diastolic blood pressure. However, pioglitazone was associated with weight gain (MD: 2.38 kg) and a higher risk of adverse drug reactions.

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.

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.