Pioglitazone as Add-On to Metformin and Dapagliflozin Yields Significant Enhancements in Glycemic Control in Poorly Controlled Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Abstract

This systematic review and meta-analysis aimed to evaluate the efficacy and safety of pioglitazone as an add-on therapy to dual treatment with metformin and dapagliflozin in adults with type 2 diabetes mellitus (T2DM) inadequately controlled on this regimen. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pioglitazone (15 or 30 mg) versus placebo as an add-on to metformin (1,000 mg/day) and dapagliflozin (10 mg/day). Four databases (PubMed, Scopus, Cochrane CENTRAL, and Web of Science) were searched through December 2024. Primary outcomes included changes in hemoglobin A1c (HbA1c), the proportion of patients achieving a therapeutic glycemic response, and fasting plasma glucose (FPG). Secondary outcomes were insulin resistance, β-cell function, lipid parameters, body weight, blood pressure, and adverse events. Mean difference (MD) and standard deviation (SD) were used to describe the continuous variables. For categorical variables, we used the risk ratio (RR) and 95% confidence interval (CI). We included three RCTs, comprising a total of 856 patients: 363 received pioglitazone 15 mg, 124 received the 30 mg dose, and 369 received a placebo. Pioglitazone 15 mg significantly reduced HbA1c (MD = -0.42 percentage point, 95% CI = -0.51 to -0.33; p < 0.00001) and FPG (MD = -12.41 mg/dL). The 30 mg dose yielded greater reductions in HbA1c (MD = -0.84 percentage point) and FPG (MD = -21.49 mg/dL). It also improved homeostatic model assessment of insulin resistance, high-density lipoprotein cholesterol, and triglycerides, but increased body weight. No significant differences in serious adverse events or hypoglycemia were observed. Most outcomes had moderate to high certainty. Adding pioglitazone to metformin and dapagliflozin significantly enhances glycemic control and improves metabolic parameters with an acceptable safety profile, supporting its role as an effective triple oral therapy in T2DM.