Synergistic Metabolic Effects of Dapagliflozin Added to Pioglitazone in Type 2 Diabetes: a randomized comparative study

Dapagliflozin Added to Pioglitazone in Type 2 Diabetes

Abstract

Background:
Pioglitazone is an effective insulin sensitizer for type 2 diabetes mellitus (T2DM) but its use is limited by weight gain, edema, and heart failure risk. Sodium–glucose cotransporter-2 (SGLT2) inhibitors such as dapagliflozin improve glycemic control, promote weight loss, and reduce cardiovascular and renal adverse effects. Evidence evaluating the combined use of dapagliflozin with pioglitazone, particularly in real-world clinical settings, is lacking.

Objective:
To compare the efficacy and safety of dapagliflozin 10 mg added to pioglitazone-based conventional therapy versus pioglitazone with conventional therapy alone over 24 weeks in patients with T2DM.

Methods:
A 24-week, randomized, comparative study was conducted involving 196 adults with T2DM (98 per group). Participants were assigned to either (1) dapagliflozin 10 mg + pioglitazone + standard oral therapy, or (2) pioglitazone + standard therapy alone. The primary outcome was the change in HbA1c. Secondary outcomes included fasting plasma glucose (FPG), HOMA-IR, weight, BMI, waist circumference, blood pressure, lipid profile, eGFR, urinary albumin-to-creatinine ratio (UACR), and adverse events, including edema, macular edema, heart-failure–related events, and genital infections. Analyses included ANCOVA, paired t-tests, and logistic regression.

Results:
The dapagliflozin + pioglitazone group showed significantly greater reduction in HbA1c compared with pioglitazone alone (adjusted mean difference −0.5% to −0.8%; p < 0.001). Improvements in FPG, fasting insulin, and HOMA-IR were also superior (p < 0.01). Weight decreased in the dapagliflozin group (−1.5 to −2.8 kg) but increased with pioglitazone alone (+0.6 to +1.4 kg), producing a significant between-group difference (p < 0.001). Greater reductions occurred in waist circumference, blood pressure, triglycerides, and UACR with dapagliflozin. Edema and heart-failure–related events were significantly lower in the dapagliflozin group, with no cases of macular edema or hospitalization for heart failure. Safety outcomes were similar to known drug profiles.

Conclusion:
 Many patients with type 2 diabetes are reluctant to initiate insulin therapy. Pioglitazone improves insulin sensitivity and glycemic control, but its use is constrained by weight gain and heart failure risk. The addition of dapagliflozin, through insulin-independent glucose-lowering and natriuretic effects, may mitigate these effects and provide a complementary treatment method. Adding dapagliflozin to pioglitazone-based therapy provides superior glycemic, metabolic, cardiovascular, and renal benefits compared with pioglitazone alone, while reducing fluid-retention related harmful effects. The combination represents a safe, effective, and clinically advantageous option for patients requiring intensified therapy for T2DM.

Keywords: Dapagliflozin, Pioglitazone, Type 2 diabetes, Weight gain, Edema, Heart failure, Dapagliflozin added to pioglitazone