Efficacy and Safety of Pioglitazone Added to Metformin and SGLT2 Inhibitors in Type 2 Diabetes: An Updated Systematic Review and Meta-analysis
Abstract
Objective: 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; 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…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 1,213 participants or records.
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