Efficacy and safety of fixed-dose dapagliflozin–pioglitazone in Indian adults with type 2 diabetes: a phase 3 PRO-1 trial

To assess the efficacy and safety of a fixed-dose combination (FDC) of dapagliflozin and pioglitazone versus a loose combination (LC) as an add-on therapy to metformin in Indian adults with inadequately controlled type 2 diabetes mellitus (T2DM). This 12-week PRO-1 study was a randomized, open-label, multicenter phase 3 trial that enrolled 180 Indian adults with T2DM Glycated Hemoglobin (HbA1c) > 7.5 to 10% inadequately controlled with metformin. The participants received once-daily FDC (dapagliflozin 10 mg/pioglitazone 15 mg) or equivalent LC therapy (1:1 randomization). The primary endpoint was the HbA1c change (non-inferiority margin, 0.3%). The secondary endpoints included fasting plasma glucose (FPG), postprandial glucose (PPG), and HbA1c < 7.5%. At week 12, the least-squares mean HbA1c reduction was − 1.20% (FDC) versus − 1.02% (LC). A between-group difference of − 0.18% (95% CI: −0.56 to 0.20) demonstrated non-inferiority. FPG decreased by − 8.6 mg/dL (FDC) and − 12.0 mg/dL (LC); PPG decreased by − 28.2 mg/dL and − 29.5 mg/dL, respectively. Target HbA1c < 7.5% was achieved in 52.9% (FDC) versus 54.8% (LC) of patients. (p = 0.884). Pooled analysis showed significant improvements: HbA1c − 1.11% (p < 0.001), FPG − 10.3 mg/dL, and PPG − 28.9 mg/dL. Both regimens were generally well tolerated; adverse events were more frequent with the fixed-dose combination than with the loose combination (8.9% versus 1.1%, p = 0.034), but were mild and self-limiting, with no serious events, hypoglycemia, or treatment discontinuation in either group. The fixed-dose combination of dapagliflozin and pioglitazone was non inferior to separate administration in terms of improving glycemic outcomes and showed excellent tolerability. Pooled data reinforce the clinical utility of dual sodium glucose co transporter 2 (SGLT2) inhibitor plus pioglitazone therapy as a formulation-independent strategy for Indian adults with inadequately controlled type 2 diabetes mellitus. CTRI/2024/09/073221. What is known about this topic? Fixed-dose combinations improve adherence and reduce pill burden in T2DM management. Dapagliflozin (an SGLT2 inhibitor) and pioglitazone (a thiazolidinedione) have complementary mechanisms that target different defects. Global evidence supports the efficacy of dapagliflozin–pioglitazone, but real-world Indian data are limited. What this study adds and its future implications. The first randomized controlled trial demonstrated the non-inferiority of dapagliflozin–pioglitazone FDC versus loose combination in Indian T2DM patients. Establishes clinical equivalence between formulations, enabling simplified prescribing and improved compliance. Confirms favorable safety with no hypoglycemia, supporting use across diverse Indian settings. This study provides an evidence base for incorporating this dual therapy into Indian diabetes treatment practice and guidelines.